neuroregeneration fix beutt
DESCRIPTION
kjhgbvcTRANSCRIPT
![Page 1: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/1.jpg)
JOURNAL READING
Presented by : FK UKISupervisor : dr. Sabar Siregar,
SpKJDepartment of Psychiatry Faculty of medicineChristian University of Indonesia,Jakarta
![Page 2: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/2.jpg)
ABSTRACT
![Page 3: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/3.jpg)
ABSTRACTIn the last years,
physiological aging became a general
concept that includes all the changes that occur
in organism with old age
One of these major concerns is probably
dementia.
Sooner or later, all forms of dementia lead
to learning deficit, memory loss, low attention span,
impairment of speech and poor problem
solving skills.
In this review, try to highlight some of the
newest aspects of therapeutic
strategies that can improve natural
neuroregeneration
![Page 4: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/4.jpg)
Introduction
![Page 5: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/5.jpg)
INTRODUCTION In developing and developed countries, new health
problems concerning specific needs of older populations arise. One of the major health concerns in this aspect is dementia.
Dementia is a clinical term used to characterize a number of diseases with neuropsychiatric symptoms, that are not explained by delirium or major psychiatric disorder
![Page 6: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/6.jpg)
INTRODUCTION All changes that occur in all organs and systems
associated with old age is now generally accepted as physiological ageing
![Page 7: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/7.jpg)
INTRODUCTIONBrain ageing is associated with structures and functions decline both is neurons and glia. This is generally referred as neurodegeneration
It is a normal process that can lead to reductions in communication and in memory function but also to poor recovery after stroke
Neurodegeneration is a progressive process that occurs because of a decline in the total number of neurons; generally, this process is due to apoptosis and is associated with a loss of neuronal structure and function
![Page 8: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/8.jpg)
INTRODUCTION
AIMED
and by discussing contradictory results
of different researcher groups
summarizing up to-date findings
described evaluated by a
number of different authors
![Page 9: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/9.jpg)
Neuroregeneration and aging
![Page 10: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/10.jpg)
Physiological ageing is now generally accepted as a concept that includes all the changes that occur in all organs and systems associated with old age, characterized by the declining ability to respond to different types of stress, homeostatic imbalance and diseases.
The phenomena involved in brain ageing are associated with a decline of the neuronal and glial structures and functions, which can lead to reductions in communication and in memory function and also to poor recovery after stroke
![Page 11: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/11.jpg)
Neurodegeneration is a process is due to apoptosis and is associated with a loss of neuronal structure and function.
Ageing is considered the most important risk factor for brain degeneration and age-related cognitive disorders
![Page 12: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/12.jpg)
An increasing susceptibility to poor recovery from brain injury has been observed in the elderly. Regeneration of neuronal tissue makes no exception however the pathways for the cellular processes that characterize these phenomena have yet to be found.
The concept of neuregeneration can be also defined as the superposition of three distinctive processes including neurogenesis, neuroplasticity and neurorestoration
![Page 13: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/13.jpg)
However, older organisms, including humans, have reported a decline in the rate of neurogenesis. Hippocampal neurogenesis seems to persist also in adult age. With ageing, the proliferation and differentiation of neural progenitors are significantly decreased with a higher number of newborn death neurons.
![Page 14: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/14.jpg)
The neural stem cells are entering in a quiescent state.
Another possibility can be that the expression of some transcription
factors (Er81 and Dlx2) associated with neural development are
reduced in the elderly
Another effect can be the reduction in telomerase activity.
• supported by the hypothesis that aged neural stem cells are intrinsically different from the younger one
• A study on adult mice deficient in telomerase activity, reported poor neurogenesis in hippocampal areas, associated with a lower number of proliferation (Ki67+) or immature (Dcx+) cells
![Page 15: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/15.jpg)
Potential mechanisms responsible for the age-
related decline in neurogenesis
Artegiani B, Calegari F. Age-related cognitive decline: can neural stem cells help us?. 2012 (1)
![Page 16: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/16.jpg)
Nevertheless, extrinsic factors from the local environment neurogenic niche) can regulate neurogenesis. In old age, lower levels for different growth factors that can facilitate neurogenesis (fibroblast growth factor-2, insulin growth factor-1 or vascular endothelial growth factor) were registered in the hippocampal area.
![Page 17: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/17.jpg)
Ageing and dementia
![Page 18: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/18.jpg)
Dementia has many different causes. Dementia is seen as a clinical term used to characterize a number of diseases such as Alzheimer's disease dementia, Lewy bodies dementia, vascular dementia, behavior variant frontotemporal dementia, primary progressive aphasia or any cognitive/behavioral changes with neuropsychiatric symptoms, that are not explained by delirium or major psychiatric disorder and interfere with one's ability to function with usual activities
![Page 19: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/19.jpg)
Common basis for neurodegenerationLevine D. Ninety percent of major disease are related to aging; understanding the genetics of aging is key to a longer healthier life. 2013 (2)
![Page 20: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/20.jpg)
PREVALENCE
At the moment it is estimated that 35.6
million people worldwide are diagnosed with
dementia
It is predicted that in approximately
20 years this number will
double
triple in the next 40 years
![Page 21: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/21.jpg)
Based on all the information the scientific community has gathered, the diagnostic criteria for dementia has became more accurate .
Treatment and management of dementia are generated by research based on results from studies.
Test subjects are patients with early stages of dementia.
As the population gets older, new criteria for diagnosing old elderly persons (>75 years old) are needed because the border between non pathological aged brain and dementia brain is becoming more unclear with age
![Page 22: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/22.jpg)
FIGURE 1
![Page 23: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/23.jpg)
As one gets older, multiple risk factors varying from: - childhood IQ , - obesity in middle age, - smoking,- hypertension, - high cholesterol - diabetes at midlife to stroke - atrophy in old age
contributeto dementia in
the elderly
![Page 24: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/24.jpg)
Scientific progress has found that a small number of highly conserved genes can have a positive effect on the length of a life span.
These genes act through a number of metabolic processes like the “reactive oxygen species” (ROS) representing one of the most incriminated and poorly understood contributors to brain ageing.
Acquiring defense from dietary antioxidants can protect against ROS induced damage
![Page 25: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/25.jpg)
Regardless of the risk factors, dementia is still a consequence of neuronal populations loss that cannot be compensated. It is unclear as to why there is such large individual variability in our population.
![Page 26: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/26.jpg)
Studies done on old elderly persons As people get older harder to distinguish between
a normal aged brain and a dementia affected brain The only objective and quantifiable diagnostic
criteria still remaining valid is cerebral atrophy Neuropathological examination can sometimes
detect individual with microscopic features typical of late-onset Alzheimer’s but no clinical history of dementia.
Other times, individuals diagnosed with late stage dementia during their life can show only mild pathological features of Alzheimer’s disease
![Page 27: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/27.jpg)
Relation between CVD and dementia
It is still not clear if cerebrovascular disease induces
dementia or.. if both have the same risk factors and thus
are indirectly linked
Studies on cerebrovascular system in elderly population have found that..The blood brain
barrier permeability
increases with normal age
can lead to the initiation/worsenig
n of cerebral microvasculr
disease/dementia
![Page 28: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/28.jpg)
An overlap can be found between vascular dementia (VaD) and Alzheimer dementia (AD) Spontaneous cerebral emboli were detected in
43% of AD patients and 45% in VaD cases
Associated with a cognitive and functional decline within 2 years
The patient also had an increase in psychiatric symptoms
![Page 29: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/29.jpg)
Neuropathological findings have shown that the burden and location of cerebral infarcts are associated with a cognitive decline
However.. No evidence was found that stroke
prevention treatment (esp antihypertensive agents) have any effect on dementia incidence.
![Page 30: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/30.jpg)
The best available neuropathological evidence and dementia are scarce, suggesting there are no boundaries between them.
![Page 31: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/31.jpg)
Treatment
![Page 32: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/32.jpg)
In order to remove various behavioral and psychological symptoms of dementia Many studies seek other ways of renewing
the natural cargo of brain neurons
Early onset dementia / late onset dementia
lead to the patient to be disoriented
in time, place, and identity
![Page 33: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/33.jpg)
Molecular modulation of mRNA expression
Recombinant DNA vaccine Composed of multiple specific inhibitory
domains of neurite growth inhibitors (NOIs) Mechanisms of action immunological, inducing
antibodies against the specific domains
3 good responses were observed
Little formation of soluble Aβ oligomer and amyloid plaques in the co-transgenic
mice brain
Attenuated neuronal degeneration
Protection against behavioral deficits
![Page 34: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/34.jpg)
Molecular modulation of mRNA expression
The modulation of mRNA expression regarding NOIs was also obtained using generated channelrhodopsin-mutant protein expressing microglia
By increasing the intracellular level of
the ion
can control microglial activation
cause repair/regeneration of
neural and oligodendrocytic
damage
![Page 35: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/35.jpg)
Zhang H, Wang FW, Yao IL, Hao AJ. Microglia-Friend or Foe. Frontiers in Bioscience. 2011; 3: 869-83
![Page 36: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/36.jpg)
Stem Cells Therapy Stem cells capable of being integrated into a
degenerative environment & releasing neurotrophic cytokines
may sustain endogenous neurogenesis and/or activate neuroprotective pathways (for nestin and connexin 43)
Quantification of these cytokines revealed a neurogenic/angiogenic predisposition of naive human chorial villi and amniotic fluid derived cells.
These cells also release significant amounts of brain-derived neurotrophic factors, as well as vascular endothelial growth factor
![Page 37: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/37.jpg)
Neurotrophic factors Among others:
the neurotrophin nerve growth factor (NGF), glial cell-derived neurotrophic factor (GDNF)
and brain-derived neurotrophic factor (BDNF)
Some degree of success has been obtained regarding survival, existence and regeneration of specific neuronal populations in the adult brain suffering from Parkinson's or Alzheimer's disease
![Page 38: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/38.jpg)
Natural Substances Cerebrolysin
A peptide preparation mimicking the action of neurotrophic factors
In vitro and in vivo studies showed that it enhances neurogenesis in dentate gyrus and subventricular zone
Other effect:Promotes neural progenitor cell
migration
Increases synaptic density
rebuilding neuronal
cytoarchitecture
Induces restorative processes
Decreases the infarct volume
and edema formation
And promotes functional recovery
![Page 39: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/39.jpg)
Natural Substances Quercetin, a natural flavonoid could be protective of
neuronal precursors of adult brain It neutralizes the oxidative stress by reducing peroxynitrite
formation, protein nitration and M2 isoform of pyruvate kinase depletion
Isoquercitrin (other flavonoid) also promotes neuronal differentiation through multiple Rho GTPase mediated mechanisms
Inactivation of RhoA/Rho kinase: isoquercitrin reduces 47% of the RhoA activity and induces neurite growth (at concentrations ≥ 40 μM).
Another mechanism is the affection of RhoA localization that underwent translocation to the cytoplasm
![Page 40: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/40.jpg)
Pathways in olygodendrocyte.Bhat P, Chakrabarty M, Thawani V, Saxena A. Signalled roads to Memory and Its Degeneration. Annals of Neurosciences. 2012; 19(2)
![Page 41: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/41.jpg)
Hormonal Substances Neurosteroid allopregnanolone (APα,
3α-hydroxy-5α-pregnan-20-one), a metabolite of progesterone that is normally generated in the nervous system
It promoted neurogenesis,
improved the cognitive function,
reversed the neurogenic
deficits in the hippocampal
dentate gyrus and the cerebral
subventricular zone
![Page 42: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/42.jpg)
Mechanism of allopregnanolone-induced neural stem cell and oligodendrocyte precursor progenitor mitosis.
Brinton RD. Neurosteroids as regenerative agents in the brain: therapeutic implications. Nature Reviews Endocrinology. 2013; 9: 241-50
![Page 43: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/43.jpg)
Hormonal Substances Melatonin has good antioxidant
properties In clinical trials using treatments with
melatonin has been effective in slowing the progression of Alzheimer's disease, but not of Parkinson's disease.
Melatonin has multiple ways of preserving mitochondrial homeostasis. It reduces free
radical generation by enhancing
mitochondrial glutathione levels
and
it safeguards proton potential and ATP
synthesis by stimulating complex I
and IV activities
![Page 44: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/44.jpg)
Conclusion Elucidating the cellular and molecular basis for
involved in neurodegeneration and neuroregeneration in the aging brain could reveal new therapeutic approaches to dementia in the elderly.
Development of novel and effective therapies to sustain the brain's self-repair will hopefully lead to an improved management of dementia in older population.
Multiple strategies should be targeted to prevent the development and the progression of the disease. Further investigation to update these strategies are required for an efficient therapeutic response in dementia.
![Page 45: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/45.jpg)
Critical Appraisal
![Page 46: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/46.jpg)
The critical appraisal instrument we used are the DISCERN instrument which has been designed to judge the quality of written information about treatment options.
![Page 47: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/47.jpg)
Are the aims clear? Yes, the publication has clear aims.
![Page 48: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/48.jpg)
Does it achieve its aims ? ? Yes, it is achieved its first aim which is to
summarize up to date findings describes and evaluates by a number of different authors
For example:
![Page 49: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/49.jpg)
Does it achieve its aims ? Cont’d But, the publication did not achieved its
second aim. This article does not discussing contradictory results of different research group
![Page 50: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/50.jpg)
Is it clear what source of information were used to compile the publication ??
Yes, it is clear. The article provided both in the text and in the bibliography.
![Page 51: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/51.jpg)
Is it clear when the information used/reported in the publication was produced ?
No. It is partially clear when the information used/reported in the publication was produced
??
?
![Page 52: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/52.jpg)
Is it balanced and unbiased ?? Yes the information is completely balanced
and unbiased.
![Page 53: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/53.jpg)
Does it provide details of additional sources of support & information ?
Yes, the publication provides full details of any additional source in bibliography
For example...
![Page 54: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/54.jpg)
Does it refer to areas of uncertainty ? No uncertainty about treatment choices is
mentioned
The author does not includes a clear reference to any uncertainty regarding treatment choice
![Page 55: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/55.jpg)
Does it describe how each treatment works? No, the details provided are unclear or
incomplete
There are no details of how the treatment is given or administeredNor the details of how the treatment works
![Page 56: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/56.jpg)
Does it describe the benefits of each treatment ? Yes, the benefit is described for each
treatment
![Page 57: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/57.jpg)
Does it describe the risk for each treatment? No risks are described for any of these
treatment
NO RISKS
![Page 58: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/58.jpg)
Does it describe what would happen if no treatment is used? No, the publication does not include any
reference to the risks or benefits of no treatment option
Does it describe how the treatment choices affect overall quality of life ? No, there is no reference to overall
quality of life in relation to treatment choices
![Page 59: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/59.jpg)
Is it clear that there may be more than one possible treatment choice ? It is partially clear. The publication indicate
that there may be more than one possible choice but the information is unclear on incomplete
Does it provide support for shared-decision making?
No, the publication does not provide any support for shared decision making.
![Page 60: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/60.jpg)
Conclusion Based on the question above, the overall
quality of the publication are moderate. The publication is a useful source of
information about treatment options but has some limitations. Additional information or support would definitely be needed.
![Page 61: Neuroregeneration FIX BEUTT](https://reader036.vdocuments.site/reader036/viewer/2022062411/577cc6751a28aba7119e47ff/html5/thumbnails/61.jpg)
THANK YOU