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Vaccination to Alzheimer Disease. Is it a Promising Tool or a Blind Way?
Alzheimer disease (AD) is an irreversible neurodegenerative disorder associated with cognitive dysfunction. The disease incidence has growing tendency worldwide with strong impact on healthcare funds. The fact that there is no effective therapy makes the disorder more serious. Currently, AD manifestation can be suppressed by having impact on enzyme acetylcholinesterase: donepezil, rivastigmine, and galantamine or ionotropic glutamate NMDA receptor ( memanitine). Contrary to the drugs effecting symptomatically, vaccination against amyloid plaques or neurofibrillary tangles and their precursors amyloid beta and hyperphosphorylated tau are expected to be more suitable. Huge numbers of works have been done on the issue. Unfortunately, the promising vaccines like the AN 1792 were halted during clinical trials because of adverse effects like meningoencephalitis. Monoclonal antibody specific to amyloid plaques, Bapineuzumab, was closest to the practical performance but the clinical trials were also stopped. The review summarizes facts about AD, opportunities in AD vaccination, and obstacles that limit the vaccination including reasons why the recent trials have fallen.
H2020 and Beyond: Skip Discrepancy between Theory and Practice of Personalized Medicine. A Position Paper by the Italian Society of Personalized Medicine
Many unsolved practical issues, from technical and scientific to ethical, legal and economic topics, are slowing down the translation of Personalized Medicine principles into medical practice. The Italian Society of Personalized Medicine exposes here its point of view, based on the real-world practice of precision medicine carried-out in Italian healthcare structures.
Traumatic Brain Injury as a Risk Factor for Alzheimer’s Disease: Is Inflammatory Signaling a Key Player?
Traumatic brain injury (TBI) has become a significant medical and social concern within the last 30 years. TBI has acute devastating effects, and in many cases, seems to initiate long-term neurodegeneration. With advances in medical technology, many people are now surviving severe brain injuries and their long term consequences. Post trauma effects include communication problems, sensory deficits, emotional and behavioral problems, physical complications and pain, increased suicide risk, dementia, and an increased risk for chronic CNS diseases, such as Alzheimer’s disease (AD). </p><p> In this review, we provide an introduction to TBI and hypothesize how it may lead to neurodegenerative disease in general and AD in particular. In addition, we discuss the evidence that supports the hypothesis that TBI may lead to AD. In particular, we focus on inflammatory responses as key processes in TBI-induced secondary injury, with emphasis on nuclear factor kappa B (NF-κB) signaling. </p><p>
Serotonergic Drugs: Agonists/Antagonists at Specific Serotonergic Subreceptors for the Treatment of Cognitive, Depressant and Psychotic Symptoms in Alzheimer’s Disease
Background: Alzheimer’s disease is a neurodegenerative disease showing alterations in classical neurotransmitters, above all in the hippocampus and prefrontal/temporal cortices. In this disease, acetylcholine shows hypoactivity, noradrenaline first shows hyperactivity, and during the course of the disease an increasing hypoactivity, glutamate shows hyperactivity and excitotoxicity and GABA shows hypoactivity. In post-mortem studies, serotonin levels and the number of specific serotonergic subreceptors, for example 5-HT<sub>1B</sub> receptors, decreased. Methods: We summarized the alterations of classical neurotransmitters in the brain regions involved in cognitive, depressive and psychotic symptoms in Alzheimer’s disease. Starting from these neurotransmitter alterations, we describe neural networks including specific serotonergic subreceptors in the involved brain regions. Results: In the hippocampus and prefrontal cortex, serotonin levels are associated with cognitive functions, whereas in the brainstem serotonin levels are related with affective symptoms. Psychotic symptoms which can occur in patients with Alzheimer’s disease are associated with dopamine and serotonin hyperactivity in the mesolimbic system and hippocampus. The interaction between classical neurotransmitters and their specific subreceptors is shown in different brain areas. Conclusion: In clinical trials, the therapeutic effects of 5-HT<sub>4</sub>, 5-HT<sub>7</sub> agonists and 5-HT<sub>3</sub>, 5-HT<sub>6</sub> antagonists have been examined to improve cognitive symptoms in Alzheimer’s disease. In these trials, 5-HT<sub>4</sub> agonists and 5-HT<sub>4</sub> antagonists showed a significant better effect in improving cognitive functions than placebo. The effect of such drugs on the formation of amyloid plaques is also examined. The appropriate use of antidepressant and antipsychotic drugs with an agonism or antagonism at specific serotonergic subreceptors is pointed out. Serotonin-selective antidepressant drugs significantly improve depressant symptoms and daily activities in Alzheimer patients and they are used to treat aggressive behaviour. Among the second-generations antipsychotic drugs (D<sub>2</sub> and 5-HT<sub>2A</sub> antagonists), drugs with a favorable metabolic profile should be used.
Promising Therapies for Alzheimer's Disease
Background: Alzheimer’s disease (AD) is the most frequent progressive neurodegenerative disease. Cholinergic dysfunction is one of the major pathological alteration, although depletion of cholinergic neurons is caused by the well-established toxicity of the beta-amyloid plaques and neurofibrillary tangles. Cholinergic dysfunctions are consequences of the decrease in acetylcholine synthesis and release, and altered function of muscarinic and nicotinic cholinergic receptors. In addition, a direct correlation between cholinergic alteration, amyloidbeta production and tau phosphorylation, two main AD-pathology hallmarks, has been identified. Methods: In the present review we focused our discussion on the identification of new allosteric or bitopic ligands able to modulate the cholinergic receptor activity. Moreover drug delivery methodology (nanoparticeles, liposomes, etc.) that might contribute to drive the drug in the brain, reducing their toxicity and potential side effects have been also discussed. Results: Many drugs are currently in use for AD (e.g. donepezil, rivastigmine etc.) and several of those in development such as muscarininc and nicotinic agonists, target specifically the cholinergic system; the main mechanism aims to rescue the cholinergic dysfunction, to reduce neurotoxic protein accumulation and improve the cholinergic impairments responsible of the cognitive deficits. Promising approaches aim to either improve drug delivery into the brain or develope new compounds targeting known or new molecular pathways. Nanoparticles and liposomes are also described as new nanotechnology tools that overcome traditional routes of administration, with a particular focus on their employment for compounddelivery that targets the cholinergic system. Ultimately, a new fields of research is emerging as the use of induced pluripotent stem cells, a technology that allows to obtain cells directly from the patients that can be propagated indefinetely and differentiated into the susceptible neuronal subtypes. This may significantly contribute to improve the understanding of AD pathological processes and enhance current AD pharmacology beyond the cholinergic dysfunction. Conclusion: From the topics discussed in the present review, emerges that the combination between pharmacological studies and nanotechnological approaches for drug delivery and the identification of new specific models may largely enhance and improve the therapeutic strategies for different neurological disease including AD.
Designing Multi-Targeted Therapeutics for the Treatment of Alzheimer's Disease
Due to multi-faceted pathology of AD; no drug can seize the progress of the disease, whereas only the symptomatic treatment is available at the moment. Several drug classes to treat AD are available in clinical use, AChEIs being the most prescribed. In addition to AChEIs, secretase enzymes and iron chelators have turned out to be the focus of research and the popular targets in drug discovery against AD. The latest approaches such as immunotherapy, multi-targeted drug ligand design, AChE inhibitors, antioxidants, metal chelators, monoamine oxidase (MAO) inhibitors, antiinflammatory drugs, and N-methyl-D-aspartate (NMDA) inhibitors are currently in use to cure this disease to some extent. But, there is a certain need to develop new drugs to fight with AD, particularly acting on multi-targets or with dual mechanisms of action. In this review, a particular emphasis will be focused on multitargets aiming at AD to design new drug molecules with respect to treatment strategies and preventive measures. Since the underlying pathogenesis of AD is complicated and still under investigation, the attempts to design highly selective and potent agents to treat AD are quite intensively continuing. In this respect, designing novel drugs with dual/multi-acting mechanisms seems to be more rational.
Treatment for Cancer Patients with Oral Mucositis: Assessment Based on the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer in International Society of Oral Oncology (MASCC/ISOO) in 2013 and Proposal of Possible Novel Treatment with a Japanese Herbal Medicine
The cancer patients who received chemotherapy, radiotherapy, hematopoietic stem cell transplant and terminal care often have a wide range of stomatitis, which induces severe pain and limits fundamental life behaviors such as “eating, drinking and talking”. In addition, oral mucositis frequently leads to systemic infection through opportunistic microorganisms, which causes extension of hospitalization. Severe oral mucositis often causes cancer patients to partially or completely discontinue/modify cancer therapy regimen, which adversely affects the curative effects of cancer. Therefore, the control of oral mucositis is important and indispensable for improvement of quality of life and prognosis. In this review, we introduce recent trends of the oral mucositis management in cancer patients, according to the following sentences; 1) pathophysiological mechanisms of oral mucositis, 2) assessment, 3) risk factors, 4) prevention and treatment, and 5) development of novel therapy for oral mucositis.
Left Anterior Temporal Glucose Metabolism and not Amyloid-beta Load Predicts Naming Impairment in Alzheimer’s Disease
Naming impairment in Alzheimer’s disease dementia (AD) is associated with atrophy of the left anterior temporal lobe (ATL). We aimed to elucidate if regional cerebral glucose metabolism, as a biomarker of synaptic dysfunction and neurodegeneration, of the left ATL predicts naming impairment, and if amyloid-beta (Aβ) deposition, a pathological hallmark of AD, contributes to the prediction. </p> <p> Twenty-nine patients with AD underwent combined [<sup>11</sup>C]PIB and [<sup>18</sup>F]FDG PET examinations for assessment of Aβ load and regional cerebral glucose metabolism. An a priori defined region of interest was used for regional PET analyses of the left ATL. In linear stepwise regression analyses, glucose metabolism of the left ATL was the only significant predictor of naming performance, independent of sex, age, and education. Neither regional nor global Aβ load contributed to the prediction. </p> <p> Left ATL glucose metabolism predicts naming impairment in AD. By contrast, Aβ deposition does not predict naming impairment. </p>
High Content, Multi-Parameter Analyses in Buccal Cells to Identify Alzheimer’s Disease
Alzheimer’s disease (AD) is a degenerative brain disorder and is the most common form of dementia. Minimally invasive approaches are required that combine biomarkers to identify individuals who are at risk of developing mild cognitive impairment (MCI) and AD, to appropriately target clinical trials for therapeutic discovery as well as lifestyle strategies aimed at prevention. Buccal mucosa cells from the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing cohort (n=60) were investigated for cytological markers that could be used to identify both MCI and AD individuals. Visual scoring of the buccal cytome demonstrated a significantly lower frequency of basal and karyorrhectic cells in the MCI group compared with controls. A high content, automated assay was developed using laser scanning cytometry to simultaneously measure cell types, nuclear DNA content and aneuploidy, neutral lipid content, putative Tau and amyloid-β (Aβ) in buccal cells. DNA content, aneuploidy, neutral lipids and Tau were similar in all groups. However, there was significantly lower Tau protein in both basal and karyolytic buccal cell types compared with differentiated buccal cells. Aβ, as measured by frequency of cells containing Aβ signal, as well as area and integral of Aβ signal, was significantly higher in the AD group compared with the control group. Buccal cell Aβ was correlated with mini-mental state examination (MMSE) scores (r = -0.436, P=0.001) and several blood-based biomarkers. Combining newly identified biomarkers from buccal cells with those already established may offer a potential route for more specific biomarker panels which may substantially increase the likelihood of better predictive markers for earlier diagnosis of AD.
The Interaction Between Gender and Diabetes Mellitus in the Coronary Heart Disease Risk
Background: Cardiovascular disease (CVD) despite the advances in medical management keeps on as the primary cause of morbidity and mortality for both genders in Western societies. Sex differences though modify the clinical picture as well as the effectiveness of treatment. </p><p> Methods and Results: In this literature review article we searched publications in Englishlanguage on MEDLINE and the Cochrane Database from the beginning of the databases to January 2016. Among the specific key words and phrases we used were Diabetes Mellitus; Gender; Coronary artery disease; Stroke and Cardiovascular disease. Various studies have found that diabetic women have increased risk of coronary heart disease than their male counterparts; however, further research into this field has questioned this finding and there is much controversy among many researchers. Women have a different risk factor profile, are usually treated less effectively than men, and have a variance in the levels of sex hormones throughout their life which complicate the study and understanding of the mechanisms involved in insulin resistance, diabetes mellitus and cardiovascular risk profile. </p><p> Conclusion: The connection between diabetes mellitus and cardiovascular disease is variable according to gender and further studies are needed to elucidate the lenient differentiations in gender specific hormones, risk factor profile, and therapeutic implications between genders. </p><p>
The Role of α7 Nicotinic Acetylcholine Receptors and α7-Specific Antibodies in Neuroinflammation Related to Alzheimer Disease
Background: Alzheimer disease (AD) is a neurodegenerative disorder occurring in elderly people and leading to the loss of memory, practical and speaking habits. In spite of extensive efforts undertaken during the last decades, there is still no generally recognized explanation of the origin and primary pathological changes leading to AD development. Consequently, the suggested pharmacological approaches to treat the AD patients are mostly symptomatic and do not stop the disease progression. Neuroinflammation and cholinergic deficit usually accompany AD development. However, their impact in AD progression still waits for being properly recognized. </p> <p> Objective: The present review aims at analysis of the role of inflammation and nicotinic acetylcholine receptors, primarily of α7 subtype (α7 nAChRs), in the development of AD in humans and AD-like symptoms in experimental animals. </p> <p> Results: The reviewed data describe the involvement of α7 nAChRs in the AD pathogenesis, in particular, through their interaction with amyloid-β, maintenance of brain cell viability and regulation of neuroinflammation. They also delineate the role of α7-specific (auto)antibodies in stimulating neuroinflammation, memory impairment in mice and AD progression in humans. </p> <p> Conclusion: Neuroinflammation is suggested as a primary stimulus sufficient to trigger accumulation of pathologically processed amyloid-β, degeneration of cholinergic neurons and memory impairment. The level of α7 nAChR expression in the brain is critical for supporting the resistance to inflammatory and apoptogenic agents. The data presented may be a basis to create a new strategy for preventing and, possibly, slowing AD development in humans.
Omega-3 Fatty Acids in the Management of Epilepsy
Omega-3 and omega-6 fatty acids are polyunsaturated fatty acids (PUFAs) with multiple double bonds. Linolenic and alpha-linolenic acids are omega-6 and omega-3 PUFAs, precursors for the synthesis of long-chain PUFAs (LC-PUFAs), such as arachidonic acid (omega-6 PUFA), and eicosapentaenoic and docosahexaenoic acids (omega-3 PUFAs). The three most important omega-3 fatty acids are alpha-linolenic, eicosapentaenoic and docosahexaenoic acids, which cannot be synthesized in enough amounts by the body, and therefore they must be supplied by the diet. Omega-3 fatty acids are essential for the correct functioning of the organism and participate in many physiological processes in the brain. Epilepsy is a common and heterogeneous chronic brain disorder characterized by recurrent epileptic seizures leading to neuropsychiatric disabilities. The prevalence of epilepsy is high achieving about 1% of the general population. There is evidence suggesting that omega-3 fatty acids may have neuroprotective and anticonvulsant effects and, accordingly, may have a potential use in the treatment of epilepsy. In the present review, the potential use of omega-3 fatty acids in the treatment of epilepsy, and the possible proposed mechanisms of action are discussed. The present article summarizes the recent knowledge of the potential protective role of dietary omega-3 fatty acids in epilepsy.
Glial Cells – The Key Elements of Alzheimer´s Disease
Alzheimer’s disease (AD) is a complex neurodegenerative disorder with major clinical hallmarks of memory loss, dementia, and cognitive impairment. Besides the extensive neuron-oriented research, an increasing body of evidence suggests that glial cells, namely astrocytes, microglia, NG2 glia and oligodendrocytes, may play an important role in the pathogenesis of this disease. In the first part of this review, AD pathophysiology in humans is briefly described and compared with disease progression in routinely used animal models. The relevance of findings obtained in animal models of AD is also discussed with respect to AD pathology in humans. Further, this review summarizes recent findings regarding the role/participation of glial cells in pathogenesis of AD, focusing on changes in their morphology, functions, proteins and gene expression profiles. As for astrocytes and microglia, they are fundamental for the progression and outcome of AD either because they function as effector cells releasing cytokines that play a role in neuroprotection, or because they fail to fulfill their homeostatic functions, ultimately leaving neurons to face excitotoxicity and oxidative stress. Next, we turn our attention towards NG2 glia, a novel and distinct class of glial cells in the central nervous system (CNS), whose role in a variety of human CNS diseases has begun to emerge, and we also consider the participation of oligodendrocytes in the pathogenesis and progression of AD. Since AD is currently an incurable disease, in the last part of our review we hypothesize about possible glia-oriented treatments and provide a perspective of possible future advancements in this field.
In Silico Analysis of Green Tea Polyphenols as Inhibitors of AChE and BChE Enzymes in Alzheimer’s Disease Treatment
Alzheimer’s disease (AD) is the most frequent cause of dementia, especially in the elderly. AD is the most common progressive neurodegenerative disorder, which involves the loss of structure and function of cholinergic neurons. Moreover, if these neuronal changes cannot be compensated, this may ultimately lead to neurodegenerative processes. Therefore, most of the drug therapies are based on the cholinergic hypothesis, which suggests that AD begins as a deficiency in the production of the neurotransmitter acetylcholine. In this context, many inhibitors play an important role in AD treatment among which acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) have more potential in the treatment process of AD. In this study, we selected tea polyphenols of green tea which are reported as AChE and BChE inhibitors used in the treatment of AD. The molecular docking results revealed that polyphenols exhibit interactions and inhibit by binding with AChE and BChE. The amount of energy to bind with AChE and BChE needed by Epigallocatechin-3-gallate was lowest at about -14.45 and -13.30 kcal/mol, respectively. All compounds showed binding energy values ranging between -14.45 to -9.75 kcal/mol for both types of enzymes. The present docking study suggests that tea polyphenols inhibit AChE as well as BChE and enhance the cholinergic neurotransmission by prolonging the time. However, AChE molecules remain in the synaptic cleft. In consideration to these findings, cholinesterase inhibitors are suggested as the standard drugs for the treatment of AD.
Resveratrol as a Potential Therapeutic Candidate for the Treatment and Management of Alzheimer’s Disease
Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytochemical present in red wine, grapes, berries, chocolate and peanuts. Clinically, resveratrol has exhibited significant antioxidant, anti-inflammatory, anti-viral, and anti-cancer properties. Although resveratrol was first isolated in 1940, it was not until the last decade that it was recognised for its potential therapeutic role in reducing the risk of neurodegeneration, and Alzheimer's disease (AD) in particular. AD is the primary cause of progressive dementia. Resveratrol has demonstrated neuroprotective effects in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that resveratrol also facilitates non-amyloidogenic breakdown of the amyloid precursor protein (APP), and promotes removal of neurotoxic amyloid beta (Aβ) peptides, a critical step in preventing and slowing down AD pathology. Resveratrol also reduces damage to neuronal cells via a variety of additional mechanisms, most notably is the activation of NAD<sup>+</sup>-dependent histone deacetylases enzymes, termed sirtuins. However in spite of the considerable advances in clarifying the mechanism of action of resveratrol, it is unlikely to be effective as monotherapy in AD due to its poor bioavailability, biotransformation, and requisite synergism with other dietary factors. This review summarizes the relevance of resveratrol in the pathophysiology of AD. It also highlights why resveratrol alone may not be an effective single therapy, and how resveratrol coupled to other compounds might yet prove an effective therapy with multiple targets.
Intracellular Aβ and its Pathological Role in Alzheimer’s Disease: Lessons from Cellular to Animal Models
Accumulation of intraneuronal amyloid-β peptide (Aβ) appears to be an early event in Alzheimer's disease (AD), suggesting its important role in the neurodegenerative process of AD. It is indicated that intracellular Aβ originates from a portion of Aβ, which is not secreted and consequently remains intracellular, or alternatively from the secreted Aβ, which is internalized into intracellular Aβ pool. A number of cell and transgenic animal models are established to study the pathological role of intracellular Aβ, and to screen for drugs against Aβ aggregation and associated toxicity. Aβ aggregates, particularly oligomers, may lead to synaptic dysfunction and neuronal loss. Screened from high-throughput methods, a number of cellpermeable agents reduce the aggregation of intracellular Aβ and antagonize its cytotoxicity by inhibiting the formation of Aβ oligomers in vivo. The multi-functional roles of Aβ in alternate pathways and associated clinical implications for AD treatment are also discussed.
The TT allele of rs405509 synergizes with APOE ε4 in the impairment of cognition and its underlying default mode network in non-demented elderly
Background: Evidence demonstrates that the T allele of the single-nucleotide polymorphism rs405509 as the apolipoprotein E (APOE) promoter is a risk factor for Alzheimer’s disease (AD). However, it is unclear the APOE-rs405509 interaction effect on brain spontaneous activity. Methods: We analyzed the interaction of the rs405509 TT allele and the APOE ε4 allele on cognitive performances measured using neuropsychological tests and brain default mode network (DMN) defined by independent component analysis using based on resting-state functional magnetic resonance imaging data among the non-demented elderly people. Results: Significant interaction was found between rs405509 and APOE on general mental status, memory and attention (p<0.05). Functional network analysis showed a significantly APOE-rs405509 interaction on anterior cingulate gyrus, medial frontal region and precuneus at anterior and posterior DMN (False Discovery Rate p<0.05). Additionally, significant correlations were found between cognitive performance and DMN connectivity (p<0.05). Conclusion: The data indicates that the APOE-rs405509 interaction impairs elderly’s cognitive performance through brain functional network.
Lack of Association Between SLC24A4 Polymorphism and Late-onset Alzheimer's Disease in Han Chinese
Recently, a single nucleotide polymorphism rs10498633 on solute carrier family 24 member 4 (SLC24A4) was revealed to be closely related to the risk of late-onset Alzheimer's disease (LOAD) in a large genome-wide association study containing 74046 individuals in Caucasians. However, no study was performed to validate this relation in other ethnic populations, including Han Chinese. Therefore, we recruited 992 LOAD patients and 1358 age- and sex- matched healthy controls to validate the association between rs10498633 and LOAD susceptibility in Han Chinese. In our total sample, no significant difference was observed between the minor (T) allele of rs10498633 and LOAD risk under a dominant genetic model (OR=0.903, 95% CI: 0.738-1.104, P=0.320). In addition, no significant relation was noted between rs10498633 and LOAD risk in neither apolipoprotein E (APOE) ε4 carriers nor non-carriers after adjusting for age and gender. Therefore, our findings indicate that rs10498633 may not play a major role in LOAD susceptibility in Han Chinese.
Effects of Yokukansan, a Japanese Kampo Medicine for Symptoms Associated Autism Spectrum Disorder
A neuropsychiatric syndrome, Autism spectrum disorder (ASD) is qualified via impairments in qualitative communication, social interaction, and stereotyped or restricted, repetitive patterns of behavior, interests, or activities. While all ASDs are considered to have qualitative deficits in social relatedness to others, many people with ASDs have other symptoms, including irritability (which includes aggression, self-injurious behavior, and severe tantrums). In order to decrease these behaviors, it is often helpful to make use of behavioral therapy. In addition, due to the intensity and severity of irritability, adjunctive medications are sometimes needed. Although many of the adjunctive medications have been tested and demonstrated to be useful in treating ASD, no clear standardized treatment has emerged. While the adjunctive medications have shown efficacy, the associated side effects have proven to be a barrier to their accepted use. A traditional Japanese medicine, Yokukansan (YKS), is composed of seven kinds of dried herbs and is widely clinically prescribed for treating psychiatric disorders by acting mainly on the glutamatergic and serotonergic nervous systems. YKS may be safe and useful in treating dementia patients’ behavioral and psychological symptoms according to indications from recent studies. We introduce in this review, the ameliorative effects of YKS on Asperger's disorder in open-label studies and on ASDs including pervasive developmental disorder not otherwise specified (PDD-NOS). This review will suggest that YKS is well tolerated and effective for the treatment for subjects with ASD who have severe hyperactivity/noncompliance and irritability/agitation. Additionally, the serotonergic, glutamatergic, anti-inflammatory and neurogenesis effects are explored which are thought to be involved in the mechanisms underlying the efficacy of YKS.
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