UC is an idiopathic IBD that affects the colonic mucosa.
Hallmark of UC is bloody diarrhea often with prominent symptoms of rectal urgency and tenesmus.
The clinical course is marked by exacerbations and remissions.
The diagnosis of UC is suspected on clinical grounds and supported by the appropriate findings on
Proctosigmoidoscopy or colonoscopy
Biopsy
By negative stool examination for infectious causes
Join us for a lecture on inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Roger S. Klein, MD, FACP, will highlight the latest in diagnostic technologies and treatment approaches for IBD. He also will discuss the importance of comprehensive care to help prevent IBD-associated health problems.
UC is an idiopathic IBD that affects the colonic mucosa.
Hallmark of UC is bloody diarrhea often with prominent symptoms of rectal urgency and tenesmus.
The clinical course is marked by exacerbations and remissions.
The diagnosis of UC is suspected on clinical grounds and supported by the appropriate findings on
Proctosigmoidoscopy or colonoscopy
Biopsy
By negative stool examination for infectious causes
Join us for a lecture on inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Roger S. Klein, MD, FACP, will highlight the latest in diagnostic technologies and treatment approaches for IBD. He also will discuss the importance of comprehensive care to help prevent IBD-associated health problems.
A seminar on colon cancer including topics of Epidemiology, Aetiology, Molecular Biology, Pathology, Clinical presentation, Screening, Diagnosis and Staging.
Non-communicable Diseases And Interventions to minimize itGaaJeen Parmal
Rise of non-communicable diseases like RTA, obesity, psychological disturbance, etc. Its impact towards the healthcare of a nation. The steps or approach that can be taken to minimize the disease.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
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.
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.
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
- 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
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
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
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!
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.
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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
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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.
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
2. DEFINITIONS
• Ulcerative colitis — Ulcerative colitis is a chronic inflammatory
condition characterized by relapsing and remitting episodes of
inflammation limited to the mucosal layer of the colon.
• Ulcerative Proctitis Disease limited to the rectum
• Ulcerative Proctosigmoiditis Rectum and Sigmoid colon and not
involving the descending colon
• Left-sided or distal ulcerative colitis beyond the rectum and as far
proximally as the splenic flexure
• Extensive colitis Extending proximal to the splenic flexure but
sparing the cecum
• Pancolitis is used when the inflammatory process extends
throughout the colon to the cecum
3.
4. EPIDEMIOLOGY
WESTERN
INCIDENCE
• 6–15.6/100,000North
America
• 10–20.3/100,000North
Europe
PREVALENCE RATES
• 37.5–229/100,000North
America
• 21.4–243/100,000North
Europe
INDIAN
HARYANA STUDY(1984)
• 21,971 persons
• prevalence rate of 42.8/
100,000
Ludhiana, Punjab
• 51,910 persons(23definite
UC)
• Prevalence44.3/100,000,
• Crude incidence calculated
after a second visit 1 year later
was 6.02 per 100,000
5. EPIDEMIOLOGY
INDIANS
• Incidence rate of 6.02 per
100,000 recorded in India
REST OF ASIAN
• Incidence of UC in Asian0.4 to
2.1/100,000 population
• Prevalence rates Lower in Asia,
ranging from 6 to 30/100,000
• Studies from Singapore & Malaysia comparing populations of Indian,
Chinese and Malay ethnic origin have shown that residents of Indian
origin had a higher prevalence of UC than those of Chinese or Malay
origin.
• Indians in these studies had odds ratios of 2.9–4.8 compared to Chi-
nese or Malays of having UC.
6.
7.
8. ETIOLOGY & PATHOGENESIS
Age and gender —15 and 40 years
• Bimodal age distribution second peak 50 and 80 years
• Slight male predominance in ulcerative colitis
UC stratified by age
• A1: <16 More aggressive initial course
• A2:16–40
• A3: >40 years Lower risk of colectomy
9. Racial and ethnicity
REST OF WORLD
• Jews > non-Jews
Within Israel Ashkenazi >
Sephardic Jews
• whites > black & Hispanic
• Related to environmental and
lifestyle factors as well as due
to underlying genetic
differences.
SOUTH-ASIAN ETHIC GROUPS
• South Asians in the UK was
about twice as high as that in
Europeans.
• South Asian ethnic groups –
Hindus10.8/100,000/y
Sikhs16.5/100,000/y
Muslims6.2/100,000/y
Europeans5.3/100,000/y
10. Smoking
• Current smoking may be protective
• Non Smoker > Smoker
Light-smoker > Heavy-smoker
• 229,111 women current smokers = non smoker
• Former smokers > Non smoker (HR 1.6)
• The risk of ulcerative colitis increased two years after cessation of
smoking and persisted for over 20 years.
• Smoking cessation in patients with ulcerative colitis is associated with
an increase in the disease activity and hospitalization
• Transdermal nicotine patches Improve ulcerative colitis associated
symptoms Not shown any effects on objective measures of
disease
11. Protective effect??
• Appendicectomy Early age may be protective against the onset
and subsequent severity of UC69% risk reduction
• The protective effect of appendicectomy is additional to that of
smoking, but does not appear to protect against the development
of PSC.
• Appendicectomy is performed after the onset of ulcerative colitis,
the effect (if any) on the course of the disease is far less clear.
12. Family History
• First-degree relatives 10–15 fold risk of developing the disease.
• Life time risk of UC for a first degree relative 2%
• Familial cases of UC there is a slight female & younger age of
onset compared to sporadic cases
• Western patients with UC 14.6 % to 29.4 %
• Asian patients with UC 0.6 % to 8 %
• ISG-IBD Task Force data collection found a positive family history
in only 2.3 % of UC patients
14. Diet
• "Western" style diet (processed, fried, and sugary foods) Ulcerative
colitis.
• Hypersensitivity to cow's milk protein in infancy cause of IBD
• IBD patients V/S controls noted cow's milk hypersensitivity
Ulcerative colitis(21%) > Controls (3%)
• Total fat
• Animal fat INCIDENCE & RELAPSE
• Polyunsaturated fatty acids
• Milk protein
15. GENETIC FACTORS
Genetic susceptibility
• Non-Mendelian pattern of inheritance
• 80 twins with IBD concordance rate for monozygotic twins
was markedly higher in CD (50%) than UC (19%).
• First-degree relatives 3 to 20 times more likely.
In one report both parents had IBD (CD or UC) had up to a
33% IBD by age 28
• In Asia, a positive family history 0.6 % to 8 %
16. Specific genes
• TOTAL 163 LOCI INCREASED RISK OF IBD
• 7.5 % UC
• 13.6% CD
• 23/163 SPECIFIC FOR UC
• 30/163 SPECIFIC FOR CD
• 110/163BOTH UC/CD
• 113/163Other autoimmune diseases
• Psoriasis
• Ankylosing spondylitis
• Primary immunodeficiency
• Mycobacterial infection
17. Genetics
• NOD2 has the strongest association with IBD CD.
• NOD2 polymorphisms in Indians could not find such an association,
• 2 of these studies could find a weak association of rs2066842
(Pro268Ser) with UC
• Juyal et al
• UC/CD-specific genetic loci North Indian population.
• 53 such loci
• 25 SNPs IBD in Indians
• 15 were CD specific.
• Only 5 SNPs, HLA-DRA,IL10,RNF186,BTNL2,NOD2 retained
significance after Bonferroni correction.
Juyal G, Prasad P, Senapati S, Midha V, Sood A, Amre D, Juyal RC, BK T: An investigation of
genome-wide studies reported susceptibility loci for ulcerative colitis shows limited replication
in north Indians. PLoS One 2011; 6:e16565.
18. Genetics
• Strong protective TNFSF15 Gene polymorphisms and IBD in
the Indian population
• TNFSF15 has also been associated with an IBD risk in studies
from Japan and the UK
• Autophagy-related gene, the IRGM gene
Baskaran K, Pugazhendhi S, Ramakrishna BS: Protective association of tumor necrosis fac-
tor superfamily 15 (TNFSF15) polymorphic haplotype with Ulcerative Colitis and Crohn’s
disease in an Indian population. PLoS One 2014;9:e114665.
19. Genetics
Verma R, Ahuja V et al (2012)
• Reported polymorphisms of the NOD1 protein in UC patients
• 3 SNPs which led to significant mutations in ATP and Mg2+-binding
domains of Exon 6 of the NOD1 gene that may cause defective
oligomerization and subsequently the “loss of function” of the protein,
thereby preventing the recognition of muramyl dipeptide that is
necessary for a subsequent NF- κB activation
• Verma R, Ahuja V, Paul J: Detection of single- nucleotide polymorphisms in the intron 9 re-
gion of the nucleotide oligomerization do- main-1 gene in ulcerative colitis patients of North
India. J Gastroenterol Hepatol 2012;27: 96–103.
• Verma R, Ahuja V, Paul J: Frequency of single nucleotide polymorphisms in NOD1 gene of
ulcerative colitis patients: a case-control study in the Indian population. BMC Med Genet
2009;10:82.
20. Genetics
• TLR4 D299G polymorphism UC and CD
• T399I polymorphisms only in UC
• Modulating the transcription of inflammatory cytokines in UC,
leading to an aberrant immune response.
• TLR5 variants R392X and N592S showed significant association with
UC
Disease phenotype
Combination of multiple SNPs both in the TLR5 and the TLR4 gene
suffered from early-onset disease which had a severe long-term
course.
Meena NK, Ahuja V, Meena K, Paul J: Association of TLR5 gene polymorphisms in ulcerative colitis patients of north
India and their role in cytokine homeostasis. PLoS One 2015;10:e0120697.
Juyal G, Midha V, Amre D, Sood A, Seidman E, Thelma BK: Associations between com- mon variants in the MDR1 (ABCB1)
gene and ulcerative colitis among North Indians. Pharmacogenet Genomics 2009;19:77–85.
21. Genetics
• MDR1 (ABC B1) gene polymorphisms early age at disease onset,
left-sided disease, and steroid response in UC
• A recent GWAS on UC in a North Indian population revealed 3 novel
HLA-independent loci as susceptibility genes located in 3.81, BAT2,
MSH5, HSPA1L, SLC44A4, CFB, and NOTCH4
• Juyal G, Midha V, Amre D, Sood A, Seidman E, Thelma BK: Associations between com- mon
variants in the MDR1 (ABCB1) gene and ulcerative colitis among North Indians. Phar-
macogenet Genomics 2009;19:77–85.
• Juyal G, Negi S, Sood A, et al: Genome-wide association scan in north Indians reveals three
novel HLA-independent risk loci for ulcer- ative colitis. Gut 2015;64:571–579.
22. GENETIC SYNDROMES ASSOCIATED WITH
IBD
Turner syndrome
• Absence of an X chromosome
• Dysfunctional X chromosome.
• 1:5000 live female births
• Short stature,
• webbed neck,
• widely spaced nipples,
• Cubitus valgus,
• Cardiac defects (especially
bicuspid aortic valve,
coarctation, and aortic
stenosis).
Association with IBD
• In one of the largest series, 4 of
135 (3 percent) adults with
Turner syndrome developed
IBD (two with UC and two with
CD), an incidence much higher
than an age-matched
population
23. GENETIC SYNDROMES ASSOCIATED WITH
IBD
Hermansky-Pudlak syndrome — Granulomatous colitis similar to CD
• Autosomal recessive disorder
• Oculocutaneous albinism
• Abnormal platelet aggregation with bleeding diathesis
• Pulmonary fibrosis
• Genetic linkage Chromosome 10q23
• In one study, 8 of 49 (16 percent) patients with HPS had IBD; four of
the eight had a mutation in this gene
24. Microbiome
• IBD Abnormal immune response to intestinal microbiota in
genetically susceptible individuals.
• Gut microbiome studies in IBD patients Reduced diversity within
the Firmicutes phylum
Verma R, Verma AK et al (2010)
– Mucosa- associated bacterial flora Control v/s IBD patients
There was a significant decline in the population of
• Bacteroides,
• Lactobacillus,
• Ruminococcus,
• Bifidobacterium bacteria
Verma R, Verma AK, Ahuja V, Paul J: Real- time
analysis of mucosal flora in patients with
inflammatory bowel disease in India. J Clin
Microbiol 2010;48:4279–4282.
25. Microbiome
• Increased Lactobacilli in the faecal samples of patients Active UC
v/s healthy controls.
• Lactobacilli significantly reverted back to normal during remission
• Increase in faecal lactate level Severe UC patient v/s controls.
• Interplay between butyrate concentration and butyrate-producing
bacteria in faecal samples of UC patients and healthy individuals.
Clostridium coccoides
Clostridium leptum Faecal samples of the UC patients
32. Ulcerative Colitis
When the whole colon is involved, inflammation extends 1-2 cm in Terminal ileum ( Back
wash ileitis)
40-50% 30-40% 20%
33. WHY EXTENT IMPORTANT
• Extent of inflammation will influence the patient's management &
the choice of delivery system for a given therapy.
• Start and the frequency of surveillance
• Study from Sweden Extent of disease colorectal cancer
• 3117 UC patients followed up from 1 to 60 years after diagnosis.
• No increased RR Disease confined to the rectum
• RR for left-sided colitis2.8 Surveillance colonoscopy
• extensive colitis14.8
35. Classification according to disease severity
Activity & Pattern of disease:
• Copenhagen County, Langholz et al 50% of patients clinical
remission at any time during a given year
• Relapsing course after 25 years of follow up amounted to 90%.
• Disease activity in the first 2 years after diagnosis indicated an
increased probability of 5 consecutive years of active disease.
36. Activity & Pattern of disease:
Quiescent UC
• Chronic inflammatory cell infiltrate all biopsy specimens
• Crypt architectural irregularities Two thirds
• 52% acute inflammatory cell infiltrate relapsed after 12 months of
follow-up
• 25% relapsed in the absence of such an infiltrate
• Relapse rates
• Presence of crypt abscesses
• Mucin depletion
• Breaches in the surface epithelium
40. Clinical features of ulcerative colitis
• Visible blood in the stools > 90%
• Loose stools (or a decrease in stool consistency) > six weeks
differentiates UC from most infectious diarrhoea.
• Extensive active UC Chronic diarrhoea
• Rectal bleeding
• Rectal urgency
• Tenesmus
• Passage of mucopurulent exudates
• Nocturnal defaecation
• Crampy abdominal pain
• Ache over the left iliac fossa prior to and relieved by defaecation
41. Clinical features of ulcerative colitis
Proctitis
• Rectal bleeding
• Urgency
• Tenesmus
• Occasionally severe constipation
• Anal and minor perianal lesions may complicate severe diarrhoea
• Simple fistulae may occasionally occur in UC
• Recurrent or complex perianal fistulae should always raise the
suspicion of Crohn's colitis.
42. • The onset of UC Insidious
• Symptoms Weeks or even months before medical advice is sought
• Disease may present
– Intermittent episodes of symptoms
– Severe attack (15%)
Systemic symptoms including
– weight loss
– Fever
– tachycardia
– even nausea and vomiting
43. Extraintestinal manifestations Indian
Perspective
Kochhar
34.7 % of UC patients
• Sacroilitis 14 %,
• Peripheral arthritis10.7%
• Ocular manifestations8%
• Mucocutaneous lesions2.7%
• Vascular 2 %
• Hepatobiliary 1.3 %.
Habeeb et al
39 % of UC patients
• Sacroilitis 5 %
• Arthralgia 21 %
• Ocular involvement7 %
Overall Prevalence 6 % to 39 %
44. DERMATOLOGIC MANIFESTATION
• Erythema nodosum 3 to
10% UC
• 4 to 15% Crohn disease
• Lesions typically consist of
raised, tender, red or violet
subcutaneous nodules that
are 1 to 5 cm in diameter
• Extensor surfaces of the
extremities, particularly
over the anterior tibial area.
• Biopsy focal panniculitis.
45. DERMATOLOGIC MANIFESTATION
• Pyoderma gangrenosum is
the second most common
• 2402 patients with IBD,
pyoderma gangrenosum
0.75%
• The lesions initially appear
as single or multiple
erythematous papules or
pustules that are often
preceded by trauma to the
skin
46. DERMATOLOGIC MANIFESTATION
• Most commonly on the legs,
but can develop in any area
of the body.
• Subsequent necrosis of the
dermis deep ulcerations
that contain purulent
material
• Usually sterile on culture
• Biopsy reveals nonspecific
findings consistent with a
sterile abscess.
47. Neutrophilic dermatoses
Sweet syndrome
• Acute inflammatory dermatitis
characterized by tender
papules, plaques, and nodules
distributed on the face, arms,
and trunk
• Skin lesions are most commonly
seen on the head, neck, and
upper extremities.
• Biopsy of the lesion reveals an
intense neutrophilic infiltrate
without evidence of vasculitis.
48. Neutrophilic dermatoses
Aseptic abscess syndrome –
• Typical presentation includes fever, weight loss, abdominal
pain, and leukocytosis
• Aseptic sterile collections with a neutrophil predominant
infiltrate.
• Sterile abscesses are usually located in the spleen, but
approximately 20 percent of patients have cutaneous
abscesses.
51. Primary sclerosing cholangitis (PSC)
• Chronic cholestatic disease of the liver and bile ducts that is
frequently progressive and can lead to end-stage liver disease.
• progressive inflammation, fibrosis, and stricturing of the intrahepatic
and extrahepatic bile ducts.
• 1 case per 100,000 person years.
• 70 % men
• Mean age at diagnosis of 40 years.
• First-degree relatives of patients with PSC have an increased risk of
PSC and ulcerative colitis (UC)
52. Primary sclerosing cholangitis (PSC)
• Up to 90 % of PSC also have UC
• < 10 percent of patients with UC have PSC.
• etiologies have been proposed
• Autoimmune process.
• An inflammatory reaction in the liver and bile ducts may be induced
by chronic or recurrent entry of bacteria into the portal circulation.
Liver damage may also result from the accumulation of toxic bile
acids that are abnormally produced by colonic bacteria or chronic
viral infection.
• Ischemic damage to the bile ducts may occur.
53. Investigations
A) Laboratory Findings
• Thrombocytosis chronic inflammatory response,
• Anaemia severity
• Leucocytosis Infectious complication.
• Hypoalbuminaemia (in extensive disease).
• Elevated ESR and CRP Clinical activity
– CRP >10 mg/L after a year of extensive colitis, predicted an increased rate
of surgery.
• Stool analysis: leucocytes and fecal lactoferrin.
54. Investigations
• Stool specimens should be cultured for common pathogens
• C. difficile toxin A and B
• Campylobacter spp
• Escherichia coli 0157:H7
• P-ANCA is the most commonly associated serologic marker
• P-ANCA
up to 65% of patients with UC
< 10% of patients with Crohn's
• associated ulcerative colitis medically refractory
• require early surgery
• result in chronic pouchitis in patients who have undergone
ileal pouch anal anastomosis (IPAA)
55. Microbial investigations
• Not routinely recommended C. difficile infrequent positive
results
• Microbial stool tests should be performed during a treatment-
refractory or severe relapse.
• Flexible sigmoidoscopy stool test is negative.
• Reactivation of CMV Immunosuppressed patients with severe
colitis.
• CMV infection may cause refractory or severe relapse.
• Most commonly used technique CMV DNA through PCR
• Occasional intranuclear inclusion bodies Not significant
• Multiple intranuclear inclusions Significant
56. Investigations
Faecal calprotectin
• most sensitive,
• non-invasive biomarker
• Recent studies emphasise the value of calprotectin in selecting
patients for diagnostic investigation, assessing, disease severity
(correlating with endoscopic indices), diagnosing relapse and
response to treatment.
57. Imaging Studies
Plain Abdominal X-ray:
Symptoms of severe or fulminant colitis.
Thumbprinting appearance Thickening of the colonic wall + bowel
wall edema.
• Colonic segmental dilatation exceeding 5 cm with an irregular edge
outlined by gas, correlates strongly with ulceration.
• In toxic megacolon, the bowel is dilated with loss of haustral
markings.
63. Double-contrast barium enema.
• The colon is affected with a
coarsely granular mucosal pattern.
• Numerous polypoid filling defects
also are present.
64. Contrast-enhanced CT
• Typically reveals
colonic wall
thickening.
• Innumerable
enhancing polypoid
filling defects are
present throughout
the rectosigmoid
colon.
• The wall of the colon
is hyperenhancing
and slightly irregular
in contour.
65. Coronal MDCT image
• Mild symmetric wall
thickening (arrows) of the left
colon with associated
lymphadenopathy in the
mesocolon.
66. Abdominal ultrasound
• Screen for small bowel or
colonic inflammation with a
sensitivity of 80–90%.
• Low cost
• Easy to perform without
prior preparation
• Non-invasive
• Accuracy skill of operator
• Low specificity for
differentiating UC from other
causes of colonic inflammation.
• Monitoring treatment success
• initial data that ultrasound
might help to predict the course
of the disease
67. Abdominal ultrasound
Hydrocolonic ultrasound
• Abdominal ultrasonography in
conjunction with retrograde
instillation of water in the colon
• High sensitivity for identifying
active colitis
• Disadvantage cumbersome
for day to day clinical practice
Doppler ultrasound
• Superior and inferior
mesenteric arteries has been
used to evaluate disease
activity and risk of relapse.
• Complementary technique for
assessing disease activity in
expert hands.
68. Leukocyte scintigraphy
• Safe
• Non-invasive
• Potentially allows assessment of the presence, extent and
activity of inflammation.
• Lacks specificity
• Not be recommended as a standard diagnostic tool for
ulcerative colitis
• Unreliable if patients are taking steroids.
71. Endoscopic features of ulcerative colitis
Mild inflammation
• erythema,
• vascular congestion of the
mucosa
• Loss of visible vascular
pattern
Moderately active colitis
• complete loss of vascular
pattern,
• blood adherent to the
surface of the mucosa and
erosions
• a coarse granular
appearance
• mucosal friability
72. Endoscopic features of ulcerative colitis
• Severe colitis is characterised by spontaneous bleeding and
ulceration
• In contrast to Crohn's disease, ulcers in severe UC are always
embedded in inflamed mucosa.
• The presence of deep ulceration is a poor prognostic sign.
• In longstanding disease,
• mucosal atrophy can result in loss of haustral folds,
• luminal narrowing
• post-inflammatory (‘pseudo’) polyps
75. • OGD Mucosal biopsy are recommended in patients with
upper gastrointestinal symptoms.
• Wireless capsule endoscopy (WCE) Colitis unclassified
• Normal Not exclude Crohn's disease
• Very high negative predictive value
• Using WCE, Lopes et al. IBDU to Crohn's disease in 7/14
patients, though this did not lead to change in management.
76. Assessment of extent, severity and activity
Signs of discontinuous inflammation in ulcerative colitis-
RECTAL SPARING & CAECAL PATCH
• Macroscopic and microscopic rectal sparing Children presenting
with UC prior to treatment
• In adults normal or patchy inflammation in the rectum Topical or
Systemic therapy for UC.
• Patchy inflammation in the caecum ‘caecal patch’ and is observed
in patients with left-sided colitis.
• Macroscopic and Histological rectal sparing
• Presence of a caecal patch in newly diagnosed colitis
77. Assessment of extent, severity and activity
Appendiceal skip lesions
• Involvement of the appendix as a skip lesion is reported in up
to 75% of patients with UC.
• Appendiceal inflammation has been associated both with a
• More responsive course of disease
• Higher risk of pouchitis after ileal pouch anastomosis
78. Assessment of extent, severity and activity
Backwash ileitis
Continuous extension of macroscopic or histological inflammation from
the caecum into the most distal ileum is defined as ‘backwash ileitis’
• up to 20% of patients with pancolitis.
• RARELY Ileal erosions may occur in patients without caecal
involvement
• A more refractory course backwash ileitis.
• Small bowel UC v/s Crohn's disease.
Small bowel radiology not routinely recommended.
• Diagnostic difficulty (rectal sparing, atypical symptoms, macroscopic
backwash ileitis)
80. Crypt architectural abnormalities
Crypt branching:
• Two or more branched (bifurcated) crypts in a well oriented section,
whether the branching is in the vertical or horizontal axis.
• Applied to a single crypt Less specific
• The pathogenesis can be accounted for by regeneration following
previous damage or destruction (cryptolysis)
Mucosal (crypt) distortion:
• Irregularities in crypt size (i.e. variable diameter)
• Spacing
• Orientation (i.e. loss of parallelism)
81. Mucosal (crypt) atrophy and crypt density:
• Combination of crypt depletion
• Increase in the distance between the muscularis mucosae and the
base of the crypts.
• An increase in the intercryptal space and the crypt–muscularis
mucosae distance may be normal in the caecum and distal rectum.
• The pathogenesis crypt death
• All crypt cells die, crypts cannot regenerate and disappear within 48
h.
• If one or more clonogenic cell survives the insult, rapid proliferation
regenerates the crypt within 72–96 h.
• The mucosa subsequently heals by clonal expansion and the number
of crypts that survive to regenerate following a cytotoxic insult
correlates with symptom severity
82. Surface irregularity:
• Surface irregularity (synonyms include villous surface, villiform
surface, or villous mucosa)
• Wide crypt mouths, giving the mucosal surface a finger-like
appearance.
• The impression is due to separation of crypts and a semantic
distinction between “irregular surface” and “villous surface”
has been proposed, according to the villous-crypt ratio
83. Epithelial cell abnormalities
Paneth cell metaplasia:
• Paneth cells are normally extremely uncommon in the colon distal
to the splenic flexure, being present in 0–1.9% of non-IBD controls.
• The presence of Paneth cells in the distal colon can be termed
Paneth cell metaplasia.
• Pathogenesis epithelial regeneration and repair.
• Mucin depletion: defined as a reduction in number of goblet cells
or depleted mucin within cells.
84. Inflammatory features
Basal plasmacytosis:
• Presence of plasma cells around (deep 1/5th of the lamina propria) or
below the crypts, alongside or penetrating the muscularis mucosae
• Basal plasmacytosis
• subcryptal plasma cells
– plasmacytosis with extension in the base of the mucosa
• Accumulation of plasma cells between the base of the crypts and the
muscularis mucosae.
• The abnormality can be focal or diffuse and subcryptal location of the
cells is not always present
85. • Lamina Propria cellularity: An increase in the total number of plasma
cells, lymphocytes, histiocytes and eosinophils is a feature of all types
of colorectal inflammation and is of limited discriminant value. In UC
the cellular infiltrate is diffuse and transmucosal.
• Neutrophils may be present in the lamina propria or between
epithelial cells, are readily recognised and a reproducible feature of
inflammation.
• More than three neutrophils in the lamina propria outside
capillaries may be abnormal, but the exact number has not been
agreed.
86. • Neutrophils are a feature of cryptitis with migration of
neutrophils through the crypt epithelium, inducing crypt
disruption and crypt abscesses, which may be responsible for
cell surface damage or disruption.
• Eosinophils in the lamina propria are highly variable.
– An increase UC and a potential diagnostic value has
been proposed.
87. Distribution of the lamina propria cellular
inflammatory infiltrate
• Focal (normal background cellularity with areas of increased
cellularity);
• Patchy (abnormal background cellularity with variable intensity)
• Diffuse (abnormal background cellularity with an overall increase in
density).
• To avoid diagnostic error
• Early onset disease in children
• After treatment
• Disease is resolving or quiescent
88. • Basal lymphoid aggregates: Nodular collections of lymphocytes
between the crypt base and muscularis mucosae,without germinal
centres.
Two aggregates Abnormal
• Stromal changes: Diffuse thickening of the muscularis mucosae or a
double muscularis mucosae (which is unusual, but characteristic
when present) have been observed in longstanding active and
quiescent UC
89. Backwash ileitis
• ‘Backwash ileitis’ should be in continuity with colonic inflammation
and the lesions in the caecum should show a similar, or greater
degree of active inflammation.
• The ileal lesions in ‘backwash ileitis’
– active inflammation in the villi and lamina propria
– Shortening
– blunting of the villi
• Focal, isolated ileal erosions, mucous gland metaplasia or patchy
oedema with mild active inflammation are features suggestive of
Crohn's disease.
90. Microscopic features—appraisal of the diagnosis
Early stage disease
• Non-specific increase in the inflammatory infiltrate in the lamina
propria in combination with absent crypt architectural distortion,
indicates a diagnosis of acute, infective colitis rather than UC.
• Not confirmed in those studies of patients with early onset colitis
• Basal plasmacytosis Early onset in 38–100% of adult patients
and can help differentiate between UC and infectious colitis.
• Feature in young children
• Early feature, sometimes the first lesion to appear
• Good predictive marker
91. • Glandular abnormalities can be identified with good (83-90%) inter-
observer agreement.
• According to most studies, diffuse crypt architectural irregularity and
reduced crypt numbers or atrophy indicate UC.
• Crypt architectural changes were observed in biopsies obtained
between 16 and 30 days after onset,but not in earlier biopsies.
• Crypt distortion and mucosal atrophy may return to normal or
remain unchanged after resolution of symptoms.
92. Established disease
• Basal plasmacytosis (defined as presence of plasma cells around
(deep part of the lamina propria)
• Below the crypts (subcryptal)
• Heavy, diffuse transmucosal lamina propria cell increase
• Widespread mucosal or crypt architectural distortion
• Mucosal atrophy
• Villous or irregular mucosal surface appear later during the evolution
of the disease (4 weeks or more).
93. • General or widespread crypt epithelial neutrophils (cryptitis and
crypt abscesses) favour ulcerative colitis
• Paneth cell metaplasia distal to the splenic flexure is a non
specific feature.
– Suggestive of a diagnosis of ulcerative colitis in established
disease.
– Severe, widespread mucin depletion is helpful for the diagnosis
of ulcerative colitis in active disease
94. Indeterminate colitis
• Restricted to resection specimens.
• When patients have colitis that has yet to be classified after
all clinical, radiologic, endoscopic and histological results are
taken into account, then the preferable term is IBD
unclassified (IBDU)
Editor's Notes
Taken together, the incidence of UC in Hindus was about twice as high as that in Muslims; the higher frequency of smoking among Muslims was used to explain the observed difference.
There is some support for "genetic anticipation," which refers to the development of earlier onset and more severe disease in offspring of affected parents in subsequent generations [15,22,23].
In one study, for example, 48 of 57 children with CD born of parents with CD developed symptoms a median of 16 years earlier than the onset of disease in their parents [22]. Rather than reflecting genetic anticipation, the preceding observations may in part be explained by ascertainment bias because children of parents with IBD may be subjected to earlier diagnostic evaluation [17,24]. In addition, apparent genetic anticipation may be explained in part by bias secondary to the lack of adjustment for different observation times among subjects [25]. Since children of affected parents are typically followed for a much shorter time span than their parents (up to a lower average age), the average age of disease onset in children may be lower than would be found if this group were followed for a longer time. However, this cannot be the entire explanation since the parents may be first diagnosed after the child (12 of 49 cases in one series)
IRGM:IMMUNITY RELATED GTPase FAMILY M GENE
In addition, we could also demonstrate decreased concentrations of faecal SCFAs, especially of n-butyrate, iso-butyrate, and acetate, in the faecal sam- ples of the UC patients.
Genetic and environmental factors induce impaired barrier function in the intestinal mucosa. Initiating triggers may involve infections in some patients. Altered barrier function subsequently induces the translocation of commensal bacteria and microbial products from the gut lumen into the bowel wall, which leads to immune cell activation and cytokine production. If acute mucosal inflammation cannot be resolved by anti-inflammatory mechanisms and the suppression of pro-inflammatory immune responses, chronic intestinal inflammation develops. In turn, chronic inflammation may cause complications of the disease and also tissue destruction, which are both drivenby mucosal cytokine responses. DC, dendritic cell; IBD, inflammatory bowel disease; NSAIDs, non-steroidal anti-inflammatory drugs; TReg cell, regulatory T cell
In patients with inflammatory bowel disease (IBD) and in experimental mouse models of colitis, pro-inflammatory and anti-inflammatory cytokines produced by various cells of the mucosal immune system in response to environmental triggers, such as commensal microorganisms. In particular, dendritic cells (DCs), neutrophils, macrophages, natural killer (NK) cells, intestinal epithelial cells (IECs), innate lymphoid cells (ILCs), mucosal effector T cells (T helper 1 (TH1), TH2 and TH17) and regulatory T (TReg) cells produce cytokines in the inflamed mucosa. The key transcription factors and cytokines produced by T helper cell subsets in IBD-affected mucosa are shown. The balance between pro-inflammatory and anti-inflammatory cytokines in the mucosa regulates the development and potential perpetuation of mucosal inflammation in patients with IBD. The dashed arrow indicates that ILCs, which produce cytokines that are involved in intestinal inflammation, may respond to IL-18. GATA3, GATA-binding protein 3; IL, interleukin; RORγt, retinoic acid receptor-related orphan receptor-γt; TGFβ, transforming growth factor-β; TNF tumour necrosis factor.
IN IBD increased amounts of soluble and membrane-bound tumour necrosis factor (TNF) are produced by various immune and stromal cell populations, such as macrophages, dendritic cells s , effector T cells, adipocytes and fibroblasts TnF has been shown to exert various pro-inflammatory functions in the inflamed mucosa in IBD. In particular, TNF induces hypervasculariation and
angiogenesis, augments pro-inflammatory cytokine production by macrophages and T cells, causes barrier alterations and promotes cell death of intestinal epithelial cells (IECs) and Paneth cells. TNF also promotes tissue destruction by increasing the production of matrix metalloproteinases by myofibroblasts and drives T cell resistance to apoptosis via the induction of TNF receptor-associated factor 2 (TRAF2) and the activation of nuclear factor-κB (NF-κB). TNF-specific antibodies may alleviate disease by simultaneously suppressing several pro-inflammatory pathways in patients with IBD. IL, interleukin; MLCK, myosin light chain kinase; RIPK, receptor-interacting protein kinase; TIMP1, tissue inhibitor of matrix metalloproteinases 1.
Intestinal epithelial cells (IECs) are exposed to numerous pro-inflammatory and anti-inflammatory cytokines during
chronic intestinal inflammation in inflammatory bowel disease (IBD). These cytokines are produced by cells in the local microenvironment and by IECs themselves. Local cytokine responses have major effects on mucosal healing and cancer development in patients with IBD. The cellular sources of key cytokines and their signalling cascades that regulate IEC survival, cell death and proliferation are shown. In the context of mucosal healing in ulcers (left), green boxes indicate beneficial effects of cytokines, whereas red boxes highlight pathogenic effects of cytokines. In colitis-associated cancer (right), blue boxes indicate pro-tumour effects of cytokines. DC, dendritic cell; IFN, interferon; IL, interleukin; ILC, innate lymphoid cell; TH cell, T helper cell; TNF, tumour necrosis factor.
Cytokine signalling pathways and intracellular Janus kinase(JAK)–signal transducer and activator of transcription (STAT) signalling cascades in mucosal immune cells are shown.
In IBD, the activation of certain STATs in mucosal T cells results in augmented cytokine production Several pro-inflammatory cytokines have been implicated in IBD pathogenesis and are potential targets for therapy. Antibodies targeting soluble tumour necrosis factor (TNF) and membrane-bound TNF (such as infliximab, adalimumab, certolizumab pegol and golimumab) are routinely used in the clinic. In addition, cytokine blockers (for example, tocilizumab, which targets interleukin-6 (IL-6) and ustekinumab, which targets the p40 subunit of IL-12 and IL-23) have been recently tested in clinical studies. In addition, inhibitors of JAK and STAT signalling (for example, the JAK3 and JAK1 inhibitor tofacitinib, which blocks IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 signalling) have yielded promising results in clinical trials. Future therapy of IBD may also use bispecific tetravalent dual variable domain IgG (DVD-Ig) antibodies. Finally, the identification of specific cytokines and cytokine expression patterns that are unique to certain subsets of patients with IBD may open new avenues for future personalized medicine for these disorders. βc, cytokine receptor common subunit-β; γc, cytokine receptor common subunit-γ; gp130, IL-6R subunit-β; LIFR, leukaemia inhibitory factor receptor; OSMR, oncostatin-M-specific receptor subunit-β; TRAF2, TNFR-associated factor 2; TYK2, tyrosine kinase 2.
For instance, topical therapy in the form of suppositories (for proctitis) or enemas (for left-sided colitis) is often the first line choice, but oral therapy - often combined with topical therapy is appropriate for extensive colitis [EL1b, RG B].
The appearance of erythema nodosum usually parallels intestinal disease activity, and treatment directed at the underlying IBD usually results in resolution of the lesions.
Pyoderma gangrenosum lesions usually do not parallel IBD activity [12]. In patients with active IBD and pyoderma gangrenosum, therapy with systemic steroids usually results in healing.
Evaluation of small bowel if Macroscopic and Histological rectal sparing
Presence of a caecal patch in newly diagnosed colitis
and this challenges the pathogenic theory that backwash ileitis is caused simply by reflux of caecal contents into the ileum.
The diagnostic value of neutrophils in UC, however, is limited because they are also present in infective colitis and other forms of colitis.
To avoid diagnostic error, the criteria of diffuse transmucosal inflammation for diagnosing ulcerative colitis should be avoided in biopsies from early onset disease in children,159 or after treatment and when disease is resolving or quiescent. In these circumstances the biopsy may be normal or show focal changes.
However these lesions may occur in infections and other types of colitis. Lamina propria and intraepithelial neutrophils are absent in inactive or quiescent disease.