veronika borbélyová, msc., phd. · 2019. 3. 15. · (baron-cohen a kol., 2005) environmental...
TRANSCRIPT
![Page 2: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/2.jpg)
History • Eugen Bleuler
• autism (from the Greek words autos = self, ismus = orientation, status)
• the patient reduces the contact with the outside and he drifts into his own world (Bleuler, 1911)
![Page 3: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/3.jpg)
• Leo Kanner • “early infantile autism” • the inability of the child to relate to people and objects
in an appropriate manner
• lack of social relatedness = “extreme autistic aloneness”
• difficulties in adapting to changes in routines, the desire for sameness, impaired speech, limited spontaneous activity and abnormal reactions to some common stimuli from the environment (Kanner, 1943).
History
![Page 4: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/4.jpg)
• Hans Asperger
• children with impaired social interaction, motor stereotypies and clumsiness, stereotyped interests and impaired communication
• well-developed language and high intelligence (Asperger, 1944)
History
![Page 5: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/5.jpg)
Autism Spectrum Disorder (ASD)
![Page 6: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/6.jpg)
Survaillance year Number of ADDM
Sites Reporting Prevalence/
10 000 children
This is about 1 in X children
[year of publication]
2000 6 67 1 z 150 [2007]
2002 14 66 1 z 150 [2007]
2004 8 80 1 z 125 [2009]
2006 11 90 1 z 110 [2009]
2008 14 113 1 z 88 [2012]
2010 11 147 1 z 68 [2014]
2012 11 146 1 z 68 [2014]
Autism and Developmental Disabilities Monitoring (ADDM) Network
>
1 z 45
Prevalence of autism spectrum disorder (ASD) (ADDM Network: 2000 – 2012)
![Page 7: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/7.jpg)
What is the exact cause of the higher rates of ASD?
• Still not clear
•different methodologies used across studies •different screening and diagnostic instruments •the ever-changing diagnostic criteria for the disorder •the increased public awareness and increased availability of educational services •inaccurate diagnoses •geographical location (rural or urban area) • variations in the size and type of the target population
![Page 8: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/8.jpg)
How is ASD diagnosed?
• No medical test that can diagnose autism
• autism-specific behavioral evaluations - specially trained physicians and psychologists
• parents notice the first signs of unusual behaviors
![Page 9: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/9.jpg)
How is ASD diagnosed? • The most overt symptoms tend to emerge 6 months
after birth
• However, some studies suggest that differences in development can be observed around 2 to 12 months of age
• “red flags” (signs that appear by 12 months of age in typically developing children)
• ICD-10
• DSM-V
![Page 10: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/10.jpg)
![Page 11: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/11.jpg)
Screening tools
• CHAT (Checklist for Autism in Toddlers)
• M-CHAT (Modified Checklist for Autism in Toddlers)
• STAT (Screening Tool for Autism in Toddlers and Young Children)
• SCQ (Social Communication Questionnaire) ASSQ (Autism Spectrum Screening Questionnaire) CAST (Childhood Autism Spectrum Test)
![Page 12: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/12.jpg)
ARCA (Academic Research Center for Autism) - 2013
• Prof. Ostatníková et al.
• Clinical Servis • Education • Research
https://vyskum-autizmu.webnode.sk/
![Page 13: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/13.jpg)
Etiology
• The specific cause of ASD is still unknown
• Multifactorial disease :
– Psychological
– Environmental (non-genetic)
– Genetic
![Page 14: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/14.jpg)
Psychological factors
• Theory of mind: expresses the ability to infer the
mental states of other people by observing their behavior
• Theory of executive dysfunction: executive function -
mechanisms that allow us to focus our attention and control impulsive reactions
• Weak central coherence theory: basic deficit in autistic
children is the inability to integrate information into coherent or meaningful wholes
![Page 15: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/15.jpg)
• Empathizing-systemizing theory
• Measuring the strength of interest in empathy (E)
• Measuring the strength of interest in systems (S)
• 5 groups of people
Psychological factors
S – ♂
E – ♀
![Page 16: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/16.jpg)
• Sex differences in E and S (experience and socialization ) • fetal testosterone
• fetal testosterone concentration positively correlates with
systemizing ability and negatively correlates with empathizing ability
• The extreme male brain theory : ↑ fetal testosterone concentrations ↑ autistic phenotype.
(Baron-Cohen a kol., 2005)
![Page 17: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/17.jpg)
![Page 18: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/18.jpg)
Environmental factors
• BEFORE CONCEPTION/PRENATAL RISK FACTORS:
– Parental age
– Maternal physical health (bleeding, and mother infection during
pregnancy)
– Maternal mental health (depression, anxiety)
– Maternal prenatal medication use
(valproate, thalidomide)
![Page 19: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/19.jpg)
![Page 20: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/20.jpg)
Environmental factors
• NATAL RISK FACTORS
• preterm (<35 weeks) and postterm pregnancy (>42 weeks
• bleeding during pregnancy
• fetal complications (umbilical-cord complications and cesarean delivery (26% increased risk of autism) – hypoxia
![Page 21: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/21.jpg)
Environmental factors
• POSTNATAL RISK FACTORS
– Low birth weight (<2500g)
– Jaundice
– Postnatal infection
![Page 22: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/22.jpg)
Genetic factors
• ASD – a gene-based disorder • monozygotic twins – (60-90%) • dizygotic twins – (10%)
• genetic research - to identify candidate genes of ASD • the number of ASD-implicated genes: 200 – 1000
• many of these genes are also associated with other
neurodevelopmental disorders (epilepsy and schizophrenia)
![Page 23: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/23.jpg)
Risk genes for ASD
![Page 24: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/24.jpg)
Genetic syndromes associated with ASD
• Fragile X syndrome (FXS)
• Down syndrome (DS)
• Tuberous sclerosis
• Neurofibromatosis
• Phenylketonuria
![Page 25: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/25.jpg)
Syndromic and non-syndromic autism
• predominantly ‘non-syndromic’ or ‘idiopathic’ autism
• autism coincides with a genetic syndromes (FXS, DS etc.) - ‘syndromic’ autism
What differentiates individuals with syndromic autism from those with FXS or DS in isolation?
![Page 26: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/26.jpg)
What differentiates individuals with syndromic autism from those with FXS or DS in isolation?
![Page 27: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/27.jpg)
Animal models of autism
1. Animal models based on lesions in specific areas of the brain
2. Animal models based on modifications of the genome – use either transgenic animals (mainly knockout mice) or spontaneous mutants
3. Microtine model – Montane vole model
![Page 28: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/28.jpg)
![Page 29: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/29.jpg)
![Page 30: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/30.jpg)
![Page 31: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/31.jpg)
![Page 32: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/32.jpg)
SHANK 3 gene
• SH3 and multiple ankyrin repeat domains 3
• Cytogenetic Location: 22q13.33
![Page 33: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/33.jpg)
SHANK 3 protein
• scaffold protein at excitatory synapses
• functioning of synapses (cell to cell communication)
• formation and maturation of dendritic spines (transmission of nerve impulses)
![Page 34: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/34.jpg)
SHANK 3 and ASD
• ~ 43 SHANK3 gene mutations:
1. disruption of the function of the SHANK3 protein
2. prevention of the the protein production
disruption in cell to cell communication
ASD
![Page 35: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/35.jpg)
SHANK proteins – mice
• Encoded by SHANK1,2,3 genes
• Shank1 gene – mouse chromosome 7B4
• Shank2 gene – mouse chromosome 7F5
• Shank3 gene – mouse chromosome 15E3
![Page 36: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/36.jpg)
![Page 37: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/37.jpg)
CNS expression • SHANK1 – cortex, thalamus, amygdala, hippocampus
(CA1 and CA3), cerebellum
• SHANK2 – cortex, thalamus, hippocampus (CA1 and CA3), dentate gyrus, cerebellum, (kidney and liver)
• SHANK3 – heart, spleen, cortex, thalamus, striatum, hippocampus (more in CA3 than in CA1), dentate gyrus, cerebellum
![Page 38: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/38.jpg)
SHANK3 isoforms expression in the brain
![Page 39: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/39.jpg)
The link between SHANK genes and ASD
• ASD – etiologically heterogenous
• mutations or disruptions in the SHANK gene family account for ~1% of all patients with ASD
• correlation between SHANK1–3 mutations and the degree of cognitive impairment
• difference in impairment severity - expression pattern of the mutated SHANK gene
![Page 40: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/40.jpg)
• Is autism reversible in adulthood?
• re-expression of the Shank3 gene in adult mice:
– improvements in synaptic protein composition, spine density and neural function in the striatum
– social interaction deficit and repetitive grooming behavior - rescued
– anxiety and motor coordination deficit - not recovered
![Page 41: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/41.jpg)
3 HIT model
1. Genetic factor (Cntnap2-/-)
2. Environmental factor (LPS-MIA)
3. Sex (male mice)
autism
![Page 42: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/42.jpg)
Science at IMBM
• IMBM is not a standard research institute focusing on one molecule in one pathomechanism
• Different research background of people in our labs
![Page 43: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/43.jpg)
ecDNA
• The extracellular DNA (plasma) • Measuring the activity of the enzyme that cleaves this DNA -
deoxyribonuclease (DNase)
• The exogenous application of this enzyme is protective in sepsis, liver and kidney injury
• Any inflammation leads to an increase of extracellular DNA - IS activation
• We try to uncover the details of its role in sepsis, colitis and periodontitis in both, animal experiments and clinical studies
![Page 44: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/44.jpg)
![Page 45: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/45.jpg)
![Page 46: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/46.jpg)
Inflammation and autism
![Page 47: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/47.jpg)
Prenatal testosterone and ASD
![Page 48: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/48.jpg)
Metabolic syndrome
![Page 49: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/49.jpg)
Steroid hormones
![Page 50: Veronika Borbélyová, MSc., PhD. · 2019. 3. 15. · (Baron-Cohen a kol., 2005) Environmental factors ... periodontitis in both, animal experiments and clinical studies . Inflammation](https://reader036.vdocuments.net/reader036/viewer/2022071503/61229b38eb77464593794474/html5/thumbnails/50.jpg)
Acute and chronic kidney injury