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The primary aim of this study was to investigate the accuracy of the Alberta Infant Motor Scale (AIMS) and Neuro-Sensory Motor Developmental Assessment (NSMDA) over the first year of life for predicting motor impairment at 4 years in preterm children. The secondary aims were to assess the predictive value of serial assessments over the first year and when using a combination of these two assessment tools in follow-up.Children born

Chronic pancreatitis is often secondary to alcohol abuse, but pancreatitis with no other aetiology is frequently associated with variants in genes encoding proteins related to zymogen granule activation. Our goal was to identify genomic variants in a patient by analyzing an extended panel of genes associated with the intra-pancreatic activation of the trypsin pathway. A 23-year-old woman was addressed at our institution because of chronic pancreatitis of unknown aetiology presenting recurrent episodes since she was the age of four. Next Generation Sequencing was performed to analyze a panel of nine genes associated with pancreatitis ( CaSR , CFTR , CPA1 , CTRC , CTSB, KRT8 , PRSS1 , PRSS2 , and SPINK1 ). Three missense variants were found: p.Leu997Phe, maternally inherited, in the CFTR gene; p.Ile73Phe, paternally inherited, in the SPINK1 gene; and p.Phe790Ser, a de novo variant, in the CaSR gene. They were classified, respectively as probably benign, a Variant of Uncertain Significance, and the last one, which has never been described in the literature, as likely being pathogenic following American College of Medical Genetics and Genomics standard guidelines. Extensive intra-pancreatic activation of trypsin pathway gene sequencing detected rare variants that were not found with other gene screening and showed that variants in different genes may interact in contributing to the onset of the pancreatitis phenotype.

Virus-encoded microRNAs were first reported in the Epstein-Barr virus in 2004. Subsequently, a few hundred viral miRNAs have been identified, mainly in DNA viruses belonging to the herpesviridae family. To date, only 30 viral miRNAs encoded by RNA viruses are reported by miRBase. Since the outbreak of the SARS-CoV-2 pandemic, several studies have predicted and, in some cases, experimentally validated miRNAs originating from the positive strand of the SARS-CoV-2 genome. By integrating NGS data analysis and qRT-PCR approaches, we found that SARS-CoV-2 also encodes for a viral miRNA arising from the minus (antisense) strand of the viral genome, in the region encoding for ORF1ab, herein referred to as SARS-CoV-2-miR-AS1. Our data show that the expression of this microRNA increases in a time course analysis of SARS-CoV-2 infected cells. Furthermore, enoxacin treatment enhances the accumulation of the mature SARS-CoV-2-miR-AS1 in SARS-CoV-2 infected cells, arguing for a Dicer-dependent processing of this small RNA. In silico analysis suggests that SARS-CoV-2-miR-AS1 targets a set of genes which are translationally repressed during SARS-CoV-2 infection. We experimentally validated that SARS-CoV-2-miR-AS1 targets FOS, thus repressing the AP-1 transcription factor activity in human cells.

Crohn's disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the gastrointestinal tract. Chronic inflammation is the main factor leading to intestinal fibrosis, resulting in recurrent stenosis, especially in CD patients. Currently, the underlying molecular mechanisms of fibrosis are still unclear. ZNF281 is a zinc-finger transcriptional regulator that has been characterized as an epithelial-to-mesenchymal transition (EMT)-inducing transcription factor, suggesting its involvement in the regulation of pluripotency, stemness, and cancer. The aim of this study is to investigate in vivo and in vitro the role of ZNF281 in intestinal fibrogenesis. Intestinal fibrosis was studied in vivo in C57BL/6J mice with chronic colitis induced by two or three cycles of administration of dextran sulfate sodium (DSS). The contribution of ZNF281 to gut fibrosis was studied in vitro in the human colon fibroblast cell line CCD-18Co, activated by the pro-fibrotic cytokine TGFβ1. ZNF281 was downregulated by siRNA transfection, and RNA-sequencing was performed to identify genes regulated by TGFβ1 in activated colon fibroblasts via ZNF281. Results showed a marked increase of ZNF281 in in vivo murine fibrotic colon as well as in in vitro human colon fibroblasts activated by TGFβ1. Moreover, abrogation of ZNF281 in TGFβ1-treated fibroblasts affected the expression of genes belonging to specific pathways linked to fibroblast activation and differentiation into myofibroblasts. We demonstrated that ZNF281 is a key regulator of colon fibroblast activation and myofibroblast differentiation upon fibrotic stimuli by transcriptionally controlling extracellular matrix (ECM) composition, remodeling, and cell contraction, highlighting a new role in the onset and progression of gut fibrosis.

Calcifying pseudoneoplasm of the neuroaxis (CAPNON) is a rare, slow growing, and generally benign fibro osseous mass that can emerge throughout the entire central nervous system (CNS). When diagnosed, prompt surgical treatment can determine a good neurological outcome and possibly curative resolution. The objective of the present work is to present a step by step technical report with its video. We present a 37 year old female presented with occipital headache and cervical pain associated with dysphagia, nausea, and gait disturbances. Computed tomography (CT) scan showed a focal calcified lesion on the floor of the IV ventricle projecting toward the vermis with associated supratentorial hydrocephalus and transependymal edema. The telovelar approach was chosen for the procedure. The outcome was favorable, with no complications. Postoperative CT was performed, which revealed no residual lesion. A step by step report of a IV ventricle CAPNON that manifested with hydrocephalus is described., Competing Interests: None

Biallelic mutations in the BRAT1 gene, encoding BRCA1-associated ATM activator 1, result in variable phenotypes, from rigidity and multifocal seizure syndrome, lethal neonatal to neurodevelopmental disorder, and cerebellar atrophy with or without seizures, without obvious genotype-phenotype associations. We describe two families at the mildest end of the spectrum, differing in clinical presentation despite a common genotype at the BRAT1 locus. Two siblings displayed nonprogressive congenital ataxia and shrunken cerebellum on magnetic resonance imaging. A third unrelated patient showed normal neurodevelopment, adolescence-onset seizures, and ataxia, shrunken cerebellum, and ultrastructural abnormalities on skin biopsy, representing the mildest form of NEDCAS hitherto described. Exome sequencing identified the c.638dup and the novel c.1395G>A BRAT1 variants, the latter causing exon 10 skippings. The p53-MCL test revealed normal ATM kinase activity. Our findings broaden the allelic and clinical spectrum of BRAT1-related disease, which should be suspected in presence of nonprogressive cerebellar signs, even without a neurodevelopmental disorder., (© 2021 Wiley Periodicals LLC.)

In the last decade, the field of epitranscriptomics highlighted a wide array of post-transcriptional modifications in human RNAs, including microRNAs (miRNAs). Recent reports showed that human miRNAs undergo cytosine methylation. We describe the first high-throughput NGS-based method (BS-miRNA-seq) and an analysis pipeline (MAmBA) to attain high-resolution mapping of (hydroxy)-methyl-5-cytosine ((h)m5C) modifications in human miRNAs. Our method uncovers that miRNAs undergo widespread cytosine modification in various sequence contexts.Furthermore, validation of our data with specific antibodies reveals both m5C and hm5C residues in human mature miRNAs. BS-miRNA-seq and MAmBA may contribute to the precise mapping of (h)m5C on miRNAs in various cell types and tissues, a key achievement towards the understanding of the functional implications of this modification in miRNAs. MAmBA is available for download at https://github.com/flcvlr/MAmBA.

Objective: The open-door laminoplasty technique is widely used in the treatment of multilevel cervical myelopathy. Despite the satisfactory functional and radiological results of this technique, postoperative C5 palsy is still a severe and disabling complication with a variable incidence in the literature. The objective of this article is to describe and demonstrate the surgical technique step by step with the addition of unilateral C4-5 foraminotomy and to evaluate the results obtained to date, with special emphasis on C5 palsy., Material and Methods: Retrospective study of 20 patients operated on for cervical myelopathy using the "extended" laminoplasty technique, which is described step by step., Results: Between January 2013 and April 2019, 20 patients were operated on using the extended laminoplasty technique. Only one patient (5%) presented postoperative C5 palsy. The postoperative recovery rate of the modified JOA (Japanese Orthopaedic Association) score was 54.5%, similar to that observed in other series., Conclusion: The extended cervical laminoplasty technique with unilateral C4-5 foraminotomy was developed and demonstrated for the prevention of C5 palsy. The results were analysed and an incidence of C5 palsy coinciding with the lowest percentage reported in the literature was obtained. A prospective randomised study would be useful to assess the role of preventive unilateral C4-5 foraminotomy., (Copyright © 2021. Published by Elsevier España, S.L.U.)

MicroRNAs are pervasive regulators of gene expression at the post-transcriptional level in metazoan, playing key roles in several physiological and pathological processes. Accordingly, these small non-coding RNAs are also involved in cancer development and progression. Furthermore, miRNAs represent valuable diagnostic and prognostic biomarkers in malignancies. In the last twenty years, the role of RNA modifications in fine-tuning gene expressions at several levels has been unraveled. All RNA species may undergo post-transcriptional modifications, collectively referred to as epitranscriptomic modifications, which, in many instances, affect RNA molecule properties. miRNAs are not an exception, in this respect, and they have been shown to undergo several post-transcriptional modifications. In this review, we will summarize the recent findings concerning miRNA epitranscriptomic modifications, focusing on their potential role in cancer development and progression.

Objective: Intracranial hemangiopericytoma (HPC) is a rare central nervous system tumor characterized by its low incidence, high rate of local recurrence and risk of metastasis. The main objectives of this paper are two: to show the results in the treatment of HPC in our institution in the last 20years and to make a review of the literature on this topic., Methods: Retrospective review that includes patients diagnosed with intracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC) that have undergone surgery from 1997 to 2017. It includes patients that had nuclear expression of STAT-6 (detected by immunohistochemistry) and gradeII/III histopathological diagnosis (defined by the World Health Organization in 2016). We collected demographic data, tumor characteristics, treatment and survival of these patients., Results: A total of 19 patients fulfilled inclusion criteria. The median follow up was 96 months (12-230). The mortality rate was 21% (n=4). 57.9% of patients presented at least one tumor recurrence (n=11) (recurrences of 6%, 67% y 90% at 1, 5 and 10years). Five patients presented extracranial metastasis. Patients with tumors <6cm had greater survival (P<.05)., Conclusions: A series of patients undergoing SFT/HPC were presented according to the new WHO criteria. Size is a predictor of survival. Currently there are no validated criteria for surgical resection in this pathology. A classification with surgical guidance would be useful., (Copyright © 2020 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: The open-door laminoplasty technique is widely used in the treatment of multilevel cervical myelopathy. Despite the satisfactory functional and radiological results of this technique, postoperative C5 palsy is still a severe and disabling complication with a variable incidence in the literature. The objective of this article is to describe and demonstrate the surgical technique step by step with the addition of unilateral C4-5 foraminotomy and to evaluate the results obtained to date, with special emphasis on C5 palsy., Material and Methods: Retrospective study of 20 patients operated on for cervical myelopathy using the "extended" laminoplasty technique, which is described step by step., Results: Between January 2013 and April 2019, 20 patients were operated on using the extended laminoplasty technique. Only one patient (5%) presented postoperative C5 palsy. The postoperative recovery rate of the modified JOA (Japanese Orthopaedic Association) score was 54.5%, similar to that observed in other series., Conclusion: The extended cervical laminoplasty technique with unilateral C4-5 foraminotomy was developed and demonstrated for the prevention of C5 palsy. The results were analysed and an incidence of C5 palsy coinciding with the lowest percentage reported in the literature was obtained. A prospective randomised study would be useful to assess the role of preventive unilateral C4-5 foraminotomy., (Copyright © 2020 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Suboccipital lateral approach is a common practice in neurosurgery to expose the region of the cerebellopontine angle. Postcraniectomy headache (PCH) is one of the most frequent complications that diminish the quality of life of patients., Objective: To compare postcraniectomy pain in patients operated on for vestibular neurinomas by a suboccipital lateral approach by 2 different incisions., Material and Methods: Prospective randomized research study. Follow-up of patients operated for vestibular neurinomas between July 2017 and May 2019 (n=40) by the same surgeon. One group received the classical linear incision (n=20) and another group the alternative incision in an inverted "U" (modified Dandy) (n=20). Pain intensity was evaluated by numerical scale. A minimum follow-up of 3 months was carried out. The impact on quality of life was measured by the SF-36 questionnaire short version both before and after surgery., Results: The average age was 46.1 years. The overall PCH index was 27.5% (n=11) of the patients. The incidence of pain in the group that received the classical incision (A) was 20% (n=4) and in group B was 35% (n=7)., Conclusions: We found a higher rate of post-craniectomy headache in patients who underwent a "modified Dandy" incision. These are preliminary data of an undergoing study and we hope to obtain more representative information in the future. We recommend interdisciplinary follow up for the integral treatment of PCH., (Copyright © 2020 Sociedad Española de Neurocirugía. Publicado por Elsevier España, S.L.U. All rights reserved.)

Basal ganglia are subcortical grey nuclei that play essential roles in controlling voluntary movements, cognition and emotion. While basal ganglia dysfunction is observed in many neurodegenerative or metabolic disorders, congenital malformations are rare. In particular, dysplastic basal ganglia are part of the malformative spectrum of tubulinopathies and X-linked lissencephaly with abnormal genitalia, but neurodevelopmental syndromes characterized by basal ganglia agenesis are not known to date. We ascertained two unrelated children (both female) presenting with spastic tetraparesis, severe generalized dystonia and intellectual impairment, sharing a unique brain malformation characterized by agenesis of putamina and globi pallidi, dysgenesis of the caudate nuclei, olfactory bulbs hypoplasia, and anomaly of the diencephalic-mesencephalic junction with abnormal corticospinal tract course. Whole-exome sequencing identified two novel homozygous variants, c.26C>A; p.(S9*) and c.752A>G; p.(Q251R) in the GSX2 gene, a member of the family of homeobox transcription factors, which are key regulators of embryonic development. GSX2 is highly expressed in neural progenitors of the lateral and median ganglionic eminences, two protrusions of the ventral telencephalon from which the basal ganglia and olfactory tubercles originate, where it promotes neurogenesis while negatively regulating oligodendrogenesis. The truncating variant resulted in complete loss of protein expression, while the missense variant affected a highly conserved residue of the homeobox domain, was consistently predicted as pathogenic by bioinformatic tools, resulted in reduced protein expression and caused impaired structural stability of the homeobox domain and weaker interaction with DNA according to molecular dynamic simulations. Moreover, the nuclear localization of the mutant protein in transfected cells was significantly reduced compared to the wild-type protein. Expression studies on both patients' fibroblasts demonstrated reduced expression of GSX2 itself, likely due to altered transcriptional self-regulation, as well as significant expression changes of related genes such as ASCL1 and PAX6. Whole transcriptome analysis revealed a global deregulation in genes implicated in apoptosis and immunity, two broad pathways known to be involved in brain development. This is the first report of the clinical phenotype and molecular basis associated to basal ganglia agenesis in humans., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Ventriculoperitoneal shunting is considered a relatively straightforward procedure, though it might ensure multiple complications. Our surgical team developed and implemented a new protocol since June 2016. The objective of this paper is to describe and illustrate the surgical technique step by step and to demonstrate that the use of the "new protocol" significantly reduces the complications associated with the procedure., Methods: A retrospective descriptive study of 184 patients related with cerebrospinal fluid derivation systems from June 2014 to November 2017. One hundred and fourteen patients complied with the inclusion criteria. They were divided into two groups according to the protocol involved, previous ( n = 59) and new ( n = 55). The technique was described by photographic archive and surgical protocols., Results: The technique consisting in seven phases was described. With the used of the new protocol the complications decreased significantly. After the new protocol, no ventriculoperitoneal shunt associated infections were observed., Conclusion: The technique for ventriculoperitoneal shunt consisting in seven phases was described thoroughly. This technique as well as a series of rules constitutes the new protocol. The implementation of the latter lessened the number of complications associated with the procedure. The "zero infection" rate is not a utopia., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Surgical Neurology International.)

Background: The assessment of fibrosis degree in liver diseases is based on several non-invasive techniques, but none has been accurate., Aim: This study employed proton nuclear magnetic resonance spectroscopy to identify metabolic profiles in serum and urine, specific for different fibrosis degree in chronic hepatitis C patients., Method: 71 plasma, 73 serum, and 578 urine samples were collected. All samples were analyzed using 1 H-NMR spectroscopy technique and three different NMR spectra were acquired for each serum/plasma sample. The data analyses were performed by partial least square regression, principal component analysis, and Monte Carlo cross-validation in a supervised methodology., Results: The cross-validation test correctly assigned each sample to its specific donor with 98.44% accuracy for urine samples and 65% for serum/plasma samples. Advanced fibrosis and cirrhosis were recognized with 71% sensitivity for CPMG plasma spectra and 69% specificity for NOESY serum spectra. Accuracy for NOESY serum spectra was 68%. Noesy spectra recognized advanced fibrosis and cirrhosis with 71% sensitivity, 30% specificity, and 50% accuracy in urine samples., Conclusion: Metabolomic analysis of urine spectra using 1 H-NMR spectroscopy can recognize a specific individual profile in all patients with chronic hepatitis C. However, this method cannot yet differentiate with sufficient accuracy, patients with advanced fibrosis from patients with milder disease., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The Sonic Hedgehog (SHH) pathway is a key signaling pathway orchestrating embryonic development, mainly of the CNS and limbs. In vertebrates, SHH signaling is mediated by the primary cilium, and genetic defects affecting either SHH pathway members or ciliary proteins cause a spectrum of developmental disorders. SUFU is the main negative regulator of the SHH pathway and is essential during development. Indeed, Sufu knock-out is lethal in mice, and recessive pathogenic variants of this gene have never been reported in humans. Through whole-exome sequencing in subjects with Joubert syndrome, we identified four children from two unrelated families carrying homozygous missense variants in SUFU. The children presented congenital ataxia and cerebellar vermis hypoplasia with elongated superior cerebellar peduncles (mild "molar tooth sign"), typical cranio-facial dysmorphisms (hypertelorism, depressed nasal bridge, frontal bossing), and postaxial polydactyly. Two siblings also showed polymicrogyria. Molecular dynamics simulation predicted random movements of the mutated residues, with loss of the native enveloping movement of the binding site around its ligand GLI3. Functional studies on cellular models and fibroblasts showed that both variants significantly reduced SUFU stability and its capacity to bind GLI3 and promote its cleavage into the repressor form GLI3R. In turn, this impaired SUFU-mediated repression of the SHH pathway, as shown by altered expression levels of several target genes. We demonstrate that germline hypomorphic variants of SUFU cause deregulation of SHH signaling, resulting in recessive developmental defects of the CNS and limbs which share features with both SHH-related disorders and ciliopathies., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The only currently recommended treatment for nonalcoholic fatty liver disease (NAFLD) is lifestyle modification. Preliminary studies of silybin showed beneficial effects on liver function. Realsil (RA) comprises the silybin phytosome complex (silybin plus phosphatidylcholine) coformulated with vitamin E. We report on a multicenter, phase III, double-blind clinical trial to assess RA in patients with histologically documented NAFLD. Patients were randomized 1:1 to RA or placebo (P) orally twice daily for 12 months. Prespecified primary outcomes were improvement over time in clinical condition, normalization of liver enzyme plasma levels, and improvement of ultrasonographic liver steatosis, homeostatic model assessment (HOMA), and quality of life. Secondary outcomes were improvement in liver histologic score and/or decrease in NAFLD score without worsening of fibrosis and plasma changes in cytokines, ferritin, and liver fibrosis markers. We treated 179 patients with NAFLD; 36 were also HCV positive. Forty-one patients were prematurely withdrawn and 138 patients analyzed per protocol (69 per group). Baseline patient characteristics were generally well balanced between groups, except for steatosis, portal infiltration, and fibrosis. Adverse events (AEs) were generally transient and included diarrhea, dysgeusia, and pruritus; no serious AEs were recorded. Patients receiving RA but not P showed significant improvements in liver enzyme plasma levels, HOMA, and liver histology. Body mass index normalized in 15% of RA patients (2.1% with P). HCV-positive patients in the RA but not the P group showed improvements in fibrogenesis markers. This is the first study to systematically assess silybin in NAFLD patients. Treatment with RA but not P for 12 months was associated with improvement in liver enzymes, insulin resistance, and liver histology, without increases in body weight. These findings warrant further investigation., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Transient elastography (TE) has received increasing attention as a means to evaluate disease progression in patients with chronic liver disease., Aim: To assess the value of TE for predicting the stage of fibrosis., Methods: Liver biopsy and TE were performed in 150 consecutive patients with chronic hepatitis C-related hepatitis (92 men and 58 women, age 50.6 (SD 12.5) years on the same day. Necro-inflammatory activity and the degree of steatosis at biopsy were also evaluated., Results: The areas under the curve for the prediction of significant fibrosis (> or = F2), advanced fibrosis (> or = F3) or cirrhosis were 0.91, 0.99 and 0.98, respectively. Calculation of multilevel likelihood ratios showed that values of TE < 6 or > or = 12, < 9 or > or = 12, and < 12 or > or = 18, clearly indicated the absence or presence of significant fibrosis, advanced fibrosis, and cirrhosis, respectively. Intermediate values could not be reliably associated with the absence or presence of the target condition. The presence of inflammation significantly affected TE measurements in patients who did not have cirrhosis (p<0.0001), even after adjusting for the stage of fibrosis. Importantly, TE measurements were not influenced by the degree of steatosis., Conclusions: TE is more suitable for the identification of patients with advanced fibrosis than of those with cirrhosis or significant fibrosis. In patients in whom likelihood ratios are not optimal and do not provide a reliable indication of the disease stage, liver biopsy should be considered when clinically indicated. Necro-inflammatory activity, but not steatosis, strongly and independently influences TE measurement in patients who do not have cirrhosis.

Interferon therapy is indicated for the treatment of chronic hepatitis C and prevention of hepatocellular carcinoma. We describe the case of a 66-year-old Italian woman who received pegylated interferon alpha-2a plus ribavirin combined therapy for HCV-related chronic liver disease. Preliminary hematochemical, ultrasound and bioptic investigations did not show liver cirrhosis or hepatocarcinoma. After 24 weeks of treatment transaminase serum levels were in the normal range and circulating HCVRNA was undetectable by PCR qualitative assay. On week 46 a serious adverse event occurred, with rapid transaminase increase, severe hyperpyrexia, and abdominal pain, leading to interruption of interferon and ribavirin. Liver biopsy was repeated and it revealed poorly differentiated hepatocellular carcinoma. Only palliative care could be performed and the patient died of liver failure within 2 months. The present case underlines that hepatocellular carcinoma can be misdiagnosed in spite of laboratory and instrumental follow-up. More sensitive tools are needed for tumor detection, to avoid IFN impairment of the liver, even though it eradicates HCV.