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4KK3 Triple Jump

Brandon Webber Rono Hasan Nicholas Irwin David Tsoulis
by

Nick Irwin

on 16 April 2010

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Transcript of 4KK3 Triple Jump

4KK3 Triple Jump by B. Webber, D. Tsoulis, N. Irwin, and R. Hasan Friday April 16th, 2010 Clostridium Botulinum Outline:

1. General Information
2. Transmission
3. Clinical Presentation - Cattle and Humans
4. Pathophysiology of Infection
5. Differential and Diagnosis
6. Vaccine
7. Cosmetic & Therapeutic Uses
8. Other Clostridial Infections Transmission to Cattle 3 Routes 1. Ingestion of the pre-formed toxin
2. Wound botulism
3. Intestinal toxicoinfectious botulism
General Information Can affect all mammals, fish, and birds Spore forming organism – produces a potent toxin Eight immunogically distinct types of this exotoxin: A, B, C1, C2, D, E, F, and G
Only B, C, and D produce disease in cattle Commonly found in soil....pH sensitive

Grows best under anaerobic conditions in neutral, acidic, or alkaline conditions depending on the subtype



Only B, C, and D produce disease in cattle Type B - 2 forms 1. Proteolytic toxin – maximal toxicity
2. Nonproteolytic toxin – must be activated by trypsin to become fully toxic Most North American outbreaks in cattle are a result of Type B
Often associated with feeding cattle contaminated forage
...toxin may grow in decaying vegetation or animal carcasses Kelch et al. (2000) reported eleven Holstein cattle fed round bale barley haylage
Type C:
Associated with feeding cows chicken litter
...less common than type B
Type D:
Large outbreaks in cattle that were fed chicken litter in Australia and Israel
...less common than type B
For example, if cows were to feed on the carcass of a deer that had been infected where the toxin (B) is pre-forming Human Infection 1. Foodborne botulism
2. Wound botulism
3. Infant botulism
4. Adult intestinal toxemia botulism
5. Inhalational botulism
6. Iatrogenic botulism
Types/Transmission: Consumption of foods contaminated with pre-formed botulinum toxin (grows in contaminated vegetables, meat, etc.)
Canned foods are a major source for human infection
Outbreaks are typically small, involving 2 or 3 individuals
Fermented dishes, or dishes that are uncooked can pose a significant risk
Human Transmission: Foodborne Botulism Human Transmission: Wound Botulism Caused by contamination of a wound with C. botulinum spores and production of toxin combined with anaerobic environment of an abscess
Dramatic increase in the 1990s among injection drug users (incidence is almost exclusively among these individuals)
Abscesses should be cleaned and debrided
Sobel (2005)
Sobel (2005)
Human Transmission: Infant Botulism Absorption of toxin produced in situ by C. Botulinum colonization of the intestines
This is the most common form of human botulism
Approximately 80-100 cases/year in US
Normal bowel florae that could compete with C. Botulinum have not yet been established ( usually in infants <1 year)
Honey consumption – causes 20% of these cases
Human Transmission: Adult Intestinal Toxemia Botulism Results from absorption of toxin produced in situ by rarely occurring colonization in adults
Typically, those affected have anatomical or functional bowel abnormality or are using antimicrobials
This allows C. Botulinum to colonize and produce toxin
Sobel (2005)
Sobel (2005)
Sobel (2005)
Sobel (2005)
Human Transmission: Inhalational Botulism Not a naturally occurring disease
Described once among German lab workers
Deliberate dissemination of botulinum toxin by aerosol could produce an outbreak of inhalational botulism
Between 1990 and 1995 the Japanese Aum cult attempted a number of attacks on US military installations of Japanese civilian centers
Used aerosol-generating equipment
Al Qaeda has expressed a special interest in using this toxin
Human Transmission: Iatrogenic Botulism Caused by injection of botulinum toxin for cosmetic or therapeutic purposes
Doses recommended for these purposes are too low to cause botulism
Higher doses injected for treatment of muscle movement disorders may cause the disease
Injection of unlicensed, highly concentrated botulinum toxin can cause severe botulism
For example, by ‘sketchy’ unlicensed doctors or cosmeticians
Kelch et al. (2000)
Kelch et al. (2000)
Classic Symptoms in Humans Generally begin 18-36 hours after eating a contaminated food, but can occur as early as six hours or as late as 10 days afterward:

Double vision
Blurred vision
Drooping eyelids
Slurred speech
Difficulty swallowing
Dry mouth
Muscle weakness
Constipation
Decreased/absent gag reflex and deep tendon reflexes
(Davis & Stöppler, 2010) In Infants Constipated – often first symptom to occur
Lethargy
Weak and floppy
Feed poorly
Weak cry
Poor muscle tone

(Davis & Stöppler, 2010)
If Left Untreated... Symptoms may lead to paralysis

Progessive paralysis of:
Arms
Legs
Trunk
Respiratory muscles

(Davis & Stöppler, 2010)

Symptoms in Cattle Clinical signs of disease may appear in 24 hours to 7 days
Lack of muscle tone progressively weak and wobbly.
Weakness first appears in the hindlimbs first, steadily moves toward the head
Paralysis of tongue and chest muscles
Many cows lie down in a "milk fever" position with the head in the flank

(Kelch et al., 2000; Kirk & Adaska 1998)



Often have an abnormal facial expressions
droopy eyelids
drooling
lack of ability to grasp food with their mouth
tongue may hang out of the mouth due to lack of muscle tone
Gut is usually shuts down
no rumen activity
bloated
hard, dry manure
Acute death within 24 hours to moderate, generalized weakness that may persist for weeks

(Kirk & Adaska 1998; Kelch et al., 2000)

Symptoms in Cattle Clinical Presentation in Cows and Humans Transmission to Humans/Types: Pathophysiology Seven distinct neurotoxins (types A-G) produced by Clostridium botulinum
types A, B, and E (and rarely F) are the most common that produce the flaccid paralysis in humans
most Clostridium species produce only one type of neurotoxin
effects of A, B, E, or F on humans are essentially the same.

(Davis & Stöppler, 2010)
Flaccid paralysis of muscles
caused by a neurotoxin
generically called botulinum toxin
produced by the bacterium Clostridium botulinum
rarely by C. butyricum and C. baratii.
(Davis & Stöppler, 2010)
Develops when...
toxin is ingested
rarely, if inhaled or injected
Clostridium spp. organisms grow in the intestines or wounds in the body and toxin is released.
Not transmitted person to person.

(Davis & Stöppler, 2010)
Vaccine Vaccine development currently being investigated

No vaccine commercially available/ approved for public use by the FDA

(Davis & Stöppler, 2010)



In the United States, an investigational pentavalent (against neurotoxins A, B, C, D, and E) botulinum toxoid vaccine
CDC for laboratory workers
military for protection of troops
takes several months to induce immunity

(Davis & Stöppler, 2010)


2009 new research
molecules that mimic botulism toxin binding sites may provide another method to block toxin from binding to nerve tissues
approach is only in the research phase of development.
(Davis & Stöppler, 2010)



Gram-positive, rod shaped sporoform bacteria Botulinum Toxin: Mode of Action Botox Toxin affects primarily cholinergic neurons of the somatic & autonomic nervous system

Affects progress by:
Cell endocytosis of toxin
Activation of the zinc-dependent endopetidase
Cleavage of multiple SNARE proteins
Inhibition of vesicle docking and fusion in the synaptic cleft

Timeframe of action: Reduced neurotransmitter release within hours, lasting effects for <6 months

(Aoki, Smith & Atassi, 2010)



Beyond Toxins Because Botulism Toxin can reduce cholinergic depolarization, it has been used in therapeutic causes for both the autonomic and somatic nervous system.
Neurobloc / Myobloc use BotX A & B variants, these are the only two toxins to be proven efficacious for clinical use.
Autonomic:
Glandular hypersecretions (hyperhidrosis)
Hyperlacrimations
Somatic:
Focal Spasticity
Urological Disorders
Detrusor sphincter, dyssynergia, Hyperreflexive bladder
GI Disorders
Anal fissure, Achalasia, Upper esophageal sphincter Anismus

(Cordivari, Misra, Catania & Lees, 2004; Bhidayasiri & Truong, 2005; Arezzo, 2009)

Cosmetic Use “Botox” therapy involves injection of botulinum toxin (type A) into facial nerves to relax smooth muscle and reduce wrinkles.

Questions of safety do arise
Systemic dissemination through blood and lymph
Local reactivity at site of injection

(Bhidayasiri & Truong, 2005)

“Walk-in Clinic” locations are sprouting in shopping malls, allowing individuals to get Botox A injections in a 5 minute outpatient procedure.
Cosmetic & Therapeutic Uses Differential Diagnosis Disorders that may be confused with C. Botulinum include:
Guillain-Barré syndrome (especially Miller-Fisher variant)
Acute poliomyelitis
Myasthenia gravis
Lambert-Eaton syndrome
Tick paralysis
Stroke
Aminoglycoside toxicity
Atropine poisoning
Paralytic shellfish poisoning (saxitoxin)
Puffer fish ingestion (tetrodotoxin)
Sepsis
Meningitis/encephalitis
Congenital myopathy
Electrolyte imbalance
Genetic metabolic disorders

(Tolan, 2010)

To differentiate, some tests include… Best diagnostic test: Culture from stool or wound extract
Gentian Violet stain of Clostridium Botulinum
60% of food-borne cases provide positive culture
Presence of flaccid paralysis is key

MRI may be used to rule out stroke

Electromyography can prove useful in determining widespread non-specific decrease in action potentials

Lumbar Puncture to rule out Guillain-Barré syndrome

(Tolan, 2010) Other Clostridial Infections C. difficile

C. tetani

C. perfrigens

C. sordellii C. difficile C. difficile – General Information Toxin-mediated intestinal disease

Found in:
Human
Horses
Pigs
Cows

Rarely has manifestations outside of the gut

Opportunistic disease that mainly develops after and antibiotic use
Can only colonize the gut if normal bacteria are disturbed or killed

(Rupnik, Wilcox, Gerdin, 2009) C. difficile – Clinical Presentation Mild disease
Asymptomatic
Mild diarrhea Severe disease
Abdominal pain
Fever
Leukocytosis Fulminant disease
Toxic megacolon
Bowl perforation
Sepsis and shock
death

(Rupnik, Wilcox, Gerdin, 2009)

C. difficile – Toxins Produces three toxins
Enterotoxin TcdA
Cytotoxin TcdB
Binary toxin CDT
Main symptoms caused by TcdA and B
Cytotoxic toxins which destroy intestinal epithelium by disruption of tight junctions and actin cytoskeleton
Role of CDT is unknown

(Rupnik, Wilcox, Gerdin, 2009)

C. difficile – Pathogenesis Image from: Rupnik, Wilcox, Gerdin, 2009. Bacterial cells adhere to the gut epithelium
Toxins are released, disrupting the epithelial wall
Immune reaction is mediated through the toxins
Pseudomembranes are formed as the result of inflammation
(Rupnik, Wilcox, Gerdin, 2009)

C. tetani – General Information C. tetani C. tetani – Toxin C. tetani – Clinical Presentation Toxin-mediated disease which affects the muscles
Muscles of the head and neck are the first to be affected
Normally contracted following a deep wound
Contracted neonatally in the developing world where traditional midwifery practices prevail
Diagnosis is based on clinical presentation

(Goonetilleke & Harris, 2004)

Muscle spasms
Muscle rigidity
Respiratory compromise from decreased chest wall compliance due to rigidity and spasms
Pain due to contraction of agonist and antagonist muscle pairs
Autonomic disturbances
Hypertension
Tachycardia
Diarrhea
Sweating

(Goonetilleke & Harris, 2004)

Two chains which are internalized
Separate upon acidification of the endocytic vesicle
The light chain, a zinc activated protease, migrates to the nerve terminal
Interrupts synaptobrevin which is involved in vesicle docking

(Goonetilleke & Harris, 2004)
C. perfrigens – General Information C. perfrigens – Food Poisoning C. perfrigens – Human Necrotic Enteritis Causes three different diseases
Gas gangrene
Type A food poisoning
Type C human necrotic enteritis
(Brynestad & Granum, 2001)
Caused by the production of enterotoxin

Presents with:
Diarrhea
Abdominal pain
Nausea

Death can result from dehydration

(Brynestad & Granum, 2001) Rare in the developed world
Symptoms begin with abdominal pain, blood diarrhea and vomiting
This leads to necrotic inflammation of the small intestine
Disease is often fatal (even with treatment)
Caused by -toxin mainly, but -toxin an d -toxin play a role
Associated with low levels of proteolytic enzymes
(Brynestad & Granum, 2001)
C. perfrigens C. sordellii C. sordellii – General Information C. sordellii – Clinical Presentation C. sordellii – Toxins Tissue edema is characteristic of infection
Non-pathogenic forms commonly found in the soil and intestines of animals (including humans)
Pathogenic forms cause myonecrosis and gangrene in humans
(Aldape, Bryant & Stevens, 2006)
Early symptoms
Nausea
Dizziness
Lethargy
Tenderness and rash at sites of infection

Later symptoms
Hypotension
Tachycardia
Septic shock
Pulmonary, peritoneal or viseral edema
Leukocytosis known as the “leukemoid reaction”

(Aldape, Bryant & Stevens, 2006) Seven toxins are produced

Two are considered major virulence factors
Lethal toxin
Hemorrhagic toxin
Table from: Aldape, Bryant & Stevens, 2006. (Aldape, Bryant & Stevens, 2006) Aoki, K., Smith, L.A., Atassi, M. (2010). Mode of action of botulinum neurotoxins: current vaccination strategies and molecular immune recognition. Critical Reviews in Immunology. 30(2), 167-187.
Aldape, M., Bryant, A. & Stevens, D. (2006). Clostridium sordellii Infection: Epidemiology, Clinical Findings, and Current Perspectives on Diagnosis and Treatment. Clinical Infectious Diseases, 43, 1436-1446.
Arezzo, J.C. (2009). Neurobloc/Myobloc: Unique features and findings. Toxicon. 54, 690-696.
Bhidayasiri, R., Truong, D.D. (2005). Expanding use of botulinum toxin. Journal of the Neurological Sciences. 235, 1-9.
Brynestad, S. & Granum, P. (2001). Clostridium perfringens and foodborne. International Journal of Food Microbiology, 74, 195-202.
Cordivari, C., Misra, P.V., Catania, S., Lees, A.J. (2004). New Therapeutic Indications for Botulinum Toxins. Movement Disorders. 19, 157-161.
Davis, C. & Stöppler, M. C. (2010). Botulism. Retrieved from http://www.medicinenet.com/botulism/article.htm
Goonetilleke, A. & Harris, J. (2004). Clostridial Neurotoxin. J Neurol Neurosurg Psychiatry, 75(Suppl III), iii35-iii39.
Kelch, W.J., Kerr, L.A., Pringle, J.K., Rohrbach, B.W., & Whitlock, R. H. (2000). Fatal Clostridium botulinum toxicosis in eleven Holstein cattle fed round bale barley haylage. Journal of Veterinary Diagnostic Investigation, 12, 453–455.
Kirk J. & Adaska J. (1998). Botulism in cattle. Retrieved from http://www.vetmed.ucdavis.edu/vetext/INF-DA/INF-DA_Botulism.html on 16 April 2010
Rupnik, M., Wilcox, M. & Gerding, D. (2009). Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nature Review: Microbiology, 7, 526-536.
Tolan, R.W. (2010). Botulism: Differential Diagnoses & Workup. eMedicine. Retrieved from http://emedicine.medscape.com/article/961833-diagnosis on 16 April 2010.

References
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