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Objectives: To report a novel imaging finding of bilateral dentate nuclei hyperintensities in a case of childhood-onset GAA- FGF14 -related ataxia (spinocerebellar ataxia 27B, SCA27B) and response to 4-aminopyridine (4-AP)., Methods: A 53-year-old woman with unsolved progressive cerebellar ataxia of childhood onset underwent clinical and imaging assessment and extensive genetic investigation., Results: After excluding Friedreich ataxia, most common spinocerebellar ataxia-related expansions, and pathogenic variants in ataxia-related genes through exome sequencing, targeted long-range PCR and repeat-primed PCR analysis revealed a heterozygous pathogenic (GAA) 302 expansion in FGF14. Brain MRI showed bilateral dentate nuclei hyperintensities and peridentate white matter degeneration, a feature never reported before in SCA27B. Gait ataxia and frequency of falls improved after starting 4-AP., Discussion: We confirm that SCA27B, initially considered a late-onset condition, can present with very early onset in childhood and describe a novel imaging feature of this common hereditary ataxia. Previous imaging studies had described a spectrum of findings, variably including cerebellar vermian and hemispheric atrophy, hyperintensities of the superior cerebellar peduncles, cerebral and brainstem atrophy, ventricular enlargement, and corpus callosum thinning. In this case, T2/FLAIR bilateral dentate nuclei hyperintensities and peridentate white matter degeneration expand the neuroradiologic spectrum associated with GAA- FGF14 -related ataxia of long duration., Competing Interests: M. Avenali is supported by Ministry of University and Research (MUR), National Recovery 231 and Resilience Plan (NRRP), project MNESYS (PE0000006). E.M. Valente is the Associate Editor of Journal of Medical Genetics, Genetics Section Editor of Pediatric Research, Genetics Section Editor of The Cerebellum, Genetics Section Editor of Neurological Sciences, a member of the Editorial Board of Movement Disorders Clinical Practice, and a member of the Steering Committee of ASAP GP2 (Global Parkinson Genetic Program) and has received research support from the Italian Ministry of Health, CARIPLO Foundation, Telethon, Foundation Italy, Pierfranco and Luisa Mariani Foun-dation, and European Community (Eranet Neuron). Go to Neurology.org/NG for full disclosures., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Neuropsychological data suggest that being overweight or obese is associated with a tendency to perseverate behavior despite negative feedback. This deficit might be observed due to other cognitive factors, such as working memory (WM) deficits or decreased ability to deduce model-based strategies when learning by trial-and-error. In the present study, a group of subjects with overweight or obesity (Ow/Ob, n = 30) was compared to normal-weight individuals (n = 42) in a modified Reinforcement Learning (RL) task. The task was designed to control WM effects on learning by manipulating cognitive load and to foster model-based learning via deductive reasoning. Computational modelling and analysis were conducted to isolate parameters related to RL mechanisms, WM use, and model-based learning (deduction parameter). Results showed that subjects with Ow/Ob had a higher number of perseverative errors and used a weaker deduction mechanism in their performance than control individuals, indicating impairments in negative reinforcement and model-based learning, whereas WM impairments were not responsible for deficits in RL. The present data suggests that obesity is associated with impairments in negative reinforcement and model-based learning., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Inc.)

Background: SNCA p.V15A was reported in five families. In vitro models showed increased aggregation and seeding activity, mitochondrial damage, and apoptosis. Mutant flies had reduced flying ability and survival., Objectives: To clinically and functionally evaluate SNCA p.V15A in a large Italian family with Parkinson's disease (PD)., Methods: Genetic diagnosis was reached through next-generation sequencing. Pathogenicity was assessed by molecular dynamics simulation and biochemical studies on peripheral blood mononuclear cells (PBMCs)., Results: Five siblings carried SNCA p.V15A; three developed bradykinetic-rigid PD in their 50s with rapid motor progression and variable cognitive impairment. A fourth sibling had isolated mood disturbance, whereas the fifth was still unaffected at age 47. The mutant protein showed decreased stability and an unstable folded structure. Proband's PBMCs showed elevated total and phosphorylated α-synuclein (α-syn) levels and significantly reduced glucocerebrosidase activity., Conclusion: This study demonstrates accumulation of α-syn V15A in PBMCs and strengthens the link between α-syn pathophysiology and glucocerebrosidase dysfunction. © 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

In recent decades, industrialization, intensive agriculture, and urban development have severely impacted marine environments, compromising the health of aquatic and terrestrial organisms. Inadequate disposal results in hundreds of tons of plastic products released annually into the environment, which degrade into microplastics (MPs), posing health risks due to their ability to biomagnify and bioaccumulate. Among these, polystyrene MPs (PS-MPs) are significant pollutants in marine ecosystems, widely studied for their reproductive toxicological effects. This research aimed to evaluate the reproductive cytotoxic and genotoxic effects of PS-MPs on sea urchin ( Paracentrotus lividus ) spermatozoa in vitro . Results showed that PS-MPs significantly reduced sperm viability and motility without altering morphology, and induced sperm DNA fragmentation mediated by reactive oxygen species production. Furthermore, head-to-head agglutination of the spermatozoa was observed exclusively in the sample treated with the plastic agents, indicating the ability of microplastics to adhere to the surface of sperm cells and form aggregates with microplastics on other sperm cells, thereby impeding movement and reducing reproductive potential. These findings suggest that PS-MPs can adversely affect the quality of sea urchin sperm, potentially impacting reproductive events., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Male fertility can be affected by oxidative stress (OS), which occurs when an imbalance between the production of reactive oxygen species (ROS) and the body's ability to neutralize them arises. OS can damage cells and influence sperm production. High levels of lipid peroxidation have been linked to reduced sperm motility and decreased fertilization ability. This literature review discusses the most commonly used biomarkers to measure sperm damage caused by ROS, such as the high level of OS in seminal plasma as an indicator of imbalance in antioxidant activity. The investigated biomarkers include 8-hydroxy-2-deoxyguanosine acid (8-OHdG), a marker of DNA damage caused by ROS, and F2 isoprostanoids (8-isoprostanes) produced by lipid peroxidation. Furthermore, this review focuses on recent methodologies including the NGS polymorphisms and differentially expressed gene (DEG) analysis, as well as the epigenetic mechanisms linked to ROS during spermatogenesis along with new methodologies developed to evaluate OS biomarkers. Finally, this review addresses a valuable insight into the mechanisms of male infertility provided by these advances and how they have led to new treatment possibilities. Overall, the use of biomarkers to evaluate OS in male infertility has supplied innovative diagnostic and therapeutic approaches, enhancing our understanding of male infertility mechanisms.

Background: GBA variants increase the risk of developing Parkinson disease (PD) and influence its outcome. Deep brain stimulation (DBS) is a recognised therapeutic option for advanced PD. Data on DBS long-term outcome in GBA carriers are scarce., Objective: To elucidate the impact of GBA variants on long-term DBS outcome in a large Italian cohort., Methods: We retrospectively recruited a multicentric Italian DBS-PD cohort and assessed: (1) GBA prevalence; (2) pre-DBS clinical features; and (3) outcomes of motor, cognitive and other non-motor features up to 5 years post-DBS., Results: We included 365 patients with PD, of whom 73 (20%) carried GBA variants. 5-year follow-up data were available for 173 PD, including 32 mutated subjects. GBA-PD had an earlier onset and were younger at DBS than non-GBA-PD. They also had shorter disease duration, higher occurrence of dyskinesias and orthostatic hypotension symptoms.At post-DBS, both groups showed marked motor improvement, a significant reduction of fluctuations, dyskinesias and impulsive-compulsive disorders (ICD) and low occurrence of most complications. Only cognitive scores worsened significantly faster in GBA-PD after 3 years. Overt dementia was diagnosed in 11% non-GBA-PD and 25% GBA-PD at 5-year follow-up., Conclusions: Evaluation of long-term impact of GBA variants in a large Italian DBS-PD cohort supported the role of DBS surgery as a valid therapeutic strategy in GBA-PD, with long-term benefit on motor performance and ICD. Despite the selective worsening of cognitive scores since 3 years post-DBS, the majority of GBA-PD had not developed dementia at 5-year follow-up., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: High repeat expansion (HRE) alleles in C9orf72 have been linked to both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD); ranges for intermediate allelic expansions have not been defined yet, and clinical interpretation of molecular data lacks a defined genotype-phenotype association. In this study, we provide results from a large multicenter epidemiological study reporting the distribution of C9orf72 repeats in healthy elderly from the Italian population., Methods: A total of 967 samples were collected from neurologically evaluated healthy individuals over 70 years of age in the 13 institutes participating in the RIN (IRCCS Network of Neuroscience and Neurorehabilitation) based in Italy. All samples were genotyped using the AmplideXPCR/CE C9orf72 Kit (Asuragen, Inc.), using standardized protocols that have been validated through blind proficiency testing., Results: All samples carried hexanucleotide G 4 C 2 expansion alleles in the normal range. All samples were characterized by alleles with less than 25 repeats. In particular, 93.7% of samples showed a number of repeats ≤10, 99.9% ≤20 repeats, and 100% ≤25 repeats., Conclusion: This study describes the distribution of hexanucleotide G 4 C 2 expansion alleles in an Italian healthy population, providing a definition of alleles associated with the neurological healthy phenotype. Moreover, this study provides an effective model of federation between institutes, highlighting the importance of sharing genomic data and standardizing analysis techniques, promoting translational research. Data derived from the study may improve genetic counseling and future studies on ALS/FTD., Competing Interests: VS received compensation for consulting services and/or speaking activities from AveXis, Cytokinetics, Italfarmaco, Liquidweb S.r.l., Novartis Pharma AG, Zambon Biotech SA, and Asuragen. He receives or has received research supports form the Italian Ministry of Health, AriSLA, E-Rare Joint Transnational Call, and the ERN Euro-NMD. He is in the Editorial Board of Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, European Neurology, American Journal of Neurodegenerative Diseases, Frontiers in Neurology, and Exploration of Neuroprotective Therapy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Giardina, Mandich, Ghidoni, Ticozzi, Rossi, Fenoglio, Tiziano, Esposito, Capellari, Nacmias, Mineri, Campopiano, Di Pilla, Sammarone, Zampatti, Peconi, De Angelis, Palmieri, Galandra, Nicodemo, Origone, Gotta, Ponti, Nicsanu, Benussi, Peverelli, Ratti, Ricci, Di Fede, Magri, Serpente, Lattante, Domi, Carrera, Saltimbanco, Bagnoli, Ingannato, Albanese, Tagliavini, Lodi, Caltagirone, Gambardella, Valente and Silani.)

Background and Objective: Early-onset Parkinson's disease (EOPD) commonly recognizes a genetic basis; thus, patients with EOPD are often addressed to diagnostic testing based on next-generation sequencing (NGS) of PD-associated multigene panels. However, NGS interpretation can be challenging in a diagnostic setting, and few studies have addressed this issue so far., Methods: We retrospectively collected data from 648 patients with PD with age at onset younger than 55 years who underwent NGS of a minimal shared panel of 15 PD-related genes, as well as PD-multiplex ligation-dependent probe amplification in eight Italian diagnostic laboratories. Data included a minimal clinical dataset, the complete list of variants included in the diagnostic report, and final interpretation (positive/negative/inconclusive). Patients were further stratified based on age at onset ≤40 years (very EOPD, n = 157). All variants were reclassified according to the latest American College of Medical Genetics and Genomics criteria. For classification purposes, PD-associated GBA1 variants were considered diagnostic., Results: In 186 of 648 (29%) patients, the diagnostic report listed at least one variant, and the outcome was considered diagnostic (positive) in 105 (16%). After reanalysis, diagnosis changed in 18 of 186 (10%) patients, with 5 shifting from inconclusive to positive and 13 former positive being reclassified as inconclusive. A definite diagnosis was eventually reached in 97 (15%) patients, of whom the majority carried GBA1 variants or, less frequently, biallelic PRKN variants. In 89 (14%) cases, the genetic report was inconclusive., Conclusions: This study attempts to harmonize reporting of PD genetic testing across several diagnostic labs and highlights current difficulties in interpreting genetic variants emerging from NGS-multigene panels, with relevant implications for counseling. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA -related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF)., Methods and Analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat., Ethics and Dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences., Trial Registration Numbers: NCT05287503, EudraCT 2021-004565-13., Competing Interests: Competing interests: RC has received speaking honoraria from Zambon Italia; Zambon SAU; Bial Italia Srl; advisory board fees from Bial; research support from the Italian Ministry of Health; he is Editor-in-Chief of the neuromuscular and movement disorders section of Brain Sciences (MDPI); Associate Editor of Parkinsonism and Related Disorders (Elsevier) and Frontiers in Ageing Neuroscience., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Online experiments are an alternative for researchers interested in conducting behavioral research outside the laboratory. However, an online assessment might become a challenge when long and complex experiments need to be conducted in a specific order or with supervision from a researcher. The aim of this study was to test the computational validity and the feasibility of a remote and synchronous reinforcement learning (RL) experiment conducted during the social-distancing measures imposed by the pandemic. An additional feature of this study was to describe how a behavioral experiment originally created to be conducted in-person was transformed into an online supervised remote experiment. Open-source software was used to collect data, conduct statistical analysis, and do computational modeling. Python codes were created to replicate computational models that simulate the effect of working memory (WM) load over RL performance. Our behavioral results indicated that we were able to replicate remotely and with a modified behavioral task the effects of working memory (WM) load over RL performance observed in previous studies with in-person assessments. Our computational analyses using Python code also captured the effects of WM load over RL as expected, which suggests that the algorithms and optimization methods were reliable in their ability to reproduce behavior. The behavioral and computational validation shown in this study and the detailed description of the supervised remote testing may be useful for researchers interested in conducting long and complex experiments online., (© 2022. The Psychonomic Society, Inc.)

Background: Joubert syndrome (JS) is a neurodevelopmental ciliopathy characterised by a distinctive mid-hindbrain malformation, the 'molar tooth sign'. Over 40 JS-associated genes are known, accounting for two-thirds of cases., Methods: While most variants are novel or extremely rare, we report on 11 recurring variants in seven genes, including three known 'founder variants' in the Ashkenazi Jewish, Hutterite and Finnish populations. We evaluated variant frequencies in ~550 European patients with JS and compared them with controls (>15 000 Italian plus gnomAD), and with an independent cohort of ~600 JS probands from the USA., Results: All variants were markedly enriched in the European JS cohort compared with controls. When comparing allele frequencies in the two JS cohorts, the Ashkenazim founder variant ( TMEM216 c.218G>T) was significantly enriched in American compared with European patients with JS, while MKS1 c.1476T>G was about 10 times more frequent among European JS. Frequencies of other variants were comparable in the two cohorts. Genotyping of several markers identified four novel European founder haplotypes.Two recurrent variants ( MKS1 c.1476T>G and KIAA0586 c.428delG), have been detected in homozygosity in unaffected individuals, suggesting they could act as hypomorphic variants. However, while fibroblasts from a MKS1 c.1476T>G healthy homozygote showed impaired ability to form primary cilia and mildly reduced ciliary length, ciliary parameters were normal in cells from a KIAA0586 c.428delG healthy homozygote., Conclusion: This study contributes to understand the complex genetic landscape of JS, explain its variable prevalence in distinct geographical areas and characterise two recurrent hypomorphic variants., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype-phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin ( GYG1 -muscle, GYG2 , and other tissues), glycogen synthase ( GYS1 -muscle and GYS2 -liver), GBE1 , EPM2A, NHLRC1 , GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA , while two cytoplasmic enzymes, phosphorylase ( PYGB -brain, PGL -liver, and PYGM -muscle) and glycogen debranching ( AGL ) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.

Background: Mutations of the Glucocerebrosidase (GBA) gene are the most common genetic risk factor yet discovered for Parkinson's Disease (PD), being found in about 5-14% of Caucasian patients., Objective: We aimed to assess motor and non-motor symptoms (NMS) in patients with GBA-related PD (GBA-PD) in comparison with idiopathic PD (iPD) subjects using standardized and validated scales., Methods: Eleven (4 M, 7 F) patients with GBA-PD and 22 iPD patients, selected from the same cohort and matched for gender, age, and disease duration, were enrolled. The disease severity was assessed by Unified Parkinson's Disease Rating Scale-section III, gait disorder and falls by Freezing of Gait Questionnaire, and motor fluctuations by Wearing off questionnaire. NMS were evaluated using the following scales: Mini-Mental State Examination and extended neuropsychological battery, if required, Non-Motor Symptoms Scale, SCOPA-AUT Questionnaire, Apathy Evaluation Scale, Beck Depression Inventory, Epworth Sleepiness Scale, Restless Legs Syndrome Rating Scale, REM Sleep Behavior Disorder Screening Questionnaire, and Questionnaire for Impulsive-Compulsive Disorders in Parkinson's disease., Results: GBA-PD patients showed a more severe and rapidly progressive disease, and more frequent positive family history for PD, akinetic-rigid phenotype, postural instability, dementia, and psychosis in comparison to iPD. Two of three subjects carrying L444P mutation presented with early dementia. We also found a higher occurrence of fatigue, diurnal sleepiness, and intolerance to heat/cold in the carriers group., Conclusions: Our results confirm that NMS and a more severe and faster disease course more frequently occur among GBA-PD patients in comparison to iPD., (© 2023. The Author(s) under exclusive licence to Belgian Neurological Society.)

The surgical approach to chronic pilonidal disease has been significantly changed by minimally invasive and targeted procedures, with the aim to minimize costs and favoring less dressings, faster recovery, and prompt return to work or to school activity. Less invasive procedures are gaining wide acceptance as first approach. We present a single-center experience with the Gips technique, also called Israeli technique or trephine technique, and a brief review of the literature, focusing on minimally invasive procedures. KEY WORDS: Pilonidal Disease, Punch, Minimally Invasive Surgery, Trephines.

Background: Parkinsonian features have been described in patients harboring variants in nuclear genes encoding for proteins involved in mitochondrial DNA maintenance, such as TWNK., Objectives: The aim was to screen for TWNK variants in an Italian cohort of Parkinson's disease (PD) patients and to assess the occurrence of parkinsonism in patients presenting with TWNK-related autosomal dominant progressive external ophthalmoplegia (TWNK-adPEO)., Methods: Genomic DNA of 263 consecutively collected PD patients who underwent diagnostic genetic testing was analyzed with a targeted custom gene panel including TWNK, as well as genes causative of monogenic PD. Genetic and clinical data of 18 TWNK-adPEO patients with parkinsonism were retrospectively analyzed., Results: Six of 263 PD patients (2%), presenting either with isolated PD (n = 4) or in combination with bilateral ptosis (n = 2), carried TWNK likely pathogenic variants. Among 18 TWNK-adPEO patients, 5 (28%) had parkinsonism., Conclusions: We show candidate TWNK variants occurring in PD without PEO. This finding will require further confirmatory studies. © 2022 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society., (© 2022 Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.)

Alzheimer's disease (AD) and Lewy body dementia (LBD) are two different forms of dementia, but their pathology may involve the same cortical areas with overlapping cognitive manifestations. Nonetheless, the clinical phenotype is different due to the topography of the lesions driven by the different underlying molecular processes that arise apart from genetics, causing diverse neurodegeneration. Here, we define the commonalities and differences in the pathological processes of dementia in two kindred cases, a mother and a son, who developed classical AD and an aggressive form of AD/LBD, respectively, through a neuropathological, genetic (next-generation sequencing), and transcriptomic (RNA-seq) comparison of four different brain areas. A genetic analysis did not reveal any pathogenic variants in the principal AD/LBD-causative genes. RNA sequencing highlighted high transcriptional dysregulation within the substantia nigra in the AD/LBD case, while the AD case showed lower transcriptional dysregulation, with the parietal lobe being the most involved brain area. The hippocampus (the most degenerated area) and basal ganglia (lacking specific lesions) expressed the lowest level of dysregulation. Our data suggest that there is a link between transcriptional dysregulation and the amount of tissue damage accumulated across time, assessed through neuropathology. Moreover, we highlight that the molecular bases of AD and LBD follow very different pathways, which underlie their neuropathological signatures. Indeed, the transcriptome profiling through RNA sequencing may be an important tool in flanking the neuropathological analysis for a deeper understanding of AD and LBD pathogenesis.

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurological diseases which, respectively, and primarily affect motor neurons and frontotemporal lobes. Although they can lead to different signs and symptoms, it is now evident that these two pathologies form a continuum and that hallmarks of both diseases can be present within the same person in the so-called ALS-FTD spectrum. Many studies have focused on the genetic overlap of these pathologies and it is now clear that different genes, such as C9orf72, TARDBP, SQSTM1, FUS , and p97/VCP can be mutated in both the diseases. VCP was one of the first genes associated with both FTD and ALS representing an early example of gene overlapping. VCP belongs to the type II AAA (ATPases Associated with diverse cellular activities) family and is involved in ubiquitinated proteins degradation, autophagy, lysosomal clearance and mitochondrial quality control. Since its numerous roles, mutations in this gene lead to different pathological features, first and foremost TDP-43 mislocalization. This review aims to outline recent findings on VCP roles and on how its mutations are linked to the neuropathology of ALS and FTD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Scarian, Fiamingo, Diamanti, Palmieri, Gagliardi and Pansarasa.)

Cholecystogastric fistulas is a rare complication of gallstone. Even if well described in the literature, this condition still poses a debate on diagnosis and surgical treatment. We present a case of a 35 year's old female which unexpectedly presented a cholecystogastric fistula during a laparoscopic cholecystectomy, treated successfully with fistula transection and repair and cholecystectomy through an open access. The open access remains the preferable option in this cases but laparoscopic techniques are being used worldwide with increasing success. The preoperative diagnosis remains difficult for the unspecific symptoms. KEY WORDS: Biliodigestive Fistula, Gallstone Ileus, Gastric Fistula, Biliary Fistula, Cholecystitis.

Background: Injective procedures using polynucleotides-based products to promote dermal rejuvenation and revitalization are steadily evolving, yet no structured protocols are available that discuss and provide guidance in aesthetic treatments with highly purified polynucleotides. The goal of this document was to provide consensus-based recommendations for the safe and effective use of Polynucleotides Highly Purified Technology™ (PN-HPT™) devices for skin rejuvenation., Patients/methods: A team of eight experts with extensive experience in treatments for skin rejuvenation and revitalization integrated the best available evidence and clinical judgment and devised a series of practical guidance to support dermatologists, plastic surgeons, and aesthetic physician in the use of PN-HPT™ products, alone and in combination, in aesthetic medicine., Results: For most items, the expert group achieved a majority consensus. "Recommendations" (consensus >80%) were reached for the face, periocular area, décolleté and neck, hands, scalp, and stretch marks. Recommendations include details of techniques, information on dosage, volumes to be injected, and the ideal number of required treatment sessions, as well as time intervals between them for different areas of face and body. A lower agreement level of 60% was reached on but one item related to the initial treatment cycle for the face, leading to a "Consensus statement" for that area instead of a full "Recommendation.", Conclusion: The expert consensus illustrates the value of natural-origin, highly purified polynucleotides (PN-HPT™) as biostimulatory booster strategy for skin priming and revitalization of face and body and provides a detailed guide for the use., (© 2020 The Authors. Journal of Cosmetic Dermatology published by Wiley Periodicals LLC.)

Bacteria-fungi interactions (BFIs) are essential in ecosystem functioning. These interactions are modulated not only by local nutritional conditions but also by the physicochemical constraints and 3D structure of the environmental niche. In soils, the unsaturated and complex nature of the substrate restricts the dispersal and activity of bacteria. Under unsaturated conditions, some bacteria engage with filamentous fungi in an interaction (fungal highways) in which they use fungal hyphae to disperse. Based on a previous experimental device to enrich pairs of organisms engaging in this interaction in soils, we present here the design and validation of a modified version of this sampling system constructed using additive printing. The 3D printed devices were tested using a novel application in which a target fungus, the common coprophilous fungus Coprinopsis cinerea, was used as bait to recruit and identify bacterial partners using its mycelium for dispersal. Bacteria of the genera Pseudomonas, Sphingobacterium and Stenotrophomonas were highly enriched in association with C. cinerea. Developing and producing these new easy-to-use tools to investigate how bacteria overcome dispersal limitations in cooperation with fungi is important to unravel the mechanisms by which BFIs affect processes at an ecosystem scale in soils and other unsaturated environments., (© The Author(s) 2021. Published by Oxford University Press on behalf of FEMS.)

Neoadjuvant chemoradiotherapy (NCRT) combined with total mesorectal excision (TME) is currently the gold standard for locally advanced low-lying rectal cancer (LACR). Around 20-30% of patients after NCRT can achieve clinical complete response (cCR); 5-44% of the patients who underwent TME achieve pathological complete response (pCR) on postoperative histopathologic studies. In the present study we perform a review of current Literature and retrospectively analyze our personal experience on “watch and wait” approach after cCR. Further studies are needed to establish an internationally accepted definition of clinical complete response, to delineate the real role of MRI in the post-treatment staging and to determine more precise predictors of sustained clinical complete response. The eventual presence of long-term morbidity and adverse effects after chemoradiation needs as well to be better evaluated. Evidence suggests that watch and wait approach is associated with substantially better quality of life and functional outcomes compared with standard surgical resection.

Background: Variants in GBA are the most common genetic risk factor for Parkinson's disease (PD). The impact of different variants on the PD clinical spectrum is still unclear., Objectives: We determined the frequency of GBA-related PD in Italy and correlated GBA variants with motor and nonmotor features and their occurrence over time., Methods: Sanger sequencing of the whole GBA gene was performed. Variants were classified as mild, severe, complex, and risk. β-glucocerebrosidase activity was measured. The Kaplan-Meier method and Cox proportional hazard regression models were performed., Results: Among 874 patients with PD, 36 variants were detected in 14.3%, including 20.4% early onset. Patients with GBA-PD had earlier and more frequent occurrence of several nonmotor symptoms. Patients with severe and complex GBA-PD had the highest burden of symptoms and a higher risk of hallucinations and cognitive impairment. Complex GBA-PD had the lowest β-glucocerebrosidase activity., Conclusions: GBA-PD is highly prevalent in Italy. Different types of mutations underlie distinct phenotypic profiles. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Any inguinal hernia containing the vermiform appendix is called Amyand's hernia. Amyand hernias are very rare and even rarer is the association of Amyand hernia with acute appendicitis. Due to the rarity of this entity, it constitutes a challenging case in terms of diagnosis and treatment. The surgical management is not yet standardized and there are no clear guidelines. There are some controversies regarding whether to perform an appendectomy if appendix appears normal or whether mesh can be used for the hernia repair if appendectomy is performed. We describe a case of Amyand hernia in a 90-year old man with acute appendicitis and we review current literature regarding surgical strategy.

Poly-extreme terrestrial habitats are often used as analogs to extra-terrestrial environments. Understanding the adaptive strategies allowing bacteria to thrive and survive under these conditions could help in our quest for extra-terrestrial planets suitable for life and understanding how life evolved in the harsh early earth conditions. A prime example of such a survival strategy is the modification of vegetative cells into resistant resting structures. These differentiated cells are often observed in response to harsh environmental conditions. The environmental strain (strain Lr5/4) belonging to Serratia ureilytica was isolated from a geothermal spring in Lirima, Atacama Desert, Chile. The Atacama Desert is the driest habitat on Earth and furthermore, due to its high altitude, it is exposed to an increased amount of UV radiation. The geothermal spring from which the strain was isolated is oligotrophic and the temperature of 54°C exceeds mesophilic conditions (15 to 45°C). Although the vegetative cells were tolerant to various environmental insults (desiccation, extreme pH, glycerol), a modified cell type was formed in response to nutrient deprivation, UV radiation and thermal shock. Scanning (SEM) and Transmission Electron Microscopy (TEM) analyses of vegetative cells and the modified cell structures were performed. In SEM, a change toward a circular shape with reduced size was observed. These circular cells possessed what appears as extra coating layers under TEM. The resistance of the modified cells was also investigated, they were resistant to wet heat, UV radiation and desiccation, while vegetative cells did not withstand any of those conditions. A phylogenomic analysis was undertaken to investigate the presence of known genes involved in dormancy in other bacterial clades. Genes related to spore-formation in Myxococcus and Firmicutes were found in S. ureilytica Lr5/4 genome; however, these genes were not enough for a full sporulation pathway that resembles either group. Although, the molecular pathway of cell differentiation in S. ureilytica Lr5/4 is not fully defined, the identified genes may contribute to the modified phenotype in the Serratia genus. Here, we show that a modified cell structure can occur as a response to extremity in a species that was previously not known to deploy this strategy. This strategy may be widely spread in bacteria, but only expressed under poly-extreme environmental conditions.