This document discusses the pathophysiology of bilirubin-induced neurological dysfunction (BIND), commonly known as kernicterus. It begins with a brief history of kernicterus and describes the areas of the brain that are most intensely stained by bilirubin, including the basal ganglia. It then explains bilirubin chemistry and solubility, how the blood-brain barrier influences bilirubin entry into the brain, and various cellular mechanisms by which high bilirubin levels can damage neurons. Specifically, bilirubin can uncouple oxidative phosphorylation, interact with and damage membranes, and alter neurotransmitter metabolism. The document concludes by outlining the clinical spectrum of BIND, from acute
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
HOT NEW PRODUCT! BIG SALES FAST SHIPPING NOW FROM CHINA!! EU KU DB BK substit...GL Anaacs
Contact us if you are interested:
Email / Skype : kefaya1771@gmail.com
Threema: PXHY5PDH
New BATCH Ku !!! MUCH IN DEMAND FAST SALE EVERY BATCH HAPPY GOOD EFFECT BIG BATCH !
Contact me on Threema or skype to start big business!!
Hot-sale products:
NEW HOT EUTYLONE WHITE CRYSTAL!!
5cl-adba precursor (semi finished )
5cl-adba raw materials
ADBB precursor (semi finished )
ADBB raw materials
APVP powder
5fadb/4f-adb
Jwh018 / Jwh210
Eutylone crystal
Protonitazene (hydrochloride) CAS: 119276-01-6
Flubrotizolam CAS: 57801-95-3
Metonitazene CAS: 14680-51-4
Payment terms: Western Union,MoneyGram,Bitcoin or USDT.
Deliver Time: Usually 7-15days
Shipping method: FedEx, TNT, DHL,UPS etc.Our deliveries are 100% safe, fast, reliable and discreet.
Samples will be sent for your evaluation!If you are interested in, please contact me, let's talk details.
We specializes in exporting high quality Research chemical, medical intermediate, Pharmaceutical chemicals and so on. Products are exported to USA, Canada, France, Korea, Japan,Russia, Southeast Asia and other countries.
2. History
• Jaundice in newborn first described in 610AD
in Chinese textbook-On the origins and
symptoms of diseses.
• In 1847 French medical student Francois
Hervieux in his dessertation described
jaundice in brain of 31 of 44 infants who had
been noticed of jaundice at birth.
• Kernicterus-German term for Jaundice of
nuclei(or basal ganglia) was coined by
Christian Gerge Schorl in1904
3.
4. Kernicterus:What is & what is not
• Kernicterus refers to pathoanatomic finding of
intense yellow coloring of basal ganglia
superimposed on paler yellow background.
• Areas that are found stained –in descending
order-Basal
ganglia,Hippocampus,thalamus,hypothalamus,co
rpus striatum,medulla,olives,pons and dentate
nucleus.
• In these areas structural findings are-dense
cytoplasmic bodies which are degenerated
mitochondria,membrane alterations and calcium
granules.
• Changes of this nature are usually irreversible.
5. • Bilirubin has effects on brain that are likely to
be transitory.
• Significantly jaundiced infants exhibit
lethargy,hypotonia and feeding problems.
• This type of reversibl toxicity cannot be called
Kernicterus.
• Milder alteration in neuronal signalling may
explain reversibility while cell death eplain
irreversibility.
6. Bilirubin chemistry and solubility:
• Bilirubin isomer in humans is bilirubin-IXa exists
in 1)Charged Dianion 2)Bilirubin acid.
• Dianion form is some water soluble whereas acid
is insoluble in water.
• Hydrophobic isomer is toxic while hydrophillic are
thought to be non toxic.
• Bilirubin IXa behaves in lipophillic way ,it bind to
and crosses phospholipid membranes,enabling it
to cross BBB
7. • Bilirubin is transported in plasma bound to
albumin and does not cross intact BB barrier.
• Minute amount of bilirubin (in nanomolar)is
present as free bilirubin-Bf in plasma.
• According to” free bilirubin theory” its
unbound form which enters brain producing
neuronal injury.
8. BLOOD-BRAIN BARRIER & BILIRUBIN-
BRAIN KINETICS
• Entry of bilirubin is a sine qua non for
neurotoxicity.
• Characteristics of molecules that are able to cross
BBB in significant amounts-MW<400 daltons,lipid
soluble and should not be substrate for efflux
transporters at BBB.
• Bilirubin is 585 daltons,lipophillic and is substrate
for efflux transpoter P-gp.
• These characteristics limit bilirubin entry to brain.
9.
10. • An unstable equilibrium exists between
bilirubin in blood and bilirubin in brain .
• This equilibrium is influenced by several
factors.
1)Serum albumin
2)Bilirubin
3)Damaged or immature BBB
4)Efflux transporters-P-gp,MRP
5)Brain blood flow
11. 1)Albumin
• Bilirubin is bound to albumin in primary and
secondary site with high affinity such that conc.
of free bilirubin is very low.
• Bilirubin
displacers(Eg:sulfonamides,PCT,NSAIDS,Valproic
acid,Tetracyclines,Nitrofurantoin,RZE,Erythromyci
n) increase risk of bilirubin neurotoxicity.
• Blood brain equilibrium is shifted towards brain
when bilirubin displacing drugs are used.
• Sepsis ,inflammatory conditions and prematurity
may decrease bilirubin binding affinity of
albumin.
• B/A ratio has been studied ,and it does not
improve prediction over TSB alone.
12. 2)Bilirubin
• Bilirubin may interact with biological
membranes affecting their functions.
• Bilirubin has toxicity towards astrocyte which
may translate into effects on BBB.
• Studies have shown pre exposure to bilirubin
increases the permeability of BBB to both dye
and bilirubin.
13. 3)P-gp
• Efflux transporter,member of ATP binding
superfamily of membrane transporters.
• Bilirubin is substrate for P-gp and also inhibits
it.
• P-gp function is phosphorylation dependent
and bilirubin has been shown to inhibit
phosphorylation.
14. MRP(multi drug resistance associated
proteins)
• Have role in limiting CSF accumulation of
bilirubin.
• MRP1 helps in kepping bilirubin out of cell
15. 4)Altered BBB(immature or damaged BBB)
• Opening of BBB produced by
radiation,asphyxia,hyperosmalarity and
hypercarbia,infection and infalmmation
increases bilirubin entry into brain.
• Cytokines TNF-a,IL-1,IL-6 and endotoxins increase
BBB permeability.
• These condition are commonly encountered in
sick babies in NICU.
• In hyperosmalarity significant entry of bilirubin is
in albumin bound form whereas in hypercarbia
unbound bilirubin enters brain.
16. 5)Brain blood flow
• Increased brain blood flow is associated with
increased bilirubin entry to brain.
• Increased flow each circulating bilirubin
molecule passes BBB more often thus has
more oppurtunity to equilibrate with bilirubin
in brain.
17.
18. Why Basal ganglia????
• Whether localisation is related to bilirubin
entry or its clearance is not clear.
• Bilirubin extracted from 4 infants who died of
severe jaundice-35nmol/g in nuclei region and
8nmol/g in other brain areas.
• Studies on rat pups and piglets have also
shown similar differential staining of brain.
• No studies have been able to explain staining
pattern of kernicterus.
19. • Basal ganglia(esp GP and subthalmic nucleus)-
movement disorders dystonia and athetosis.
• Auditory (cochlear nucleus,inferior colliculus)-
deafness,hearing loss,auditory neuropathy.
• Oculomotor nuclei-strabismus and gaze
palsies.
• Other susceptible areas-hippocampus and
cerebellum.
20.
21. How bilirubin damages cell at cellular
level???
1. Uncoupling of oxidative phosphorylation.
2. Interaction with membranes.
3. Altering neuro transmitter metabolism.
22. 1)Inhibition –uncoupling of oxidative
phosphorylation
• The classical theory,bilirubin uncouples
oxidative phosphorylation
• Bilirubin effects mitochondrial membrane.
• Resulting in increased permebility,decreased
membrane potential,release of cytochrome c
and triggering of apoptosis.
23. 2)Interaction with membranes
• Bilirubin content is more in the myelin membrane
compartment than other,especially more affinity to
neuronal cell membrane.
• Bilirubin interacts with polar lipids and is associated
with cytosolic enzymes leakage.
• Bilirubin alters ion permeability and effects membrane
potential.
• Bilirubin was shown to inhibit Ca dependent exocytosis
and disrupt vesicular storage of norepinephrine.
• Bilirubin interacts with membrane localised enzymes
,pumps and transporters like Na-K ATPase and NOS and
acetylcholinesterase
• Bilirubin acid may form irreversible aggregates inside
cell.
• Bilirubi acid has also been proposed to bind reversibly
to membranes.
24. 3)Neurotransmitter metabolism
• Inhibits uptake or release of NT by either altering
membrane potential or altering energy
metabolism.
• Phosphorylation of synapsin 1 is imp step in
neurotransmitter release and bilirubin inhibits
this.
• Inhibits uptake of tyrosine and inhibits formtaion
of dopamine.
• Inhibits release of acetylcholine and dopamine.
• Bilirubin modifies the NMDA recetor ion channel
complex.NMDA medaited excitotoxicity may be
involved in bilirubin encephalopathy.
25.
26. Bilirubin metabolism in brain:
• Estimated half life in brain is 16-18 mins.
• Clearance from brain is more rapid than from
blood(1.7 hrs)
• Enzyme capable of oxidizing bilirubin was found
in inner mitochondrial membrane in brain and
other tissues.
• Activity of enzyme is lower in immature organism
and in neurons compared to glia ,this may explain
vulnerabilty of infants and neuronal cell
compared to adults and glial cells.
27. How cells die when exposed to
bilirubin???
• High bilirubin concentration induce early
necrosis whereas low to moderate bilirubin
predominantly induce delayed apoptosis.
• NMDA receptor mediated pathway and
caspase mediated pathway are involved in
bilirubin induced neuronal death.
28. Summary
• Involved structures-
Basalganglia,Hippocampus,thalamus,hypothalam
us,corpus striatum,medulla,olives,pons and
dentate nucleus.
• Bilirubin-dianionic water soluble form,acid
insoluble form.
• Brain blood bilrubin equilibrium maintained by-
albumin,immature or damaged BBB,transporters-
P gp,Brain blood flow.
• Damages cell-uncoupling oxidative
phosphorylation,altering mebrane,inhibiting NT
release uptake and release.
29. Clinical spectrum of BIND
1. Acute bilirubin encephalopathy
2. Chronic bilirubin encephalopathy
3. Subtle BIND-neurological,cognitive,isolated
hearing loss and auditory dysfunction.
33. References
• Fetal and neonatal physiology/Richard a
Polin,William W.Fox.-4th ed.p1295-303.
• Steven M.Shapiro:Definition and clinical
spectrum of kernicterus and BIND,Journal of
perinatology 2005;25:54-59.
• Imam Iskander et al:Serum bilirubin and
bilirubin/albumin ratio as perdictors of bilirubin
encephalopathy ,Pediatrics Nov 2014,134(5) e
1330-e1339
• Bhutani VK:The clinical syndrome of BIND,Semin
Fetal Neonatal Med.2015 Feb;20:6-13