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The dopamine D4 receptor (D4R), a G protein-coupled receptor, is predominantly expressed in the prefrontal cortex in which it plays an important role in cognition, attention, and decision making. Studies have indicated D4R-selective ligands as promising therapeutic targets for the treatment of neuropsychiatric conditions such as substance use disorders (SUD). D4R ligands have been shown to alter cognition and behavior in animal models of drug addiction. A better understanding of D4R-mediated signaling is essential to treating D4R-associated disorders, including SUD. Despite its clinical importance, there are currently no FDA approved medications that target the D4R, and for example, treat cocaine use disorder. The present study focuses on the design of D4R-selective ligands based on the parental phenylpiperazine scaffold and pharmacokinetic analysis in rat and human liver microsomes, followed by in vivo pharmacokinetic and behavioral analysis. We identified several compounds with high binding affinity and D4R selectivity (Ki ≤ 6.87 nM and >91-fold vs. other D2-like receptors (D2R, D3R)) with diverse partial agonist and antagonist profiles. Based on the affinity profiles, 5f (CAB-01-019) was selected for an in vitro metabolic stability assay in rat and human liver microsomes which displayed an acceptable stability profile. Based on these results, we moved 5f forward into in vivo pharmacokinetic analysis in rats where it displayed excellent brain penetration with AUCbrain/plasma > 3. The full antagonist 5f (5, 15 and 30 mg/kg, i.p.) was tested in cocaine self-administration studies in rats, using a within-session multidosing procedure. 5f dose-dependently decreased the number of i.v. infusions obtained for three-unit doses of cocaine under a fixed ratio (FR) FR3 schedule of reinforcement, suggesting that the selected D4R antagonist reduced the rewarding effects of cocaine. Together, these results support the development of D4R-selective antagonists for SUDs and support 5f as a new probe for studying D4R-specific behaviors.

Introduction: Idiopathic intracranial hypertension (IIH) is one of the most common causes of papilloedema seen by ophthalmologists and neurologists. Patients with IIH routinely undergo lumbar puncture (LP) for diagnosis. Dural venous sinus thrombosis (DVST) is a rare complication of cerebrospinal fluid pressure (CSF)-lowering procedures such as lumbar puncture and epidural and may be an intracranial complication of IIH. Case Description: A 29-year-old obese woman was diagnosed with severe idiopathic intracranial hypertension (IIH) after she presented with new-onset headache, pulsatile tinnitus and blurred vision. Magnetic resonance imaging (MRI) and venography (MRV) were normal apart from signs of intracranial hypertension. Lumbar puncture (LP) revealed an opening pressure of 40 cm of water. Due to the severity of the papilloedema and vision loss, she was referred for a ventriculoperitoneal shunt and found to have venous sinus thrombosis involving the superior sagittal sinus on the pre-operative computed tomography (CT) head 5 days after the LP. CT venography (CTV) one day later and MRV 3 days later showed significant worsening as the thrombosis extended into the deep venous system. She was started on therapeutic heparin and her symptoms and vision improved and she did not develop any neurological complications. Conclusions: DVST should be considered in IIH patients who have worsening papilloedema or symptoms of intracranial hypertension. Repeat venous imaging can prevent devastating consequences such as venous infarcts of haemorrhage in these patients.

Background and ObjectivesNo evidence of disease activity (NEDA)-4 has been suggested as a treatment target for disease-modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS). However, the ability of NEDA-4 to discriminate long-term outcomes in MS and how its performance compares with NEDA-3 remain uncertain. We conducted a systematic review and meta-analysis to evaluate (1) the association between NEDA-4 and no long-term disability progression in MS and (2) the comparative performance of NEDA-3 and NEDA-4 in predicting no long-term disability progression.MethodsEnglish-language abstracts and manuscripts were systematically searched in MEDLINE, Embase, and the Cochrane databases from January 2006 to November 2021 and reviewed independently by 2 investigators. We selected studies that assessed NEDA-4 at 1 or 2 years after DMT start and had at least 4 years of follow-up for determination of no confirmed disability progression. We conducted a meta-analysis using random-effects model to determine the pooled odds ratio (OR) for no disability progression with NEDA-4 vs EDA-4. For the comparative analysis, we selected studies that evaluated both NEDA-3 and NEDA-4 with at least 4 years of follow-up and examined the difference in the association of NEDA-3 and NEDA-4 with no disability progression.ResultsFive studies of 1,000 patients (3 interferon beta and 2 fingolimod) met inclusion criteria for both objectives. The median duration of follow-up was 6 years (interquartile range: 4–6 years). The prevalence of NEDA-4 ranged from 4.2% to 13.9% on interferon beta therapy and 24.9% to 25.1% on fingolimod therapy. The pooled OR for no long-term confirmed disability progression with NEDA-4 vs EDA-4 was 2.14 (95% confidence interval: 1.36–3.37; I2= 0). We did not observe any significant difference between NEDA-4 and NEDA-3 in the comparative analyses.DiscussionIn patients with RRMS, NEDA-4 at 1–2 years was associated with 2 times higher odds of no long-term disability progression, at 6 years compared with EDA-4, but offered no advantage over NEDA-3.

M55 belongs to a class of innovative nanomaterials, constituted by doped ferrite, with potential application in tumor therapy, as agents for Magnetic Fluid Hyperthermia (MFH), and in diagnosis, as contrast agents for MRI and MPI. Interestingly, such nanomaterials are characterized by a self-limiting temperature that can be modulated by adjusting the composition of the nanomaterial itself. M55 was coated with a double shell of citrate and glucose. We demonstrated that it has good capability as contrast agent for MRI and MPI. Moreover we tested its biocompatibility in a triple negative human breast cancer line and its efficacy as MFH agent in the same cell line. Despite relatively low SAR values in water solution, this agents was highly efficient in decreasing cell viability after two MFH treatments. Finally, we demonstrated that it can be useful to label cells for cell tracking in MPI. Although preliminary, these results are encouraging and push toward in vivo tests of such material., International Journal on Magnetic Particle Imaging, Vol 8 No 1 Suppl 1 (2022)

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disorder. There is no cure and current treatments fail to slow the progression of the disease. Epigenetic modulation in the acetylation state of NF-kB RelA and the histone 3 (H3) protein, involved in the development of neurodegeneration, is a drugable target for the class-I histone deacetylases (HDAC) inhibitors, entinostat or valproate, and the AMP-activated kinase (AMPK)-sirtuin 1 pathway activator, resveratrol. In this study, we demonstrated that the combination of valproate and resveratrol can restore the normal acetylation state of RelA in the SOD1(G93A) murine model of ALS, in order to obtain the neuroprotective form of NF-kB. We also investigated the sexually dimorphic development of the disease, as well as the sex-sensibility to the treatment administered. We showed that the combined drugs, which rescued AMPK activation, RelA and the histone 3 acetylation state, reduced the motor deficit and the disease pathology associated with motor neuron loss and microglial reactivity, Brain-Derived Neurotrophic Factor (BDNF) and B-cell lymphoma-extra large (Bcl-xL) level decline. Specifically, vehicle-administered males showed earlier onset and slower progression of the disease when compared to females. The treatment, administered at 50 days of life, postponed the time of onset in the male by 22 days, but not in a significant way in females. Nevertheless, in females, the drugs significantly reduced symptom severity of the later phase of the disease and prolonged the mice’s survival. Only minor beneficial effects were produced in the latter stage in males. Overall, this study shows a beneficial and sexually dimorphic response to valproate and resveratrol treatment in ALS mice.

The tetraploid domesticated emmer wheat, Triticum turgidum L. subsp. dicoccon, expresses α-amylase protein inhibitors of varying sizes and assemblies, i.e. dimers and heterotetramers of polypeptide chains of about 12–15 kDa. Although genetic studies have shown the presence of coding sequences for monomeric inhibitors in tetraploid wheat and whole-seeds proteomic studies have indicated their expression, until now there has been no isolation nor characterization of such proteins. In this study, for the first time, an inhibitory protein of human salivary and Tenebrio molitor, Tribolium castaneum, Sitophilus oryzae, and Ephestia kuehniella α-amylase (EC 3.2.1.1), was isolated from whole flour extracts of a tetraploid wheat and its sequence was determined by MS analyses. The inhibitor acts more strongly against coleopteran α-amylases than against those from E. kuheniella and human saliva. The inhibitory characteristics along with the putative sequence determination reported in the present study, allows for further evaluation towards its utilization as a post-harvest protection strategy against insect infestations.

No evidence of disease activity (NEDA)-4 has been suggested as a treatment target for disease-modifying therapy (DMT) in relapsing-remitting multiple sclerosis (RRMS). However, the ability of NEDA-4 to discriminate long-term outcomes in MS and how its performance compares with NEDA-3 remain uncertain. We conducted a systematic review and meta-analysis to evaluate (1) the association between NEDA-4 and no long-term disability progression in MS and (2) the comparative performance of NEDA-3 and NEDA-4 in predicting no long-term disability progression. English-language abstracts and manuscripts were systematically searched in MEDLINE, Embase, and the Cochrane databases from January 2006 to November 2021 and reviewed independently by 2 investigators. We selected studies that assessed NEDA-4 at 1 or 2 years after DMT start and had at least 4 years of follow-up for determination of no confirmed disability progression. We conducted a meta-analysis using random-effects model to determine the pooled odds ratio (OR) for no disability progression with NEDA-4 vs EDA-4. For the comparative analysis, we selected studies that evaluated both NEDA-3 and NEDA-4 with at least 4 years of follow-up and examined the difference in the association of NEDA-3 and NEDA-4 with no disability progression. Five studies of 1,000 patients (3 interferon beta and 2 fingolimod) met inclusion criteria for both objectives. The median duration of follow-up was 6 years (interquartile range: 4-6 years). The prevalence of NEDA-4 ranged from 4.2% to 13.9% on interferon beta therapy and 24.9% to 25.1% on fingolimod therapy. The pooled OR for no long-term confirmed disability progression with NEDA-4 vs EDA-4 was 2.14 (95% confidence interval: 1.36-3.37; I 2 = 0). We did not observe any significant difference between NEDA-4 and NEDA-3 in the comparative analyses. In patients with RRMS, NEDA-4 at 1-2 years was associated with 2 times higher odds of no long-term disability progression, at 6 years compared with EDA-4, but offered no advantage over NEDA-3.

ObjectiveTo identify the prevalence of self-reported symptoms of depression and anxiety among patients in remission from autoimmune encephalitis (AE).BackgroundAlthough prior studies have found a high prevalence of residual cognitive deficits among patients in remission from AE, there is a paucity of data on long-term psychiatric outcomes for this patient population. In normal populations, median Patient Health Questionaire-9 (PHQ9) and General Anxiety Disorder-7 (GAD7) scores were reported to be, respectively, around 3 and 2, with prevalence of depressive and anxiety symptoms on these questionnaires reported as around 24% and 23%.Design/MethodsRetrospective cross-sectional cohort study at a tertiary center AE clinic between 2012-01-01 and 2021-12-31. Patients were contacted via phone or regular follow-up and completed the PHQ9 and GAD7.ResultsForty-one patients were contacted; 29 responded (71%) and were included. Seventeen (59%) were female. Median age was 32.5 years (range 5-77). Autoantibody results were N-methyl-D-aspartate receptor (n = 14, 48%), negative (n = 7, 24%), leucine-rich glioma-inactivated 1 (n = 6, 21%), and contactin-associated protein-like 2 (n = 1, 3%). Median time from disease onset to questionnaire collection was 6.3 years (range 1.5-23.0). Ten patients (37%) were experiencing symptoms of depression as measured by the PHQ9, with six (60%) reporting moderate-to-severe symptoms. Median PHQ9 score was 3 (range 0-18). Six patients (22%) were experiencing symptoms of anxiety on the GAD7, with one (17%) reporting moderate-to-severe symptoms. Median GAD7 score was 2 (range 0-10). Eight patients (28%) reported a psychiatric history prior to the onset of AE, which was associated with increased PHQ9 scores (p = 0.04, Wilcoxon rank sum test).ConclusionsThe prevalence of self-reported depressive and anxious symptoms in this cohort in remission from AE was similar to general populations. Patients with a psychiatric history that preceded onset of AE had higher PHQ9 scores. These results may be affected by censoring bias and lower sensitivity of self-reported diagnostic tools.

ObjectiveTo describe features of central nervous system (CNS) demyelinating events following vaccination against coronavirus disease 19 (COVID-19).BackgroundSeveral reports suggest a potential association between COVID-19 vaccines and acute CNS inflammation.Design/MethodsA case series was performed at the BARLO MS Centre in Toronto, Ontario, Canada. Clinicians reported patients who experienced an acute CNS demyelinating event within 60 days after receiving at least one COVID-19 vaccination from March 2021 to January 2022. Clinical characteristics were evaluated.ResultsTwenty patients were identified (median age 39 years (range 25-82); 13 (65.0%) female). Two had pre-existing multiple sclerosis (MS). Individuals received the Pfizer (n = 14), Moderna (n = 5) or Astrazeneca (n = 1) COVID-19 vaccines. Within 1-53 days (median 12) of the first (n = 8) or second (n = 12) vaccine dose, patients developed transverse myelitis (TM) (n = 15), optic neuritis (n = 4) or brain demyelination (n = 4). Diagnoses at last follow up (median 114 days (range 39-255)) were relapsing remitting MS (n = 8), post-vaccine TM (n = 5), clinically isolated syndrome (n = 3), myelin oligodendrocyte glycoprotein antibody disease (n = 2), MS relapse (n = 1) and neuromyelitis optica spectrum disorder (n = 1). Thirteen patients received pulse corticosteroids, and of these, 4 received plasma exchange. Seven did not receive acute treatment. 20.0% returned to baseline (n = 4), 75.0% partially recovered (n = 15) and 5.0% worsened (n = 1). At last follow up, 11 were on disease modifying therapy and 9 were not. Nine patients received a subsequent COVID-19 vaccine. Of these, one experienced symptom recrudescence without radiologic evidence of a new demyelinating attack.ConclusionsTo our knowledge, this is the largest series to date describing acute CNS demyelination after vaccination against COVID-19. The rate of vaccination in the eligible general population was high during the time of the cases and we could not determine whether the number of demyelinating events was higher than expected. Repeat vaccination was not associated with recurrent adverse events in this small observational series.