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Epidermolysis bullosa (EB) is a rare inherited genetic disease characterized by an abnormal response of the skin and mucosa to mechanical trauma. Dystrophic EB (DEB) is very often associated with many extra cutaneous complications. Those complications involve either epithelial associated tissues or other organs. In particular, several renal complications have been described for DEB in the recessive form, such as amyloidosis, post-infection glomerulonephritis, upper and lower urinary tract obstruction and IgA-Nephropathy (IgAN). In the cases reported below we have two patients diagnosed with DEB that showed compromised renal function and proteinuria. The switch of the normal diet toward a gluten free diet resulted beneficial for both patients, since renal function was rescued and proteinuria cured. Moreover, a general health status improvement was recognised, given that nutritional condition was ameliorated and bone growing enhanced. Furthermore, in both patients the presence of autoantibodies anti-COL7 indicating an autoimmune form of the disease. Therefore, patients received low doses of betametasone useful to reduce inflammatory state and to control immune system function. In conclusion, our results prompt us to hypothesized that in these patients, due to the fragility of the intestinal mucosa, the absence in the diet of gluten may be beneficial. [ABSTRACT FROM AUTHOR]

Correlations between germline APC mutation sites and colorectal pathophenotypes, as evaluated by the direct count of adenomas at colectomy, were investigated analysing colectomy specimens from 29 FAP patients carrying one mis-sense (codon 208) and 14 frame-shift or non-senseAPC mutations (codons 232, 367, 437, 623, 876, 995, 1061, 1068, 1075, 1112, 1114, 1309, 1324, 1556). The mis-sense mutation at codon 208 was associated with a relatively mild colorectal pathophenotype. The mutation at codon 367, subject to alternative splicing, was associated with attenuated FAP. The mutation at codon 1309 was associated with the profuse colorectal adenomatosis. For 13 mutations, predicted to result in null alleles or truncated APC proteins, we correlated density and distribution of colorectal adenomas with the predicted functional effects of the mutation. The most severe colorectal pathophenotype was significantly associated with the truncating mutation at codon 1309, which is located downstream to the Iβ-catenin binding domain but upstream IIβ-catenin-binding domain. Mutations between codons 867 and 1114, which affect the Iβ-catenin binding domain, as well as mutations occurring in exons 6 and 9, predicted to result in null alleles, were associated with a less severe colorectal pathophenotype. Overall, the highest number of adenomas was detected in the right colon, followed by the left colon, transverse colon sigma and rectum. However, the highest density of adenomas was observed in the left colon, followed by the right colon, sigma, transverse colon and rectum. Colorectal carcinomas, observed in only five patients, were all in the left colon. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to determine whether nocturnal enuresis (NE) can be caused by absorptive hypercalciuria. Materials and Methods: From 1981 to 1995, 406 patients with primary monosymptomatic nocturnal enuresis were studied. Up to 1989 (Group 1), urinary electrolytes and urinary creatinine were not evaluated, but since 1990 (Group 2) these tests have been performed routinely. In doing so, we noticed that in 8 patients in Group 2 and in 13 patients in Group 1 with persistent NE the urinary calcium and the urinary calcium/creatinine ratios were significantly high (p < 0.001). These patients were submitted to Pak's test and parathyroid hormone (PTH) and antidiuretic hormone (ADH) measurements. Results: In all 21 patients, PTH and ADH levels were normal, while the Pak's test showed absorptive hypercalciuria. They were given an appropriate diet. After 3 months, NE had ceased completely in 4 patients (19%); bedwetting episodes diminished and calciuria levels were found to be borderline in the remaining 17. A new urodynamic evaluation showed normal patterns in 12 and detrusor instability (DI) in 5. Patients with DI received oxybutinine: enuresis disappeared in all. The remaining 12 children with persistent NE and normal urodynamic findings and the child with DI and persistent NE empirically received DDAVP; enuresis ceased in all of them within 1 month and calciuria stabilized at normal levels. Conclusions: This study revealed that absorptive hypercalciuria can be responsible for NE and can be treated with the combination of diet and DDAVP. [ABSTRACT FROM AUTHOR]

Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na + channel 1.6 (Na v 1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14 R117 , a critical residue located within a druggable pocket at the FGF14/Na v 1.6 PPI interface. We found that 1028 modulates FGF14/Na v 1.6 complex assembly and depolarizes the voltage-dependence of Na v 1.6 channel inactivation with nanomolar potency by modulating the intramolecular interaction between the III-IV linker and C-terminal domain of the Na v 1.6 channel. Consistent with the compound's effects on Na v 1.6 channel inactivation, 1028 enhances MSN excitability ex vivo and accumbal neuron firing rate in vivo in murine models. Systemic administration of 1028 maintains behavioral motivation preferentially during motivationally deficient conditions in murine models. These behavioral effects were abrogated by in vivo gene silencing of Fgf14 in the NAc and were accompanied by a selective reduction in accumbal dopamine levels during reward consumption in murine models. These findings underscore the potential to selectively regulate complex behaviors associated with neuropsychiatric disorders through targeting of PPIs in neurons., Competing Interests: Competing interests: The corresponding author, F.L., is the founder and president of IonTx Inc., a start-up company focusing on developing regulators of voltage-gated Na+ channels. The following patent is related to the present study: LAEZ-F-22A: TMB-0170000. Additional information related to the patent is as follows: Patent Int’l Application No: PCT/US24/32688; Title: Non-Peptide Small Molecule FGF14:Nav1.6 Channel Complex Protein-Protein Interaction Modulators; Tech ID: LAEZ-F-22A; Patent Applicant: The Board of Regents of the University of Texas System; Name of the Inventors: Drs. Jia Zhou, Fernanda Laezza, Pingyuan Wang, Nolan M. Dvorak, Paul A. Wadsworth; Status of the Application: Pending; Specific Aspect of the manuscript covered in the patent application: the synthetic route and chemical structure of 1028 is covered in the patent application. All other authors declare that they have no competing interests., (© 2024. The Author(s).)

Background: Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by the accumulation of pathological proteins and synaptic dysfunction. This study aims to investigate the molecular and functional differences between human induced pluripotent stem cells (hiPSCs) derived from patients with sporadic AD (sAD) and age-matched controls (healthy subjects, HS), focusing on their neuronal differentiation and synaptic properties in order to better understand the cellular and molecular mechanisms underlying AD pathology., Methods: Skin fibroblasts from sAD patients (n = 5) and HS subjects (n = 5) were reprogrammed into hiPSCs using non-integrating Sendai virus vectors. Through karyotyping, we assessed pluripotency markers (OCT4, SOX2, TRA-1-60) and genomic integrity. Neuronal differentiation was evaluated by immunostaining for MAP2 and NEUN. Electrophysiological properties were measured using whole-cell patch-clamp, while protein expression of Aβ, phosphorylated tau, Synapsin-1, Synaptophysin, PSD95, and GluA1 was quantified by western blot. We then focused on PAK1-LIMK1-Cofilin signaling, which plays a key role in regulating synaptic structure and function, both of which are disrupted in neurodegenerative diseases such as AD., Results: sAD and HS hiPSCs displayed similar stemness features and genomic stability. However, they differed in neuronal differentiation and function. sAD-derived neurons (sAD-hNs) displayed increased levels of AD-related proteins, including Aβ and phosphorylated tau. Electrophysiological analyses revealed that while both sAD- and HS-hNs generated action potentials, sAD-hNs exhibited decreased spontaneous synaptic activity. Significant reductions in the expression of synaptic proteins such as Synapsin-1, Synaptophysin, PSD95, and GluA1 were found in sAD-hNs, which are also characterized by reduced neurite length, indicating impaired differentiation. Notably, sAD-hNs demonstrated a marked reduction in LIMK1 phosphorylation, which could be the underlying cause for the changes in cytoskeletal dynamics that we found, leading to the morphological and functional modifications observed in sAD-hNs. To further investigate the involvement of the LIMK1 pathway in the morphological and functional changes observed in sAD neurons, we conducted perturbation experiments using the specific LIMK1 inhibitor, BMS-5. Neurons obtained from healthy subjects treated with the inhibitor showed similar morphological changes to those observed in sAD neurons, confirming that LIMK1 activity is crucial for maintaining normal neuronal structure. Furthermore, administration of the inhibitor to sAD neurons did not exacerbate the morphological alterations, suggesting that LIMK1 activity is already compromised in these cells., Conclusion: Our findings demonstrate that although sAD- and HS-hiPSCs are similar in their stemness and genomic stability, sAD-hNs exhibit distinct functional and structural anomalies mirroring AD pathology. These anomalies include synaptic dysfunction, altered cytoskeletal organization, and accumulation of AD-related proteins. Our study underscores the usefulness of hiPSCs in modeling AD and provides insights into the disease's molecular underpinnings, thus highlighting potential therapeutic targets., Competing Interests: Declarations. Ethics approval and consent to participate: Isolation and culture of skin fibroblasts from patients and hiPSC generation were performed in accordance with the international standard of GCP (Legislative Decree D.M. 15 July 1997) with the ethical permit granted by the Fondazione Policlinico Gemelli Ethics Committee (protocol #0005057 dated 16/02/2023). Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Protein post-translational modifications (PTM) play a crucial role in the modulation of synaptic function and their alterations are involved in the onset and progression of neurodegenerative disorders. S-palmitoylation is a PTM catalyzed by zinc finger DHHC domain containing (zDHHC) S-acyltransferases that affects both localization and activity of proteins regulating synaptic plasticity and amyloid-β (Aβ) metabolism. Here, we found significant increases of both zDHHC7 expression and protein S-palmitoylation in hippocampi of both 3×Tg-AD mice and post-mortem Alzheimer's disease (AD) patients. Chronic intranasal administration of the S-palmitoylation inhibitor 2-bromopalmitate counteracted synaptic plasticity and cognitive deficits, reduced the Aβ deposition in the hippocampus and extended the lifespan of both male and female 3×Tg-AD mice. Moreover, hippocampal silencing of zDHHC7 prevented the onset of cognitive deficits in the same experimental model. We also identified a FoxO1-mediated epigenetic mechanism inducing zDHHC7 expression, which was triggered by brain insulin resistance in 3×Tg-AD mice. Finally, in hippocampi of AD patients S-palmitoylation levels of Beta-Secretase 1 were associated with Aβ 1 to 42 load and they inversely correlated with Mini Mental State Examination scores. Our data reveal a key role of both zDHHC7 overexpression and protein hyperpalmitoylation in the onset and progression of AD-related alterations of synaptic plasticity and memory., Competing Interests: Competing interests statement:The authors declare no competing interest.

Dopamine D3 receptors (D3Rs) modulate neuronal activity in several brain regions including the hippocampus. Although previous studies reported that blocking D3Rs exerts pro-cognitive effects, their involvement in hippocampal synaptic function and memory in the healthy and aged brain has not been thoroughly investigated. We demonstrated that in adult wild type (WT) mice, D3R pharmacological blockade or genetic deletion as in D3 knock out (KO) mice, converted the weak form of long-term potentiation (LTP1) into the stronger long-lasting LTP (LTP2) via the cAMP/PKA pathway, and allowed the formation of long-term memory. D3R effects were mainly mediated by post-synaptic mechanisms as their blockade enhanced basal synaptic transmission (BST), AMPAR-mediated currents, mEPSC amplitude, and the expression of the post-synaptic proteins PSD-95, phospho(p)GluA1 and p-CREB. Consistently, electron microscopy revealed a prevalent expression of D3Rs in post-synaptic dendrites. Interestingly, with age, D3Rs decreased in axon terminals while maintaining their levels in post-synaptic dendrites. Indeed, in aged WT mice, blocking D3Rs reversed the impairment of LTP, BST, memory, post-synaptic protein expression, and PSD length. Notably, aged D3-KO mice did not exhibit synaptic and memory deficits. In conclusion, we demonstrated the fundamental role of D3Rs in hippocampal synaptic function and memory, and their potential as a therapeutic target to counteract the age-related hippocampal cognitive decline., (© 2024 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Background: Reduction of adult hippocampal neurogenesis is an early critical event in Alzheimer's disease (AD), contributing to progressive memory loss and cognitive decline. Reduced levels of the nucleoporin 153 (Nup153), a key epigenetic regulator of NSC stemness, characterize the neural stem cells isolated from a mouse model of AD (3×Tg) (AD-NSCs) and determine their altered plasticity and gene expression., Methods: Nup153-regulated mechanisms contributing to NSC function were investigated: (1) in cultured NSCs isolated from AD and wild type (WT) mice by proteomics; (2) in vivo by lentiviral-mediated delivery of Nup153 or GFP in the hippocampus of AD and control mice analyzing neurogenesis and cognitive function; (3) in human iPSC-derived brain organoids obtained from AD patients and control subjects as a model of neurodevelopment., Results: Proteomic approach identified Nup153 interactors in WT- and AD-NSCs potentially implicated in neurogenesis regulation. Gene ontology (GO) analysis showed that Nup153-bound proteins in WT-NSCs were involved in RNA metabolism, nuclear import and epigenetic mechanisms. Nup153-bound proteins in AD-NSCs were involved in pathways of neurodegeneration, mitochondrial dysfunction, proteasomal processing and RNA degradation. Furthermore, recovery of Nup153 levels in AD-NSCs reduced the levels of oxidative stress markers and recovered proteasomal activity. Lentiviral-mediated delivery of Nup153 in the hippocampal niche of AD mice increased the proliferation of early progenitors, marked by BrdU/DCX and BrdU/PSANCAM positivity and, later, the integration of differentiating neurons in the cell granule layer (BrdU/NeuN + cells) compared with GFP-injected AD mice. Consistently, Nup153-injected AD mice showed an improvement of cognitive performance in comparison to AD-GFP mice at 1 month after virus delivery assessed by Morris Water Maze. To validate the role of Nup153 in neurogenesis we took advantage of brain organoids derived from AD-iPSCs characterized by fewer neuroepithelial progenitor loops and reduced differentiation areas. The upregulation of Nup153 in AD organoids recovered the formation of neural-like tubes and differentiation., Conclusions: Our data suggest that the positive effect of Nup153 on neurogenesis is based on a complex regulatory network orchestrated by Nup153 and that this protein is a valuable disease target., (© 2024. The Author(s).)

It has been recently established that GPR158, a class C orphan G protein-coupled receptor, serves as a metabotropic glycine receptor. GPR158 is highly expressed in the nucleus accumbens (NAc), a major input structure of the basal ganglia that integrates information from cortical and subcortical structures to mediate goal-directed behaviors. However, whether glycine modulates neuronal activity in the NAc through GPR158 activation has not been investigated yet. Using whole-cell patch-clamp recordings, we found that glycine-dependent activation of GPR158 increased the firing rate of NAc medium spiny neurons (MSNs) while it failed to significantly affect the excitability of cholinergic interneurons (CIN). In MSNs GPR158 activation reduced the latency to fire, increased the action potential half-width, and reduced action potential afterhyperpolarization, effects that are all consistent with negative modulation of potassium M-currents, that in the central nervous system are mainly carried out by Kv7/KCNQ-channels. Indeed, we found that the GPR158-induced increase in MSN excitability was associated with decreased M-current amplitude, and selective pharmacological inhibition of the M-current mimicked and occluded the effects of GPR158 activation. In addition, when the protein kinase A (PKA) or extracellular signal-regulated kinase (ERK) signaling was pharmacologically blocked, modulation of MSN excitability by GPR158 activation was suppressed. Moreover, GPR158 activation increased the phosphorylation of ERK and Kv7.2 serine residues. Collectively, our findings suggest that GPR158/PKA/ERK signaling controls MSN excitability via Kv7.2 modulation. Glycine-dependent activation of GPR158 may significantly affect MSN firing in vivo, thus potentially mediating specific aspects of goal-induced behaviors., (© 2024. The Author(s).)

Background: Systems capable of automating and enhancing the management of research and clinical data represent a significant contribution of information and communication technologies to health care. A recent advancement is the development of imaging biobanks, which are now enabling the collection and storage of diagnostic images, clinical reports, and demographic data to allow researchers identify associations between lifestyle and genetic factors and imaging-derived phenotypes., Objective: The aim of this study was to design and evaluate the system performance of a network for an operating biobank of diagnostic images, the Bio Check Up Srl (BCU) Imaging Biobank, based on the Extensible Neuroimaging Archive Toolkit open-source platform., Methods: Three usage cases were designed focusing on evaluation of the memory and computing consumption during imaging collections upload and during interactions between two kinds of users (researchers and radiologists) who inspect chest computed tomography scans of a COVID-19 cohort. The experiments considered three network setups: (1) a local area network, (2) virtual private network, and (3) wide area network. The experimental setup recorded the activity of a human user interacting with the biobank system, which was continuously replayed multiple times. Several metrics were extracted from network traffic traces and server logs captured during the activity replay., Results: Regarding the diagnostic data transfer, two types of containers were considered: the Web and the Database containers. The Web appeared to be the more memory-hungry container with a higher computational load (average 2.7 GB of RAM) compared to that of the database. With respect to user access, both users demonstrated the same network performance level, although higher resource consumption was registered for two different actions: DOWNLOAD & LOGOUT (100%) for the researcher and OPEN VIEWER (20%-50%) for the radiologist., Conclusions: This analysis shows that the current setup of BCU Imaging Biobank is well provisioned for satisfying the planned number of concurrent users. More importantly, this study further highlights and quantifies the resource demands of specific user actions, providing a guideline for planning, setting up, and using an image biobanking system., (©Giuseppina Esposito, Ciro Allarà, Marco Randon, Marco Aiello, Marco Salvatore, Giuseppe Aceto, Antonio Pescapè. Originally published in JMIR Formative Research (https://formative.jmir.org), 21.12.2023.)

Background: In amyotrophic lateral sclerosis (ALS), gait abnormalities contribute to poor mobility and represent a relevant risk for falls. To date, gait studies in ALS patients have focused on the motor dimension of the disease, underestimating the cognitive aspects., Methods: Using a wearable gait analysis device, we compared gait patterns in ambulatory ALS patients with mild cognitive impairment (ALS MCI+; n = 18), and without MCI (ALS MCI-; n = 24), and healthy subjects (HS; n = 16) under two conditions: (1) normal gait (single task) and (2) walking while counting backward (dual task). Finally, we examined if the occurrence and number of falls in the 3 months following the baseline test were related to cognition., Results: In the single task condition, ALS patients, regardless of cognition, displayed higher gait variability than HS, especially for stance and swing time (p < 0.001). The dual task condition revealed additional differences in gait variability parameters between ALS MCI+ and ALS MCI- for cadence (p = 0.005), stance time (p = 0.04), swing time (p = 0.04) and stability index (p = 0.02). Moreover, ALS MCI+ showed a higher occurrence (p = 0.001) and number of falls (p < 0.001) at the follow-up. Regression analyses demonstrated that MCI condition predicted the occurrence of future falls (β = 3.649; p = 0.01) and, together with executive dysfunction, was associated with the number of falls (cognitive impairment: β = 0.63; p < 0.001; executive dysfunction: β = 0.39; p = 0.03), regardless of motor impairment at clinical examination., Conclusion: In ALS, MCI is associated with exaggerated gait variability and predicts the occurrence and number of short-term falls., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Several studies including ours reported the detrimental effects of extracellular tau oligomers (ex-oTau) on glutamatergic synaptic transmission and plasticity. Astrocytes greatly internalize ex-oTau whose intracellular accumulation alters neuro/gliotransmitter handling thereby negatively affecting synaptic function. Both amyloid precursor protein (APP) and heparan sulfate proteoglycans (HSPGs) are required for oTau internalization in astrocytes but the molecular mechanisms underlying this phenomenon have not been clearly identified yet. Here we found that a specific antibody anti-glypican 4 (GPC4), a receptor belonging to the HSPG family, significantly reduced oTau uploading from astrocytes and prevented oTau-induced alterations of Ca 2+ -dependent gliotransmitter release. As such, anti-GPC4 spared neurons co-cultured with astrocytes from the astrocyte-mediated synaptotoxic action of ex-oTau, thus preserving synaptic vesicular release, synaptic protein expression and hippocampal LTP at CA3-CA1 synapses. Of note, the expression of GPC4 depended on APP and, in particular, on its C-terminal domain, AICD, that we found to bind Gpc4 promoter. Accordingly, GPC4 expression was significantly reduced in mice in which either APP was knocked-out or it contained the non-phosphorylatable amino acid alanine replacing threonine 688, thus becoming unable to produce AICD. Collectively, our data indicate that GPC4 expression is APP/AICD-dependent, it mediates oTau accumulation in astrocytes and the resulting synaptotoxic effects., Competing Interests: Declaration of Competing Interest None declared., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodeling complexes frequently inactivated in cancers. Cells deficient in either ATPase have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4/2 occurs in a subset of cancers associated with very poor outcomes. Here, we uncover that SMARCA4/2-loss represses expression of the glucose transporter GLUT1, causing reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/2-deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/2-deficient cells and tumors are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activity in patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/2-loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers., (© 2023. The Author(s).)

Aims: Early dysfunction in Alzheimer's disease (AD) is characterised by alterations of synapse structure and function leading to dysmorphic neurites, decreased spine density, impaired synaptic plasticity and cognitive deficits. The class II member HDAC4, which recently emerged as a crucial factor in shaping synaptic plasticity and memory, was found to be altered in AD. We investigated how the modulation of HDAC4 may contribute to counteracting AD pathogenesis., Methods: Using a cytoplasmic HDAC4 mutant (HDAC4 SD ), we studied the recovery of synaptic function in hippocampal tissue and primary neurons from the triple-transgenic mouse model of AD (3×Tg-AD)., Results: Here, we report that in wild-type mice, HDAC4 is localised at synapses and interacts with postsynaptic proteins, whereas in the 3×Tg-AD, it undergoes nuclear import, reducing its interaction with synaptic proteins. Of note, HDAC4 delocalisation was induced by both amyloid-β and tau accumulation. Overexpression of the HDAC4 SD mutant in CA1 pyramidal neurons of organotypic hippocampal slices obtained from 3×Tg-AD mice increased dendritic length and promoted the enrichment of N-cadherin, GluA1, PSD95 and CaMKII proteins at the synaptic level compared with AD neurons transfected with the empty vector. Moreover, HDAC4 overexpression recovered the level of SUMO2/3ylation of PSD95 in AD hippocampal tissue, and in AD organotypic hippocampal slices, the HDAC4 SD rescued spine density and synaptic transmission., Conclusions: These results highlight a new role of cytoplasmic HDAC4 in providing a structural and enzymatic regulation of postsynaptic proteins. Our findings suggest that controlling HDAC4 localisation may represent a promising strategy to rescue synaptic function in AD, potentially leading to memory improvement., (© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)

Down syndrome (DS) is the most frequent genetic cause of intellectual disability and is strongly associated with Alzheimer's disease (AD). Brain insulin resistance greatly contributes to AD development in the general population and previous studies from our group showed an early accumulation of insulin resistance markers in DS brain, already in childhood, and even before AD onset. Here we tested the effects promoted in Ts2Cje mice by the intranasal administration of the KYCCSRK peptide known to foster insulin signaling activation by directly interacting and activating the insulin receptor (IR) and the AKT protein. Therefore, the KYCCSRK peptide might represent a promising molecule to overcome insulin resistance. Our results show that KYCCSRK rescued insulin signaling activation, increased mitochondrial complexes levels (OXPHOS) and reduced oxidative stress levels in the brain of Ts2Cje mice. Moreover, we uncovered novel characteristics of the KYCCSRK peptide, including its efficacy in reducing DYRK1A (triplicated in DS) and BACE1 protein levels, which resulted in reduced AD-like neuropathology in Ts2Cje mice. Finally, the peptide elicited neuroprotective effects by ameliorating synaptic plasticity mechanisms that are altered in DS due to the imbalance between inhibitory vs. excitatory currents. Overall, our results represent a step forward in searching for new molecules useful to reduce intellectual disability and counteract AD development in DS.

Multiple sclerosis (MS) is a chronic, debilitating disease characterised by demyelination of the nerves of the central nervous system that results in patients progressively losing the ability to perform daily tasks. As there is no cure for this disease, rehabilitation therapy is an important aspect of care; assisting patients to regain or retain function and improve their physical, mental and social wellbeing. At present there is no current consistent model of care for MS, likely due to the variable symptom presentation. Various forms of rehabilitation therapy are available, and these include physical rehabilitation methods, such as balance and gait therapy, speech and respiration rehabilitation, and occupational therapy. Contrary to previous understanding, exercise-based therapies have shown various benefits for patients with MS, and in addition to improving MS-related physical symptoms, have been shown to reduce the risk of developing cardiovascular disease and can improve cognitive function. Cognition rehabilitation therapy specifically focuses on behavioural tasks and is divided into two main forms: compensatory rehabilitation, which offers cognitive functioning benefits, and restorative rehabilitation, which offers memory benefits. Excitation therapies include cranial stimulation and other stimulation rehabilitation methods such as focal muscle vibration therapy and these non-invasive techniques may improve patient's physical ability. Additionally, more novel rehabilitation methods include robot-assisted gait therapy and telerehabilitation, both of which are expected to play progressively more prominent roles in the future of rehabilitation therapy. The structure of the care team has been found to impact patient outcomes, and both in- and out-patient care settings have been found to be beneficial, dependant on the patient's circumstances, with certain patients better suited to a particular setting. While a single point of care is recommended for patients, a multidisciplinary care team and regular reassessment is recommended to manage changing symptoms and ensure continuity of care. The importance of the critical components of rehabilitation have been identified, and these are of vital importance in achieving beneficial outcomes. These components include the patients' participation in the treatment, goal setting with a multidisciplinary care team, a guiding-light purpose for the patient, which focusses on recognizing their personal potential and obtaining improvements through a tailored plan. The final critical component of rehabilitation is the results measurement, which highlights the need for a quantifiable reduction in impairment and improvement in activity and participation. Overall, a lack of standardisation in outcome measurements makes comparison challenging. This is particularly important when comparing standard methods of care with more novel rehabilitation techniques. However, within the broad area of rehabilitation therapies, it is clear that patients with MS can benefit from rehabilitation practices; physically, mentally and socially., Competing Interests: Declaration of Competing Interest None, (Copyright © 2022. Published by Elsevier B.V.)

The COVID-19 pandemic has reshaped Internet traffic due to the huge modifications imposed to lifestyle of people resorting more and more to collaboration and communication apps to accomplish daily tasks. Accordingly, these dramatic changes call for novel traffic management solutions to adequately countermeasure such unexpected and massive changes in traffic characteristics. In this paper, we focus on communication and collaboration apps whose traffic experienced a sudden growth during the last two years. Specifically, we consider nine apps whose traffic we collect, reliably label, and publicly release as a new dataset (MIRAGE-COVID-CCMA-2022) to the scientific community. First, we investigate the capability of state-of-art single-modal and multimodal Deep Learning-based classifiers in telling the specific app, the activity performed by the user, or both. While we highlight that state-of-art solutions reports a more-than-satisfactory performance in addressing app classification (96%-98% F-measure), evident shortcomings stem out when tackling activity classification (56%-65% F-measure) when using approaches that leverage the transport-layer payload and/or per-packet information attainable from the initial part of the biflows. In line with these limitations, we design a novel set of inputs (namely Context Inputs) providing clues about the nature of a biflow by observing the biflows coexisting simultaneously. Based on these considerations, we propose Mimetic-All a novel early traffic classification multimodal solution that leverages Context Inputs as an additional modality, achieving ≥ 82 % F-measure in activity classification. Also, capitalizing the multimodal nature of Mimetic-All, we evaluate different combinations of the inputs. Interestingly, experimental results witness that Mimetic-ConSeq-a variant that uses the Context Inputs but does not rely on payload information (thus gaining greater robustness to more opaque encryption sub-layers possibly going to be adopted in the future)-experiences only ≈ 1 % F-measure drop in performance w.r.t. Mimetic-All and results in a shorter training time., (© 2022 Elsevier B.V. All rights reserved.)

Histamine, a monoamine implicated in stress-related arousal states, is synthesized in neurons exclusively located in the hypothalamic tuberomammillary nucleus (TMN) from where they diffusely innervate striatal and mesolimbic networks including the nucleus accumbens (NAc), a vital node in the limbic loop. Since histamine-containing TMN neuron output increases during stress, we hypothesized that exposure of mice to acute restrain stress (ARS) recruits endogenous histamine type 2 receptor (H2R) signaling in the NAc, whose activation increases medium spiny neurons (MSNs) intrinsic excitability via downregulation of A-type K + currents. We employed an ARS paradigm in which mice were restrained for 120 min, followed by a 20-min recovery period, after which brain slices were prepared for ex vivo electrophysiology. Using whole-cell patch-clamp recordings, we found that pharmacological activation of H2R failed to affect MSN excitability and A-type K + currents in mice that underwent ARS. Interestingly, in mice treated with H2R-antagonist prior to ARS paradigm, H2R activation increased evoked firing and decreased A-type K + currents similarly to what observed in control mice. Furthermore, H2R-antagonist treatment ameliorated anxiety-like behavior in ARS mice. Together, our findings indicate that ARS paradigm recruits endogenous H2R signaling in MSNs and suggest the involvement of H2R signaling in stress-related motivational states., Competing Interests: Declaration of competing interest All authors declare that the research was conducted in the absence of any commercial and financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Histaminergic neurons are exclusively located in the hypothalamic tuberomammillary nucleus, from where they project to many brain areas including the nucleus accumbens (NAc), a brain area that integrates diverse monoaminergic inputs to coordinate motivated behaviours. While the NAc expresses various histamine receptor subtypes, the mechanisms by which histamine modulates NAc activity are still poorly understood. Using whole-cell patch-clamp recordings, we found that pharmacological activation of histamine 2 (H2) receptors elevates the excitability of NAc medium spiny neurons (MSNs), while activation of H1 receptors failed to significantly affect MSN excitability. The evoked firing of MSNs increased after seconds of local H2 agonist administration and remained elevated for minutes. H2 receptor (H2R) activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential afterhyperpolarization and increased the action potential half-width. The increased excitability was protein kinase A-dependent and associated with decreased A-type K + currents. In addition, selective pharmacological inhibition of the Kv4.2 channel, the main molecular determinant of A-type K + currents in MSNs, mimicked and occluded the increased excitability induced by H2R activation. Our results indicate that histaminergic transmission in the NAc increases MSN intrinsic excitability through H2R-dependent modulation of Kv4.2 channels. Activation of H2R will significantly alter spike firing in MSNs in vivo, and this effect could be an important mechanism by which these receptors mediate certain aspects of goal-induced behaviours. KEY POINTS: Histamine is synthesized and released by hypothalamic neurons of the tuberomammillary nucleus and serves as a general modulator for whole-brain activity including the nucleus accumbens. Histamine receptors type 2 (HR2), which are expressed in the nucleus accumbens, couple to Gαs/off proteins which elevate cyclic adenosine monophosphate levels and activate protein kinase A. Whole-cell patch-clamp recordings revealed that H2R activation increased the evoked firing in medium spiny neurons of the nucleus accumbens via protein kinase A-dependent mechanisms. HR2 activation accelerated subthreshold depolarization in response to current injection, reduced the latency to fire, diminished action potential medium after-hyperpolarization and increased the action potential half-width. HR2 activation also reduced A-type potassium current. Selective pharmacological inhibition of the Kv4.2 channel mimicked and occluded the increased excitability induced by H2R activation., (© 2022 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Glycogen synthase kinase 3β (GSK3) is a multifaceted serine/threonine (S/T) kinase expressed in all eukaryotic cells. GSK3β is highly enriched in neurons in the central nervous system where it acts as a central hub for intracellular signaling downstream of receptors critical for neuronal function. Unlike other kinases, GSK3β is constitutively active, and its modulation mainly involves inhibition via upstream regulatory pathways rather than increased activation. Through an intricate converging signaling system, a fine-tuned balance of active and inactive GSK3β acts as a central point for the phosphorylation of numerous primed and unprimed substrates. Although the full range of molecular targets is still unknown, recent results show that voltage-gated ion channels are among the downstream targets of GSK3β. Here, we discuss the direct and indirect mechanisms by which GSK3β phosphorylates voltage-gated Na + channels (Na v 1.2 and Na v 1.6) and voltage-gated K + channels (K v 4 and K v 7) and their physiological effects on intrinsic excitability, neuronal plasticity, and behavior. We also present evidence for how unbalanced GSK3β activity can lead to maladaptive plasticity that ultimately renders neuronal circuitry more vulnerable, increasing the risk for developing neuropsychiatric disorders. In conclusion, GSK3β-dependent modulation of voltage-gated ion channels may serve as an important pharmacological target for neurotherapeutic development.

This paper is designed to evaluate the results (at long-term follow-up of) children affected by dilating VUR. Our attention was focused on how VUR grade, laterality, bladder dysfunction (BD), the double renal system, and the type of bulking substance may affect VUR resolution in the long-term period. The charts of 93 children with dilating VUR who underwent endoscopic treatment (ET) and with a minimum post-operative follow-up of 7 years were reviewed (mean follow-up time was 9.6 + 1.4). The majority of patients had severe and bilateral VUR. Polydimetilsiloxane or hyaluronic acid/dextranomer (PDS or Ha/Dx) were used as bulking agents. VUR persistence following endoscopic injection was independent with respect to grade, laterality, duplex renal system, and BD. However, the rate of VUR persistence was significantly higher in children with BD. Children treated with Ha/Dx had a higher rate of VUR persistence. This research demonstrated that ET of VUR is also effective at very long term follow up (and without the development of significant complications). We also showed that patients treated with absorbable bulking agents such as Ha/Dx may experience a higher recurrence rate at the long-term follow-up). We also confirm that the only preoperative condition affecting VUR recurrence was bladder dysfunction.

Early diagnosis of Alzheimer's disease (AD) supposedly increases the effectiveness of therapeutic interventions. However, presently available diagnostic procedures are either invasive or require complex and expensive technologies, which cannot be applied at a larger scale to screen populations at risk of AD. We were looking for a biomarker allowing to unveil a dysfunction of molecular mechanisms, which underly synaptic plasticity and memory, before the AD phenotype is manifested and investigated the effects of transcranial direct current stimulation (tDCS) in 3×Tg-AD mice, an experimental model of AD which does not exhibit any long-term potentiation (LTP) and memory deficits at the age of 3 months (3×Tg-AD-3M). Our results demonstrated that tDCS differentially affected 3×Tg-AD-3M and age-matched wild-type (WT) mice. While tDCS increased LTP at CA3-CA1 synapses and memory in WT mice, it failed to elicit these effects in 3×Tg-AD-3M mice. Remarkably, 3×Tg-AD-3M mice did not show the tDCS-dependent increases in pCREB Ser133 and pCaMKII Thr286 , which were found in WT mice. Of relevance, tDCS induced a significant increase of plasma BDNF levels in WT mice, which was not found in 3×Tg-AD-3M mice. Collectively, our results showed that plasticity mechanisms are resistant to tDCS effects in the pre-AD stage. In particular, the lack of BDNF responsiveness to tDCS in 3×Tg-AD-3M mice suggests that combining tDCS with dosages of plasma BDNF levels may provide an easy-to-detect and low-cost biomarker of covert impairment of synaptic plasticity mechanisms underlying memory, which could be clinically applicable. Testing proposed here might be useful to identify AD in its preclinical stage, allowing timely and, hopefully, more effective disease-modifying interventions., (Copyright © 2020 Cocco, Rinaudo, Fusco, Longo, Gironi, Renna, Aceto, Mastrodonato, Li Puma, Podda and Grassi.)

The voltage-gated sodium (Nav) channel complex is comprised of pore-forming α subunits (Nav1.1-1.9) and accessory regulatory proteins such as the intracellular fibroblast growth factor 14 (FGF14). The cytosolic Nav1.6 C-terminal tail binds directly to FGF14 and this interaction modifies Nav1.6-mediated currents with effects on intrinsic excitability in the brain. Previous studies have identified the FGF14 V160 residue within the FGF14 core domain as a hotspot for the FGF14:Nav1.6 complex formation. Here, we used three short amino acid peptides around FGF14 V160 to probe for the FGF14 interaction with the Nav1.6 C-terminal tail and to evaluate the activity of the peptide on Nav1.6-mediated currents. In silico docking predicts FLPK to bind to FGF14 V160 with the expectation of interfering with the FGF14:Nav1.6 complex formation, a phenotype that was confirmed by the split-luciferase assay (LCA) and surface plasmon resonance (SPR), respectively. Whole-cell patch-clamp electrophysiology studies demonstrate that FLPK is able to prevent previously reported FGF14-dependent phenotypes of Nav1.6 currents, but that its activity requires the FGF14 N-terminal tail, a domain that has been shown to contribute to Nav1.6 inactivation independently from the FGF14 core domain. In medium spiny neurons in the nucleus accumbens, where both FGF14 and Nav1.6 are abundantly expressed, FLPK significantly increased firing frequency by a mechanism consistent with the ability of the tetrapeptide to interfere with Nav1.6 inactivation and potentiate persistent Na + currents. Taken together, these results indicate that FLPK might serve as a probe for characterizing molecular determinants of neuronal excitability and a peptide scaffold to develop allosteric modulators of Nav channels., (© 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3β in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3β in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3β. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K + currents, as a potential downstream target of GSK3β. We found increased levels of active GSK3β and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3β knockdown. Furthermore, knockdown of GSK3β in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3β-dependent tLTP changes in CUMS mice. Our results identify GSK3β regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3β-Kv4.2 axis may be an attractive therapeutic target for MDD., Competing Interests: The authors declare no competing interest.

Type III and IV Bartter syndromes (BS) are rare kidney tubulopathies caused by loss-of-function mutations in the CLCNKB and BSND genes coding respectively for the ClC-Kb chloride channels and accessory subunit barttin. ClC-K channels are expressed in the Henle's loop, distal convoluted tubule, and cortical collecting ducts of the kidney and contribute to chloride absorption and urine concentration. In our Italian cohort, we identified two new mutations in CLCNKB , G167V and G289R, in children affected by BS and previously reported genetic variants, A242E, a chimeric gene and the deletion of the whole CLCNKB . All the patients had hypokalemia and metabolic alkalosis, increased serum renin and aldosterone levels and were treated with a symptomatic therapy. In order to define the molecular mechanisms responsible for BS, we co-expressed ClC-Kb wild type and channels with point mutations with barttin in HEK 293 cells and characterized chloride currents through the patch-clamp technique. In addition, we attempted to revert the functional defect caused by BS mutations through barttin overexpression. G167V and A242E channels showed a drastic current reduction compared to wild type, likely suggesting compromised expression of mutant channels at the plasma membrane. Conversely, G289R channel was similar to wild type raising the doubt that an additional mutation in another gene or other mechanisms could account for the clinical phenotype. Interestingly, increasing ClC-K/barttin ratio augmented G167V and A242E mutants' chloride current amplitudes towards wild type levels. These results confirm a genotype-phenotype correlation in BS and represent a preliminary proof of concept that molecules functioning as molecular chaperones can restore channel function in expression-defective ClC-Kb mutants., (Copyright © 2020 Sahbani, Strumbo, Tedeschi, Conte, Camerino, Benetti, Montini, Aceto, Procino, Imbrici and Liantonio.)

Spike timing-dependent plasticity (STDP) is a form of activity-dependent remodeling of synaptic strength that underlies memory formation. Despite its key role in dictating learning rules in the brain circuits, the molecular mechanisms mediating STDP are still poorly understood. Here, we show that spike timing-dependent long-term depression (tLTD) and A-type K+ currents are modulated by pharmacological agents affecting the levels of active glycogen-synthase kinase 3 (GSK3) and by GSK3β knockdown in layer 2/3 of the mouse somatosensory cortex. Moreover, the blockade of A-type K+ currents mimics the effects of GSK3 up-regulation on tLTD and occludes further changes in synaptic strength. Pharmacological, immunohistochemical and biochemical experiments revealed that GSK3β influence over tLTD induction is mediated by direct phosphorylation at Ser-616 of the Kv4.2 subunit, a molecular determinant of A-type K+ currents. Collectively, these results identify the functional interaction between GSK3β and Kv4.2 channel as a novel mechanism for tLTD modulation providing exciting insight into the understanding of GSK3β role in synaptic plasticity., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose:  The aim of the study was to investigate urinary levels of monocyte chemotactic protein-1 (MCP-1), epidermal growth factor (EGF), β-2-microglobulin (β2M), and FAS-ligand (FAS-L) in children with congenital anomalies of kidney and urinary tract (CAKUT) disease at risk of developing glomerular hyperfiltration syndrome. For this reason, we selected patients with multicystic kidney, renal agenesia and renal hypodysplasia, or underwent single nephrectomy., Materials and Methods:  This prospective, multicentric study was conducted in collaboration between the Pediatric Surgery Unit in Foggia and the Pediatric Nephrology Unit in Bari, Italy. We enrolled 80 children with CAKUT (40 hypodysplasia, 22 agenetic; 10 multicystic; 8 nephrectomy) who underwent extensive urological and nephrological workup. Exclusion criteria were recent urinary tract infections or pyelonephritis, age > 14 years, presence of systemic disease, or hypertension. A single urine sample was collected in a noninvasive way and processed for measuring by enzyme-linked immunosorbent assay urine levels of MCP-1, EGF, β2M, and FAS-L. As control, urine samples were taken from 30 healthy children.Furthermore, we evaluated the urinary ratios uEGF/uMCP-1 (indicator of regenerative vs inflammatory response) and uEGF/uβ2M (indicator of regenerative response vs. tubular damage)., Results:  These results suggest that urinary levels of MCP-1 are overexpressed in CAKUT patients. Furthermore, our findings clearly demonstrated that both uEGF/uMCP-1 and uEGF/uβ2M ratios were significantly downregulated in all patient groups when compared with the control group., Conclusion:  These findings further support that CAKUT patients may, eventually, experience progressive renal damage and poor regenerative response. The increased urinary levels of MCP-1 in all groups of CAKUT patients suggested that the main factor responsible for the above effects is chronic renal inflammation mediated by local monocytes., Competing Interests: None., (Georg Thieme Verlag KG Stuttgart · New York.)

The dopamine D 3 receptor (D 3 R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D 3 R increases GABA A α6 subunit in the ventral striatum. Here we tested the hypothesis that D 3 R-dependent changes in GABA A α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D 3 R knockout (D 3 R -/- ) mice and wild type littermates (D 3 R +/+ ). Ro 15-4513, a high affinity α6-GABA A ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D 3 R +/+ , whereas it was robust in D 3 R -/- ; other relevant GABA A subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D 3 R +/+ , but increased it in D 3 R -/- ; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABA A antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D 3 R -/- compared to D 3 R +/+ ; Ro 15-4513 reduced the peak amplitude in the NAc of D 3 R -/- , but not in D 3 R +/+ . We conclude that D 3 R-dependent enhanced expression of α6 GABA A subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Context: Childhood type 1 diabetes mellitus (T1DM) is associated with decreased bone mass. Sclerostin and dickkopf-1 (DKK-1) are Wnt inhibitors that regulate bone formation., Objective: To evaluate sclerostin and DKK-1 levels in T1DM children and to analyze the influence of glycemic control on bone health., Design and Setting: Cross-sectional study conducted at a clinical research center., Participants: One hundred and six T1DM subjects (12.2 ± 4 years), 66 on multiple daily injections (MDIs) and 40 on continuous subcutaneous infusion of insulin (CSII), and 80 controls., Results: The average bone transmission time (BTT) and amplitude-dependent speed of sound (AD-SoS) z scores were lower in patients with diabetes than in controls. Significantly increased DKK-1 (3593 ± 1172 vs 2652 ± 689 pg/mL; P < 0.006) and sclerostin (29.45 ± 12.32 vs 22.53 ± 8.29; P < 0.001) levels were found in patients with diabetes with respect to controls, particularly in patients on MDI compared with ones on CSII. Glycemic control was improved in CSII patients compared with MDI ones (P < 0.001) and was also associated with significantly higher BMI-SDS (P < 0.002) and BTT z scores (P < 0.02). With adjustment for age, multiple linear regression analysis of DKK-1 and sclerostin as dependent variables showed that levels of glycated hemoglobin, glucose, 25(OH) vitamin D, osteocalcin, and parathyroid hormone; years of diabetes; and BMI-SDS and AD-SoS z score were the most important predictors (P < 0.0001)., Conclusions: Our study highlighted (1) the high serum levels of DKK-1 and sclerostin in T1DM children and their relationship with altered glycemic control and (2) the effect of CSII on improvement of glycemic control and bone health in T1DM children., (Copyright © 2017 Endocrine Society)

N-methyl-D-aspartate receptor (NMDAR) hypofunction has been considered a key alteration in schizophrenia pathophysiology. Thus, several strategies aimed at enhancing glutamatergic transmission, included the introduction in therapy of D-amino acids, such as D-serine and D-cycloserine augmentation, have been proposed to counteract difficult-to-treat symptoms or treatment-resistant forms of schizophrenia. Another D-amino acid, D-aspartate, has recently gained increasing interest for its role in NMDAR activation and has been found reduced in post-mortem cortex of schizophrenia patients. NMDAR is the core of the postsynaptic density (PSD), a postsynaptic site involved in glutamate signaling and responsive to antipsychotic treatment. In this study, we investigated striatal and cortical gene expression of key PSD transcripts (i.e. Homer1a, Homer1b/c, and PSD-95) in mice with persistently elevated brain D-aspartate-levels, i.e. the D-aspartate-oxidase knockout mice (Ddo(-/-)). These animal models were analyzed both in naive condition and after phencyclidine (PCP) treatment. Naive Ddo(-/-) mice showed decreased Homer1a expression in the prefrontal cortex, increased Homer1b/c expression in the striatum, and decreased PSD-95 expression in the striatum and in the cortex. Acute PCP treatment restored, and even potentiated, Homer1a expression in the prefrontal cortex of mutant mice, while it had limited effects on the other genes. These results suggest that persistently elevated D-aspartate, by enhancing NMDA transmission, may cause complex adaptive mechanisms affecting Homer1a, which in turn may explain the recently demonstrated protective effects of this D-amino acid against PCP-induced behavioral alterations, such as ataxic behavior., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: The optimal therapeutic regimen for managing childhood idiopathic nephrotic syndrome (INS) is still under debate. We have evaluated the choice of steroid regimen and of symptomatic treatment adopted by pediatricians and pediatric nephrologists in a large number of centers as the first step towards establishing a shared protocol, Methods: This was a multicenter, retrospective study. A total of 231 children (132 admitted to pediatric units) aged 6 months to <15 years who presented with onset of nephrotic syndrome to 54 pediatric units and six pediatric nephrology units in Italy between 2007 and 2009 were eligible for entry into the study., Results: Median steroid dosing was 55 (range 27-75) mg/m(2)/day. The overall median cumulative dose regimen for the first episode was 3,440 (1,904-6,035) mg/m(2), and the median duration of the therapeutic regimen was 21 (9-48) weeks. The total duration and cumulative steroid dose were significantly higher in patients treated by pediatricians than in those treated by pediatric nephrologists (p = 0.001 and p = 0.008). Among the patient cohort, 55, 64 and 22 % received albumin infusions, diuretics and acetyl salicylic acid treatment, respectively, but the laboratory and clinical data did not differ between children treated or not treated with symptomatic drugs. Albumin and diuretic use did not vary between patients in pediatric units and those in pediatric nephrology units., Conclusions: This study shows major differences in steroid and symptomatic treatment of nephrotic syndrome by pediatricians and pediatric nephrologists. As these differences can influence the efficacy of the treatments and the appearance of side-effects, shared guidelines and their implementation through widespread educational activities are necessary.

Background: The management of steroid-sensitive nephrotic syndrome (SSNS) requires treatment with high-dose glucocorticoids (GCs), but GC usage causes the most frequent form of drug-induced osteoporosis. The aim of our study was to evaluate the impact of GCs on bone mineralization in patients with SSNS using two diagnostic tools, dual-energy X-ray densitometry (DXA) and quantitative ultrasound (QUS), and to compare the diagnostic efficacy of these two imaging tools., Methods: A total of 30 children with SSNS (age 5.20 ± 2.20 years) were evaluated at the start (T0) and after 1 (T1), 2.44 ± 0.75 (T2, 18 patients) and 5.96 ± 2.33 years (T4, 12 patients) of GC treatment. Patients who stopped at T2 were also evaluated at the 1-year timepoint after ceasing GC treatment (T3)., Results: Of the patients assessed at T2, 11 had bone mineralization at the lower limit of normal versus those at T0 and T1, with bone mineralization rescue at the 1-year timepoint after GC discontinuation. At T4, 6/12 patients had densitometric parameters at the lower limit of normal values, and 3/12 patients showed reduced bone mineralization. The parameters derived from measurements of DXA and QUS were significantly related to each timepoint., Conclusions: Patients with SSNS receiving GC therapy undergo bone status alteration related to the dosage and duration of the therapy. In terms of diagnostic efficacy, DXA and QUS were comparable, indicating that QUS is a reliable tool to evaluate bone health in children with SSNS.

Premenopausal breast cancer (BC) is one of the most common cancers of women in rural Africa and part of the disease load may be related to hereditary predisposition, including mutations in the BRCA1 gene. However, the BRCA1 mutations associated with BC in Africa are scarcely characterized. We report here 33 BRCA1 point mutations, among which 2 novel missense variants, found in 59 Central Sudanese premenopausal BC patients. The high fractions of mutations with intercontinental and uniquely African distribution (17/33, 51.5 % and 14/33, 42.4 %, respectively) are in agreement with the high genetic diversity expected in an African population. Overall 24/33 variants (72.7 %) resulted neutral; 8/33 of unknown significance (24.3 %, including the 2 novel missense mutations); 1 (3.0 %) overtly deleterious. Notably, in silico studies predict that the novel C-terminal missense variant c.5090G>A (p.Cys1697Tyr) affects phosphopeptide recognition by the BRCA1 BRCT1 domain and may have a pathogenic impact. Genetic variation and frequency of unique or rare mutations of uncertain clinical relevance pose significant challenges to BRCA1 testing in Sudan, as it might happen in other low-resource rural African contexts.

We report a case of xanthogranulomatous pyelonephritis (XGP) complicated by shaped urolithiasis, severe hydroureteronephrosis and kidney exclusion treated by laparoscopic-assisted nephroureterectomy. A 9 year-old boy was referred to us for recurrent episodes of urinary tract infection, abdominal pain and severe hydronephrosis. Abdominal CT and a Tc-99m MAG3 scan showed a non-functioning obstructed kidney with shaped urolithiasis of the distal ureter. XGP was suspected, and nephroureterectomy was performed by laparoscopic distal ureterectomy and open extraperitoneal nephrectomy. This technique avoided the need for a more extended nephrectomy incision or even a second iliac incision. It also ensured complete excision of the distal ureter with minimal risk of developing the ureteral stump syndrome, which sometimes follows nephroureterectomy. We believe that laparoscopic-assisted nephroureterectomy may be a suitable technique in those cases of difficult nephrectomy where a ureteral stump syndrome is likely to develop.

Size-dependent characteristics of novel engineered nanomaterials might result in unforeseen biological responses and toxicity. To address this issue, we used cDNA microarray analysis (13443 genes) coupled with bioinformatics and functional gene annotation studies to investigate the transcriptional profiles of Balb/3T3 cells exposed to a low dose (1 &#956;M) of cobalt nanoparticles (CoNP), microparticles (CoMP) and ions (Co2+). CoNP, CoMP and Co2+ affected 124, 91 and 80 genes, respectively. Hierarchical clustering revealed two main gene clusters, one up-regulated, mainly after Co2+, the other down-regulated, mainly after CoNP and CoMP. The significant Gene Ontology (GO) terms included oxygen binding and transport and hemoglobin binding for Co2+, while the GOs of CoMP and CoNP were related to nucleus and intracellular components. Pathway analysis highlighted: i) mitochondrial dysfunction for Co2+, ii) signaling, activation of innate immunity, and apoptosis for CoNP, and iii) cell metabolism, G1/S cell cycle checkpoint regulation and signaling for CoMP. Unlike ions, particles affected toxicologically-relevant pathways implicated in carcinogenesis and inflammation.

We report on a case of autoimmune thyroiditis in a 6-month-old patient with cortico-resistant nephrotic syndrome. Normal serum levels of thyroid hormons and thyroid-stimulating hormone were detected with high titers of circulant antithyroid antibodies and a dysomogeneous ultrasound appearance of the gland, typical of autoimmune thyroiditis. The research of maternal thyroid antibodies was negative. This is the first case of autoimmune thyroiditis found in such a young patient with pre-existing nephrotic syndrome ever described in literature. This association is random because nephrotic syndrome does not have an autoimmune pathogenesis and the genes involved in autoimmune thyroiditis are not related to those of nephrotic syndrome.

Objective: VUR in patients with a duplex system (DS) is often treated by open surgery. The aim of this study was to evaluate the efficacy of subureteric polydimethylsiloxane (Macroplastique(®)) injection (SMING) in the management of VUR in duplex and single (SS) renal systems., Patients and Methods: Fifteen children (24 refluxing renal units) with VUR in DS underwent SMING. VUR was more frequent in the lower moiety. VUR was graded moderate/severe in 88% of renal units. There was a history of urinary tract infections in 40% of cases. The outcome for DS patients was compared with 44 children (60 refluxing renal units) with moderate/severe VUR in SS., Results: The VUR resolution/improvement rate was 88% in DS and 95% in SS patients. Ureteric reimplantation was required because of recurrent VUR in 13% and 7% of DS and SS groups, respectively. Transient ureteral obstruction was observed in 1/15 and 5/44 patients. Two required double-J ureteric stenting for 3 months., Conclusion: SMING seems an effective treatment for VUR in both DS and SS patients, even in severe cases. The complication rate does not significantly differ between the two groups., (Copyright © 2010 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.)

Background/purpose: We demonstrated down-regulation of epidermal growth factor (EGF) and up-regulation of monocyte chemotactic protein-1 (MCP-1) in the renal parenchyma in children who underwent pyeloplasty for ureteropelvic junction obstruction (UPJO). These findings were paralleled by urinary levels of EGF and MCP-1 before and after surgery. The aim of this study is to evaluate the urinary excretion of these cytokines and β2-microglobulin (β2M) in children with urine flow impairment at the ureteropelvic junction or who underwent pyeloplasty., Methods: Seventy-six patients with UPJO and 30 normal children (CTRL) were enrolled in the study. The UPJO patients were divided into obstructive (12), functional (36), and operated (28). Epidermal growth factor, MCP-1, and β2M urinary levels were measured by enzyme-linked immunosorbent assay and normalized to urine creatinine., Results: Urinary β2M and MCP-1 increased significantly in the UPJO groups compared with the CTRL and significantly improved in the operated group. The obstructive group displayed reduced EGF excretion compared with the CTRL group. The urinary (u)EGF/uMCP-1, and uEGF/uβ2M ratios significantly decreased in both untreated groups. In the operated group, these ratios improved significantly., Conclusions: The present study substantiates the role of urinary EGF, MCP-1, and β2M as markers of tubulointerstitial damage in human obstructive nephropathy. Furthermore, it suggests that surgical intervention is effective in the management of children with UPJO., (Copyright © 2011 Elsevier Inc. All rights reserved.)