Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia characterized by a translocation between chromosomes 15 and 17, resulting in the PML-RARα fusion gene in leukemic cells. This causes life-threatening coagulopathy and differentiation of promyelocytes into neutrophils in response to all-trans retinoic acid (ATRA). Treatment involves ATRA and chemotherapy, with monitoring for differentiation syndrome as a potential complication. Prognosis depends on initial white blood cell count, with high counts associated with worse outcomes.
Thrombocytopenia is generally defined as platelet count <150 × 109/L. It can occur due to several reasons, like decreased platelet production (e.g., inherited bone marrow failure syndromes, acquired aplastic anemia, leukemia), ineffective platelet production (myelodysplastic syndrome, megaloblastic anemia), increased destruction (ITP, HLH), increased consumption (DIC, TTP, HUS), sequestration (hypersplenism), or may be due to combination of multiple mechanisms described above.
During evaluating a case of thrombocytopenia, the first step is getting a detailed history and doing a proper clinical examination. Then the next step would be checking the other parameters of complete blood count (CBC), especially hemoglobin (Hb) and the total WBC count, complemented by a peripheral smear (PS) examination, which will clear many doubts and will help us pinpointing our diagnostic approach.
Many a times pseudo-thrombocytopenia is encountered in a PS due to platelet clumping by EDTA and can be rectified by collecting blood samples in a citrate or heparin vials or by doing a direct finger prick smear. Any accompanying cytopenia will expand the differential diagnosis and an isolated thrombocytopenia will further narrow it down. Presence of any additional abnormalities of red cells (megaloblasts) or white cells (presence of hyper-segmented neutrophils, atypical lymphoid/myeloid cells) could be present in megaloblastic anemia/MDS, leukemia respectively, while in the presence of fragmented red cells microangiopathic hemolytic anemia should always be ruled out by doing PT and aPTT (DIC, TTP, HUS). In case of isolated thrombocytopenia, the platelet morphology is also important. In many patients in India, especially in eastern region many people have large platelets with their normal platelet count around 100 × 109/L with normal platelet function (Harris platelet syndrome). However, presence of any abnormal platelet morphology along with a low platelet count may indicate a platelet function disorder (large platelets in Bernard Soulier syndrome/ Glanzmann thrombasthenia or small platelets in Wiskott-Aldrich syndrome), especially if encountered in early part of life during evaluation for bleeding symptoms. In case of isolated thrombocytopenia, presence of additional congenital anomalies may point out towards an inherited marrow failure syndrome, e.g. amegakayocytic thrombocytopenia. Exposure to certain drugs may result in isolated low platelet count, e.g., ceftriaxone, piperacillin, heparin. Presence of toxic changes in neutrophils may indicate sepsis related thrombocytopenia. By excluding all these, immune thrombocytopenia (ITP) to be thought as no specific tests or markers are available for this entity and its diagnosis is largely clinical. A further work up complemented by bone marrow examination and in few cases a platelet function test will definitely help in reaching the final diagnosis.
So, summarizing, in the evaluation of a case of thrombocytopenia, all the
Thrombotic Microangiopathies and AntiPhospholipid SyndromeRichard McCrory
This was a Nephrology seminar from last year on Thrombotic Microangiopathies, and I covered a small piece on Antiphospholipid Syndrome at the end. I hope it's informative!
Eddy Wouters, APL Logistics on '3PL Branding & Marketing'eyefortransport
Eddy Wouters, VP Logistics Europe, APL Logistics gets many laughs and lots of good feedback as he speaks on '3PL Branding & Marketing' at the 7th European 3PL Summit in Brussels, November 25th 2009.
To download all of the slides from the conference for free visit www.3PLsummit.com/eu_2009ppts
Thrombocytopenia is generally defined as platelet count <150 × 109/L. It can occur due to several reasons, like decreased platelet production (e.g., inherited bone marrow failure syndromes, acquired aplastic anemia, leukemia), ineffective platelet production (myelodysplastic syndrome, megaloblastic anemia), increased destruction (ITP, HLH), increased consumption (DIC, TTP, HUS), sequestration (hypersplenism), or may be due to combination of multiple mechanisms described above.
During evaluating a case of thrombocytopenia, the first step is getting a detailed history and doing a proper clinical examination. Then the next step would be checking the other parameters of complete blood count (CBC), especially hemoglobin (Hb) and the total WBC count, complemented by a peripheral smear (PS) examination, which will clear many doubts and will help us pinpointing our diagnostic approach.
Many a times pseudo-thrombocytopenia is encountered in a PS due to platelet clumping by EDTA and can be rectified by collecting blood samples in a citrate or heparin vials or by doing a direct finger prick smear. Any accompanying cytopenia will expand the differential diagnosis and an isolated thrombocytopenia will further narrow it down. Presence of any additional abnormalities of red cells (megaloblasts) or white cells (presence of hyper-segmented neutrophils, atypical lymphoid/myeloid cells) could be present in megaloblastic anemia/MDS, leukemia respectively, while in the presence of fragmented red cells microangiopathic hemolytic anemia should always be ruled out by doing PT and aPTT (DIC, TTP, HUS). In case of isolated thrombocytopenia, the platelet morphology is also important. In many patients in India, especially in eastern region many people have large platelets with their normal platelet count around 100 × 109/L with normal platelet function (Harris platelet syndrome). However, presence of any abnormal platelet morphology along with a low platelet count may indicate a platelet function disorder (large platelets in Bernard Soulier syndrome/ Glanzmann thrombasthenia or small platelets in Wiskott-Aldrich syndrome), especially if encountered in early part of life during evaluation for bleeding symptoms. In case of isolated thrombocytopenia, presence of additional congenital anomalies may point out towards an inherited marrow failure syndrome, e.g. amegakayocytic thrombocytopenia. Exposure to certain drugs may result in isolated low platelet count, e.g., ceftriaxone, piperacillin, heparin. Presence of toxic changes in neutrophils may indicate sepsis related thrombocytopenia. By excluding all these, immune thrombocytopenia (ITP) to be thought as no specific tests or markers are available for this entity and its diagnosis is largely clinical. A further work up complemented by bone marrow examination and in few cases a platelet function test will definitely help in reaching the final diagnosis.
So, summarizing, in the evaluation of a case of thrombocytopenia, all the
Thrombotic Microangiopathies and AntiPhospholipid SyndromeRichard McCrory
This was a Nephrology seminar from last year on Thrombotic Microangiopathies, and I covered a small piece on Antiphospholipid Syndrome at the end. I hope it's informative!
Eddy Wouters, APL Logistics on '3PL Branding & Marketing'eyefortransport
Eddy Wouters, VP Logistics Europe, APL Logistics gets many laughs and lots of good feedback as he speaks on '3PL Branding & Marketing' at the 7th European 3PL Summit in Brussels, November 25th 2009.
To download all of the slides from the conference for free visit www.3PLsummit.com/eu_2009ppts
Slides were presented via a poster board in a class symposium of cancer genes. I reviewed primary literature to present the structure and function of cancer gene Retinoic Acid Receptor Alpha and its implications in Acute Promyelocytic Leukemia.
Newer biomarkers,techniques & their inclusion in 2016 WHO classification for leukaemia/lymphomas increases the responsibility of the pathologists, requiring to develop an integrated multidisciplinary approach for reporting.
HAP/VAP 2016 ATS/IDSA Guidelines. Our Data available at: https://rdcu.be/Mx8EDr Sandeep Kumar
Management of Adults With Hospital-acquired and
Ventilator-associated Pneumonia: 2016 Clinical Practice
Guidelines by the Infectious Diseases Society of America
and the American Thoracic Society.
To see our study results on HCAP and HAP, VISIT https://link.springer.com/article/10.1007/s00408-018-0117-7
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.
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.
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.
Basavarajeeyam is a Sreshta Sangraha grantha (Compiled book ), written by Neelkanta kotturu Basavaraja Virachita. It contains 25 Prakaranas, First 24 Chapters related to Rogas& 25th to Rasadravyas.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
Follow us on: Pinterest
Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of the 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 lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
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. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Recomendações da OMS sobre cuidados maternos e neonatais para uma experiência pós-natal positiva.
Em consonância com os ODS – Objetivos do Desenvolvimento Sustentável e a Estratégia Global para a Saúde das Mulheres, Crianças e Adolescentes, e aplicando uma abordagem baseada nos direitos humanos, os esforços de cuidados pós-natais devem expandir-se para além da cobertura e da simples sobrevivência, de modo a incluir cuidados de qualidade.
Estas diretrizes visam melhorar a qualidade dos cuidados pós-natais essenciais e de rotina prestados às mulheres e aos recém-nascidos, com o objetivo final de melhorar a saúde e o bem-estar materno e neonatal.
Uma “experiência pós-natal positiva” é um resultado importante para todas as mulheres que dão à luz e para os seus recém-nascidos, estabelecendo as bases para a melhoria da saúde e do bem-estar a curto e longo prazo. Uma experiência pós-natal positiva é definida como aquela em que as mulheres, pessoas que gestam, os recém-nascidos, os casais, os pais, os cuidadores e as famílias recebem informação consistente, garantia e apoio de profissionais de saúde motivados; e onde um sistema de saúde flexível e com recursos reconheça as necessidades das mulheres e dos bebês e respeite o seu contexto cultural.
Estas diretrizes consolidadas apresentam algumas recomendações novas e já bem fundamentadas sobre cuidados pós-natais de rotina para mulheres e neonatos que recebem cuidados no pós-parto em unidades de saúde ou na comunidade, independentemente dos recursos disponíveis.
É fornecido um conjunto abrangente de recomendações para cuidados durante o período puerperal, com ênfase nos cuidados essenciais que todas as mulheres e recém-nascidos devem receber, e com a devida atenção à qualidade dos cuidados; isto é, a entrega e a experiência do cuidado recebido. Estas diretrizes atualizam e ampliam as recomendações da OMS de 2014 sobre cuidados pós-natais da mãe e do recém-nascido e complementam as atuais diretrizes da OMS sobre a gestão de complicações pós-natais.
O estabelecimento da amamentação e o manejo das principais intercorrências é contemplada.
Recomendamos muito.
Vamos discutir essas recomendações no nosso curso de pós-graduação em Aleitamento no Instituto Ciclos.
Esta publicação só está disponível em inglês até o momento.
Prof. Marcus Renato de Carvalho
www.agostodourado.com
Adv. biopharm. APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMSAkankshaAshtankar
MIP 201T & MPH 202T
ADVANCED BIOPHARMACEUTICS & PHARMACOKINETICS : UNIT 5
APPLICATION OF PHARMACOKINETICS : TARGETED DRUG DELIVERY SYSTEMS By - AKANKSHA ASHTANKAR
2. Introduction
Acute promyelocytic leukemia (APL) is a subtype distinct from all
other acute myeloid leukemias (AMLs) with respect to the clinical,
morphologic, cytogenetic, and molecular characteristics of a highly
curable disease. These include the presence of life-threatening
consumptive coagulopathy at diagnosis, high sensitivity of leukemic
blasts to anthracyclines, and a balanced reciprocal translocation
between chromosomes 15 and 17, t(15;17)(q22;q21), which results
in a fusion between the promyelocytic leukemia (PML) gene on
chromosome 15 and retinoic acid receptor-alpha (RAR alpha;
RARα) on chromosome 17. The ability of leukemic promyeloblasts
to undergo differentiation into neutrophils with all-trans retinoic acid
(ATRA) depends on the presence of the PML-RARα fusion gene in
leukemic cell.
3. Epidemiology
APL accounts for 5-8% of pediatric AML cases.
Approximately 600-800 children & adoloscents develop
acute leukemia each year in USA. In contrast to other
subtypes of AML, which are equally present in various
races and ethnic groups, APL incidence varies widely
among nations, with an increased incidence of APL in
children from Italy & Central and South America.
Age distribution of APL also differs from other forms of AML,
APL being uncommon in first decade of life, the incidence
increasing during second decade of life reaching plateau
during early adulthood; then the incidence remains
constant until it decreases after 60 years of age.
Gender – slightly more in females.
4. APL Biology in India-a study done in
AIIMS
• Male-to-female ratio was 0.9:1 (males--17 and females--18) with median age 25
years (range 11-57 years). Presenting features included anemia, bleeding, fever,
gum hypertrophy and scrotal ulceration. All cases showed hypergranular abnormal
promyelocytes. Median hemoglobin was 6.3 g/dL (range - 3.0-9.0 g/dL), total
leukocyte count (TLC) was 33.88 x 10(9) /L (range - 1-170 x 10(9) /L). Platelet count
was 28 x 10(9) /L (range - 4-170 x 10(9) /L). All cases were positive for
myeloperoxidase and sudan black (SB), whereas 60% cases also showed non
specific esterase (NSE) positivity with 40% cases being fluoride sensitive. RT-PCR
showed PML-RARalpha in 33/35 cases with the bcr3 isoform being present in
24/33 positive cases (72.7%). The two cases negative for PML-RARalpha showed
typical morphology and responded to ATRA. On statistical analysis, no correlation
was found between bcr isoform and TLC, platelet count, age sex and early death.
Unusual features included gum hypertrophy and scrotal ulceration at presentation
and high median presenting TLC (33.8 x 10(9) /L). There was, however, no
microgranular variant. Another interesting feature was a high incidence of NSE
positivity (60%), which was fluoride sensitive in 40%. Moreover, the bcr3 isoform
was significantly overexpressed (72.7%) in comparison to other studies. APML in
India has certain unusual features, which may reflect a different biology.
• Does acute promyelocytic leukemia in Indian patients have biology different from the West? Dutta P1, Sazawal S, Kumar
R, Saxena R., Indian J Pathol Microbiol. 2008 Jul-Sep;51(3):437-9.
5. Clinical presentations
• 1-Hyperleucocytosis (children (40%) >
adult(20-25%)
• 2-leukopenia is more commoner than other
AML forms
• 3- hepatosplenomegaly is less common
• 4-CNS involvement is rare
• 5-bleeding secondary to DIC – at diagnosis or
initiation of CT
6. Mechanism of DIC in APL
• It can cause a 10‒20% incidence of early death due to
hemorrhage27). The risk of DIC is higher in patients with the
microgranular variant of APL. Starting treatment with a
differentiation agent (e.g., all-trans retinoic acid [ATRA]) plus
supportive care as soon as the diagnosis is suspected, irrespective
of definitive cytogenetic or molecular confirmation, is important to
rapidly improve the coagulopathy. Although the mechanism for
APL-induced DIC is not fully understood, bleeding coagulopathy is
caused by the enhanced fibrinolytic activity involving 3 factors—
tissue factor, cancer procoagulant, and increased annexin II
receptor expression on the surface of the leukemic
promyelocytes28). Tissue factor forms a complex with factor VII to
activate factors X and IX. Cancer procoagulant activates factor X.
Annexin II receptor binds plasminogen and its activator, tissue
plasminogen activator, thus increasing plasmin formation.
7. MOLECULAR PATHOGENESIS
• More than 95% of APL patients have a balanced reciprocal
translocation between chromosome 15q22 and 17q21,
which results in a fusion between the PML gene and RARα
called PML-RARα.
• RARα is encoded on the long arm of chromosome 17 and is
a member of the retinoic acid (RA) nuclear receptor family
that acts as a ligand-inducible transcription factor by
binding to specific response elements (RARE) at the
promoter region of target genes.
• The promyelocytic gene (PML) is encoded on the long arm
of chromosome 15 is thought to be involved in apoptosis
and tumor suppression.
8. MOLECULAR PATHOGENESIS
• The breakpoint in chromosome 17 is consistently found
in intron 2. However, there are 3 possible isoforms
caused by the translocation based on the PML
breakpoint location in chromosome 15. The 3
breakpoints in PML occur at intron 3 (L form), intron 6
(S form), and exon 6 (V form). Compared with the L
form, the S form is associated with a shorter remission
duration and overall survival (OS)
• PML-RARα homodimerizes via the PML coiled-coil
domain and causes the RAR to bind more tightly to the
nuclear corepressor factor and histone deacetylases
(HDACs) on RARα target genes, thereby enforcing DNA
methylation.
9. MOLECULAR PATHOGENESIS
• Pharmacological doses of RA convert PML-RARα into a
transcriptional activator, thus enhancing the expression of
crucial RARα targets and restoring normal differentiation.
• In about 5% of cases, alternative rearrangements of
chromosome 17q21 with other gene partners are observed.
These include promyelocytic leukemia zinc finger
(PLZF)/RARα t(11;17)(q23;q21), nucleophosmin
(NPM)/RARα t(5;17)(q35;q12-21), nuclear mitotic
apparatus (NuMa)/RARα t(11;17)(q13;q21), and/or signal
transducer and activator of transcription 5b (STAT5b)/RARα
t(17;17)(q11;q21). All of these rearrangements are ATRA-sensitive,
except for PLZF/RARα, which is not sensitive to
ATRA or ATO31
22. Treatment-associated adverse events
• 1. APL differentiation syndrome-A potentially life-threatening
complication, formerly known as retinoic acid syndrome, occurs in
2.5‒30% of newly diagnosed APL patients receiving ATRA treatment. This
syndrome has also been described in patients with relapsed APL who
received induction therapy with ATO. Typically during 30 days of therapy.
• The clinical symptoms of DS are unexplained fever, cough, dyspnea,
peripheral edema, weight gain, pleural fluid retention, interstitial
pulmonary infiltrates, hypotension, pericardial effusion, and acute renal
failure.
• This is often mistaken for fluid overload with pleural effusion or
pneumonia, congestive heart failure, and diffuse alveolar hemorrhage.
The syndrome usually develops within 2 weeks of therapy and is
commonly associated with a rapidly rising leukocyte count. The probable
risk factors for DS are a high leukocyte count and a rapidly increasing
leukocyte count.
23. Treatment-associated adverse events
• 2. Pseudotumor cerebri - Another complication of
induction therapy with ATRA is pseudotumor cerebri (PTC),
which is more commonly observed in children with APL
than in adults, and occurs in 5‒15% of those enrolled in
clinical trials5, 6). It is characterized by increased
intracranial pressure, severe headache, nausea, vomiting,
and in severe cases by vision disturbances and
papilledema.
• To decrease these risks, some groups have used a reduced
dose of ATRA (e.g., 25 mg/m2 instead of 45 mg/m2 ), and a
decreased incidence of PTC with excellent results has been
reported at an ATRA dose of 25 mg/m2 /d than with 45
mg/m2/d in children and adolescents with APL
24. Prognostic factors in APL
• The most important prognostic factor in patients with APL is
leukocyte count at initial presentation. Children with WBCs higher
than 5,000/mm3 or 10,000/mm3 have a high risk of relapse.
• FMSlike tyrosine kinase 3 internal tandem duplications (FLT3/ITD),
which are mutations in a tyrosine kinase receptor, have recently
been considered as another prognostic indicator in pediatric APL.
The incidence of FLT3/ITD mutations is 22.2% in non-APL patients,
compared with 34.9% in children with APL47).
• These mutations are often associated with hyperleukocytosis at
diagnosis and higher mortality during induction therapy. The
microgranular variant form of APL is frequently associated with
FLT3/ITD. However, the clinical impact of these mutations on
relapse rate or OS is not yet entirely clear, and more clinical studies
are needed.