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This study aims to determine if high-voltage PRF could effectively adjunct epidural adhesiolysis (EA) in treating patients with chronic lumbosacral radiating pain (LSRP) and neuropathic characteristics. A total of 409 patients suffering from a single leg-radiating pain lasting for > six months and unresponsive to previous treatments were divided into three different groups: Group 1 consisted of 227 patients suffering from LSRP in lumbar stenosis, 84 treated with EA alone and 143 with PRF-EA; group 2 consisted of 99 patients suffering from LSRP in FBSS (Failed Back Surgery Syndrome), 24 treated with EA alone and 75 with PRF-EA; group 3 consisted of 83 patients suffering for LSRP in discal herniation, 20 treated with EA and 63 with PRF-EA. NRS evaluated the outcome at rest and in movement, SF-12 Physical and Mental Health Summary Scales, and present pain intensity scale (PPI), before the treatment and at the 1-month follow-up for all the patients included in the study. Descriptive statistics (mean ± SD) were reported for NRSrest, NRSmov, PPI, PCS, and MCS scores. A dependent sample T-test was used to compare pre and post-treatment outcome measures (NRS, PPI, PCS, MCS), in patients treated for discal herniation, FBSS and stenosis, respectively. A potential difference in outcome between the different procedures performed in the three groups (EA + PRF versus EA alone) was analyzed by applying an independent two-tailed t-test. P value less than 0.05 represented a significant difference. A significant reduction of radiating pain was observed at one-month follow-up in NRSrest and NRSmov, PPI scores, for all the three groups of patients, independently of the treatment adopted (p < 0.001). PCS12 and MCS12 significantly increased for all three groups of patients at 1-month follow-up (p < 0.001). No significant differences in outcome were detected for both procedures (EA vs. PRF-EA) in all three groups (p > 0.05). PRF and PRF-EA effectively reduce neuropathic pain intensity and improve the quality of life in patients who suffer from lumbosacral radiating pain in the context of lumbar stenosis, FBSS, or discal herniation. Adding pulsed radiofrequency (PRF) to epidural adhesiolysis alone does not improve the outcome.

Convergent evidence associates exposure to endocrine disrupting chemicals (EDCs) with major human diseases, even at regulation-compliant concentrations. This might be because humans are exposed to EDC mixtures, whereas chemical regulation is based on a risk assessment of individual compounds. Here, we developed a mixture-centered risk assessment strategy that integrates epidemiological and experimental evidence. We identified that exposure to an EDC mixture in early pregnancy is associated with language delay in offspring. At human-relevant concentrations, this mixture disrupted hormone-regulated and disease-relevant regulatory networks in human brain organoids and in the model organisms Xenopus leavis and Danio rerio , as well as behavioral responses. Reinterrogating epidemiological data, we found that up to 54% of the children had prenatal exposures above experimentally derived levels of concern, reaching, for the upper decile compared with the lowest decile of exposure, a 3.3 times higher risk of language delay.

Objectives:Despite the interest in scientific community, there is still poor evidence about pulsed radiofrequency (PRF) efficacy in the treatment of neuropathic pain. In order to determine whether high-voltage PRF and epidural adhesiolysis (PRF-EA) showed better results than epidural adhesiolysis al

Medulloblastoma (MB), one of the most malignant brain tumors of childhood, comprises distinct molecular subgroups, with p53 mutant sonic hedgehog (SHH)-activated MB patients having a very severe outcome that is associated with unfavorable histological large cell/anaplastic (LC/A) features. To identify the molecular underpinnings of this phenotype, we analyzed a large cohort of MBs developing in p53-deficient Ptch+/- SHH mice that, unexpectedly, showed LC/A traits that correlated with mechanistic Target Of Rapamycin Complex 1 (mTORC1) hyperactivation. Mechanistically, mTORC1 hyperactivation was mediated by a decrease in the p53-dependent expression of mTORC1 negative regulator Tsc2. Ectopic mTORC1 activation in mouse MB cancer stem cells (CSCs) promoted the in vivo acquisition of LC/A features and increased malignancy; accordingly, mTORC1 inhibition in p53-mutant Ptch+/- SHH MBs and CSC-derived MBs resulted in reduced tumor burden and aggressiveness. Most remarkably, mTORC1 hyperactivation was detected only in p53-mutant SHH MB patients' samples and treatment with rapamycin of a human preclinical model phenocopying this subgroup decreased tumor growth and malignancy. Thus, mTORC1 may act as a specific druggable target for this subset of SHH MB, resulting in the implementation of a stringent risk stratification and in the potentially rapid translation of this precision medicine approach into the clinical setting.

Background Autism spectrum disorder (ASD) is a highly prevalent neurodevelopmental condition affecting almost 1% of children, and represents a major unmet medical need with no effective drug treatment available. Duplication at 7q11.23 (7Dup), encompassing 26–28 genes, is one of the best characterized ASD-causing copy number variations and offers unique translational opportunities, because the hemideletion of the same interval causes Williams–Beuren syndrome (WBS), a condition defined by hypersociability and language strengths, thereby providing a unique reference to validate treatments for the ASD symptoms. In the above-indicated interval at 7q11.23, defined as WBS critical region, several genes, such as GTF2I, BAZ1B, CLIP2 and EIF4H, emerged as critical for their role in the pathogenesis of WBS and 7Dup both from mouse models and human studies. Methods We performed a high-throughput screening of 1478 compounds, including central nervous system agents, epigenetic modulators and experimental substances, on patient-derived cortical glutamatergic neurons differentiated from our cohort of induced pluripotent stem cell lines (iPSCs), monitoring the transcriptional modulation of WBS interval genes, with a special focus on GTF2I, in light of its overriding pathogenic role. The hits identified were validated by measuring gene expression by qRT-PCR and the results were confirmed by western blotting. Results We identified and selected three histone deacetylase inhibitors (HDACi) that decreased the abnormal expression level of GTF2I in 7Dup cortical glutamatergic neurons differentiated from four genetically different iPSC lines. We confirmed this effect also at the protein level. Limitations In this study, we did not address the molecular mechanisms whereby HDAC inhibitors act on GTF2I. The lead compounds identified will now need to be advanced to further testing in additional models, including patient-derived brain organoids and mouse models recapitulating the gene imbalances of the 7q11.23 microduplication, in order to validate their efficacy in rescuing phenotypes across multiple functional layers within a translational pipeline towards clinical use. Conclusions These results represent a unique opportunity for the development of a specific class of compounds for treating 7Dup and other forms of intellectual disability and autism.

We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest (NC) stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 7q11.23 copy number variants. Our results reveal a key contribution of BAZ1B to NCSC in vitro induction and migration, coupled with a crucial involvement in NC-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we found a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets, thereby providing the first empirical validation of the human self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face. In so doing, we provide experimental evidence that the craniofacial and cognitive/behavioral phenotypes caused by alterations of the Williams-Beuren syndrome critical region can serve as a powerful entry point into the evolution of the modern human face and prosociality.

Introduction Scientific data about neurophysiological changes subsequent to pulsed radiofrequency (PRF) are still lacking. The goal of this study was to evaluate sural nerve conduction and Hoffmann reflex (H-reflex) in soleus muscle following adhesiolysis and PRF in patients with unilateral chronic lumbosacral L5-S1 neuropathic radiating pain. Methods Seventeen patients received two cycles of 240 seconds high-voltage PRF and epidural adhesiolysis. Sural nerve action potential (SNAP) and the ratio of maximum H-reflex to maximum M response (H/M ratio) as well as pain scores were collected in both lower limbs before, immediately following, and 1 month after the treatment. Results At follow-up, a significant reduction in numeric rating scale (NRS) and Douleur Neuropathique 4 Questions (DN4) scores was observed in 53% of patients reporting pain improvement of ≥ 30% over baseline. The H/M ratio was decreased in the affected limb following PRF (P = 0.01) and 1 month after the treatment (P = 0.04). A direct correlation was observed between H/M ratio variation and NRS score at follow-up in the treated limb (P = 0.04). No significant difference in sural nerve latency, amplitude, and velocity was detected between affected and normal side after treatment and at follow-up. Conclusions Epidural adhesiolysis and PRF of the dorsal root ganglion seem to significantly affect spinal reflexes in patients with lumbosacral neuropathic radiating pain.

One of most debated aspects around Nitinol quality is microcleanliness, nowadays considered as the main factor affecting fatigue life. Recent results demonstrate that fatigue is undoubtedly associated with inclusions which can act as crack initiators. However, type, size, and distribution of such particles have been observed to strongly depend on Ni/Ti ratio as well as melting and thermo-mechanical processes. Therefore, if a general reduction of non-metallic inclusions is expected to generate a beneficial effect in improving lifetime of Nitinol, on the other hand this necessarily involves a hard review of both material melting and processing. In this work, the characterization of the fatigue behavior of SMA wires with diameter below 100 µm is presented. The wires were prepared by a peculiar, non-standard combination of melting and thermo-mechanical processes (Clean Melt technology). Thermo-mechanical cycling was carried out and the fracture surfaces of all failed wires were investigated by scanning electron microscopy. A robust set of data was collected and analyzed by using the statistics of extremes. Results clearly demonstrate that in the new NiTi Clean Melt alloy the maximum inclusion size and area fraction are significantly reduced compared to standard Nitinol. This offers meaningful improvement in fatigue resistance over standard wires.

Key Clinical Message The coexistence of median and cervical nerve root damage might hide a complex pathophysiology. Here, we describe and discuss the case of a patient suffering from numbness and painful tingling of the hand, whose symptoms were effectively treated with pulsed radiofrequency and epidural administration of bupivacaine and morphine.

We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest (NC) stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 7q11.23 copy number variants. Our results reveal a key contribution of BAZ1B to NCSC in vitro induction and migration, coupled with a crucial involvement in NC-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we found a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets, thereby providing the first empirical validation of the human self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face. In so doing, we provide experimental evidence that the craniofacial and cognitive/behavioral phenotypes caused by alterations of the Williams-Beuren syndrome critical region can serve as a powerful entry point into the evolution of the modern human face and prosociality., This work was funded by the Telethon Foundation (grant number GGP14265 to G.T. and G.M.), the EPIGEN Flagship Project of the Italian National Research Council (to G.T.), the European Research Council (consolidator grant number 616441-DISEASEAVATARS to G.T.), the Horizon 2020 Innovative Training Network EpiSyStem (to G.T.), Ricerca Corrente granted by the Italian Ministry of Health (to G.T. and G.M.) Giovani Ricercatori granted by the Italian Ministry of Health (to G.T.), Daunia Plast (to G.M.), Fondazione Umberto Veronesi (to P.-L.G.), the Foundation IEO-CCM (fellowship to A.V.), the Spanish Ministry of Economy and Competitiveness/FEDER funds (grant FFI2016-78034-C2-1-P to C.B.), the Generalitat de Catalunya (grant 2017-SGR-341 to C.B. and doctoral fellowships to T.O. and S.S.), the MEXT/JSPS Grant-in-Aid for Scientific Research on Innovative Areas 4903 [Evolinguistics: JP17H06379 (C.B.; PI: K. Okanoya)], a Marie Curie International Reintegration Grant from the European Union (PIRG-GA-2009-256413 to C.B.), the European Social Fund (grant BES-2017-080366 to A.A.), and the Portuguese Foundation for Science and Technology (PhD grant number SFRH/BD/131640/2017 to P.T.M.). M.Z., A.V., A.S., and S.T. conducted this study as fulfillment of their Ph.D. within the European School of Molecular Medicine (SEMM), Milan, Italy.

Symmetrical 7q11.23 dosage alterations cause craniofacial and cognitive/behavioral phenotypes that provide a privileged entry point into the evolution of the modern human face and (pro-) sociality. We undertook a functional dissection of chromatin remodeler BAZ1B in neural crest stem cells (NCSCs) from a uniquely informative cohort of typical and atypical patients harboring 7q11.23 Copy Number Variants (CNVs). Our results reveal a key contribution of BAZ1B to NCSCin vitroinduction and migration, coupled with a crucial involvement in neural crest (NC)-specific transcriptional circuits and distal regulation. By intersecting our experimental data with new paleogenetic analyses comparing modern and archaic humans, we uncover a modern-specific enrichment for regulatory changes both in BAZ1B and its experimentally defined downstream targets, thereby providing the first empirical validation of the self-domestication hypothesis and positioning BAZ1B as a master regulator of the modern human face.One Sentence SummaryBAZ1B dosage shapes the modern human face.

Simone Vigneri,1,2 Gianfranco Sindaco,2 Marco La Grua,2 Matteo Zanella,2 Laura Ravaioli,2 Valentina Paci,2 Gilberto Pari2 1Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, 2Advanced Algology Research and Pain Medicine Unit, Santa Maria Maddalena Hospital, Occhiobello, RO, Italy Objective: The aim of this study was to investigate the therapeutic effectiveness of epidural morphine and bupivacaine in patients with chronic lumbosacral radicular neuropathic pain after the cessation of treatment.Methods: Twenty-two patients with chronic lumbosacral pain with neuropathic features were enrolled. An indwelling catheter was placed into the epidural space, and each patient received an epidural injection of morphine chlorhydrate and bupivacaine up to three times a day. The medication was administered for 4 weeks. The pain intensity score on a 0–10 numeric rating scale (NRS), the total pain rating index rank (PRIr-T), and its coefficients were evaluated before treatment and 1 month after catheter removal. P-value 30% in NRS) was reached and maintained in half of the patients at follow-up.Conclusion: Combined epidural morphine and bupivacaine seems to be effective in the treatment of neuropathic pain. Keywords: epidural, opioids, bupivacaine, neuropathic pain, chronic pain

Nature Methods, 13 (9), ISSN:1548-7105, ISSN:1548-7091

Convergent evidence associates endocrine disrupting chemicals (EDCs) with major, increasingly-prevalent human disorders. Regulation requires elucidation of EDC-triggered molecular events causally linked to adverse health outcomes, but two factors limit their identification. First, experiments frequently use individual chemicals, whereas real life entails simultaneous exposure to multiple EDCs. Second, population-based and experimental studies are seldom integrated. This drawback was exacerbated until recently by lack of physiopathologically meaningful human experimental systems that link epidemiological data with results from model organisms.We developed a novel approach, integrating epidemiological with experimental evidence. Starting from 1,874 mother-child pairs we identified mixtures of chemicals, measured during early pregnancy, associated with language delay or low-birth weight in offspring. These mixtures were then tested on multiple complementary in vitro and in vivo models. We demonstrate that each EDC mixture, at levels found in pregnant women, disrupts hormone-regulated and disease-relevant gene regulatory networks at both the cellular and organismal scale.

Pulsed radiofrequency (PRF) short-lasting bursts allow pain modulation with no tissue necrosis. Neurophysiological evaluation of PRF possible effects has not been described yet. Objective of this study was to investigate the effects of PRF on sensory nerve conduction and H-reflex in patients with lumbosacral radicular pain. We evaluated 23 patients with unilateral L5-S1 root pain who underwent PRF at the corresponding level of radicular symptoms. PRF was applied through a multifunctional electrode introduced via trans-sacral access for 240 s. at a frequency of 2 Hz, amplitude of 45 V and a tip temperature between 40 and 42 °C. Neurophysiological evaluation was performed with the patient lying on a fluoroscopy table in the prone position. Sural sensory action potentials (SAP) and soleus H-reflex were bilaterally evaluated. Outcome measures included variation of sural nerve conduction and H-reflex parameters pre-, post-treatment with PRF and after 30 days from the procedure. P values A significant decrease in H/M ratio was observed in the affected side of patients with paresthesia either post-treatment (p = 0.007) and at one month follow-up (p = 0.04). PRF might exert its clinical effects beyond DRG through an action on spinal inhibitory interneuronal circuitry.

Cell reprogramming promises to make characterization of the impact of human genetic variation on health and disease experimentally tractable by enabling the bridging of genotypes to phenotypes in developmentally relevant human cell lineages. Here we apply this paradigm to two disorders caused by symmetrical copy number variations of 7q11.23, which display a striking combination of shared and symmetrically opposite phenotypes--Williams-Beuren syndrome and 7q-microduplication syndrome. Through analysis of transgene-free patient-derived induced pluripotent stem cells and their differentiated derivatives, we find that 7q11.23 dosage imbalance disrupts transcriptional circuits in disease-relevant pathways beginning in the pluripotent state. These alterations are then selectively amplified upon differentiation of the pluripotent cells into disease-relevant lineages. A considerable proportion of this transcriptional dysregulation is specifically caused by dosage imbalances in GTF2I, which encodes a key transcription factor at 7q11.23 that is associated with the LSD1 repressive chromatin complex and silences its dosage-sensitive targets.