Neurobiology of Vascular Dementia

Vascular dementia is, in its current conceptual form, a distinct type of dementia with a spectrum of specific clinical and pathophysiological features. However, in a very large majority of cases, these alterations occur in an already aged brain, characterized by a milieu of cellular and molecular events common for different neurodegenerative diseases. The cell signaling defects and molecular dyshomeostasis might lead to neuronal malfunction prior to the death of neurons and the alteration of neuronal networks. In the present paper, we explore some of the molecular mechanisms underlying brain malfunction triggered by cerebrovascular disease and risk factors. We suggest that, in the age of genetic investigation and molecular diagnosis, the concept of vascular dementia needs a new approach

Non-Myelinating Schwann Cells in Health and Disease

Non-myelinating Schwann cells (NMSCs) are one of the two major phenotypes of Schwann cells. NMSCs are of different types and have various locations. In the peripheral nervous system, NMSC, named Remak Schwann cells (RSC), accommodate multiple small-caliber axons, forming Remak bundles. NMSC, named perisynaptic/terminal Schwann cells, are found at the distal end of motor nerve terminals at the neuromuscular junction (NMJ). Thus, NMSCs proved to serve different functions according to their distribution such as maintenance of the axon and NMJ, peripheral nerve regeneration, or remodeling of the NMJ. Schwann cells (SCs) retain their proliferation capacity in the case of nerve injury or demyelination and provide support for the neuronal cells through paracrine signaling. Here we present an overview of their phenotypes and tissue distribution focusing on their emerging involvement in various peripheral nerve diseases

Oxidative Stress in Alzheimer’s Disease: Why Did Antioxidant Therapy Fail?

Alzheimer’s disease (AD) is the most common form of dementia in the elderly, with increasing prevalence and no disease-modifying treatment available yet. A remarkable amount of data supports the hypothesis that oxidative stress is an early and important pathogenic operator in AD. However, all clinical studies conducted to date did not prove a clear beneficial effect of antioxidant treatment in AD patients. In the current work, we review the current knowledge about oxidative stress in AD pathogeny and we suggest future paths that are worth to be explored in animal models and clinical studies, in order to get a better approach of oxidative imbalance in this inexorable neurodegenerative disease

Neuroregeneration in neurodegenerative disorders

<p>Abstract</p> <p>Background</p> <p>Neuroregeneration is a relatively recent concept that includes neurogenesis, neuroplasticity, and neurorestoration - implantation of viable cells as a therapeutical approach.</p> <p>Discussion</p> <p>Neurogenesis and neuroplasticity are impaired in brains of patients suffering from Alzheimer's Disease or Parkinson's Disease and correlate with low endogenous protection, as a result of a diminished growth factors expression. However, we hypothesize that the brain possesses, at least in early and medium stages of disease, a "neuroregenerative reserve", that could be exploited by growth factors or stem cells-neurorestoration therapies.</p> <p>Summary</p> <p>In this paper we review the current data regarding all three aspects of neuroregeneration in Alzheimer's Disease and Parkinson's Disease.</p

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Cell death and signal transduction pathways in Alzheimer's disease : The role of presenilin 1

Mutated presenilins (PSs) may cause familial Alzheimer's disease (FAD) by altering neuronal signal transduction pathways, by increasing AP production or by triggering a number of proapoptotic mechanisms. The present thesis explores mechanisms by which PSs regulate signal transduction and cell death with relevance to AD. Paper I explored the complex proteolytic processing of wild-type (WT) and FAD presenilin 1 (PS1) exon 9 deleted mutant (deltaE9 PS1) during apoptosis. PS1 was actively processed by both caspases and the proteasome during apoptosis in SH-SY5Y neuroblastoma cells non-transfected (NT) or transfected with WT PS1. Proteasome inhibitors blocked the degradation of full-length WT PS1 and caspase cleaved PS1 fragments. In contrast, the Nterminal and C-terminal fragments generated by PS1 endoproteolysis and the truncated fullength deltaE9 PS1 were not degraded by the proteasome during apoptosis. Paper II aimed to investigate whether PS1 cleavage by caspases is an early or a late event in the activation of apoptotic cascades. Overexpression of deltaE9 PS1 sensitized SH-SY5Y neuroblastoma cells to death induced by calcium ionophore A23187. We found that PS1 alternative cleavage is an early apoptotic event in deltaE9 PS1 transfected cells, simultaneous with minimal caspase-3 activation and preceding cleavage of poly(ADP-ribose) polymerase (PARP) and gelsolin. PS1 deltaE9 perturbed Ca2+ homeostasis and buffering in SH-SY5Y cells, this being at least one of the mechanisms by which mutated PS1 sensitized cells to apoptosis. We concluded that alternative cleavage of PS1 is an early apoptotic event; therefore it may play a role for the regulation of the proteolytic cascades during apoptosis. Papers III and IV aimed to characterize the role of PS1 in cholinergic muscarinic receptor signal transduction pathways. We studied the effect of three FAD PS1 mutants (deltaE9, M146V and L250S) and two dominant negative PS1 mutants (D257A and D385N) on basal and carbachol-stimulated phosphoinositide (PI) hydrolysis and intracellular calcium concentrations ([Ca2+]i) in SH-SY5Y neuroblastoma cells. We found a significant increase in basal PI hydrolysis in PS1 deltaE9 and PS1 M146V, but not in PS1 L250S, cells. All PS1 deltaE9, PS1 M146V and PS1 L250S cells showed a significant increase in carbachol-induced [Ca2+]i as compared to non-transfected or wild-type PS1 transfected cells. The elevated carbachol-induced [Ca2+]i signals were reversed by PLC inhibition and by ryanodine receptor blockade in all mutant PS1 cell lines. In PS1 M146V and PS1 L250S cells, pharmacological gamma-secretase inhibition was also able to reverse the elevated carbachol-induced [Ca2+]i signals. Cells expressing dominant negative PS1 had attenuated carbachol-stimulated PI hydrolysis and [Ca2+]i responses. In NT or WT PS1 cells pharmacological inhibition of gamma-secretase attenuated carbachol-stimulated PI hydrolysis and [Ca2+]i responses to levels found in PS1 dominant negative cells. The findings of these reports suggest that PS1 can regulate PLC activity and that this function is gamma-secretase activity dependent. In conclusion, these studies provide evidence that PS1 regulates both cholinergic signal transduction pathways and apoptotic cell death and that PS1 mutations are responsible for both sensitizing neurons to death and altering neuronal signal transduction