Molecular monitoring of CML patients and aims of treatment and management with illustration of the mechanism of action of different drugs (Tyrosine Kinase inhibitors) used in the management of the chronic myeloid leukemia (CML)
detailed discussion on cytogenetics in CML - Pathophysiology, treatment, TKI Resistance, Mutation analysis timing, various mutations in CML, BCR-ABL1 Variants, Significance of mutations and management.
Mutations in Chronic myeloid leukaemia and Imatinib resistanceDr Sandeep Kumar
some corrections over previous presentation on CML. Covers topics like - pathophysiology of CML, Mutations discussed in detail, TKI resistance in various mutations and treatment options. Also Imatinib resistance has been discussed in detail.
A myeloprolifrative stem cell disorder resulting in
Proliferation of all haematopoietic lineages but
manifestation Predominantly in the granulocytic series.
The disease occurs chiefly between 30 and 80 years, with
A peak incidence at the 55 years.
*accounts for 20% of all leukaemis.
*found in all races.
*the aetiology is unknown.
detailed discussion on cytogenetics in CML - Pathophysiology, treatment, TKI Resistance, Mutation analysis timing, various mutations in CML, BCR-ABL1 Variants, Significance of mutations and management.
Mutations in Chronic myeloid leukaemia and Imatinib resistanceDr Sandeep Kumar
some corrections over previous presentation on CML. Covers topics like - pathophysiology of CML, Mutations discussed in detail, TKI resistance in various mutations and treatment options. Also Imatinib resistance has been discussed in detail.
A myeloprolifrative stem cell disorder resulting in
Proliferation of all haematopoietic lineages but
manifestation Predominantly in the granulocytic series.
The disease occurs chiefly between 30 and 80 years, with
A peak incidence at the 55 years.
*accounts for 20% of all leukaemis.
*found in all races.
*the aetiology is unknown.
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.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
- 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
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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.
Ozempic: Preoperative Management of Patients on GLP-1 Receptor Agonists Saeid Safari
Preoperative Management of Patients on GLP-1 Receptor Agonists like Ozempic and Semiglutide
ASA GUIDELINE
NYSORA Guideline
2 Case Reports of Gastric Ultrasound
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
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
2. Chronic myeloid leukemia (CML), also known as chronic
myelogenous leukemia, is a type of cancer that starts in certain
blood-forming cells of the bone marrow.
In CML, a genetic change takes place in an early (immature) version
of myeloid cells - the cells that make red blood cells, platelets, and
most types of white blood cells (except lymphocytes). This change
forms an abnormal gene called BCR-ABL, which turns the cell into a
CML cell.
The leukemia cells grow and divide, building up in the bone marrow
and spilling over into the blood. In time, the cells can also settle in
other parts of the body, including the spleen.
CML is a fairly slow growing leukemia, but it can also change into a
fast-growing acute leukemia that is hard to treat.
Most cases of CML occur in adults, but very rarely it occurs in
children, too. In general, their treatment is the same as for adults.
3.
4.
5.
6. The diagnosis of CML is based on
Histopathologic
findings in the
peripheral blood
Philadelphia (Ph)
chromosome in
bone marrow
cells
7. Asymptomatic in 20% of cases and discovered
accidentally by routine blood counts
Fevers and sweats, fatigue and malaise are also
commonly present
Bone pain and tenderness from expanding
leukaimic mass in the marrow
Splenomegaly is present in the majority of cases
(manifested by early satiety, abdominal fullness, or
pain) hepatomegaly is less common and is usually
asymptomatic.
Marked leucytosis (WBCs >100000) can be
associted with visual changes, seizures, and
cerebral or myocardial infarctions due to
leucostasis, thrombocytosis can produce similar
symptoms.
10. Peripheral blood leucocytosis due to increasred no.
of mature and immature neutrophils (WBSs usually
exceeds 30000 / µl and usually ranges from 100000 to
300000/µl )
Prominent dysgranulopoieisis
Promeylocytes, myelocytes, and metamyelocytes
>10% of WBCs
Basophils < 2% of WBCs
Monocytes <10% of WBCs
BM examination: hypercellular with granulocytic
proliferation and dysplasia, with or without
erythroid or megacaryocytic dysplasia
< 20% blasts in the blood or bone marrow
11.
12. It requires one or more of the following:
Blasts 10% to 19% in the blood or BM.
Basophils ≥20% of peripheral blood
leucocytes.
Platelets ≥1000000/µl unresponsive to
therapy.
Increasing spleen size &/or increasing WBCs
count unresponsive to ttt.
Cytogenetic evidence of clonal evolution
(cytogenetic abnormalities in addition to Ph’
Chromsome
13. Blasts ≥20% of bone marrow cells or
peripheral WBCs or
Extramedullary blast formation (eg,
osteolytic bone lesions, lymphadenopathy)
or
Large foci or clusters of blasts in BM
14. The chronic phase varies in duration, depending
on the maintenance therapy used: it usually lasts
2-3 years with hydroxyurea (Hydrea) or busulfan
therapy, but it may last for longer than 9.5 years in
patients who respond well to interferon-alfa
therapy.
Furthermore, the advent of imatinib mesylate has
dramatically improved the duration of hematologic
and, indeed, cytogenetic remissions.
Some patients with CML progress to a transitional
or accelerated phase, which may last for several
months.The survival of patients diagnosed in this
phase is 1-1.5 years. This phase is characterized
by poor control of the blood counts with
myelosuppressive medication
15.
16. Hematologic remission (normal CBC and
physical examination [ie, no
organomegaly])
Cytogenetic remission (normal
chromosome returns with 0% Ph-positive
cells)
Molecular remission (negative polymerase
chain reaction [PCR] result for BCR/ABL
mRNA
17. Imatinib mesylate (Gleevec): For chronic,
accelerated, and blastic phases; standard
treatment of choice
Dasatinib (Sprycel): For chronic phase
Nilotinib (Tasigna): For chronic phase
Bosutinib (Bosulif): For chronic, accelerated,
and blast phases
Ponatinib (Iclusig): For chronic or blast
phase T315I -positive cases, or in appropriate
patients in whom no other TKI therapy is
tolerated or indicated
18. Interferon-alfa: Former first-line agent; now
combined with newer drugs for refractory
cases
Hydroxyurea (Hydrea): Myelosuppressive
agent for inducing hematologic remission
Busulfan: Myelosuppressive agent for
inducing hematologic remission
Omacetaxine (Synribo): Protein translation
inhibitor indicated for chronic- or accelerated-
phase CML with resistance and/or intolerance
to 2 or more tyrosine kinase inhibitors
19. Allogeneic bone marrow transplantation (BMT) or stem
cell transplantation
Only proven cure for CML
Ideally performed in the chronic phase
Candidate patients should be offered the procedure if
they have a matched or single–antigen-mismatched
related donor available
Overall survival for allogeneic BMT with matched
unrelated donors ranges from 31% to 43% for patients
younger than 30 years and from 14% to 27% for older
patients
Currently relegated to patients who do not achieve
molecular remissions or show resistance to imatinib
and failure of second-generation tyrosine kinase
inhibitors (eg, dasatinib)
20.
21. Tyrosine kinase inhibitors are also called TKIs.
They block chemical messengers (enzymes)
called tyrosine kinases.
Tyrosine kinases help to send growth signals in
cells. So blocking them stops the cell growing
and dividing.
Cancer growth blockers can block one type of
tyrosine kinase or more than one type.
TKIs that block more than one type of tyrosine
kinase are called multi-TKIs.
22. A tyrosine-kinase inhibitor (TKI) is a pharmaceutical drug that
inhibits tyrosine kinases.
Tyrosine kinases are enzymesresponsible for the activation of many
proteins by signal transduction cascades. The proteins are activated
by adding a phosphate group to the protein (phosphorylation).
TKIs are typically used as anti-cancer drugs, TKIs operate by four
different mechanisms: they can compete with adenosine
triphosphate (ATP), the phosphorylating entity, the substrate or both
or can act in an allosteric fashion, namely bind to a site outside the
active site, affecting its activity by a conformational change.[8]
Recently TKIs have been shown to deprive tyrosine kinases of
access to the Cdc37-Hsp90 molecular chaperone system on which
they depend for their cellular stability, leading to their degradation.
23.
24.
25. Five TKIs have been approved in the United States
and the European Union for the treatment of CML.
Imatinib was the forerunner. Nilotinib and dasatinib
are also approved for first- and second-line
treatment. Bosutinib and ponatinib are currently
approved only for second- or subsequent-line
treatment.
These TKIs share the same therapeutic target,
BCR-ABL1, and act by inhibiting its kinase activity,
but they differ by several other characteristics that
may influence dosing and schedule, efficacy, and
toxicity.
In vitro, in a cellular or a biochemical assay, the
most potent inhibitor of BCR-ABL1 is ponatinib—
with a 50% inhibitory concentration (IC50) of 0.5
nmol/L— followed by dasatinib (0.8–1.8 nmol/L),
nilotinib (10–25 nmol/L), bosutinib (42 nmol/L), and
imatinib (260–678 nmol/L).
26. The IC50 has a value in scoring the potency of
different TKIs, but it must be considered that the
peak and trough plasma concentrations of these
drugs are different, the IC50 values for some off-
target tyrosine kinases that can affect the
therapeutic efficacy but also the toxicity of each
agent.
It is interesting to notice that imatinib, dasatinib,
bosutinib, and ponatinib inhibit several off-target
tyrosine kinases very efficiently, sometimes with
IC50s that are lower than the respective trough
plasma concentrations.