The Emerging Role of Phosphodiesterases in Movement Disorders

Cyclic nucleotide phosphodiesterase (PDE) enzymes catalyze the hydrolysis and inactivation of the cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate, which act as intracellular second messengers for many signal transduction pathways in the central nervous system. Several classes of PDE enzymes with specific tissue distributions and cyclic nucleotide selectivity are highly expressed in brain regions involved in cognitive and motor functions, which are known to be implicated in neurodegenerative diseases, such as Parkinson's disease and Huntington's disease. The indication that PDEs are intimately involved in the pathophysiology of different movement disorders further stems from recent discoveries that mutations in genes encoding different PDEs, including PDE2A, PDE8B, and PDE10A, are responsible for rare forms of monogenic parkinsonism and chorea. We here aim to provide a translational overview of the preclinical and clinical data on PDEs, the role of which is emerging in the field of movement disorders, offering a novel venue for a better understanding of their pathophysiology. Modulating cyclic nucleotide signaling, by either acting on their synthesis or on their degradation, represents a promising area for development of novel therapeutic approaches. The study of PDE mutations linked to monogenic movement disorders offers the opportunity of better understanding the role of PDEs in disease pathogenesis, a necessary step to successfully benefit the treatment of both hyperkinetic and hypokinetic movement disorders. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

A review of migratory behaviour of sea turtles off southeastern Africa

The survival of sea turtles is threatened by modern fishing methods, exploitation of eggs and habitat destruction. Forming keystone species in the ocean, their extinction would disrupt the marine food chain in ways as yet unknown. The Indian Ocean has many breeding areas for sea turtles, the southernmost ones being on the Maputaland coast of KwaZulu-Natal, where loggerhead and leatherback turtles nest in large numbers thanks to long-lasting protection programmes. For the leatherback this is the only known nesting site in the entire western Indian Ocean. At the end of the reproductive season, both loggerheads and leatherbacks undertake migrations towards disparate feeding areas. To contribute to their conservation, the migratory behaviour of these animals needs to be understood. Here we review 10 years studying this behaviour using transmitters that telemeter data via satellite. It emerges that these species frequent widely dispersed areas ranging from the Atlantic Ocean to the Mozambique Channel. The migratory behaviour of leatherback and loggerhead turtles is, however, very different, probably due to their differing food requirements. While loggerhead postnesting movements have a truly migratory nature, the large-scale wanderings of leatherbacks are better described as prolonged sojourns in extended feeding areas

Satellite tracking identifies important foraging areas for loggerhead turtles frequenting the Adriatic Sea, Central Mediterranean

The Adriatic Sea is one of the main foraging areas for marine turtles of the Mediterranean Sea, but the specific high-use sites are poorly known, due to the scarceness of satellite tracking data available for juvenile turtles frequenting the area. In the present study, we tracked 8 juvenile and adult loggerhead turtles (Caretta caretta) that were released along the north-western Adriatic coast after a rehabilitation period having been equipped with Argos-linked satellite transmitters. Tracked turtles displayed quite variable movement patterns, but mostly remained in the north-western Adriatic, especially during the summer months. A marked preference for specific coastal sites was revealed in many turtles, that actively moved towards these specific locations when released south of it or having spent the winter away. Pooling these data with those obtained in previous studies on a further 10 turtles, we highlighted the presence of two main high-use areas, north and south of the Po River delta, where future conservation actions may then be focused

Cocirculation of Hajj and non-Hajj strains among serogroup W meningococci in Italy, 2000 to 2016

In Italy, B and C are the predominant serogroups among meningococci causing invasive diseases. Nevertheless, in the period from 2013 to 2016, an increase in serogroup W Neisseria meningitidis (MenW) was observed. This study intends to define the main characteristics of 63 MenW isolates responsible of invasive meningococcal disease (IMD) in Italy from 2000 to 2016. We performed whole genome sequencing on bacterial isolates or single gene sequencing on culturenegative samples to evaluate molecular heterogeneity. Our main finding was the cocirculation of the Hajj and the South American sublineages belonging to MenW/ clonal complex (cc)11, which gradually surpassed the MenW/cc22 in Italy. All MenW/cc11 isolates were fully susceptible to cefotaxime, ceftriaxone, ciprofloxacin, penicillin G and rifampicin. We identified the fulllength NadA protein variant 2/3, present in all the MenW/cc11. We also identified the fHbp variant 1, which we found exclusively in the MenW/cc11/Hajj sublineage. Concern about the epidemic potential of MenW/cc11 has increased worldwide since the year 2000. Continued surveillance, supported by genomic characterisation, allows high-resolution tracking of pathogen dissemination and the detection of epidemicassociated strains

Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia.

Dystonia type 4 (DYT4) was first described in a large family from Heacham in Norfolk with an autosomal dominantly inherited whispering dysphonia, generalized dystonia, and a characteristic hobby horse ataxic gait. We carried out a genetic linkage analysis in the extended DYT4 family that spanned 7 generations from England and Australia, revealing a single LOD score peak of 6.33 on chromosome 19p13.12-13. Exome sequencing in 2 cousins identified a single cosegregating mutation (p.R2G) in the β-tubulin 4a (TUBB4a) gene that was absent in a large number of controls. The mutation is highly conserved in the β-tubulin autoregulatory MREI (methionine-arginine-glutamic acid-isoleucine) domain, highly expressed in the central nervous system, and extensive in vitro work has previously demonstrated that substitutions at residue 2, specifically R2G, disrupt the autoregulatory capability of the wild-type β-tubulin peptide, affirming the role of the cytoskeleton in dystonia pathogenesis

International Expert Opinions and Recommendations on the Use of Melatonin in the Treatment of Insomnia and Circadian Sleep Disturbances in Adult Neuropsychiatric Disorders

Introduction: Insomnia and circadian rhythm disorders, such as the delayed sleep phase syndrome, are frequent in psychiatric disorders and their evaluation and management in early stages should be a priority. The aim of this paper was to express recommendations on the use of exogenous melatonin, which exhibits both chronobiotic and sleep-promoting actions, for the treatment of these sleep disturbances in psychiatric disorders. Methods: To this aim, we conducted a systematic review according to PRISMA on the use of melatonin for the treatment of insomnia and circadian sleep disorders in neuropsychiatry. We expressed recommendations for the use of melatonin in psychiatric clinical practice for each disorder using the RAND/UCLA appropriateness method. Results: We selected 41 studies, which included mood disorders, schizophrenia, substance use disorders, attention deficit hyperactivity disorders, autism spectrum disorders, neurocognitive disorders, and delirium; no studies were found for both anxiety and eating disorders. Conclusion: The administration of prolonged release melatonin at 2–10 mg, 1–2 h before bedtime, might be used in the treatment of insomnia symptoms or comorbid insomnia in mood disorders, schizophrenia, in adults with autism spectrum disorders, neurocognitive disorders and during sedative-hypnotics discontinuation. Immediate release melatonin at <1 mg might be useful in the treatment of circadian sleep disturbances of neuropsychiatric disorders

Fungal iron availability during deep seated candidiasis is defined by a complex interplay involving systemic and local events

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