Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)–rich protein aggregates [termed “Lewy bodies” (LBs)], is a well-established characteristic of Parkinson’s disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning–based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneration.
Background: Observational studies have suggested that accelerated surgery is associated with improved outcomes in patients with a hip fracture. The HIP ATTACK trial assessed whether accelerated surgery could reduce mortality and major complications. Methods:We randomised 2970 patients from 69 hospitals in 17 countries. Patients with a hip fracture that required surgery and were ≥45 years of age were eligible. Patients were randomly assigned to accelerated surgery (goal of surgery within 6 hours of diagnosis; 1487 patients) or standard care (1483 patients). The co-primary outcomes were 1.) mortality, and 2.) a composite of major complications (i.e., mortality and non-fatal myocardial infarction, stroke, venous thromboembolism, sepsis, pneumonia, life-threatening bleeding, and major bleeding) at 90 days after randomisation. Outcome adjudicators were masked to treatment allocation, and patients were analysed according to the intention-to-treat principle; ClinicalTrials.gov, NCT02027896. Findings:The median time from hip fracture diagnosis to surgery was 6 hours (interquartile range [IQR] 4-9) in the accelerated-surgery group and 24 hours (IQR 10-42) in the standard-care group, p<0.0001. Death occurred in 140 patients (9%) assigned to accelerated surgery and 154 patients (10%) assigned to standard care; hazard ratio (HR) 0.91, 95% CI 0.72-1.14; absolute risk reduction (ARR) 1%, 95% CI -1-3%; p=0.40. The primary composite outcome occurred in 321 patients (22%) randomised to accelerated surgery and 331 patients (22%) randomised to standard care; HR 0.97, 95% CI 0.83-1.13; ARR 1%, 95% CI -2-3%; p=0.71.Interpretation: Among patients with a hip fracture, accelerated surgery did not significantly lower the risk of mortality or a composite of major complications compared to standard care.
Chronic inflammation is a major characteristic feature of Parkinson’s disease (PD). Studies in PD patients show evidence of augmented levels of potent pro-inflammatory molecules e.g., TNF-α, iNOS, IL-1β whereas in experimental Parkinsonism it has been consistently demonstrated that dopaminergic neurons are particularly vulnerable to activated glia releasing these toxic factors. Recent genetic studies point to the role of immune system in the etiology of PD, thus in combination with environmental factors, both peripheral and CNS-mediated immune responses could play important roles in onset and progression of PD. Whereas microglia, astrocytes and infiltrating T cells are known to mediate chronic inflammation, the roles of other immune-competent cells are less well understood. Inflammation is a tightly controlled process. One major effector system of regulation is HPA axis. Glucocorticoids (GCs) released from adrenal glands upon stimulation of HPA axis, in response to either cell injury or presence of pathogen, activate their receptor, GR. GR regulates inflammation both through direct transcriptional action on target genes and by indirectly inhibiting transcriptional activities of transcriptional factors such as NF-κB, AP-1 or interferon regulatory factors. In PD patients, the HPA axis is unbalanced and the cortisol levels are significantly increased, implying a deregulation of GR function in immune cells. In experimental Parkinsonism, the activation of microglial GR has a crucial effect in diminishing microglial cell activation and reducing dopaminergic degeneration. Moreover, GCs are also known to regulate human brain vasculature as well as blood brain barrier (BBB) permeability, any dysfunction in their actions may influence infiltration of cytotoxic molecules resulting in increased vulnerability of dopamine neurons in PD. Overall, deregulation of glucocorticoid receptor actions is likely important in dopamine neuron degeneration through establishment of chronic inflammation.
Reliable cerebral rSO2 readings before, during, and after shunt tap were demonstrated. Left cerebral rSO2 changes from before to after shunt tap were more predictive for shunt malfunction location than right cerebral rSO2 changes. Observing cerebral rSO2 changes in relationship to shunt tap represents a potential surrogate in measuring cerebral pressures and blood flow changes after cerebral spinal fluid drainage. Significantly greater cerebral rSO2 changes occur for distal malfunction versus proximal malfunction after shunt tap, indicating its potential as an adjunct tool for detecting shunt malfunction type.
Octodon degus (O. degus) is a diurnal rodent that spontaneously develops several physiopathological conditions, analogous in many cases to those experienced by humans. In light of this, O. degus has recently been identified as a very valuable animal model for research in several medical fields, especially those concerned with neurodegenerative diseases in which risk is associated with aging. Octodon degus spontaneously develops β-amyloid deposits analogous to those observed in some cases of Alzheimer's disease (AD). Moreover, these deposits are thought to be the key feature for AD diagnosis, and one of the suggested causes of cell loss and cognitive deficit. This review aims to bring together information to support O. degus as a valuable model for the study of AD.
The expression of OL‐protocadherin, a homotypically binding cell adhesion molecule, was mapped in the visual system of the chicken embryo at intermediate to late stages of development (11–19 days of incubation). The expression was compared with that of four classic cadherins, described previously. OL‐protocadherin is expressed by the isthmooptic nucleus, its retinopetal projection, and possibly its retinal target neurons, the amacrine cells. Ganglion cells begin to express OL‐protocadherin at relatively late stages of development. The layers of the optic tectum, the projection neurons in the stratum griseum centrale, and the tectofugal pathways show differential OL‐protocadherin immunoreactivity. Several of the diencephalic target nuclei of the tectothalamic projection, such as the principal pretectal nucleus, subpretectal nucleus, and nucleus rotundus, contain distinct subregions or populations of neurons expressing OL‐protocadherin. In these centers, the expression pattern of OL‐protocadherin differs from that of the four classic cadherins, though it shows partial overlap with them. Other retinorecipient and/or tectorecipient nuclei (ventral geniculate nucleus, lateral dorsolateral nucleus, superficial synencephalic nucleus, pretectal area, and griseum tectale) also show a differential immunoreactivity for OL‐protocadherin and other cadherins. Some of these nuclei and the optic tectum display a similar sequence of cadherin expression from superficial to deep layers, in a pattern that may reflect mutual interconnections. This result indicates a partial conservation of cadherin expression across interconnected embryonic divisions, from the mesencephalon to the ventral thalamus. In conclusion, OL‐protocadherin is a marker for specific functional gray matter structures and neural circuits in the chicken visual system. J. Comp. Neurol. 470:240–255, 2004. © 2004 Wiley‐Liss, Inc.
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