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This study reports on a 9-year-old girl who developed West syndrome and showed clinical features fulfilling the main revised diagnostic criteria for typical Rett syndrome (hand washing, severe cognitive impairment with absence of language, ataxic gait, progressive scoliosis and autistic features). Mutation analyses for methyl-CpG-binding protein 2 (MECP2), cyclin-dependent kinase-like 5 (CDKL5/STK9), ARX and Forkhead box G1 (FOXG1) genes were carried out, with negative results. A known de-novo c.1217G>A missense mutation in exon 14 leading to the substitution of a conserved residue, p.R406H in domain3b of the syntaxin-binding protein 1 (STXBP1) gene, was detected. The STXBP1 gene encodes the syntaxin-binding protein 1, a neuron-specific protein involved in synaptic vesicle release at both glutaminergic and GABAergic synapses. This function is also affected by MECP2 gene mutations, which are known to lead to a decrease in glutamate and GABA receptors' density. It is possible to speculate that the impairment in synaptic plasticity represents the pathogenic link between MECP2 and STXBP1 gene mutations. On reviewing the clinical features of the reported patients with the same mutation in the STXBP1 gene, it has been observed that poor eye contact, tremour, dyskinesia, head/hand stereotypies and both cognitive and motor progressive deterioration are common symptoms, although never considered as indicative of a Rett syndrome phenotype. In conclusion, the case described here suggests a relationship between the Rett syndrome and the STXBP1 gene not described so far, making the search for STXBP1 gene mutations advisable in patients with Rett syndrome and early onset of epilepsy., (Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.)

The tubulin gene family is mainly expressed in post-mitotic neurons during cortical development with a specific spatial and temporal expression pattern. Members of this family encode dimeric proteins consisting of two closely related subunits (α and β), representing the major constituents of microtubules. Tubulin genes play a crucial role in the mechanisms of the Central Nervous System development such as neuronal migration and axonal guidance (axon outgrowth and maintenance). Different mutations in α/β-tubulin genes (TUBA1A, TUBA8, TUBB2A, TUBB4A, TUBB2B, TUBB3, and TUBB) might alter the dynamic properties and functions of microtubules in several ways, effecting a reduction in the number of functional tubulin heterodimers and causing alterations in GTP binding and disruptions of the binding of other proteins to microtubules (motor proteins and other microtubule interacting proteins). In recent years an increasing number of brain malformations has been associated with mutations in tubulin genes: malformations of cortical development such as lissencephaly and various grades of gyral disorganization, focal or diffuse polymicrogyria and open or closed-lips schizencephaly as likely consequences of an altered neuronal migration process; abnormalities or agenesis of the midline commissural structures (anterior commissure, corpus callosum and fornix), hypoplasia of the oculomotor and optic nerves, dysmorphisms of the hind-brain as expression of axon guidance disorders. Dysmorphisms of the basal ganglia (fusion between the caudate nucleus and putamen with absence of the anterior limb of the internal capsule) and hippocampi were also observed. A rare form of leukoencephalopathy characterized by hypomyelination with atrophy of the basal ganglia an cerebellum (H-ABC) was also recently described. The present review, describing the structural and functional features of tubulin genes, aims to revise the main cerebral associated malformations and related clinical aspects, suggesting a genotype-phenotype correlation., (Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Despite negative blood oxygenation level dependent (BOLD) responses to visual stimuli have recently gained considerable interest, the explanation for their underlying neuronal and vascular mechanisms is still controversial. In the present study, a multimodal experimental approach is presented to shed light on the negative BOLD phenomenon in the human brain. In particular, information from functional magnetic resonance imaging (fMRI) and near infrared spectroscopy (NIRS) was integrated to confirm and gain insight into the phenomenon of negative BOLD responses (NBRs) to unpatterned intermittent photic stimulation (IPS) in healthy subjects. Eight healthy subjects participated in the study. Consistent findings emerged from the activation analysis of fMRI and NIRS data and the comparison of BOLD and hemoglobin responses at the single channel level showed that NBRs are related to a decrease in oxyhemoglobin (HbO) combined with a lower increase in deoxyhemoglobin (HHb), corresponding to a decrease in total hemoglobin (THb) and estimated cerebral blood volume (CBV). The HbO and HHb variations were significant in at least one channel in six subjects out of eight (p<0.05). The NIRS technique allowed obtaining valuable information on the vascular determinants of the NBRs, since the discrimination between HbO, HHb and THb information provided a more comprehensive view of the negative BOLD phenomenon. The within and between subject heterogeneous BOLD-Hb temporal relations pave the way to further investigations into the neurovascular properties of NBRs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We assessed abnormalities of brain functional magnetic resonance imaging (fMRI) activity during a sustained attention task (Conners' Continuous Performance Test (CCPT)) in 20 right-handed pediatric acquired brain injury (ABI) patients versus 7 right-handed age-matched healthy controls, and we estimated the correlation of such abnormalities with clinical and cognitive deficits. Patients underwent the Wechsler Intelligence Scale for Children (WISC), Wisconsin Card Sorting Test, and Functional Independence Measure (FIM) evaluations. During fMRI, patients and controls activated regions of the attention network. Compared to controls, ABI patients experienced a decreased average fMRI recruitment of the left cerebellum and a decreased deactivation of the left anterior cingulate cortex. With increasing task demand, compared to controls, ABI patients had an impaired ability to increase the recruitment of several posterior regions of the attention network. They also experienced a greater activation of frontal regions, which was correlated with worse performance on FIM, WISC, and fMRI CCPT. Such abnormal brain recruitment was significantly influenced by the type of lesion (focal versus diffuse axonal injury) and time elapsed from the event. Pediatric ABI patients experienced an inability to optimize attention network recruitment, especially when task difficulty was increased, which likely contributes to their clinical and cognitive deficits.

Background: Homozygous and compound heterozygous mutations in SETX are associated with AOA2 disease, a recessive form of ataxia with oculomotor apraxia and neuropathy with onset of ataxia between the first and second decade of life. The majority of the AOA2 mutated cell lines tested show hypersensitivity to oxidative DNA damaging agents, with one exception., Results: We describe a patient presenting with early-onset progressive ataxia, oculomotor apraxia, axonal sensory-motor neuropathy, optic atrophy, delayed psychomotor development, and a behavior disorder. The patient carries two novel missense variants in the SETX gene. Based on the hypothesis that the patient's clinical phenotype may represent an atypical form of the AOA2 disease, we tested the patient-derived cell line for hypersensitivity to oxidative DNA damaging agents, with negative results., Conclusions: The lack of hypersensitivity we observed may be explained either by considering the atypical clinical picture of the patient analyzed or, alternatively, by hypothesizing that the variants detected are not the cause of the observed phenotype. Consistent with the first hypothesis of an atypical AOA2 form and based on the multiple functions of senataxin reported so far, it is likely that different sets of SETX mutations/variants may have variable functional effects that still need to be functionally characterized. The possibility that the severe and complicated clinical picture presented by the patient described here represents a clinical entity differing from the known recessive ataxias should be considered as well., (Copyright © 2013 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a totally noninvasive ablation technique that in the last years had an important development in a large number of applications: in particular gynaecological disorders, bone lesions, prostate, breast, brain and other organs. This review of MRgFUS is focused on the technical aspects and the current clinical application in musculoskeletal interventions. More precisely, this paper aims to review the relatively scarce literature on this topic also in comparison with our 3-year experience in the use of this technique in the field of musculoskeletal interventions.

Background: Functional Magnetic Resonance Imaging (fMRI) is used for exploring brain functionality, and recently it was applied for mapping the brain connection patterns. To give a meaningful neurobiological interpretation to the connectivity network, it is fundamental to properly define the network framework. In particular, the choice of the network nodes may affect the final connectivity results and the consequent interpretation., New Method: We introduce a novel method for the intra subject topological characterization of the nodes of fMRI brain networks, based on a whole brain parcellation scheme. The proposed whole brain parcellation algorithm divides the brain into clusters that are homogeneous from the anatomical and functional point of view, each of which constitutes a node. The functional parcellation described is based on the Tononi's cluster index, which measures instantaneous correlation in terms of intrinsic and extrinsic statistical dependencies., Results: The method performance and reliability were first tested on simulated data, then on a real fMRI dataset acquired on healthy subjects during visual stimulation. Finally, the proposed algorithm was applied to epileptic patients' fMRI data recorded during seizures, to verify its usefulness as preparatory step for effective connectivity analysis. For each patient, the nodes of the network involved in ictal activity were defined according to the proposed parcellation scheme and Granger Causality Analysis (GCA) was applied to infer effective connectivity., Conclusions: We showed that the algorithm 1) performed well on simulated data, 2) was able to produce reliable inter subjects results and 3) led to a detailed definition of the effective connectivity pattern., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel imaging-guided surgical technique that allows the performance of noninvasive and radiation-free ablation. Presently, computed tomography (CT)-guided radiofrequency ablation, a minimally invasive percutaneous technique, is the standard for treating symptomatic osteoid osteomas. The purpose of this study was to evaluate the use of MRgFUS ablation for the treatment of nonspinal osteoid osteomas in terms of technical success, complications, and clinical success through one year of follow-up., Methods: In this prospective multicenter study, thirty consecutive patients with a nonspinal osteoid osteoma were enrolled between May 2010 and April 2012 at three different university centers; twenty-nine of the patients were treated with use of MRgFUS. Lesions had been previously diagnosed on the basis of imaging, including dynamic contrast-enhanced MR. The mean number of sonications and energy deposition were determined. Technical success was evaluated through an assessment of complications immediately after treatment. Clinical success was determined on the basis of pain reduction as measured with a visual analog scale (VAS), recurrence, and long-term complications through twelve months., Results: Technical success of MRgFUS was observed for all twenty-nine patients. The mean number of sonications (and standard deviation) was 7 ± 3, and the mean delivered acoustic energy was 1180 ± 736 J. At the twelve-month follow-up, complete clinical success was observed in twenty-six (90%) of the twenty-nine patients (95% confidence interval [CI] = 84 to 95; mean VAS, 0 ± 0 points). Partial success was observed in three (10%) of the twenty-nine patients (95% CI = 5 to 16; mean VAS score, 5 ± 0 points); two of these patients subsequently underwent CT-guided radiofrequency ablation, and one underwent open surgery. Pain score values showed a significant reduction (p < 0.001) between baseline (mean VAS score, 8 ± 1 points) and post treatment (mean VAS score, 1 ± 2 points). No complications were observed., Conclusions: MRgFUS may be an effective and safe alternative approach in the treatment of nonspinal osteoid osteoma. A complete clinical success rate of 90% was demonstrated without adverse events. MRgFUS is totally noninvasive and eliminates radiation exposure.

Aim: The aim of this study was to determine the frequency of mutations in tubulin genes (TUBB2B, TUBA1A, and TUBB3) in patients with malformations of cortical development (MCDs) of unknown origin., Method: In total, 79 out of 156 patients (41 males, 38 females; age range 8mo-55y (mean age 13y 3mo, SD 11y 2mo) with a neuroradiological diagnosis of MCDs were enrolled in the study. The 77 excluded patients were excluded for the following reasons: suspected or proven diagnosis of pre- or perinatal ischaemic insult (n=13); syndromic disease (n=10); congenital infection (n=14); pregnancy complicated by twin-to-twin transfusion syndrome (n=2); proven mutations in known genes (n=13); poor magnetic resonance imaging (MRI) quality, or lack of informed consent (n=25). A genetic analysis of the TUBA1A, TUBB2B and TUBB3 genes was carried out by direct sequencing of the coding regions of the relevant genes for each participant. Previously described patients with mutations in the TUBB2B and TUBA1A genes were reviewed; clinical and neuroradiological findings were compared and discussed., Results: Two novel heterozygous mutations were detected: a heterozygous mutation in exon 4 of the TUBA1A gene (c.1160C>T) in a 5-year-old female with microcephaly, severe intellectual disability, and absence of language, and a c.1080 &#95;1084del CCTGAinsACATCTTC in exon 4 of the TUBB2B gene in a 31-year-old female with microcephaly, spastic tetraparesis, severe intellectual disability, and scoliosis. Different types of cortical abnormalities, cerebellar vermis hypoplasia, and optic nerve hypoplasia/atrophy were detected on MRI. Dysmorphisms of the basal ganglia and the hippocampi with abnormalities of the midline commissural structures were present in both cases., Interpretation: The consistent presence of hypoplastic and disorganized white matter tracts suggests that, in addition to defects in neuronal migration, disruption of axon growth and guidance is a peculiar feature of tubulin-related disorders., (© 2014 Mac Keith Press.)

Mutations in STXBP1 gene, encoding the syntaxin binding protein 1, have been recently described in Ohtahara syndrome, or early infantile epileptic encephalopathy with suppression-burst pattern, and in other early-onset epileptic encephalopathies. A 3-year-old boy affected by epileptic encephalopathy started at 8 months of age is described. Focal epilepsy was characterized by drug resistance seizures with multifocal interictal and ictal electroencephalographic (EEG) features and variable EEG focus. Direct sequencing of the STXBP1 gene showed a novel de novo mutation (c.751G>A), leading to a p.Ala251Thr substitution. Based on reported data, treatment with vigabatrin was attempted and patient became immediately seizure free for 4 months. The present case further expands the clinical spectrum of "STXBP1-related encephalopathy" suggesting molecular analysis of STXBP1 in early onset epileptic encephalopathies of unknown etiology (with onset within the first year of life). In addition, the case provides valuable suggestions on seizures treatment in STXBP1 mutated subjects.

Complicated hereditary spastic paraplegias (HSP) are a heterogeneous group of HSP characterized by spasticity associated with a variable combination of neurologic and extra-neurologic signs and symptoms. Among them, HSP with thin corpus callosum and intellectual disability is a frequent subtype, often inherited as a recessive trait (ARHSP-TCC). Within this heterogeneous subgroup, SPG11 and SPG15 represent the most frequent subtypes. We analyzed the mutation frequency of three genes associated with early-onset forms of ARHSP with and without TCC, CYP2U1/SPG56, DDHD2/SPG54 and GBA2/SPG46, in a large population of selected complicated HSP patients by using a combined approach of traditional-based and amplicon-based high-throughput pooled-sequencing. Three families with mutations were identified, one for each of the genes analyzed. Novel homozygous mutations were identified in CYP2U1 (c.1A>C/p.Met1?) and in GBA2 (c.2048G>C/p.Gly683Arg), while the homozygous mutation found in DDHD2 (c.1978G>C/p.Asp660His) had been previously reported in a compound heterozygous state. The phenotypes associated with the CYP2U1 and DDHD2 mutations overlap the SPG56 and the SPG54 subtypes, respectively, with few differences. By contrast, the GBA2 mutated patients show phenotypes combining typical features of both the SPG46 subtype and the recessive ataxia form, with marked intrafamilial variability thereby expanding the spectrum of clinical entities associated with GBA2 mutations. Overall, each of three genes analyzed shows a low mutation frequency in a general population of complicated HSP (<1 % for either CYP2U1 or DDHD2 and approximately 2 % for GBA2). These findings underline once again the genetic heterogeneity of ARHSP-TCC and the clinical overlap between complicated HSP and the recessive ataxia syndromes.

In this paper we propose a Multiple Kernel Learning (MKL) classifier to detect malformations of the Corpus Callosum (CC) and apply it in a pediatric population. Furthermore, we extend the concept of discriminative direction to the linear MKL methods, implementing it in a single subject analysis framework. The CC is characterized using different measures derived from Magnetic Resonance Imaging (MRI) data and the MKL approach is used to efficiently combine them. The discriminative direction analysis highlights those features that lead the classification for each given subject. In the case of a CC with malformation this means highlighting the abnormal characteristics of the CC that guide the diagnosis. Experiments show that the method correctly identifies the malformative aspects of the CC. Moreover, it is able to identify dishomogeneus, localized or widespread abnormalities among the different features. The proposed method is therefore suitable for supporting neuroradiologists in the decision-making process, providing them not only with a suggested diagnosis, but also with a description of the pathology.

Mutations in the conserved telomere maintenance component 1 (CTC1) gene were recently described in Coats plus syndrome and in cerebroretinal microangiopathy with calcifications and cysts. Norrie disease protein (NDP) gene was found mutated in Norrie disease, in Familial Exudative Vitreoretinopathy, and in Coats syndrome. Here we describe a boy affected by Norrie disease who developed typical features of cerebroretinal microangiopathy with calcifications and cysts. Direct sequencing of the CTC1 and NDP genes in this patient shows the presence of compound heterozygosity for 2 mutations in CTC1 (c.775G>A, pV259M and a novel microdeletion c.1213delG) and a missense mutation in the NDP gene (c.182T>C, p.L61P). Based on these genetic findings and on the expression of both genes in endothelial cells, we postulate that microangiopathy might be a primary underlying pathologic abnormality in cerebroretinal microangiopathy with calcifications and cysts. This hypothesis is further supported by magnetic resonance imaging (MRI) data showing multiple minute calcifications in the deep gray nuclei and in terminal arteriolar zones.

Functional Magnetic Resonance Imaging (fMRI) in combination with Near Infrared Spectroscopy (NIRS) is finding widespread use in the analysis of brain function. While most of the studies deal with the detection of positive responses, here we focus on negative responses to visual stimulation. In a group fMRI study on Intermittent Photic Stimulation (IPS) we detected a sustained Negative BOLD Response (NBR) in the extrastriate visual cortex. To confirm and better characterize NBR, we repeated the same protocol during NIRS recordings. In this paper we show fMRI results and demonstrate the NBR on the basis of NIRS findings.

Near Infrared Spectroscopy (NIRS) was employed for the detection of possible residual functional activations in two patients in minimally conscious state. An "ad hoc" protocol for somatosensory and motor stimulations was created and administered to the patients, synchronously to NIRS recordings. One healthy subject was also assessed with the same task for comparison. Results from the healthy subject globally agree with the literature. Moreover, we could obtain significant results from the patients data. Indeed, in one patient, the NIRS channels showing activation completely correspond to regions of residual cortex underneath. In the second patient, though, together with possible residual intact cortex insulae, some channels match large cystic formations, with fluid gathering.

Objective: Ventriculomegaly (VM) is the most common brain anomaly in prenatal ultrasound (US) diagnosis. There is a general trend to perform fetal magnetic resonance imaging (MRI) when VM is severe (greater than 15 mm) and/or it is not isolated. The role of MRI is debated when VM is borderline (between 10 and 15 mm) and isolated. Some authors have subdivided borderline VM into mild (10 to 12 mm) and moderate (>12 to 15 mm). The aim of the study was to evaluate the role of MR in the imaging protocol of fetal cases characterized by mild isolated VM and no risk factors., Method: As a retrospective study, 179 fetal MRI exams (mean gestational age: 26 weeks), performed for mild, isolated VM on US, were analyzed to search additional or different findings with respect to ultrasound. The potential impact of MRI results on prenatal counselling is described., Results: In 49/179 cases, MRI and US results differed, but only in two of these cases did MRI studies provide clinically consistent additional information. In 130/179 cases, MRI confirmed US findings., Conclusion: In this extremely selected group of fetuses with isolated, mild VM and no risk factors, MRI may not be indicated in the prenatal imaging protocol., (© 2012 John Wiley & Sons, Ltd.)

Neurological disorders characterized by abnormal neuronal migration, organization, axon guidance, and maintenance have recently been associated with missense and splice-site mutations in the genes encoding α- and β-tubulin isotypes TUBA1A, TUBB2B, TUBB3, and TUBA8. We found a novel heterozygous mutation c.419G > C in exon 4 of the gene encoding TUBB2B in a female with microcephaly, agenesis of the corpus callosum, open-lip schizencephaly of the left parietal lobe, extensive polymicrogyria, basal ganglia and thalami dysmorphisms, and vermis and right third nerve hypoplasia. The missense change results in a glycine to alanine substitution; the mutated residue falls within an invariant glycine-rich region and therefore is likely to result in impaired protein function and possibly microtubule formation. This study expands the spectrum of brain malformations associated with mutations in the β-tubulin gene TUBB2B, supporting its critical role in migration/organization and axon guidance processes. In addition, it suggests a possible genetic aetiology of schizencephaly, thus strengthening the hypothesis that there is a common pathophysiological base in polymicrogyria and schizencephaly., (© The Authors. Developmental Medicine & Child Neurology © 2012 Mac Keith Press.)

Objective: Limited information is available about the development of focal cortical gyration anomalies in the human brain. Using prenatal MRI, we characterized focal cortical gyration anomalies at an early formative stage and sought clues about the mechanisms of their development., Materials and Methods: From a large prenatal MRI database, 30 cases (gestational age, ≤ 24 weeks) with reported focal distortion of the cortical rim profile were selected. Eight cases were matched with histologic examinations; another seven had prenatal MRI, MRI autopsy, or postnatal MRI follow-up; and 15 had no follow-up but did present analogous abnormal cortical features. Focal cortical gyration anomalies were detectable when the brain was still smooth (i.e., physiological lissencephaly)., Results: Four patterns of cortical plate anomaly were identified: wartlike (11 cases), abnormal invaginating sulcus (11 cases), sawtooth (six cases), and single or multiple bumps (two cases). A thinned or blurred subplate and intermediate zone in the focal cortical gyration anomaly site was detected in 80% of cases. All but two cases had other intracranial anomalies. Seven cases were classified as hypoxic-ischemic, five as genetic, and three as infective. In 15 cases, the cause could not be established. In five fetuses with further intrauterine or postnatal MRI, focal cortical gyration anomalies increased in complexity, fulfilling postnatal imaging criteria of polymicrogyria., Conclusion: Focal cortical gyration anomalies can be detected at the early sulcation process stage. The process leading to abnormal gyration may evolve faster than physiologic ones and seems to be related to alterations of parenchymal layering occurring before 24 weeks' gestation. Most focal cortical gyration anomalies evolve toward what is currently considered polymicrogyria.

Oral-Facial-Digital Syndrome type VI (OFD VI) represents a rare phenotypic subtype of Joubert syndrome and related disorders (JSRD). In the original report polydactyly, oral findings, intellectual disability, and absence of the cerebellar vermis at post-mortem characterized the syndrome. Subsequently, the molar tooth sign (MTS) has been found in patients with OFD VI, prompting the inclusion of OFD VI in JSRD. We studied the clinical, neurodevelopmental, neuroimaging, and genetic findings in a cohort of 16 patients with OFD VI. We derived the following inclusion criteria from the literature: 1) MTS and one oral finding and polydactyly, or 2) MTS and more than one typical oral finding. The OFD VI neuroimaging pattern was found to be more severe than in other JSRD subgroups and includes severe hypoplasia of the cerebellar vermis, hypoplastic and dysplastic cerebellar hemispheres, marked enlargement of the posterior fossa, increased retrocerebellar collection of cerebrospinal fluid, abnormal brainstem, and frequently supratentorial abnormalities that occasionally include characteristic hypothalamic hamartomas. Additionally, two new JSRD neuroimaging findings (ascending superior cerebellar peduncles and fused thalami) have been identified. Tongue hamartomas, additional frenula, upper lip notch, and mesoaxial polydactyly are specific findings in OFD VI, while cleft lip/palate and other types of polydactyly of hands and feet are not specific. Involvement of other organs may include ocular findings, particularly colobomas. The majority of the patients have absent motor development and profound cognitive impairment. In OFD VI, normal cognitive functions are possible, but exceptional. Sequencing of known JSRD genes in most patients failed to detect pathogenetic mutations, therefore the genetic basis of OFD VI remains unknown. Compared with other JSRD subgroups, the neurological findings and impairment of motor development and cognitive functions in OFD VI are significantly worse, suggesting a correlation with the more severe neuroimaging findings. Based on the literature and this study we suggest as diagnostic criteria for OFD VI: MTS and one or more of the following: 1) tongue hamartoma(s) and/or additional frenula and/or upper lip notch; 2) mesoaxial polydactyly of one or more hands or feet; 3) hypothalamic hamartoma.

Background and Purpose: Different and specific MR imaging patterns of lesions involving WM are widely defined in neonatal encephalopathy. The aim of this study was to describe a novel MR imaging pattern of damage characterized by the abnormal prominence of DMVs in premature and full-term neonates., Materials and Methods: Twenty-one (11 premature and 10 full-term) neonates with MR imaging evidence of linear radially oriented fan-shaped lesions in the periventricular WM and without dural venous thrombosis were enrolled in this retrospective study. A total of 37 MR imaging examinations were performed at ages ranging from day 0 to 24 months., Results: According to the appearance of linear anomalies on T2-weighted images, we identified 2 main patterns: T2 hypointense lesions without WM cavitations and T2 hypointense lesions associated with linear cysts. The first pattern was found in 17 examinations performed between 0 and 44 days of life; the second pattern was found in another 14 examinations performed between 6 days and 4 months of life. Five examinations performed between 9 and 24 months of life showed a reduction in volume and hyperintense signal intensity of the periventricular WM on T2-weighted and FLAIR images., Conclusions: Subtle linear WM lesions with the same anatomic distribution of DMVs may be evident in premature and full-term neonates without signs of major venous thrombosis, both in the acute and subacute phases. Their appearance and evolution suggest that transient DMV engorgement/thrombosis may be responsible for WM damage that can lead to a PVL-like pattern.

Fetal magnetic resonance (MR) imaging may add to ultrasonography some valuable information in the assessment of Chiari malformations during their developmental stage. In Chiari type I, MR imaging role seems mainly related to research on pathophysiology issues rather than to real clinical applications. Some Chiari type II features may be better characterized in utero by MR imaging: such as the degree of downward displacement of cerebellum, possible abnormal signal changes within brain parenchyma and the type of meningocele (covered or uncovered).

Looking for anomalies distributed in DMV territory, we reviewed 78 fetal MR imaging examinations performed at our institution reporting unequivocal cerebral clastic lesions. We selected 3 cases, all of which had severe cardiocirculatory failure and parenchymal frontoparietal WM hemorrhagic lesions with characteristic fan-shaped distribution. Brain edema and other signs of venous hypertension were also evident. Our data suggest that in utero transient venous hypertension may be responsible for the onset of atypical frontal-located PVL.

Introduction: The main purpose was to investigate any early diffusion tensor imaging (DTI) changes in corpus callosum (CC) associated with acute cerebral hemisphere lesions in term newborns., Methods: We retrospectively analysed 19 cases of term newborns acutely affected by focal or multi-focal lesions: hypoxic-ischemic encephalopathy, hypoglycaemic encephalopathy, focal ischemic stroke and deep medullary vein associated lesions. DTI was acquired at 1.5 Tesla with dedicated neonatal coil. DTI metrics (apparent diffusion coefficient (ADC), fractional anisotropy (FA), axial λ(∐) and radial λ(⟂) diffusivity) were measured in the hemisphere lesions and in the CC. The control group included seven normal newborns., Results: The following significant differences were found between patients and normal controls in the CC: mean ADC was lower in patients (0.88 SD 0.23 versus 1.18 SD 0.07 μm(2)/s) and so was mean FA (0.50 SD 0.1 versus 0.67 SD 0.05) and mean λ(∐) value (1.61 SD 0.52 versus 2.36 SD 0.14 μm(2)/s). In CC the percentage of ADC always diminished independently of lesion age (with one exception), whereas in hemisphere lesions, it was negative in earlier lesions, but exceeded normal values in the older lesions., Conclusion: CC may undergo early DTI changes in newborns with acute focal or multi-focal hemisphere lesions of different aetiology. Although a direct insult to CC cannot be totally ruled out, DTI changes in CC (in particular λ(∐)) may also be compatible with very early Wallerian degeneration or pre-Wallerian degeneration.

Objective: Endothelial injury is central to the pathogenesis of vasculitis. The purpose of this study was to assess how indices of endothelial injury and repair change during different stages of disease activity in children with primary systemic vasculitis (PSV)., Methods: Fifty children with PSV, 17 children with nonvasculitic inflammatory diseases (pediatric inflammatory disease controls), 35 healthy age- and sex-matched pediatric controls, and 27 healthy adult controls were included in the study. Biomarkers examined were endothelial microparticles (EMPs), circulating endothelial cells (CECs), angiogenic growth factors, and endothelial progenitor cells (EPCs). EMP binding to annexin V, EMPs expressing CD144 or E-selectin, and EPCs expressing vascular endothelial growth factor receptor 2 (VEGFR-2), CD133, and CD34 were examined by flow cytometry. CECs were enumerated using immunomagnetic bead extraction techniques, and VEGF and angiopoietin 2 (Ang-2) were measured by enzyme-linked immunosorbent assay., Results: Levels of CD144+ EMPs, CECs, VEGF, and EPCs were all significantly elevated in children with active vasculitis as compared with healthy children, and the levels declined with remission-inducing therapy in the individual patients. Treatment-naive patients with active disease had significantly higher levels of VEGF and Ang-2 than did those with active disease who were receiving treatment, although the levels of CECs and EMPs remained high in both of these groups., Conclusion: Elevation of the levels of CECs, EMPS, EPCs, VEGF, and Ang-2 occurs during active vasculitis in children. EPC responses to active vasculitis are different in children as compared with that observed in adults with vasculitis, and both CECs and EMPs can be used to monitor disease activity in children with vasculitis.

Purpose: To assess the diagnostic and prognostic value of fetal cerebral magnetic resonance (MR) imaging of congenital cytomegalovirus (CMV) infection in comparison with that of level II ultrasonography (US)., Materials and Methods: Institutional review board approval and informed consent for fetal MR imaging and data collection were obtained. Thirty-eight fetuses with CMV infection, examined by using serial level II US, underwent fetal MR imaging (mean gestational age, 25 weeks; age range at first fetal MR examination, 20-34 weeks). The frequency of pathologic findings at US (29 cases with transabdominal examination and nine cases with both transabdominal and transvaginal examination) and MR imaging was calculated, and a comparison between techniques by considering number (paired Student t test) and type (McNemar test) of finding was made. A comparison (paired Student t test) in cases of repeated fetal (nine of 38) and/or postnatal (14 of 38) MR imaging was obtained. Diagnostic and prognostic sensitivity was calculated for both techniques., Results: US and MR imaging findings were both normal in 47% of cases (18 of 38). Abnormal studies were reported in 26% (10 of 38) of US and 53% (20 of 38) of MR imaging cases. In 47% of cases (18 of 38), MR imaging provided additional information (P = .0002). MR imaging had better results than US in detecting polar temporal lesions (P = .0001), microencephaly (P = .03), and cortical anomalies (P = .06). In 44.5% of cases (four of nine), the second fetal MR examination results showed new findings (P = .05). In 79% of cases, postnatal MR imaging results confirmed prenatal findings (P = .08). MR imaging had higher sensitivity than US in detecting brain anomalies (92% vs 38%) and in predicting symptomatic infection (83% vs 33%). US and MR imaging revealed low positive predictive values (29% vs 36%)., Conclusion: Fetal MR imaging results can show abnormalities in the fetal brain after CMV infection, even when US results are normal. The early detection of some brain abnormalities, such as microencephaly and cortical anomalies, may substantially influence the prognosis of fetal infection.

We report on a 22-week-gestation fetus, in which prenatal magnetic resonance (MR) imaging revealed findings suggestive of glutaric aciduria type 1, which was confirmed by postnatal biochemical and imaging data. Well-known postnatal MR imaging characteristics of glutaric aciduria type 1 (eg, reduction of the anterior pole of temporal lobes) could be already present at early stage of fetal brain development. Early prenatal MR imaging may play a pivotal role in the diagnostic workout of this condition.

Background and Purpose: Prenatal imaging data of the normal pituitary gland and in vivo information on the development of the pituitary region are lacking; however, we noticed that the pituitary stalk (PS) is visible occasionally in utero on MR images. Our main purpose was to establish the detection rate of the PS in healthy fetuses at various gestational ages (GAs) by using single-shot fast spin-echo T2-weighted images., Materials and Methods: We selected 73 fetal cases with normal findings on prenatal MR imaging and clinical postnatal follow-up. The GA ranged between 19 and 37 weeks. The 3 planes of MR imaging sections were 4 mm thick with 1.25 x 1.25 mm in-plane resolution. Two pediatric neuroradiologists evaluated in consensus whether the PS was present as a linear isointense structure connecting the hypothalamic region with the floor of sella turcica. In those cases in which the PS was visible on the sagittal section, the angle formed by the intersection of the PS and the sellar plane (SP) was measured (PS-SP angle)., Results: The PS was detectable on at least 1 coronal or sagittal section from 19 to 25 weeks' GA in 30/42 fetuses (71.4% sensitivity); from 26 to 37 weeks' GA, the PS was detected in all 31 fetuses (100% sensitivity). The PS-SP angle decreased significantly with GA, being <90 degrees in all fetuses after gestational week 25., Conclusions: At the current spatial resolution of clinical prenatal MR imaging, PS can be reliably detected after 25 weeks' GA, so in case of a missing visualization, a strong suspicion of pituitary region anomaly could be raised.

Background: Circulating endothelial cells (CECs) are biomarkers for endothelial cell (EC) injury and are quantified using immunomagnetic bead extraction (IBE), or flow cytometry (FC). Reports suggest that there is good agreement between these methods for CEC quantification., Objectives: We examined levels of agreement between these techniques in children with systemic vasculitis., Methods: We added HUVEC or human pulmonary artery EC to whole blood to optimize FC gating strategies for EC. EC-optimized FC was then compared with IBE for CEC enumeration in 25 children with vasculitis and 20 healthy controls., Results: Using Bland-Altman analysis, agreement between IBE and EC-optimized FC was poor in children with vasculitis (n = 25) and healthy controls (n = 20): IBE consistently detected higher values than the EC-optimized FC method: the mean difference between the two techniques was 60 CECs mL(-1), 95% CI +/-374 CECs mL(-1) (paired analyses of 45 individuals). Agreement was poorest for vasculitis patients: mean difference (IBE - EC-optimized FC) 120 CECs mL(-1), 95% CI +/-460 CECs mL(-1) (P = 0.018). We identified three reasons for this discrepancy: (i) sub-optimal FC gating parameters previously used for detecting CECs; (ii) inherent lack of sensitivity of FC compared with IBE for CEC rare event detection; and (iii) use of lysis buffers required for FC causing CEC lysis., Conclusions: There was poor agreement between EC-optimized FC and IBE for the quantification of CECs from children with active vasculitis and controls. We emphasize that in this clinical setting the two techniques are not directly comparable when comparing results obtained using these different methodologies.

Background: Macular oedema tends to be a more rapid complication of diabetic retinopathy and represents the major cause of blindness. Among subjects with type 2 diabetes mellitus, it can be found in 15% of those who use insulin and 4% of those who do not. Use of thiazolidinediones (glitazones) has recently been associated with some cases of macular oedema., Methods: We recalled 102 diabetic subjects treated with rosiglitazone to our diabetes centre in order to evaluate a possible association of this drug with macular oedema. Of these 102 subjects, we evaluated all 76 who provided written informed consent to participate in the analysis. All of these underwent a battery of four diagnostic tests: (1) visual acuity, (2) Amsler visual field test, (3) Ishihara colour recognition test, and (4) retinal fundus photography. All retinal photographs were examined by two experienced ophthalmologists., Results: The most noticeable result was that most subjects (80%) had satisfactory visual acuity. The Ishihara test chart showed that three subjects were colour blind, but this abnormality was already known. On the Amsler test, one subject had a positive result consisting of visual distortion of a series of straight lines. In the retinal photos, two expert ophthalmologists independently identified one case of 'paramacular oedema' in a subject with diabetes of long duration with a proliferative retinopathy. The patient developed bilateral macular oedema during treatment with rosiglitazone 8 mg/day. The patient had been diagnosed with diabetes at the age of 45 years and after a period of 6 years taking oral antihyperglycaemic agents had been switched to insulin, up to four injections per day (total 60-70 IU/day), for the next 15 years. In 2000 a routine examination demonstrated the presence of sustained hypertension and the patient was started on an ACE inhibitor. A computerized test for autonomic neuropathy demonstrated abnormal deep breathing and lying-to-standing responses. Treatment with rosiglitazone was interrupted and the subject underwent a series of retinal photocoagulations for proliferative retinopathy. Two months after rosiglitazone therapy had been discontinued, the visual acuity of the patient reversed to baseline values., Conclusion: The study shows that rosiglitazone was not linked to formation of macular oedema, with the exception of one case of bilateral and clinically reversible paramacular oedema, where rosiglitazone was given in co-administration with a long-term insulin treatment regimen in a subject with pre-existing diabetic retinopathy. This patient had a long duration of diabetes and had also been hypertensive since 2000.

Nitric oxide (NO) plays an important role in lowering pulmonary vascular resistance after birth. However, in persistent pulmonary hypertension of the newborn (PPHN) NO-mediated dilation is dysfunctional. GTP-cyclohydrolase 1 (GTP-CH1) is the rate-limiting enzyme for the biosynthesis of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (BH4) an essential cofactor for nitric oxide synthase (NOS) activity. Suboptimal levels of BH4 may result in NOS uncoupling and the subsequent generation of harmful superoxide anions. We therefore investigated the functional effects of supplementing BH4 and/or a superoxide dismutase mimetic (MnTMPyP) in porcine intrapulmonary arteries from normal animals and from a porcine model of PPHN. We investigated whether any functional effects of BH4 could be explained by changes in GTP-CH1 expression. Supplementation of BH4 significantly improved endothelium-dependent relaxations in arteries from 3- and 14-d-old healthy animals, whereas no effect was seen in vessels from younger animals and adults. GTP-CH1 protein expression was lowest at 3 and 14 d, suggesting a rate limitation of BH4 at this time. BH4 supplementation alone did not improve the relaxant response to acetylcholine in arteries obtained in a porcine model of PPHN. Furthermore, GTP-CH1 protein expression was normal for age. However, co-treatment with both BH4 and MnTMPyP restored endothelial function. GTP-CH1 is developmentally regulated in the pulmonary vasculature of neonates and this results in a functionally significant limitation of BH4. Although GTP-CH-1/BH4 levels alone do not explain the profound endothelial dysfunction seen in PPHN, increasing NO bioavailability by supplementing BH4 and quenching superoxide may prove to be therapeutically beneficial.

We start from a stochastic SIS model for the spread of epidemics among a population partitioned into M sites, each containing N individuals; epidemic spread occurs through within-site ('local') contacts and global contacts. We analyse the limit behaviour of the system as M and N increase to infinity. Two limit procedures are considered, according to the order in which M and N go to infinity; independently of the order, the limiting distribution of infected individuals across sites is a probability measure, whose evolution in time is governed by the weak form of a PDE. Existence and uniqueness of the solutions to this problem is shown. Finally, it is shown that the infected distribution converges, as time goes to infinity, to a Dirac measure at the value x(*), the equilibrium of a single-patch SIS model with contact rate equal to the sum of local and global contacts.

all-trans-Retinoic acid (atRA) has important effects on the developing and mature cardiovascular system. Nitric oxide (NO) production has been associated with the atRA-induced differentiation of neuronal cells, and we hypothesized that NO may also mediate certain actions of atRA in the cardiovascular system. We studied the effects of atRA on NO production by endothelial cells and determined whether regulation of enzymes responsible for metabolism of asymmetric dimethylarginine (ADMA) contributed to the effects seen. Murine endothelioma (sEnd.1) cells were incubated with or without atRA. Nitrite production was determined using the Griess reaction. The expression of NO synthase (NOS) and dimethylarginine dimethylaminohydrolase (DDAH) genes was determined by Northern blotting. A reporter gene assay was also used to study the effect of atRA on the DDAH II promoter. atRA significantly increased nitrite production by sEnd.1 cells despite no increase in eNOS expression. atRA also increased DDAH II gene expression and promoter activity and reduced the ratio of ADMA to symmetric dimethylarginine (SDMA) in culture medium. The DDAH inhibitor 4124W significantly reduced the induction of NO synthesis by atRA. The present study demonstrates that atRA increases NO synthesis in endothelial cells without increasing eNOS expression. atRA also increases the expression of DDAH II, the predominant DDAH isoform in endothelial cells. Our data suggests that the induction of NO synthesis by atRA may be facilitated by DDAH II. This pathway may help to explain some of the effects of atRA on the cardiovascular system.

The reactivity of pulmonary veins during adaptation from pre- to postnatal life is not well characterized. With an in vitro organ bath technique, the responses to the contractile and relaxant agonists U-46619 (10(-10) to 3 x 10(-6) M) and acetylcholine (10(-9) to 10(-4) M) were compared in adjacent conduit pulmonary vein and artery rings from 66 piglets aged 1 wk preterm to 14 days of postnatal life and from adult tissue. Five additional piglets were made hypertensive by exposure to chronic hypoxia for 3 days after birth. Both arteries and veins showed smaller contractile and relaxant responses before birth than after. By 5 min after birth, the contraction by arteries and relaxation by veins had increased (P < 0.05). By 3 days of age, arterial relaxation increased, but in all animals, venous relaxation exceeded that in arteries (P < 0.05). Veins contracted more than arteries in animals aged 3-14 days. Neonatal hypoxia diminished the responses to both agonists in the veins (P < 0.05), whereas the response in the arteries remained similar to that in the normal newborn. We speculate that veins may be more important in postnatal adaptation than previously suggested.

The diagnostic iter and treatment of peptic ulcer have evolved considerably over the past 20 years. The capillary spread of endoscopy has permitted secure and precise diagnoses to be made, in terms of both the site and size of the anatomic lesion, on the one hand, and on the other, the introduction of antisecretory drugs has led to the resolution of the majority of ulcers, so much so that the ulcer is no longer managed using strictly surgical methods but is now treated medically and only emergency cases, such as perforations, undergo surgery. Complications, such as digestive hemorrhage, penetration and stenosis, may lead to the need for surgery. In particular, perforation seems to be the only complication which has not been significantly influenced by the introduction of antisecretory therapy, the point that its status as a "complication" has been questioned leading to the suspicion of its nosological autonomy. The authors review the series of ulcer patients admitted to hospital during the period 1968 to 1991, paying special attention to the correlation with the use of antisecretory drugs which were introduced during the period 1978-1981, the trend of ulcer complications over the entire period, the duration of symptoms and the epidemiology of peptic and perforated ulcers.

Two years after the first evaluation, the authors review the results of quadrantectomy in the conservative treatment of breast carcinoma. Local control of the disease by quadrantectomy with axillary lymphadenectomy and radiotherapy has been more difficult in the T2 patients (4 local relapses out of 41 patients) compared T1 patients (3 local relapses out of 52 patients). Nodal involvement appears to be not crucial for the prognosis (7 patients out of 10 with remote metastases were N- at the time of surgery).