The mouse cortico-basal ganglia-thalamic network.

The cortico-basal ganglia-thalamo-cortical loop is one of the fundamental network motifs in the brain. Revealing its structural and functional organization is critical to understanding cognition, sensorimotor behaviour, and the natural history of many neurological and neuropsychiatric disorders. Classically, this network is conceptualized to contain three information channels: motor, limbic and associative1-4. Yet this three-channel view cannot explain the myriad functions of the basal ganglia. We previously subdivided the dorsal striatum into 29 functional domains on the basis of the topography of inputs from the entire cortex5. Here we map the multi-synaptic output pathways of these striatal domains through the globus pallidus external part (GPe), substantia nigra reticular part (SNr), thalamic nuclei and cortex. Accordingly, we identify 14 SNr and 36 GPe domains and a direct cortico-SNr projection. The striatonigral direct pathway displays a greater convergence of striatal inputs than the more parallel striatopallidal indirect pathway, although direct and indirect pathways originating from the same striatal domain ultimately converge onto the same postsynaptic SNr neurons. Following the SNr outputs, we delineate six domains in the parafascicular and ventromedial thalamic nuclei. Subsequently, we identify six parallel cortico-basal ganglia-thalamic subnetworks that sequentially transduce specific subsets of cortical information through every elemental node of the cortico-basal ganglia-thalamic loop. Thalamic domains relay this output back to the originating corticostriatal neurons of each subnetwork in a bona fide closed loop.

Dystrophin myonuclear domain restoration governs treatment efficacy in dystrophic muscle.

Dystrophin is essential for muscle health: its sarcolemmal absence causes the fatal, X-linked condition, Duchenne muscular dystrophy (DMD). However, its normal, spatial organization remains poorly understood, which hinders the interpretation of efficacy of its therapeutic restoration. Using female reporter mice heterozygous for fluorescently tagged dystrophin (DmdEGFP), we here reveal that dystrophin distribution is unexpectedly compartmentalized, being restricted to myonuclear-defined sarcolemmal territories extending ~80 µm, which we called "basal sarcolemmal dystrophin units (BSDUs)." These territories were further specialized at myotendinous junctions, where both Dmd transcripts and dystrophin protein were enriched. Genome-level correction in X-linked muscular dystrophy mice via CRISPR/Cas9 gene editing restored a mosaic of separated dystrophin domains, whereas transcript-level Dmd correction, following treatment with tricyclo-DNA antisense oligonucleotides, restored dystrophin initially at junctions before extending along the entire fiber-with levels ~2% sufficient to moderate the dystrophic process. We conclude that widespread restoration of fiber dystrophin is likely critical for therapeutic success in DMD, perhaps most importantly, at muscle-tendon junctions.

A cell autonomous regulator of neuronal excitability modulates tau in Alzheimer's disease vulnerable neurons.

Neurons from layer II of the entorhinal cortex (ECII) are the first to accumulate tau protein aggregates and degenerate during prodromal Alzheimer's disease. Gaining insight into the molecular mechanisms underlying this vulnerability will help reveal genes and pathways at play during incipient stages of the disease. Here, we use a data-driven functional genomics approach to model ECII neurons in silico and identify the proto-oncogene DEK as a regulator of tau pathology. We show that epigenetic changes caused by Dek silencing alter activity-induced transcription, with major effects on neuronal excitability. This is accompanied by the gradual accumulation of tau in the somatodendritic compartment of mouse ECII neurons in vivo, reactivity of surrounding microglia, and microglia-mediated neuron loss. These features are all characteristic of early Alzheimer's disease. The existence of a cell-autonomous mechanism linking Alzheimer's disease pathogenic mechanisms in the precise neuron type where the disease starts provides unique evidence that synaptic homeostasis dysregulation is of central importance in the onset of tau pathology in Alzheimer's disease.

A new type of phasin characterized by the presence of a helix-hairpin-helix domain is required for normal polyhydroxybutyrate accumulation and granule organization in Caulobacter crescentus.

Bacteria frequently store excess carbon in hydrophobic granules of polyhydroxybutyrate (PHB) that in some growth conditions can occupy most of the cytoplasmic space. Different types of proteins associate to the surface of the granules, mainly enzymes involved in the synthesis and utilization of the reserve polymer and a diverse group of proteins known as phasins. Phasins have different functions, among which are regulating the size and number of the granules, modulating the activity of the granule-associated enzymes and helping in the distribution of the granules inside the cell. Caulobacter crescentus is an oligotrophic bacterium that shows several morphological and regulatory traits that allow it to grow in very nutrient-diluted environments. Under these conditions, storage compounds should be particularly relevant for survival. In this work, we show an initial proteomic characterization of the PHB granules and describe a new type of phasin (PhaH) characterized by the presence of an N-terminal hydrophobic helix followed by a helix-hairpin-helix (HhH) domain. The hydrophobic helix is required for maximal PHB accumulation and maintenance during the stationary phase while the HhH domain is involved in determining the size of the PHB granules and their distribution in the cell.

Whole-genome sequencing reveals a novel pathogenic GRIN2B variant in a patient with neurodevelopmental disorder and an inv(6)(p24p11.2)pat.

INTRODUCTION: Neurodevelopmental disorders (NDDs) are diverse and can be explained by either genomic aberrations or single nucleotide variants (SNVs). Most likely due to methodological approaches and/or disadvantages, the concurrence of both genetic events in a single patient has hardly been reported and even more rarely the pathogenic variant has been regarded as the cause of the phenotype when a chromosomal alteration is initially identified. CASE PRESENTATION: Here, we describe a NDD patient with a 6p non-pathogenic paracentric inversion paternally transmitted and a de novo pathogenic variant in the GRIN2B gene. Molecular-cytogenetic studies characterized the familial 6p inversion and revealed a paternal 9q inversion not transmitted to the patient. Subsequent whole-genome sequencing (WGS) in the patient-father dyad corroborated the previous findings, discarded inversions-related cryptic genomic rearrangements as causative of the patient's phenotype, and unveiled a novel heterozygous GRIN2B variant (p.(Ser570Pro)) only in the proband. In addition, Sanger sequencing ruled out such a variant in her mother and thereby confirmed its de novo origin. Due to predicted disturbances in the local secondary structure, this variant may alter the ion channel function of the M1 transmembrane domain. Other pathogenic variants in GRIN2B have been related to the autosomal dominant neurodevelopmental disorder MRD6 (Intellectual developmental disorder, autosomal dominant 6, with or without seizures), which presents with a high variability ranging from mild intellectual disability (ID) without seizures to a more severe encephalopathy. In comparison, our patient's clinical manifestations include, among others, mild ID and brain anomalies previously documented in subjects with MRD6. CONCLUSION: Occasionally, gross chromosomal abnormalities can be coincidental findings rather than a prime cause of a clinical phenotype (even though they appear to be the causal agent). In brief, this case underscores the importance of comprehensive genomic analysis in unraveling the wide-ranging genetic causes of NDDs and may bring new insights into the MRD6 variability.

Recommendations for quantitative cerebral perfusion MRI using multi-timepoint arterial spin labeling: Acquisition, quantification, and clinical applications.

Accurate assessment of cerebral perfusion is vital for understanding the hemodynamic processes involved in various neurological disorders and guiding clinical decision-making. This guidelines article provides a comprehensive overview of quantitative perfusion imaging of the brain using multi-timepoint arterial spin labeling (ASL), along with recommendations for its acquisition and quantification. A major benefit of acquiring ASL data with multiple label durations and/or post-labeling delays (PLDs) is being able to account for the effect of variable arterial transit time (ATT) on quantitative perfusion values and additionally visualize the spatial pattern of ATT itself, providing valuable clinical insights. Although multi-timepoint data can be acquired in the same scan time as single-PLD data with comparable perfusion measurement precision, its acquisition and postprocessing presents challenges beyond single-PLD ASL, impeding widespread adoption. Building upon the 2015 ASL consensus article, this work highlights the protocol distinctions specific to multi-timepoint ASL and provides robust recommendations for acquiring high-quality data. Additionally, we propose an extended quantification model based on the 2015 consensus model and discuss relevant postprocessing options to enhance the analysis of multi-timepoint ASL data. Furthermore, we review the potential clinical applications where multi-timepoint ASL is expected to offer significant benefits. This article is part of a series published by the International Society for Magnetic Resonance in Medicine (ISMRM) Perfusion Study Group, aiming to guide and inspire the advancement and utilization of ASL beyond the scope of the 2015 consensus article.

Dynamic microglia alterations associate with hippocampal network impairments: A turning point in amyloid pathology progression.

Alzheimer's disease is a progressive neurological disorder causing memory loss and cognitive decline. The underlying causes of cognitive deterioration and neurodegeneration remain unclear, leading to a lack of effective strategies to prevent dementia. Recent evidence highlights the role of neuroinflammation, particularly involving microglia, in Alzheimer's disease onset and progression. Characterizing the initial phase of Alzheimer's disease can lead to the discovery of new biomarkers and therapeutic targets, facilitating timely interventions for effective treatments. We used the AppNL-G-F knock-in mouse model, which resembles the amyloid pathology and neuroinflammatory characteristics of Alzheimer's disease, to investigate the transition from a pre-plaque to an early plaque stage with a combined functional and molecular approach. Our experiments show a progressive decrease in the power of cognition-relevant hippocampal gamma oscillations during the early stage of amyloid pathology, together with a modification of fast-spiking interneuron intrinsic properties and postsynaptic input. Consistently, transcriptomic analyses revealed that these effects are accompanied by changes in synaptic function-associated pathways. Concurrently, homeostasis- and inflammatory-related microglia signature genes were downregulated. Moreover, we found a decrease in Iba1-positive microglia in the hippocampus that correlates with plaque aggregation and neuronal dysfunction. Collectively, these findings support the hypothesis that microglia play a protective role during the early stages of amyloid pathology by preventing plaque aggregation, supporting neuronal homeostasis, and overall preserving the oscillatory network's functionality. These results suggest that the early alteration of microglia dynamics could be a pivotal event in the progression of Alzheimer's disease, potentially triggering plaque deposition, impairment of fast-spiking interneurons, and the breakdown of the oscillatory circuitry in the hippocampus.

Field-dependent abundances of hydride molecular ions in atom probe tomography of III-N semiconductors.

We investigate the microscopic behaviour of hydrogen-containing species formed on the surface of III-N semiconductor samples by the residual hydrogen in the analysis chamber in laser-assisted atom probe tomography (APT). We analysed AlGaN/GaN heterostructures containing alternate layers with a thickness of about 20 nm. The formation of H-containing species occurs at field strengths between 22 and 26 V/nm and is independent of the analysed samples. The 3D APT reconstruction makes it possible to map the evolution of the surface behaviour of these species issued by chemical reactions. The results highlight the strong dependence of the relative abundances of hydrides on the surface field during evaporation. The relative abundances of the hydrides decrease when the surface field increases due to the evolution of the tip shape or the different evaporation behaviour of the different layers.

Building momentum through networks: Bioimaging across the Americas.

In September 2023, the two largest bioimaging networks in the Americas, Latin America Bioimaging (LABI) and BioImaging North America (BINA), came together during a 1-week meeting in Mexico. This meeting provided opportunities for participants to interact closely with decision-makers from imaging core facilities across the Americas. The meeting was held in a hybrid format and attended in-person by imaging scientists from across the Americas, including Canada, the United States, Mexico, Colombia, Peru, Argentina, Chile, Brazil and Uruguay. The aims of the meeting were to discuss progress achieved over the past year, to foster networking and collaborative efforts among members of both communities, to bring together key members of the international imaging community to promote the exchange of experience and expertise, to engage with industry partners, and to establish future directions within each individual network, as well as common goals. This meeting report summarises the discussions exchanged, the achievements shared, and the goals set during the LABIxBINA2023: Bioimaging across the Americas meeting.

Evolution of cerebrovascular imaging and associated clinical findings in children with Alagille syndrome.

PURPOSE: Alagille syndrome (ALGS) is a multisystem autosomal dominant disorder with highly variable expression. Intracranial arterial and venous anomalies have a reported prevalence of 30-40% and can increase the risk of stroke by 16%. Few reports document the frequency and evolution of cerebrovascular abnormalities (CVAs) in children with ALGS. We aimed to define the spectrum, frequency, and evolution of CVAs in a series of children with ALGS using magnetic resonance angiography (MRA). METHODS: We conducted a single-center, retrospective study in a large tertiary pediatric hospital. CVAs were grouped into 4 categories: 1) Stenosis or narrowing; 2) Aneurysms and ectasias; 3) Tortuosity; and 4) Vascular anomalies and anatomical variants. RESULTS: Thirty-two children met the inclusion criteria. The median age at initial diagnosis was 6 (3.8-10.3) years. Thirteen (40%) had follow-up MRI at a mean of 55 (31.5-66) months. Eighteen (56%) had CVAs; the most frequent fell into group 1 (n = 12, 37.5%). CVAs were stable over time, except for one patient with Moyamoya arteriopathy (MMA). One patient developed a transient ischemic attack secondary to an embolic event. Three (9.3%) had microhemorrhages at the initial diagnosis secondary to Tetralogy of Fallot. Another patient had recurrent subdural hematomas of unknown cause. CONCLUSION: CVAs were stable except in the presence of MMA. Vascular strokes, which are reported in older patients with ALGS, were not a common feature in children under 16 years of age, either at presentation or over the 31.5-66 month follow-up period.

A comprehensive evaluation of imaging features in pediatric spinal gliomas and their value in predicting tumor grade and histology.

PURPOSE: Pediatric spinal cord gliomas (PSGs) are rare in children and few reports detail their imaging features. We tested the association of tumoral grade with imaging features and proposed a novel approach to categorize post-contrast enhancement patterns in PSGs. METHODS: This single-center, retrospective study included patients <21 years of age with preoperative spinal MRI and confirmed pathological diagnosis of PSG from 2000-2022. Tumors were classified using the 5th edition of the WHO CNS Tumors Classification. Two radiologists reviewed multiple imaging features, and classified enhancement patterns using a novel approach. Fisher's exact test determined associations between imaging and histological features. RESULTS: Forty-one PSGs were reviewed. Thirty-four were intramedullary, and seven were extramedullary. Pilocytic astrocytoma was the most common tumor (39.02%). Pain and weakness were the most prevalent symptoms. Seven patients (17.07%) died. Cyst, syringomyelia, and leptomeningeal enhancement were associated with tumor grade. Widening of the spinal canal was observed only in low-grade astrocytomas. There was a significant association between tumor grade and contrast enhancement pattern. Specifically, low-grade PSGs were more likely to exhibit type 1A enhancement (mass-like, with well-defined enhancing margins) and less likely to exhibit type 1B enhancement (mass-like, with ill-defined enhancing margins). CONCLUSION: PSGs display overlapping imaging features, making grade differentiation challenging based solely on imaging. The correlation between tumor grade and contrast enhancement patterns suggests a potential diagnostic avenue, requiring further validation with larger, multicenter studies. Furthermore, Low-grade PSGs display cysts and syringomyelia more frequently, and leptomeningeal enhancement is less common.

Complications in Patients with Surgically Altered Gastrointestinal Anatomy Undergoing Endoscopic Retrograde Cholangiopancreatography: 15-Year Experience at a Tertiary Care Center in Latin America.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is a common procedure, but it poses challenges in patients with surgically altered gastrointestinal anatomy (SAGA). Alternative techniques like single-balloon enteroscopy (SBE), double-balloon enteroscopy (DBE), or push enteroscopy (PE) have been used, albeit with potential complications. Limited Latin American data exists on ERCP complications in SAGA patients. Our goal is to describe complications of ERCP in SAGA at a national referral institution. METHODS: Retrospective, single-center cohort study. All SAGA ERCP procedures performed at the Gastrointestinal Endoscopy Department of the National Institute of Medical Sciences and Nutrition Salvador Zubirán from January 2008 to May 2023 were included. Extracted data from records included procedure specifics, endoscope type, success, and complications. Complications were evaluated during procedure and 28-day post-procedure and classified using the AGREE system. RESULTS: A total of 266 procedures in 174 patients were included, 74% were women, and the median age was 44 years. Predominant modified anatomy was Roux-en-Y biliary reconstruction (79%), followed by Whipple procedure (13%) and subtotal gastrectomy with Roux-en-Y reconstruction (6.0%). The main indications were cholangitis with stricture (31%), stricture (19%), and cholangitis (19%). DBE was used in 89%, PE in 7.5%, and SBE in 3.4%. Success rates were 77% endoscopic, 72% technical, and 69% therapeutic; in 30%, the procedure was unsuccessful. Complications happened in 18% of cases, most commonly cholangitis (7.5%), followed by perforation (2.6%) and hemorrhage (1.9%). According to the AGREE classification, 10.9% were grades 1 and 2, 6.4% were grade 3, and 0.4% were grade 4 complications. No significant differences emerged between groups with and without complications. Procedures increased over time, but complications and unsuccessful procedures remained stable. CONCLUSION: ERCP complications align with international data, often not requiring invasive treatment. Enhanced exposure to such cases correlates with fewer complications and failures. Prospective studies are essential to identify complication and failure predictors.

Convergence of the dimensional assessment of personality pathology (DAPP-BQ) and the five-factor personality inventory for the international classification of diseases 11th edition (FFiCD) in the context of the five-factor model and personality disorders.

The current manuscript presents the convergence of the Dimensional Assessment of Personality Pathology (DAPP-BQ), using its short form the DAPP-90, and the Five-Factor Personality Inventory for International Classification of Diseases (ICD-11), the FFiCD, in the context of the five-factor personality model and the categorical approach of personality disorders (PDs). The current manuscript compares the predictive validity of both the FFiCD and the DAPP-90 regarding personality disorder scales and clusters. Results demonstrate a very high and meaningful convergence between the DAPP-90 and the FFiCD personality pathology models and a strong alignment with the FFM. The DAPP-90 and the FFiCD also present an almost identical predictive power of PDs. The DAPP-90 accounts for between 18% and 47%, and the FFiCD between 21% and 47% of PDs adjusted variance. It is concluded that both DAPP-90 and FFiCD questionnaires measure strongly similar pathological personality traits that could be described within the frame of the FFM. Additionally, both questionnaires predict a very similar percentage of the variance of personality disorders.

Physical Proximity of Sister Chromatids Promotes Top2-Dependent Intertwining.

Sister chromatid intertwines (SCIs), or catenanes, are topological links between replicated chromatids that interfere with chromosome segregation. The formation of SCIs is thought to be a consequence of fork swiveling during DNA replication, and their removal is thought to occur because of the intrinsic feature of type II topoisomerases (Top2) to simplify DNA topology. Here, we report that SCIs are also formed independently of DNA replication during G2/M by Top2-dependent concatenation of cohesed chromatids due to their physical proximity. We demonstrate that, in contrast to G2/M, Top2 removes SCIs from cohesed chromatids at the anaphase onset. Importantly, SCI removal in anaphase requires condensin and coincides with the hyperactivation of condensin DNA supercoiling activity. This is consistent with the longstanding proposal that condensin provides a bias in Top2 function toward decatenation. A comprehensive model for the formation and resolution of toxic SCI entanglements on eukaryotic genomes is proposed.

The Alternative Model of Personality Disorders: Assessment, Convergent and Discriminant Validity, and a Look to the Future.

The Alternative Model of Personality Disorders (AMPD) is a dimensional, empirically based diagnostic system developed to overcome the serious limitations of traditional categories. We review the mounting evidence on its convergent and discriminant validity, with an incursion into the less-studied ICD-11 system. In the literature, the AMPD's Pathological Trait Model (Criterion B) shows excellent convergence with normal personality traits, and it could be useful as an organizing framework for mental disorders. In contrast, Personality Functioning (Criterion A) cannot be distinguished from personality traits, lacks both discriminant and incremental validity, and has a shaky theoretical background. We offer some suggestions with a view to the future. These include removing Criterion A, using the real-life consequences of traits as indicators of severity, delving into the dynamic mechanisms underlying traits, and furthering the integration of currently disengaged psychological paradigms that can shape a sounder clinical science. Expected final online publication date for the Annual Review of Clinical Psychology, Volume 20 is May 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Palmitic acid conjugation enhances potency of tricyclo-DNA splice switching oligonucleotides.

Tricyclo-DNA (tcDNA) is a conformationally constrained oligonucleotide analog that has demonstrated great therapeutic potential as antisense oligonucleotide (ASO) for several diseases. Like most ASOs in clinical development, tcDNA were modified with phosphorothioate (PS) backbone for therapeutic purposes in order to improve their biodistribution by enhancing association with plasma and cell protein. Despite the advantageous protein binding properties, systemic delivery of PS-ASO remains limited and PS modifications can result in dose limiting toxicities in the clinic. Improving extra-hepatic delivery of ASO is highly desirable for the treatment of a variety of diseases including neuromuscular disorders such as Duchenne muscular dystrophy. We hypothesized that conjugation of palmitic acid to tcDNA could facilitate the delivery of the ASO from the bloodstream to the interstitium of the muscle tissues. We demonstrate here that palmitic acid conjugation enhances the potency of tcDNA-ASO in skeletal and cardiac muscles, leading to functional improvement in dystrophic mice with significantly reduced dose of administered ASO. Interestingly, palmitic acid-conjugated tcDNA with a full phosphodiester backbone proved effective with a particularly encouraging safety profile, offering new perspectives for the clinical development of PS-free tcDNA-ASO for neuromuscular diseases.

Surgical waiting lists and queue management in a Brazilian tertiary public hospital.

BACKGROUND: Centralized management of queues helps to reduce the surgical waiting time in the publicly funded healthcare system, but this is not a reality in the Brazilian Unified Healthcare System (BUHS). We describe the implementation of the "Patients with Surgical Indication" (PSI) in a Brazilian public tertiary hospital, the impact on waiting time, and its use in rationing oncological surgeries during the COVID-19 Pandemic. METHODS: Retrospective observational study of elective surgical requests (2016-2022) in a Brazilian general, public, tertiary university hospital. We recovered information regarding the inflows (indications), outflows and their reasons, the number of patients, and waiting time in queue. RESULTS: We enrolled 82,844 indications in the PSI (2016-2022). The waiting time (median and interquartile range) in days decreased from 98(48;168) in 2016 to 14(3;152) in 2022 (p < 0.01). The same occurred with the backlog that ranged from 6,884 in 2016 to 844 in 2022 (p < 001). During the Pandemic, there was a reduction in the number of non-oncological surgeries per month (95% confidence interval) of -10.9(-18.0;-3.8) during Phase I (January 2019-March 2020), maintenance in Phase II (April 2020-August 2021) 0.1(-10.0;10.4) and increment in Phase III (September 2021-December 2022) of 23.0(15.3;30.8). In the oncological conditions, these numbers were 0.6(-2.1;3.3) for Phase I, an increase of 3.2(0.7;5.6) in Phase II and 3.9(1,4;6,4) in Phase III. CONCLUSION: Implementing a centralized list of surgical indications and developing queue management principles proved feasible, with effective rationing. It unprecedentedly demonstrated the decrease in the median waiting time in Brazil.

Intravenous administration of ultrasound contrast to critically ill pediatric patients.

BACKGROUND: The off-label use of contrast-enhanced ultrasound has been increasingly used for pediatric patients. OBJECTIVE: The purpose of this retrospective study is to report any observed clinical changes associated with the intravenous (IV) administration of ultrasound contrast to critically ill neonates, infants, children, and adolescents. MATERIALS AND METHODS: All critically ill patients who had 1 or more contrast-enhanced ultrasound scans while being closely monitored in the neonatal, pediatric, or pediatric cardiac intensive care units were identified. Subjective and objective data concerning cardiopulmonary, neurological, and hemodynamic monitoring were extracted from the patient's electronic medical records. Vital signs and laboratory values before, during, and after administration of ultrasound contrast were obtained. Statistical analyses were performed using JMP Pro, version 15. Results were accepted as statistically significant for P-value<0.05. RESULTS: Forty-seven contrast-enhanced ultrasound scans were performed on 38 critically ill patients, 2 days to 17 years old, 19 of which were female (50%), and 19 had history of prematurity (50%). At the time of the contrast-enhanced ultrasound scans, 15 patients had cardiac shunts or a patent ductus arteriosus, 25 had respiratory failure requiring invasive mechanical oxygenation and ventilation, 19 were hemodynamically unstable requiring continual vasoactive infusions, and 8 were receiving inhaled nitric oxide. In all cases, no significant respiratory, neurologic, cardiac, perfusion, or vital sign changes associated with IV ultrasound contrast were identified. CONCLUSION: This study did not retrospectively identify any adverse clinical effects associated with the IV administration of ultrasound contrast to critically ill neonates, infants, children, and adolescents.

Imaging findings of children with PTEN-related hamartoma tumor syndrome: a 20-year multicentric pediatric cohort.

BACKGROUND: PTEN-related hamartoma tumor syndrome results from a mutation in the PTEN gene located at 10q23.31. This syndrome represents a spectrum of different phenotypes of variable expressions, now recognized as part of the same condition. Patients with this mutation have an increased risk of developing a wide range of findings, including malignancies. Although widely described in adults, there are no large series describing the imaging findings in patients before adulthood. Knowledge of the findings seen in children and adolescents with PTEN-related hamartoma tumor syndrome can help guide further management and improve surveillance recommendations. OBJECTIVE: To describe the spectrum of imaging abnormalities in pediatric patients with PTEN-related hamartoma tumor syndrome. MATERIALS AND METHODS: We performed a retrospective, cross-sectional, multicenter study conducted between January 2000 and October 2021 in three tertiary pediatric institutions evaluating the imaging findings in children and adolescents (≤ 18 years) with confirmed diagnoses of a PTEN mutation. For each patient, the imaging findings, histopathology reports, and at least a 2-year follow-up of clinical outcomes for non-operative cases were documented. RESULTS: The cohort included 78 children (37 girls), with a mean age at diagnosis of 7.5 years (range 0 days to 18 years). Benign brain findings included enlarged Virchow-Robin perivascular spaces, white matter changes, developmental venous anomalies, and cerebellar hamartomas. Benign thyroid findings were common, but 5/45 (11.1%) with thyroid abnormalities had a malignant nodule. Soft tissue adipocytic tumors, GI/GU polyps, other soft tissue abnormalities, along with vascular anomalies in various anatomic locations were common. CONCLUSION: Brain abnormalities, benign non-vascular soft tissue abnormalities, and vascular anomalies are commonly seen in children and adolescents with PTEN-related hamartoma tumor syndrome. However, malignancies involving the thyroid gland are not uncommon. Familiarity with the phenotype of PTEN-related hamartoma tumor syndrome in the pediatric population can improve diagnosis and prompt appropriate clinical surveillance of abnormal findings that warrant further management.

Microscopic Analysis of Nuclear Speckles in a Viviparous Reptile.

Nuclear speckles are compartments enriched in splicing factors present in the nucleoplasm of eucaryote cells. Speckles have been studied in mammalian culture and tissue cells, as well as in some non-mammalian vertebrate cells and invertebrate oocytes. In mammals, their morphology is linked to the transcriptional and splicing activities of the cell through a recruitment mechanism. In rats, speckle morphology depends on the hormonal cycle. In the present work, we explore whether a similar situation is also present in non-mammalian cells during the reproductive cycle. We studied the speckled pattern in several tissues of a viviparous reptile, the lizard Sceloporus torquatus, during two different stages of reproduction. We used immunofluorescence staining against splicing factors in hepatocytes and oviduct epithelium cells and fluorescence and confocal microscopy, as well as ultrastructural immunolocalization and EDTA contrast in Transmission Electron Microscopy. The distribution of splicing factors in the nucleoplasm of oviductal cells and hepatocytes coincides with the nuclear-speckled pattern described in mammals. Ultrastructurally, those cell types display Interchromatin Granule Clusters and Perichromatin Fibers. In addition, the morphology of speckles varies in oviduct cells at the two stages of the reproductive cycle analyzed, paralleling the phenomenon observed in the rat. The results show that the morphology of speckles in reptile cells depends upon the reproductive stage as it occurs in mammals.