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Preclinical studies indicate that diverse muscarinic receptor antagonists, acting via the M1 sub-type, promote neuritogenesis from sensory neurons in vitro and prevent and/or reverse both structural and functional indices of neuropathy in rodent models of diabetes. We sought to translate this as a potential therapeutic approach against structural and functional indices of diabetic neuropathy using oxybutynin, a muscarinic antagonist approved for clinical use against overactive bladder. Studies were performed using sensory neurons maintained in vitro, rodent models of type 1 or type 2 diabetes and human subjects with type 2 diabetes and confirmed neuropathy. Oxybutynin promoted significant neurite outgrowth in sensory neuron cultures derived from adult normal rats and STZ-diabetic mice, with maximal efficacy in the 1-100 nmol/l range. This was accompanied by a significantly enhanced mitochondrial energetic profile as reflected by increased basal and maximal respiration and spare respiratory capacity. Systemic (3-10 mg/kg/day s.c.) and topical (3% gel daily) oxybutynin reversed paw heat hypoalgesia in the STZ and db/db mouse models of diabetes and reversed paw tactile allodynia in STZ-diabetic rats. Loss of nerve profiles in the skin and cornea of db/db mice was also prevented by daily topical delivery of 3% oxybutynin for 8 weeks. A randomized, double-blind, placebo-controlled interventional trial was performed in subjects with type 2 diabetes and established peripheral neuropathy. Subjects received daily topical treatment with 3% oxybutynin gel or placebo for 6 months. The a priori designated primary endpoint, significant change in intra-epidermal nerve fibre density (IENFD) in skin biopsies taken before and after 20 weeks of treatments, was met by oxybutynin but not placebo. Secondary endpoints showing significant improvement with oxybutynin treatment included scores on clinical neuropathy, pain and quality of life scales. This proof-of-concept study indicates that muscarinic antagonists suitable for long-term use may offer a novel therapeutic opportunity for treatment of diabetic neuropathy. Trial registry number: NCT03050827.

Abstract Background Restricted and repetitive patterns of behaviour (RRBs) serve an adaptive role in development. Elevated levels of RRBs beyond the early years, however, are associated with poorer outcome in language, cognition, and wellbeing, and are seen across a range of neurodevelopmental conditions. This study aimed to characterize the association of distinct RRB subtypes at two and six years of age, with internalising and externalising difficulties in a community sample of children. Methods 485 parents reported on their child's insistence on sameness (IS) and repetitive sensory and motor (RSM) RRBs at two and six years of age using the Repetitive Behaviour Questionnaire (RBQ‐2). Emotional and behavioural difficulties were measured using the Strengths and Difficulties Questionnaire (SDQ) at age six. Results Consistent with previous research, RRBs later in development better predicted emotional and behavioural difficulties at age six than RRBs earlier in development. Moreover, IS RRBs were selectively associated with internalising behaviours and RSM RRBs with externalising behaviours. Importantly, these selective associations depended on when RRBs were measured. Only IS RRBs at age six were significantly associated with internalising behaviour. By contrast, while more RSM RRBs at age six were associated with higher rates of externalising behaviours, higher rates of RSM RRBs at age two were associated with fewer externalising behaviours, adding further support to the previously reported adaptive role of RRBs in early behaviour regulation. Conclusion Although there is a need for further research to provide a detailed profile of the adaptive periods for IS and RSM RRBs, the present findings support the potential utility of elevated RRBs as a signal for emotional and behavioural difficulties at age six.

AimsMitochondrial dysfunction contributes to many forms of peripheral and central nervous system degeneration. Therapies that protect mitochondrial number and function have the potential to impact the progression of conditions such as diabetic neuropathy. We therefore assessed indices of mitochondrial function in dorsal root ganglia (DRG) and brain cortex of the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes and tested the therapeutic impact of a neurogenic compound, NSI-189, on both mitochondrial function and indices of peripheral and central neurological dysfunction.Materials and methodsZDF rats were maintained for 16 weeks of untreated diabetes before the start of oral treatment with NSI-189 for an additional 16 weeks. Nerve conduction velocity, sensitivity to tactile and thermal stimuli, and behavioral assays of cognitive function were assessed monthly. AMP-activated protein kinase (AMPK) phosphorylation, mitochondrial protein levels, and respiratory complex activities were assessed in the DRG and brain cortex after 16 weeks of treatment with NSI-189.ResultsTreatment with NSI-189 selectively elevated the expression of protein subunits of complexes III and V and activities of respiratory complexes I and IV in the brain cortex, and this was accompanied by amelioration of impaired memory function and plasticity. In the sensory ganglia of ZDF rats, loss of AMPK activity was ameliorated by NSI-189, and this was accompanied by reversal of multiple indices of peripheral neuropathy.ConclusionsEfficacy of NSI-189 against dysfunction of the CNS and PNS function in type 2 diabetic rats was accompanied by improvement of mitochondrial function. NSI-189 exhibited actions at different levels of mitochondrial regulation in central and peripheral tissues.

Spontaneous imaginary companion (SIC) creation in childhood is a typical imaginative play behaviour associated with advanced sociocognitive skills; however, the direction of causality has not been established. To investigate this experimentally, researchers must determine whether children can create, on request, qualitatively equivalent imaginary companions (ICs) to those created spontaneously. We examined whether children could create ICs, and how these compared to SICs. Nine elementary school children were encouraged to create ICs in a 3-month intervention. Accounts of elicited ICs were compared with an age-matched sample of interviewees with SICs. Seven children maintained ICs for 6 months post intervention. Template analysis of IC interviews found four themes: Realistic Play, Multifaceted IC Mind, Utility of the IC, and Elicited IC Across Time. Analysis suggests elicited and SICs were similar in nature and utility, although intervention ICs tended to have animal rather than human appearances. Findings support the argument that children can be encouraged to create ICs similar to SICs.

Aberrant insulin-like growth factor 1 (IGF-1) signaling has been proposed as a contributing factor to the development of neurodegenerative disorders including diabetic neuropathy, and delivery of exogenous IGF-1 has been explored as a treatment for Alzheimer's disease and amyotrophic lateral sclerosis. However, the role of autocrine/paracrine IGF-1 in neuroprotection has not been well established. We therefore used in vitro cell culture systems and animal models of diabetic neuropathy to characterize endogenous IGF-1 in sensory neurons and determine the factors regulating IGF-1 expression and/or affecting neuronal health. Single-cell RNA sequencing (scRNA-Seq) and in situ hybridization analyses revealed high expression of endogenous IGF-1 in non-peptidergic neurons and satellite glial cells (SGCs) of dorsal root ganglia (DRG). Brain cortex and DRG had higher IGF-1 gene expression than sciatic nerve. Bidirectional transport of IGF-1 along sensory nerves was observed. Despite no difference in IGF-1 receptor levels, IGF-1 gene expression was significantly (P

Introduction: Metformin is currently first line therapy for type 2 diabetes (T2D). The mechanism of action of metformin involves activation of AMP-activated protein kinase (AMPK) to enhance mitochondrial function (for example, biogenesis, refurbishment and dynamics) and autophagy. Many neurodegenerative diseases of the central and peripheral nervous systems arise from metabolic failure and toxic protein aggregation where activated AMPK could prove protective. Areas covered: The authors review literature on metformin treatment in Parkinson's disease, Huntington's disease and other neurological diseases of the CNS along with neuroprotective effects of AMPK activation and suppression of the mammalian target of rapamycin (mTOR) pathway on peripheral neuropathy and neuropathic pain. The authors compare the efficacy of metformin with the actions of resveratrol. Expert opinion: Metformin, through activation of AMPK and autophagy, can enhance neuronal bioenergetics, promote nerve repair and reduce toxic protein aggregates in neurological diseases. A long history of safe use in humans should encourage development of metformin and other AMPK activators in preclinical and clinical research. Future studies in animal models of neurological disease should strive to further dissect in a mechanistic manner the pathways downstream from metformin-dependent AMPK activation, and to further investigate mTOR dependent and independent signaling pathways driving neuroprotection.

The aim of this research was to develop a new observation-based measure for assessing caregivers' mind-mindedness in the preschool years and investigate whether this measure could explain the link between mothers' early appropriate mind-related comments and children's later mentalizing abilities. The new measure was developed using a sample of mothers and 44-month-olds (N = 171), characterizing mind-mindedness in terms of (a) solicited child involvement, (b) adaptive communication, and (c) internal state talk. These indices were positively related to established assessments of mind-mindedness at 8, 44, and 61 months. Positive associations were also observed with children's later mentalizing abilities. The new measure of mind-mindedness did not, however, mediate the relation between mind-mindedness in the first year of life and children's mentalizing abilities.

Tyrosine Kinase Inhibitors (TKIs) is revolutionizing the management of pediatric Chronic Myeloid Leukemia (CML), offering alternatives to Allogeneic Hematopoietic Stem Cell Transplantation (AHSCT). We conducted a comprehensive review of 16 Randomized Controlled Trials (RCTs) encompassing 887 pediatric CML patients treated with TKIs including Imatinib, Dasatinib, and Nilotinib. The median patient age ranged from 6.5 to 14 years, with a median white blood cell count of 234 x 10^9/uL, median hemoglobin level of 9.05 g/dL, and median platelet count of 431.5 x 10^9/µL. Imatinib seems to be predominant first line TKI, with the most extensive safety and efficacy data. BCR::ABL response rates below 10% ranged from 60% to 78%, CCyR at 24 months ranged from 62% to 94%, and PFS showed variability from 56.8% to 100%, albeit with differing analysis timepoints. The Safety profile of TKIs was consistent with the known safety profile in adults. With the availability of three TKIs as first line options, multiple factors should be considered when selecting first line TKI, including drug formulation, administration, comorbidities, and financial issues. Careful monitoring of adverse events, especially in growing children, should be considered in long term follow-up clinical trials.

Muscarinic antagonists promote sensory neurite outgrowth in vitro and prevent and/or reverse multiple indices of peripheral neuropathy in rodent models of diabetes, chemotherapy-induced peripheral neuropathy, and HIV protein-induced neuropathy when delivered systemically. We measured plasma concentrations of the M1 receptor-selective muscarinic antagonist pirenzepine when delivered by subcutaneous injection, oral gavage, or topical application to the skin and investigated efficacy of topically delivered pirenzepine against indices of peripheral neuropathy in diabetic mice. Topical application of 2% pirenzepine to the paw resulted in plasma concentrations 6 hours postdelivery that approximated those previously shown to promote neurite outgrowth in vitro. Topical delivery of pirenzepine to the paw of mice with streptozotocin-induced diabetes dose-dependently (0.1%-10.0%) prevented tactile allodynia, thermal hypoalgesia, and loss of epidermal nerve fibers in the treated paw and attenuated large fiber motor nerve conduction slowing in the ipsilateral limb. Efficacy against some indices of neuropathy was also noted in the contralateral limb, indicating systemic effects following local treatment. Topical pirenzepine also reversed established paw heat hypoalgesia, whereas withdrawal of treatment resulted in a gradual decline in efficacy over 2-4 weeks. Efficacy of topical pirenzepine was muted when treatment was reduced from 5 to 3 or 1 day/wk. Similar local effects were noted with the nonselective muscarinic receptor antagonist atropine when applied either to the paw or to the eye. Topical delivery of muscarinic antagonists may serve as a practical therapeutic approach to treating diabetic and other peripheral neuropathies. SIGNIFICANCE STATEMENT: Muscarinic antagonist pirenzepine alleviates diabetic peripheral neuropathy when applied topically in mice.

Mitochondrial dysfunction is implicated in a variety of neurodegenerative diseases of the nervous system. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a regulator of mitochondrial function in multiple cell types. In sensory neurons, AMP-activated protein kinase (AMPK) augments PGC-1α activity and this pathway is depressed in diabetes leading to mitochondrial dysfunction and neurodegeneration. Antimuscarinic drugs targeting the muscarinic acetylcholine type 1 receptor (M1R) prevent/reverse neurodegeneration by inducing nerve regeneration in rodent models of diabetes and chemotherapy-induced peripheral neuropathy (CIPN). Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ) is an upstream regulator of AMPK activity. We hypothesized that antimuscarinic drugs modulate CaMKKβ to enhance activity of AMPK, and PGC-1α, increase mitochondrial function and thus protect from neurodegeneration. We used the specific M1R antagonist muscarinic toxin 7 (MT7) to manipulate muscarinic signaling in the dorsal root ganglia (DRG) neurons of normal rats or rats with streptozotocin-induced diabetes. DRG neurons treated with MT7 (100 nM) or a selective muscarinic antagonist, pirenzepine (1 μM), for 24 h showed increased neurite outgrowth that was blocked by the CaMKK inhibitor STO-609 (1 μM) or short hairpin RNA to CaMKKβ. MT7 enhanced AMPK phosphorylation which was blocked by STO-609 (1 μM). PGC-1α reporter activity was augmented up to 2-fold (p

Fateen Ata,1 Alaa Rahhal,2 Lujain Malkawi,3 Phool Iqbal,4 Ibrahim Khamees,5 Mousa Alhiyari,5 Zohaib Yousaf,6 Hana Qasim,7 Awni Alshurafa,8 Sundus Sardar,9 Saad Javed,10 Liam Fernyhough,8,11 Mohamed Yassin8 1Department of Endocrinology, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar; 2Department of Clinical Pharmacy, Hamad Medical Corporation, Doha, Qatar; 3Department of Internal Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan; 4Department of Internal Medicine, Metropolitan Hospital, New York, NY, USA; 5Department of Internal Medicine, Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar; 6Department of Internal Medicine, Reading Hospital - Tower Health, West Reading, PA, USA; 7Department of Internal Medicine, UMKC School of medicine, Kansas, MO, USA; 8Department of Medical Oncology /Hematology, National Centre for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar; 9Department of Medicine, Division of Nephrology, Pennsylvania State University College of Medicine, Hershey Medical Center, Hershey, PA, USA; 10Department of Internal Medicine, Icahn school of medicine at Mount Sinai/Queens Hospital Center, New York, NY, USA; 11Department of Medical Education, Weill Cornell Medicine – Qatar, Doha, QatarCorrespondence: Fateen Ata, Department of Endocrinology, Hamad general hospital, Doha, Qatar, Po Box 3050, Tel +974 6655176, Email docfateenata@gmail.com; FAta@hamad.qa Mohamed Yassin, Department of Medical Oncology /Hematology, National Centre for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar, Tel +974 5503739, Email Yassinmoha@gmail.comAbstract: Sickle cell disease (SCD) is a genetic disease influenced by ethnicity and regional differences in its clinical course. Recent advances in the management of SCD with newer therapies are being introduced to the Western population. However, many of these treatments are yet to be used in the Arabic SCD population. Understanding the genetic variations of SCD regionally is essential to anticipate the utilization of new treatments. This systematic review’s main objective is to pool the available data on the genetic composition of SCD in the Arabic population. Data for 44,034 patients was extracted from 184 studies (11 case reports, 8 case series, 56 retrospectives, 107 prospective observational studies, and 2 clinical trials) using PubMed, Scopus, and Google Scholar. Male (49%) and female (51%) patients were equally reported wherever gender was available (N=13105). Various SCD genotypes were reported in a total of 14,257 patients, including Hb SS (77%) Hb Sβ 0 (9.9%), and Hb Sβ+ (7.2%), while the rest of the genotypes, including HbSC, HbSD, HbSE, HbSO Arab, Hb S/α-Thal, Hb Sβ 0 + α-Thal, and HBS Oman were individually reported in < 4% of the cases. Major SCD complications in the Arab population included pain crises (48.25%) followed by neurological complications (33.46%), hepatobiliary complications (25.53%), musculoskeletal complications (24.73%), and hemolytic anemia (23.57%). The treatments reported for SCD included hydroxyurea (20%), blood transfusion (14.32%), and Deferasirox (3.03%). We did not find the use of stem cell transplantation or newer treatments such as L-Glutamine, Voxelotor, Crizanlizumab, or gene therapy reported in any of the studies included in our review. This review highlights the genetic makeup of SCD in Arab countries and its common phenotypic manifestations and will help direct further research on SCD in this region, especially concerning genetic therapy.Systematic Review Registration: The protocol has been registered in the International Prospective Register of Systematic Reviews(PROSPERO):CRD42020218,666. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=218666.Keywords: sickle cell disease, genotypes, SCD, sickle cell anemia, Arab

While peripheral neuropathy is the most common complication of long-term diabetes, cognitive deficits associated with encephalopathy and myelopathy also occur. Diabetes is a risk factor for Alzheimer disease (AD) and increases the risk of progression from mild cognitive impairment to AD. The only current recommendation for preventing or slowing the progression of peripheral neuropathy is to maintain close glycemic control, while there is no recommendation for central nervous system disorders. NSI-189 is a new chemical entity that when orally administered promotes neurogenesis in the adult hippocampus, increases hippocampal volume, enhances synaptic plasticity, and reduces cognitive dysfunction. To establish the potential for impact on peripheral neuropathy, we first showed that NSI-189 enhances neurite outgrowth and mitochondrial functions in cultured adult rat primary sensory neurons. Oral delivery of NSI-189 to murine models of type 1 (female) and type 2 (male) diabetes prevented multiple functional and structural indices of small and large fiber peripheral neuropathy, increased hippocampal neurogenesis, synaptic markers and volume, and protected long-term memory. NSI-189 also halted progression of established peripheral and central neuropathy. NSI-189, which is currently in clinical trials for treatment of major depressive disorder, offers the opportunity for the development of a single therapeutic agent against multiple indices of central and peripheral neuropathy.

OBJECTIVE:Diabetic sensorimotor polyneuropathy (DSPN) affects approximately half of diabetic patients leading to significant morbidity. There is impaired neurotrophic growth factor signaling, AMP-activated protein kinase (AMPK) activity and mitochondrial function in dorsal root ganglia (DRG) of animal models of type 1 and type 2 diabetes. We hypothesized that sub-optimal insulin-like growth factor 1 (IGF-1) signaling in diabetes drives loss of AMPK activity and mitochondrial function, both contributing to development of DSPN. METHODS:Age-matched control Sprague-Dawley rats and streptozotocin (STZ)-induced type 1 diabetic rats with/without IGF-1 therapy were used for in vivo studies. For in vitro studies, DRG neurons from control and STZ-diabetic rats were cultured and treated with/without IGF-1 in the presence or absence of inhibitors or siRNAs. RESULTS:Dysregulation of mRNAs for IGF-1, AMPKα2, ATP5a1 (subunit of ATPase), and PGC-1β occurred in DRG of diabetic vs. control rats. IGF-1 up-regulated mRNA levels of these genes in cultured DRGs from control or diabetic rats. IGF-1 treatment of DRG cultures significantly (P

Introduction Individuals who access at-risk mental state (ARMS) services often have unusual sensory experiences and levels of distress that lead them to seek help. The Managing Unusual Sensory Experiences (MUSE) treatment is a brief symptom targeted intervention that draws on psychological explanations to help account for unusual experiences. Practitioners use formulation and behavioural experiments to support individuals to make sense of their experiences and enhance coping strategies. The primary objective of this feasibility trial is to resolve key uncertainties before a definitive trial and inform parameters of a future fully powered trial.Methods and analysis 88 participants aged 14–35 accepted into ARMS services, experiencing hallucinations/unusual sensory experiences which are considered by the patient to be a key target problem will be recruited from UK National Health Service (NHS) sites and randomised using 1:1 allocation (stratified by site, gender, and age) to either 6–8 sessions of MUSE or time-matched treatment as usual. Participants and therapists will be unblinded, research assessors are blinded. Blinded assessment will occur at baseline, 12 weeks and 20 weeks postrandomisation. Data will be reported in line with Consolidated Standards of Reporting Trials. Primary trial outcomes are feasibility outcomes, primary participant outcomes are functioning and hallucinations. Additional analysis will investigate potential psychological mechanisms and secondary mental well-being outcomes. Trial progression criteria follows signal of efficacy and uses an analytical framework with a traffic-light system to determine viability of a future trial. Subsequent analysis of the NHS England Mental Health Services Data Set 3 years postrandomisation will assess long-term transition to psychosis.Ethics and dissemination This trial has received Research Ethics Committee approval (Newcastle North Tyneside 1 REC; 23/NE/0032). Participants provide written informed consent; young people provide assent with parental consent. Dissemination will be to ARMS Services, participants, public and patient forums, peer-reviewed publications and conferences.Trial registration number ISRCTN58558617.

Introduction: Adolescents and young adults (AYAs) diagnosed with chronic myeloid leukemia (CML) constitute a significant demographic group, particularly in regions with youthful populations like Qatar. Despite the global median age of CML diagnosis being 65 years, Qatar's age distribution reflects a younger cohort. This study investigates whether AYAs with CML exhibit distinct clinicopathological characteristics or outcomes compared to older age groups. Methods: A total of 224 CML patients were enrolled, including 114 AYAs (defined as ages 15 through 39). Demographic and clinical parameters, including gender, BMI, BCR-ABL1 transcript type, white blood cell (WBC) count, hemoglobin level, platelet count, and spleen size, were compared between AYAs and older patients. Prognostic scoring systems (Sokal, Hasford, EUTOS, and ELTS) and molecular response rates (MMR and DMR) were also evaluated. Results: AYAs demonstrated higher WBC counts at diagnosis (median 142.3 vs. 120; p = 0.037) and lower hemoglobin levels (10.5 vs. 11.40; p = 0.004) compared to older patients. Spleen size was significantly larger in AYAs (18.8 vs. 15.5; p = 0.001). While AYAs showed better prognostic scores by Sokal and Hasford criteria, EUTOS and ELTS scores indicated comparable risk stratification. However, AYAs exhibited lower rates of MMR (56.7 vs. 73.4%; p = 0.016) and achieved MMR at a slower pace (median time 130 vs. 103 months; p = 0.064). Similarly, the percentage of DMR was lower in AYAs (37.1 vs. 46.8%; p = 0.175). Conclusion: Despite their younger age, AYAs with CML displayed poorer prognoses compared to older patients. These findings underscore the importance of tailored management strategies for AYAs with CML to optimize outcomes in this distinct patient population. Key Point: AYAs are underrepresented in CML studies and risk scores, so this is the focus of this study. [ABSTRACT FROM AUTHOR]

The muscarinic acetylcholine type 1 receptor (M1R) is a metabotropic G protein-coupled receptor. Knockout of M1R or exposure to selective or specific receptor antagonists elevates neurite outgrowth in adult sensory neurons and is therapeutic in diverse models of peripheral neuropathy. We tested the hypothesis that endogenous M1R activation constrained neurite outgrowth via a negative impact on the cytoskeleton and subsequent mitochondrial trafficking. We overexpressed M1R in primary cultures of adult rat sensory neurons and cell lines and studied the physiological and molecular consequences related to regulation of cytoskeletal/mitochondrial dynamics and neurite outgrowth. In adult primary neurons, overexpression of M1R caused disruption of the tubulin, but not actin, cytoskeleton and significantly reduced neurite outgrowth. Over-expression of a M1R-DREADD mutant comparatively increased neurite outgrowth suggesting that acetylcholine released from cultured neurons interacts with M1R to suppress neurite outgrowth. M1R-dependent constraint on neurite outgrowth was removed by selective (pirenzepine) or specific (muscarinic toxin 7) M1R antagonists. M1R-dependent disruption of the cytoskeleton also diminished mitochondrial abundance and trafficking in distal neurites, a disorder that was also rescued by pirenzepine or muscarinic toxin 7. M1R activation modulated cytoskeletal dynamics through activation of the G protein (Gα13) that inhibited tubulin polymerization and thus reduced neurite outgrowth. Our study provides a novel mechanism of M1R control of Gα13 protein-dependent modulation of the tubulin cytoskeleton, mitochondrial trafficking and neurite outgrowth in axons of adult sensory neurons. This novel pathway could be harnessed to treat dying-back neuropathies since anti-muscarinic drugs are currently utilized for other clinical conditions.

Diabetic neuropathy affects approximately 50% of diabetic patients. Down-regulation of mitochondrial gene expression and function has been reported in both human tissues and in dorsal root ganglia (DRG) from animal models of type 1 and type 2 diabetes. We hypothesized that loss of direct insulin signaling in diabetes contributes to loss of mitochondrial function in DRG neurons and to development of neuropathy. Sensory neurons obtained from age-matched adult control or streptozotocin (STZ)-induced type 1 diabetic rats were cultured with or without insulin before determining mitochondrial respiration and expression of mitochondrial respiratory chain and insulin signaling-linked proteins. For in vivo studies age-matched control rats and diabetic rats with or without trace insulin supplementation were maintained for 5months before DRG were analyzed for respiratory chain gene expression and cytochrome c oxidase activity. Insulin (10nM) significantly (P

Sensory neurons have the capacity to produce, release, and respond to acetylcholine (ACh), but the functional role of cholinergic systems in adult mammalian peripheral sensory nerves has not been established. Here, we have reported that neurite outgrowth from adult sensory neurons that were maintained under subsaturating neurotrophic factor conditions operates under cholinergic constraint that is mediated by muscarinic receptor-dependent regulation of mitochondrial function via AMPK. Sensory neurons from mice lacking the muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth, confirming the role of M1R in tonic suppression of axonal plasticity. M1R-deficient mice made diabetic with streptozotocin were protected from physiological and structural indices of sensory neuropathy. Pharmacological blockade of M1R using specific or selective antagonists, pirenzepine, VU0255035, or muscarinic toxin 7 (MT7) activated AMPK and overcame diabetes-induced mitochondrial dysfunction in vitro and in vivo. These antimuscarinic drugs prevented or reversed indices of peripheral neuropathy, such as depletion of sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in diverse rodent models of diabetes. Pirenzepine and MT7 also prevented peripheral neuropathy induced by the chemotherapeutic agents dichloroacetate and paclitaxel or HIV envelope protein gp120. As a variety of antimuscarinic drugs are approved for clinical use against other conditions, prompt translation of this therapeutic approach to clinical trials is feasible.

Background: Restricted and repetitive patterns of behaviour (RRBs) serve an adaptive role in development. Elevated levels of RRBs beyond the early years, however, are associated with poorer outcome in language, cognition, and wellbeing, and are seen across a range of neurodevelopmental conditions. This study aimed to characterize the association of distinct RRB subtypes at two and six years of age, with internalising and externalising difficulties in a community sample of children. Methods: 485 parents reported on their child's insistence on sameness (IS) and repetitive sensory and motor (RSM) RRBs at two and six years of age using the Repetitive Behaviour Questionnaire (RBQ‐2). Emotional and behavioural difficulties were measured using the Strengths and Difficulties Questionnaire (SDQ) at age six. Results: Consistent with previous research, RRBs later in development better predicted emotional and behavioural difficulties at age six than RRBs earlier in development. Moreover, IS RRBs were selectively associated with internalising behaviours and RSM RRBs with externalising behaviours. Importantly, these selective associations depended on when RRBs were measured. Only IS RRBs at age six were significantly associated with internalising behaviour. By contrast, while more RSM RRBs at age six were associated with higher rates of externalising behaviours, higher rates of RSM RRBs at age two were associated with fewer externalising behaviours, adding further support to the previously reported adaptive role of RRBs in early behaviour regulation. Conclusion: Although there is a need for further research to provide a detailed profile of the adaptive periods for IS and RSM RRBs, the present findings support the potential utility of elevated RRBs as a signal for emotional and behavioural difficulties at age six. [ABSTRACT FROM AUTHOR]

Abstract Background Neurolymphomatosis is rare. Neoplastic lymphocytes are seen to invade nerves (cranial or peripheral), nerve roots or other related structures in patients with hematological malignancy. It is a separate entity from central nervous system lymphoma. Neurolymphomatosis has most commonly been described in association with B-cell non-Hodgkin lymphoma. Neurolymphomatosis in the context of Burkitt lymphoma and the post-renal transplant setting has not been described before. Case reports We report for the first time in the Arabian Gulf countries and nearby Arab states four cases of neurolymphomatosis (one Asian, and the other 3 are from Arabic nationals) occurring between 2012 and 2017 involving the median nerve, optic nerve, nerve root and cauda equina in patients with Burkitt lymphoma, Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia and diffuse large B-cell lymphoma. Conclusions Neurolymphomatosis is rare and can be difficult to diagnose by biopsy but reliably confirmed by a combined imaging approach. Prior treatment with high-dose dexamethasone might suppress 18F-fluorodeoxyglucose (FDG) activity and decrease the sensitivity of positron emission tomography/computed tomography (PET/CT). The prognosis is generally poor but using high-dose methotrexate as well as high-dose chemotherapy and autologous stem cell transplantation may be an effective way to treat neurolymphomatosis.

Introduction Hallucinations (hearing or seeing things that others do not) are a common feature of psychosis, causing significant distress and disability. Existing treatments such as cognitive–behavioural therapy for psychosis (CBTp) have modest benefits, and there is a lack of CBTp-trained staff. Shorter, targeted treatments that focus on specific symptoms delivered by a non-specialist workforce could substantially increase access to treatment.Managing Unusual Sensory Experiences (MUSE) explains why people have hallucinations and helps the person to develop and use coping strategies to reduce distress. MUSE focuses only on hallucinations, and treatment is short (four to six, 1-hour sessions per week). It is a digital intervention, run on National Health Service (NHS) laptops, which provides information about hallucinations in an engaging way, using audio, video and animated content. Crucially, it is designed for use by non-specialist staff like community psychiatric nurses.Methods and analysis The study is a two-arm feasibility randomised controlled trial comparing MUSE and treatment as usual (TAU) (n=40) to TAU alone (n=40), recruiting across two NHS Trusts, using 1:1 allocation and blind assessments before and after treatment (2 months) and at follow-up (3 months). Quantitative information on recruitment rates, adherence and completion of outcome assessments will be collected. Qualitative interviews will capture service users’ experience of therapy and clinicians’ experiences of the training and supervision in MUSE. Clinicians will also be asked about factors affecting uptake, adherence and facilitators/barriers to implementation. Analyses will focus on feasibility outcomes and provide initial estimates of intervention effects. Thematic analysis of the qualitative interviews will assess the acceptability of the training, intervention and trial procedures.Ethics and dissemination The trial has received NHS Ethical and Health Research Authority approval. Findings will be disseminated directly to participants and services, as well as through peer-reviewed publications and conference presentations.Trial registration number ISRCTN16793301.

Aims. Mitochondrial dysfunction contributes to many forms of peripheral and central nervous system degeneration. Therapies that protect mitochondrial number and function have the potential to impact the progression of conditions such as diabetic neuropathy. We therefore assessed indices of mitochondrial function in dorsal root ganglia (DRG) and brain cortex of the Zucker diabetic fatty (ZDF) rat model of type 2 diabetes and tested the therapeutic impact of a neurogenic compound, NSI-189, on both mitochondrial function and indices of peripheral and central neurological dysfunction. Materials and Methods. ZDF rats were maintained for 16 weeks of untreated diabetes before the start of oral treatment with NSI-189 for an additional 16 weeks. Nerve conduction velocity, sensitivity to tactile and thermal stimuli, and behavioral assays of cognitive function were assessed monthly. AMP-activated protein kinase (AMPK) phosphorylation, mitochondrial protein levels, and respiratory complex activities were assessed in the DRG and brain cortex after 16 weeks of treatment with NSI-189. Results. Treatment with NSI-189 selectively elevated the expression of protein subunits of complexes III and V and activities of respiratory complexes I and IV in the brain cortex, and this was accompanied by amelioration of impaired memory function and plasticity. In the sensory ganglia of ZDF rats, loss of AMPK activity was ameliorated by NSI-189, and this was accompanied by reversal of multiple indices of peripheral neuropathy. Conclusions. Efficacy of NSI-189 against dysfunction of the CNS and PNS function in type 2 diabetic rats was accompanied by improvement of mitochondrial function. NSI-189 exhibited actions at different levels of mitochondrial regulation in central and peripheral tissues.

Neuroimaging studies have found ‘reality monitoring’, our ability to distinguish internally generated experiences from those derived from the external world, to be associated with activity in the medial prefrontal cortex (mPFC) of the brain. Here we probe the functional underpinning of this ability using real-time fMRI neurofeedback to investigate the involvement of mPFC in recollection of the source of self-generated information. Thirty-nine healthy individuals underwent neurofeedback training in a between groups study receiving either Active feedback derived from the paracingulate region of the mPFC (21 subjects) or Sham feedback based on a similar level of randomised signal (18 subjects). Compared to those in the Sham group, participants receiving Active signal showed increased mPFC activity over the course of three real-time neurofeedback training runs undertaken in a single scanning session. Analysis of resting state functional connectivity associated with changes in reality monitoring accuracy following Active neurofeedback revealed increased connectivity between dorsolateral frontal regions of the fronto-parietal network (FPN) and the mPFC region of the default mode network (DMN), together with reduced connectivity within ventral regions of the FPN itself. However, only a trend effect was observed in the interaction of the recollection of the source of Imagined information compared with recognition memory between participants receiving Active and Sham neurofeedback, pre- and post- scanning. As such, these findings demonstrate that neurofeedback can be used to modulate mPFC activity and increase cooperation between the FPN and DMN, but the effects on reality monitoring performance are less clear.

The brain has a high demand for energy, of which creatine (Cr) is an important regulator. Studies document neurocognitive benefits of oral Cr in mammals, yet little is known regarding their physiological basis. This study investigated the effects of Cr supplementation (3%, w/w) on hippocampal function in male C57BL/6 mice, including spatial learning and memory in the Morris water maze and oxygen consumption rates from isolated mitochondria in real time. Levels of transcription factors and related proteins (CREB, Egr1, and I?B to indicate NF-?B activity), proteins implicated in cognition (CaMKII, PSD-95, and Egr2), and mitochondrial proteins (electron transport chain Complex I, mitochondrial fission protein Drp1) were probed with Western blotting. Dietary Cr decreased escape latency/time to locate the platform (P < 0.05) and increased the time spent in the target quadrant (P < 0.01) in the Morris water maze. This was accompanied by increased coupled respiration (P < 0.05) in isolated hippocampal mitochondria. Protein levels of CaMKII, PSD-95, and Complex 1 were increased in Cr-fed mice, whereas I?B was decreased. These data demonstrate that dietary supplementation with Cr can improve learning, memory, and mitochondrial function and have important implications for the treatment of diseases affecting memory and energy homeostasis.