Within the last several decades, the scientific community has made substantial progress in elucidating the complex pathophysiology underlying spinal cord injury. However, despite the many advances ...using conventional mammalian models, both cellular and axonal regeneration following spinal cord injury have remained out of reach. In this sense, turning to non-mammalian, regenerative species presents a unique opportunity to identify pro-regenerative cues and characterize a spinal cord microenvironment permissive to re-growth. Among the signaling pathways hypothesized to be dysregulated during spinal cord injury is the purinergic signaling system. In addition to its well-known role as energy currency in cells, ATP and its metabolites are small molecule neurotransmitters that mediate many diverse cellular processes within the central nervous system. While our understanding of the roles of the purinergic system following spinal cord injury is limited, this signaling pathway has been implicated in all injury-induced secondary processes, including cellular death, inflammation, reactive gliosis, and neural regeneration. Given that the purinergic system is also evolutionarily conserved between mammalian and non-mammalian species, comparisons of these roles may provide important insights into conditions responsible for recovery success. Here, we compare the secondary processes between key model species and the influence of purinergic signaling in each context. As our understanding of this signaling system and pro-regenerative conditions continues to evolve, so does the potential for the development of novel therapeutic interventions for spinal cord injury.
The Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) are the most commonly used scales to test cognitive impairment in Lewy body disease (LBD), but there is no ...consensus on which is best suited to assess cognition in clinical practice and most sensitive to cognitive decline. Retrospective cohort study of 265 LBD patients Parkinson’s disease (PD) without dementia (PDnD,
N
= 197), PD with dementia (PDD,
N
= 40), and dementia with Lewy bodies (DLB,
N
= 28) from an international consortium who completed both the MMSE and MoCA at baseline and 1-year follow-up (
N
= 153). Percentage of relative standard deviation (RSD%) at baseline was the measure of inter-individual variance, and estimation of change (Cohen’s
d
) over time was calculated. RSD% for the MoCA (21 %) was greater than for the MMSE (13 %) (
p
= 0.03) in the whole group. This difference was significant only in PDnD (11 vs. 5 %,
p
< 0.01), but not in PDD (30 vs. 19 %,
p
= 0.37) or DLB (15 vs. 14 %,
p
= 0.78). In contrast, the 1-year estimation of change did not differ between the two tests in any of the groups (Cohen’s effect <0.20 in each group). MMSE and MoCA are equal in measuring the rate of cognitive changes over time in LBD. However, in PDnD, the MoCA is a better measure of cognitive status as it lacks both ceiling and floor effects.
Background and purpose
Dementia is one of the most common disorders and is associated with increased morbidity, mortality and decreased quality of life. The present guideline addresses important ...medical management issues including systematic medical follow‐up, vascular risk factors in dementia, pain in dementia, use of antipsychotics in dementia and epilepsy in dementia.
Methods
A systematic review of the literature was carried out. Based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework, we developed a guideline. Where recommendations based on GRADE were not possible, a good practice statement was formulated.
Results
Systematic management of vascular risk factors should be performed in patients with mild to moderate dementia as prevention of cerebrovascular pathology may impact on the progression of dementia (Good Practice statement). Individuals with dementia (without previous stroke) and atrial fibrillation should be treated with anticoagulants (weak recommendation). Discontinuation of opioids should be considered in certain individuals with dementia (e.g. for whom there are no signs or symptoms of pain or no clear indication, or suspicion of side effects; Good Practice statement). Behavioral symptoms in persons with dementia should not be treated with mild analgesics (weak recommendation). In all patients with dementia treated with opioids, assessment of the individual risk–benefit ratio should be performed at regular intervals. Regular, preplanned medical follow‐up should be offered to all patients with dementia. The setting will depend on the organization of local health services and should, as a minimum, include general practitioners with easy access to dementia specialists (Good Practice statement). Individuals with dementia and agitation and/or aggression should be treated with atypical antipsychotics only after all non‐pharmacological measures have been proven to be without benefit or in the case of severe self‐harm or harm to others (weak recommendation). Antipsychotics should be discontinued after cessation of behavioral disturbances and in patients in whom there are side effects (Good Practice statement). For treatment of epilepsy in individuals with dementia, newer anticonvulsants should be considered as first‐line therapy (Good Practice statement).
Conclusion
This GRADE‐based guideline offers recommendations on several important medical issues in patients with dementia, and thus adds important guidance for clinicians. For some issues, very little or no evidence was identified, highlighting the importance of further studies within these areas.
Formation of compact dinucleosomes (CODIs) occurs after collision between adjacent nucleosomes at active regulatory DNA regions. Although CODIs are likely dynamic structures, their structural ...heterogeneity and dynamics were not systematically addressed. Here, single-particle Förster resonance energy transfer (spFRET) and electron microscopy were employed to study the structure and dynamics of CODIs. spFRET microscopy in solution and in gel revealed considerable uncoiling of nucleosomal DNA from the histone octamer in a fraction of CODIs, suggesting that at least one of the nucleosomes is destabilized in the presence of the adjacent closely positioned nucleosome. Accordingly, electron microscopy analysis suggests that up to 30 bp of nucleosomal DNA are involved in transient uncoiling/recoiling on the octamer. The more open and dynamic nucleosome structure in CODIs cannot be stabilized by histone chaperone Spt6. The data suggest that proper internucleosomal spacing is an important determinant of chromatin stability and support the possibility that CODIs could be intermediates of chromatin disruption.
Background and objectives
The last version of the EFNS dementia guidelines is from 2007. In 2010, the revised guidelines for Alzheimer's disease (AD) were published. The current guidelines involve ...the revision of the dementia syndromes outside of AD, notably vascular cognitive impairment, frontotemporal lobar degeneration, dementia with Lewy bodies, corticobasal syndrome, progressive supranuclear palsy, Parkinson's disease dementia, Huntington's disease, prion diseases, normal‐pressure hydrocephalus, limbic encephalitis and other toxic and metabolic disorders. The aim is to present a peer‐reviewed evidence‐based statement for the guidance of practice for clinical neurologists, geriatricians, psychiatrists and other specialist physicians responsible for the care of patients with dementing disorders. It represents a statement of minimum desirable standards for practice guidance.
Methods
The task force working group reviewed evidence from original research articles, meta‐analyses and systematic reviews, published by June 2011. The evidence was classified (I, II, III, IV) and consensus recommendations graded (A, B, or C) according to the EFNS guidance. Where there was a lack of evidence, but clear consensus, good practice points were provided.
Results and conclusions
New recommendations and good practice points are made for clinical diagnosis, blood tests, neuropsychology, neuroimaging, electroencephalography, cerebrospinal fluid (CSF) analysis, genetic testing, disclosure of diagnosis, treatment of behavioural and psychological symptoms in dementia, legal issues, counselling and support for caregivers. All recommendations were revised compared with the previous EFNS guidelines. The specialist neurologist together with primary care physicians play an important role in the assessment, interpretation and treatment of symptoms, disability and needs of dementia patients.
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This study examined the effects of L-dopa medication in patients with Parkinson's disease on cortical and subcortical blood flow changes during two tasks known to involve frontostriatal circuitry. ...Eleven patients with Parkinson's disease were scanned on two occasions, one ON L-dopa medication and one OFF L-dopa medication, during performance of the Tower of London planning task and a related test that emphasized aspects of spatial working memory. L-dopa-induced decreases were observed in the right dorsolateral prefrontal cortex during performance of both the planning and the spatial working memory tasks compared with the visuomotor control task. Conversely, L-dopa-induced blood flow increases were observed in the right occipital lobe during the memory task relative to the control task. Data from age-matched healthy volunteers demonstrated that L-dopa effectively normalized blood flow in these regions in the patient group. Moreover, a significant correlation was found between L-dopa-induced, planning related blood flow decreases in the right dorsolateral prefrontal cortex and L-dopa-induced changes in performance on the planning task. These data suggest that L-dopa ameliorates high-level cognitive deficits in Parkinson's disease by inducing relative blood flow changes in the right dorsolateral prefrontal cortex.
To investigate whether a specific pattern of gray matter (GM) tissue loss is associated with freezing of gait (FOG) in patients with Parkinson disease (PD).
Seventeen patients with PD with FOG ...(PD-FOG), 20 patients with PD with no FOG (PD-noFOG), and 34 healthy control subjects were recruited. PD-FOG and PD-noFOG patients were matched on an individual basis for age, disease duration, and Hoehn and Yahr stage. Patients were also administered a comprehensive neuropsychological battery focused on executive functions. The extent and distribution of GM atrophy were assessed using voxel-based morphometry.
In patients with PD, the severity of FOG correlated with frontal executive deficits. Compared with healthy control subjects, PD-FOG patients showed a distributed pattern of GM atrophy including the dorsolateral prefrontal, medial, and lateral temporal, inferior parietal, and occipital cortices. PD-noFOG patients showed only small regions of GM atrophy in the bilateral frontal and temporal cortex. The left inferior frontal gyrus, left precentral gyrus, and left inferior parietal gyrus were more atrophic in PD-FOG patients relative to both healthy control subjects and PD-noFOG patients. In PD-FOG patients, the severity of FOG was associated with GM volumes of the frontal and parietal cortices bilaterally.
GM frontal and parietal atrophy occur in PD-FOG patients. FOG in PD seems to share with executive dysfunction and perception deficits a common pattern of structural damage to the frontal and parietal cortices.
In this study, we delve into the impact of genotoxic anticancer drug treatment on the chromatin structure of human cells, with a particular focus on the effects of doxorubicin. Using Hi-C, ChIP-seq, ...and RNA-seq, we explore the changes in chromatin architecture brought about by doxorubicin and ICRF193. Our results indicate that physiologically relevant doses of doxorubicin lead to a local reduction in Hi-C interactions in certain genomic regions that contain active promoters, with changes in chromatin architecture occurring independently of Top2 inhibition, cell cycle arrest, and differential gene expression. Inside the regions with decreased interactions, we detected redistribution of RAD21 around the peaks of H3K27 acetylation. Our study also revealed a common structural pattern in the regions with altered architecture, characterized by two large domains separated from each other. Additionally, doxorubicin was found to increase CTCF binding in H3K27 acetylated regions. Furthermore, we discovered that Top2-dependent chemotherapy causes changes in the distance decay of Hi-C contacts, which are driven by direct and indirect inhibitors. Our proposed model suggests that doxorubicin-induced DSBs cause cohesin redistribution, which leads to increased insulation on actively transcribed TAD boundaries. Our findings underscore the significant impact of genotoxic anticancer treatment on the chromatin structure of the human genome.
The study focuses on the impact of life excretion and mucus released by the “biological pollutants” invasive ctenophore Mnemiopsis leidyi and its predator Beroe ovata on the marine environment and ...lower trophic levels of the Black Sea ecosystem (bacteria, pico-phytoplankton, nano-autotrophic/heterotrophic flagellates, micro-phytoplankton, chlorophyll a, primary production (PP), micro-zooplankton). The chemical and biological variables were analysed in two sets of lab experiments with natural communities from mesotrophic (Gelendzhik) and eutrophic (Varna) coastal waters. While both species altered the chemical properties of experimental media, exerting structural and functional changes in the low food-web biological compartments, the results showed a stronger effect of B. ovata, most likely related to the measured higher rate of excretion and amount of released mucus. In addition the alterations in the Gelendzhik experiment were more pronounced, indicating that environmental implications on lower food-web are more conspicuous in mesotrophic than in eutrophic coastal waters.
•Experiments with invasive ctenophores in the NW and NE shelves of the Black Sea•Life excretions and mucus secretion of Mnemiopsis leidyi and Beroe ovata•Both ctenophores induced alterations in phytoplankton, chlorophyll and primary production•Both ctenophores caused changes in bacteria and micro-zooplankton biomass•The effect has been observed much more remarkable in Gelendzhik mesotrophic area.
In contrast to mammals, zebrafish undergo successful neural regeneration following spinal cord injury. Spinal cord ependymo-radial glia (ERG) undergo injury-induced proliferation and neuronal ...differentiation to replace damaged cells and restore motor function. However, the molecular cues driving these processes remain elusive. Here, we demonstrate that the evolutionarily conserved P2X7 receptors are widely distributed on neurons and ERG within the zebrafish spinal cord. At the protein level, the P2X7 receptor expressed in zebrafish is a truncated splice variant of the full-length variant found in mammals. The protein expression of this 50 kDa isoform was significantly downregulated at 7 days post-injury (dpi) but returned to basal levels at 14 dpi when compared to naïve controls. Pharmacological activation of P2X7 following SCI resulted in a greater number of proliferating cells around the central canal by 7 dpi but did not affect neuronal differentiation at 14 dpi. Our findings suggest that unlike in mammals, P2X7 signaling may not play a maladaptive role following SCI in adult zebrafish and may also work to curb the proliferative response of ERG following injury.
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