Úvod: Defekty neurálnej rúry (NTD) sú vrodené chyby CNS, ktoré vznikajú poruchou uzáveru. Vyskytujú sa na kraniálnom a kaudálnom konci. Autori v práci retrospektívne hodnotia vlastný súbor pacientov s kraniálnym NTD riešených na klinike detskej chirurgie s cieľom poukázať na optimálne načasovanie operácie, hlavne u detí s hydrocefalom. Materiál a metódy: Súbor pacientov s kraniálnymi NTD v rokoch 2000-2008 tvorí desať detí. Sedem pacientov malo okcipitálny typ, dvaja pacienti parietálny a jeden pacient frontoorbitálny typ. Sedem pacientov malo ventrikulomegáliu. Traja pacienti majú súčasne arachnoidálnu cystu. U šiestich pacientov bol kraniálny NTD operovaný hneď po narodení, dvaja pacienti s nezávažnou meningokélou boli riešení vo veku troch mesiacov a dvaja pacienti boli poukázaní neskôr. Dvaja pacienti s rozsiahlym kostným defektom boli riešení v dvoch dobách - uzáver kély a neskôr (v štyroch, resp. v šiestich rokoch) korekcia defektu v kosti. Spolu šesť detí má pre hydrocefalus ventrikuloperitoneálny (VP) zvod likvoru. Výsledky: V súbore pacientov sa osem detí vyvíja normálne, jedna pacientka ma ľahkú poruchu svalového tonusu a jedna pacientka výrazne zaostáva vo vývoji. Pacientka bola poukázaná neskoro s nezvládnutým hydrocefalom pre dekubity na hlave. Traja pacienti s hydrocefalom majú epilepsiu zvládnutú medikamentózne. Záver: Súbor pacientov je malý, napriek tomu sa zdá, že väčšina pacientov s kraniálnym NTD má šancu na normálny vývoj, aj deti s hydrocefalom. Na zaostávaní sa podieľa predovšetkým nezvládnutý hydrocefalus. Chirurgická korekcia NTD je rezervovaná pre novorodenecký prípadne dojčenský vek a rozhodujúcim pre vývoj je optimálne načasovanie riešenia hydrocefalu. Korekcia kostného defektu môže byť druhou dobou riešenia v neskoršom veku.

Introduction: Neural tube defects (NTD) are congenital malformations of the central nervous system caused by failure of fusion in the course of embryological development. They occur in both the caudal and the cranial region. The authors present a group of patients with cranial NTD treated at the Department of Paediatric Surgery in Bratislava. The aim is to point out the importance of timing for surgery, especially in the management of hydrocephalus. Materials and methods: Ten patients with cranial NTD were treated at our surgery unit during the period 2000-2008. Seven patients presented with the occipital type of NTD, two patients with the parietal type, and one patient with the fronto-orbital type. Seven patients were suffering from current ventriculomegaly, and arachnoid cyst was also diagnosed in three patients. Six patients were operated on immediately after their birth, the following two, with non-severe meningocele, were operated upon at the age of three months, while two patients were referred to the institution at more advanced ages. Two patients with large bone defect were managed by two-stage repair - closure of the cephalocele and later, at the ages of four and six years respectively, reconstruction of the bone defect. Six patients with hydrocephalus had a ventriculoperitoneal (VP) shunt. Results: A total of eight children are developing normally, one patient has a slight impairment of muscle tone, and one patient is lagging significantly in her development. She was admitted too late, with ulcerations as a complication of hydrocephalus. Three patients with hydrocephalus have pharmacologically managed epilepsy. Conclusion: The group of patients is too small for proof, but it appears that patients with cranial NTD have a good chance of normal development, including those with hydrocephalus. Impairment of development arises largely out of maladministration of hydrocephalus. The authors suggest early surgical treatment for all cranial NTD, with ventriculoperitoneal shunt in concomitant hydrocephalus. Correction of bone defect can be performed as secondary treatment for patients in which it persists into later age.

• MeSH
• Neural Tube Defects etiology   genetics   surgery   MeSH
• Diagnostic Techniques, Neurological utilization   MeSH
• Drainage MeSH
• Encephalocele etiology   surgery   complications   MeSH
• Drug Therapy methods   utilization   MeSH
• Hydrocephalus etiology   surgery   complications   MeSH
• Humans MeSH
• Meningocele etiology   surgery   complications   MeSH
• Cerebrospinal Fluid MeSH
• Neurosurgical Procedures methods   utilization   MeSH
• Retrospective Studies MeSH
• Statistics as Topic MeSH
• Age Factors MeSH
• Ventriculoperitoneal Shunt methods   utilization   MeSH
• Outcome and Process Assessment, Health Care MeSH
• Plastic Surgery Procedures methods   utilization   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Case Reports MeSH

The neural crest (NC) is crucial for the evolutionary diversification of vertebrates. NC cells are induced at the neural plate border by the coordinated action of several signaling pathways, including Wnt/β-catenin. NC cells are normally generated in the posterior neural plate border, whereas the anterior neural fold is devoid of NC cells. Using the mouse model, we show here that active repression of Wnt/β-catenin signaling is required for maintenance of neuroepithelial identity in the anterior neural fold and for inhibition of NC induction. Conditional inactivation of Tcf7l1, a transcriptional repressor of Wnt target genes, leads to aberrant activation of Wnt/β-catenin signaling in the anterior neuroectoderm and its conversion into NC. This reduces the developing prosencephalon without affecting the anterior-posterior neural character. Thus, Tcf7l1 defines the border between the NC and the prospective forebrain via restriction of the Wnt/β-catenin signaling gradient.

• MeSH
• beta Catenin metabolism   MeSH
• Biomarkers metabolism   MeSH
• Cell Lineage * MeSH
• Neural Crest cytology   metabolism   MeSH
• Zebrafish metabolism   MeSH
• Neural Tube Defects metabolism   pathology   MeSH
• Gene Deletion MeSH
• Phenotype MeSH
• Integrases metabolism   MeSH
• Humans MeSH
• Mice, Transgenic MeSH
• Prosencephalon embryology   metabolism   MeSH
• Transcription Factor 7-Like 1 Protein metabolism   MeSH
• Zebrafish Proteins metabolism   MeSH
• Repressor Proteins metabolism   MeSH
• Wnt Signaling Pathway MeSH
• Cell Transdifferentiation MeSH
• Transcription Factor AP-2 metabolism   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

The complex shape of embryonic cartilage represents a true challenge for phenotyping and basic understanding of skeletal development. X-ray computed microtomography (μCT) enables inspecting relevant tissues in all three dimensions; however, most 3D models are still created by manual segmentation, which is a time-consuming and tedious task. In this work, we utilised a convolutional neural network (CNN) to automatically segment the most complex cartilaginous system represented by the developing nasal capsule. The main challenges of this task stem from the large size of the image data (over a thousand pixels in each dimension) and a relatively small training database, including genetically modified mouse embryos, where the phenotype of the analysed structures differs from the norm. We propose a CNN-based segmentation model optimised for the large image size that we trained using a unique manually annotated database. The segmentation model was able to segment the cartilaginous nasal capsule with a median accuracy of 84.44% (Dice coefficient). The time necessary for segmentation of new samples shortened from approximately 8 h needed for manual segmentation to mere 130 s per sample. This will greatly accelerate the throughput of μCT analysis of cartilaginous skeletal elements in animal models of developmental diseases.

• MeSH
• Cartilage diagnostic imaging   MeSH
• Deep Learning * MeSH
• Mice MeSH
• Neural Networks, Computer MeSH
• Image Processing, Computer-Assisted methods   MeSH
• X-Rays MeSH
• Developmental Biology MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

At present, more and more researchers are applying tested mathematical-engineering methods into different domains of life. One of these areas is helping people with different forms of disabilities. Research in this area is focused on searching for the relation between clinical and electrophysiological symptoms of children with developmental dysphasia. Sleep EEG and speech analyses are the primary areas under discussion, while the finding of methods acceptable for improvement of the diagnosis and determination of therapeutic procedures is the research topic. It is possible to reduce fundamentally, or to cure optimally these disorders in advanced diagnosis. Therefore it is important to search for new methods and to combine what has been used separately till now.

• MeSH
• Algorithms MeSH
• Databases as Topic MeSH
• Diagnosis, Computer-Assisted methods   instrumentation   MeSH
• Child MeSH
• Electroencephalography MeSH
• Epilepsy diagnosis   complications   MeSH
• Financing, Organized MeSH
• Humans MeSH
• Neural Networks, Computer MeSH
• Neuropsychological Tests MeSH
• Computer Simulation MeSH
• Polysomnography MeSH
• Child, Preschool MeSH
• Reference Values MeSH
• Cluster Analysis MeSH
• Case-Control Studies MeSH
• Speech Articulation Tests methods   instrumentation   MeSH
• Computational Biology MeSH
• Language Development Disorders diagnosis   complications   physiopathology   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Child, Preschool MeSH

Cranial neural crest cells populate the future facial region and produce ectomesenchyme-derived tissues, such as cartilage, bone, dermis, smooth muscle, adipocytes, and many others. However, the contribution of individual neural crest cells to certain facial locations and the general spatial clonal organization of the ectomesenchyme have not been determined. We investigated how neural crest cells give rise to clonally organized ectomesenchyme and how this early ectomesenchyme behaves during the developmental processes that shape the face. Using a combination of mouse and zebrafish models, we analyzed individual migration, cell crowd movement, oriented cell division, clonal spatial overlapping, and multilineage differentiation. The early face appears to be built from multiple spatially defined overlapping ectomesenchymal clones. During early face development, these clones remain oligopotent and generate various tissues in a given location. By combining clonal analysis, computer simulations, mouse mutants, and live imaging, we show that facial shaping results from an array of local cellular activities in the ectomesenchyme. These activities mostly involve oriented divisions and crowd movements of cells during morphogenetic events. Cellular behavior that can be recognized as individual cell migration is very limited and short-ranged and likely results from cellular mixing due to the proliferation activity of the tissue. These cellular mechanisms resemble the strategy behind limb bud morphogenesis, suggesting the possibility of common principles and deep homology between facial and limb outgrowth.

• MeSH
• Models, Anatomic MeSH
• Cell Differentiation * MeSH
• Clone Cells cytology   MeSH
• Neural Crest cytology   MeSH
• Zebrafish MeSH
• Ectoderm cytology   embryology   MeSH
• Gene Expression MeSH
• Phenotype MeSH
• Mesoderm cytology   embryology   MeSH
• Morphogenesis * MeSH
• Mice MeSH
• Face embryology   MeSH
• Organogenesis * MeSH
• Cell Movement MeSH
• Genes, Reporter MeSH
• Imaging, Three-Dimensional MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

Heterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of individual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to recapitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.

• MeSH
• Apoptosis MeSH
• Neural Crest pathology   MeSH
• Phenotype MeSH
• Craniofacial Abnormalities * genetics   pathology   MeSH
• Humans MeSH
• Mandibulofacial Dysostosis * genetics   MeSH
• Mutagenesis MeSH
• Mice MeSH
• Ribosomes genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

STUDY QUESTION: What are the long term trends in the total (live births, fetal deaths, and terminations of pregnancy for fetal anomaly) and live birth prevalence of neural tube defects (NTD) in Europe, where many countries have issued recommendations for folic acid supplementation but a policy for mandatory folic acid fortification of food does not exist? METHODS: This was a population based, observational study using data on 11,353 cases of NTD not associated with chromosomal anomalies, including 4162 cases of anencephaly and 5776 cases of spina bifida from 28 EUROCAT (European Surveillance of Congenital Anomalies) registries covering approximately 12.5 million births in 19 countries between 1991 and 2011. The main outcome measures were total and live birth prevalence of NTD, as well as anencephaly and spina bifida, with time trends analysed using random effects Poisson regression models to account for heterogeneities across registries and splines to model non-linear time trends. SUMMARY ANSWER AND LIMITATIONS: Overall, the pooled total prevalence of NTD during the study period was 9.1 per 10,000 births. Prevalence of NTD fluctuated slightly but without an obvious downward trend, with the final estimate of the pooled total prevalence of NTD in 2011 similar to that in 1991. Estimates from Poisson models that took registry heterogeneities into account showed an annual increase of 4% (prevalence ratio 1.04, 95% confidence interval 1.01 to 1.07) in 1995-99 and a decrease of 3% per year in 1999-2003 (0.97, 0.95 to 0.99), with stable rates thereafter. The trend patterns for anencephaly and spina bifida were similar, but neither anomaly decreased substantially over time. The live birth prevalence of NTD generally decreased, especially for anencephaly. Registration problems or other data artefacts cannot be excluded as a partial explanation of the observed trends (or lack thereof) in the prevalence of NTD. WHAT THIS STUDY ADDS: In the absence of mandatory fortification, the prevalence of NTD has not decreased in Europe despite longstanding recommendations aimed at promoting peri-conceptional folic acid supplementation and existence of voluntary folic acid fortification. FUNDING, COMPETING INTERESTS, DATA SHARING: The study was funded by the European Public Health Commission, EUROCAT Joint Action 2011-2013. HD and ML received support from the European Commission DG Sanco during the conduct of this study. No additional data available.

• MeSH
• Neural Tube Defects * epidemiology   prevention & control   MeSH
• Pregnancy Complications * epidemiology   etiology   prevention & control   MeSH
• Folic Acid therapeutic use   MeSH
• Humans MeSH
• Live Birth epidemiology   MeSH
• Needs Assessment MeSH
• Fetal Death MeSH
• Abortion, Eugenic statistics & numerical data   MeSH
• Food Assistance MeSH
• Dietary Supplements statistics & numerical data   MeSH
• Prevalence MeSH
• Pregnancy MeSH
• Vitamin B Complex therapeutic use   MeSH
• Pregnancy Outcome epidemiology   MeSH
• Policy Making MeSH
• Check Tag
• Humans MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Geographicals
• Europe MeSH

Clinical procedure for mild cognitive impairment (MCI) is mainly based on clinical records and short cognitive tests. However, low suspicion and difficulties in understanding test cut-offs make diagnostic accuracy being low, particularly in primary care. Artificial neural networks (ANNs) are suitable to design computed aided diagnostic systems because of their features of generating relationships between variables and their learning capability. The main aim pursued in that work is to explore the ability of a hybrid ANN-based system in order to provide a tool to assist in the clinical decision-making that facilitates a reliable MCI estimate. The model is designed to work with variables usually available in primary care, including Minimental Status Examination (MMSE), Functional Assessment Questionnaire (FAQ), Geriatric Depression Scale (GDS), age, and years of education. It will be useful in any clinical setting. Other important goal of our study is to compare the diagnostic rendering of ANN-based system and clinical physicians. A sample of 128 MCI subjects and 203 controls was selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The ANN-based system found the optimal variable combination, being AUC, sensitivity, specificity, and clinical utility index (CUI) calculated. The ANN results were compared with those from medical experts which include two family physicians, a neurologist, and a geriatrician. The optimal ANN model reached an AUC of 95.2%, with a sensitivity of 90.0% and a specificity of 84.78% and was based on MMSE, FAQ, and age inputs. As a whole, physician performance achieved a sensitivity of 46.66% and a specificity of 91.3%. CUIs were also better for the ANN model. The proposed ANN system reaches excellent diagnostic accuracy although it is based only on common clinical tests. These results suggest that the system is especially suitable for primary care implementation, aiding physicians work with cognitive impairment suspicions.

• MeSH
• Databases, Factual statistics & numerical data   MeSH
• Diagnosis, Computer-Assisted methods   statistics & numerical data   MeSH
• Cognitive Dysfunction diagnosis   psychology   MeSH
• Humans MeSH
• Neural Networks, Computer * MeSH
• Neuropsychological Tests * statistics & numerical data   MeSH
• Area Under Curve MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Sensitivity and Specificity MeSH
• Case-Control Studies MeSH
• Decision Support Systems, Clinical * statistics & numerical data   MeSH
• Computational Biology MeSH
• Check Tag
• Humans MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH

This study elucidated the stage-specific roles of FGF2 signaling during neural development using in-vitro human embryonic stem cell-based developmental modeling. We found that the dysregulation of FGF2 signaling prior to the onset of neural induction resulted in the malformation of neural rosettes (a neural tube-like structure), despite cells having undergone neural induction. The aberrant neural rosette formation may be attributed to the misplacement of ZO-1, which is a polarized tight junction protein and shown co-localized with FGF2/FGFR1 in the apical region of neural rosettes, subsequently led to abnormal neurogenesis. Moreover, the FGF2 signaling inhibition at the stage of neural rosettes caused a reduction in cell proliferation, an increase in numbers of cells with cell-cycle exit, and premature neurogenesis. These effects may be mediated by NUMB, to which expression was observed enriched in the apical region of neural rosettes after FGF2 signaling inhibition coinciding with the disappearance of PAX6+/Ki67+ neural stem cells and the emergence of MAP2+ neurons. Moreover, our results suggested that the hESC-based developmental system reserved a similar neural stem cell niche in vivo.

• MeSH
• Cell Differentiation drug effects   MeSH
• Cell Line MeSH
• Time-Lapse Imaging MeSH
• Chromones pharmacology   MeSH
• Fibroblast Growth Factor 2 pharmacology   MeSH
• Immunohistochemistry MeSH
• Humans MeSH
• Human Embryonic Stem Cells cytology   metabolism   MeSH
• RNA, Small Interfering metabolism   MeSH
• Membrane Proteins metabolism   MeSH
• Morpholines pharmacology   MeSH
• Neural Stem Cells cytology   metabolism   MeSH
• Neurogenesis drug effects   MeSH
• Neurons cytology   metabolism   MeSH
• Zonula Occludens-1 Protein antagonists & inhibitors   genetics   metabolism   MeSH
• Microtubule-Associated Proteins metabolism   MeSH
• Nerve Tissue Proteins metabolism   MeSH
• Pyrimidines pharmacology   MeSH
• Receptor, Fibroblast Growth Factor, Type 1 metabolism   MeSH
• RNA Interference MeSH
• Signal Transduction drug effects   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

This study used an experimental early rehabilitation model combining an enriched environment, multisensory (visual, acoustic and olfactory) stimulation and motor training after traumatic brain injury (via fluid-percussion model) to simulate early multisensory rehabilitation. This therapy will be used by brain injured patients to improve neural plasticity and to restore brain integration functions. Motor dysfunction was evaluated using a composite neuroscore test. Direct structural effects of traumatic brain injury were examined using Fluoro-Jade staining, which allows identification of degenerating neural cell bodies and processes. Animals in the rehabilitation model group performed significantly better when tested for neuromotor function than the animals in standard housing in the 7-day and 15-day interval after injury (7d: p=0.005; 15d: p<0.05). Statistical analysis revealed significantly lower numbers of Fluoro-Jade positive cells (degenerating neurons) in the rehabilitation model group (n=5: mean 13.4) compared to the standard housing group (n=6: mean 123.8) (p<0.005). It appears that the housing of animals in the rehabilitation model led to a clear functional increase in neuromotor functions and to reduced neural loss compared with the animal group in standard housing.

• MeSH
• Staining and Labeling methods   utilization   MeSH
• Research Support as Topic MeSH
• Data Interpretation, Statistical MeSH
• Models, Animal MeSH
• Brain Injuries rehabilitation   MeSH
• Motor Skills Disorders rehabilitation   MeSH
• Rats, Sprague-Dawley surgery   MeSH
• Rehabilitation methods   MeSH
• Animals MeSH
• Check Tag
• Animals MeSH