21 May 2010

Monocyte / Macrophage Disorders



Monocyte / Macrophage Disorders
Northeast Regional Medical Center/KCOM

Granuloma Annulare
* Localized
* Generalized
* Macular
* Deep
* Perforating
* In HIV
* In Lymphoma
* Common, Idiopathic, all races
* 50% patients IgM and C3 in vessels
* LCV changes sometimes seen
* Suggests Ab mediated vasculitis
* Common in HIV patients
* EBV sometimes found
* Occurs in resolved lesions Zoster

GA - Histology
Interstitial GA
* Upper dermis
* “Skip areas”
* Mucin
* Deep dermis, subQ
* No “skip” areas
* No mucin

Localized GA
* Young adults
* Acral
* Annular, scalloped
* White or pink flat topped papules spread peripherally
* 75% clear in 2 yrs
* 25% last 8 yrs
Diffuse GA
Subcutaneous GA
Perforating GA
GA in HIV disease
GA and Lymphoma
GA- Treatment
Annular Elastolytic Giant Cell Granuloma of Meischer/Actinic Granuloma of O’Brien
Photoexacerbated GA
Granuloma Mulitforme of Leiker
Sarcoidosis
* Multisystem Disease
* Lungs, lymph nodes, skin and eyes MC.
* 10x more frequent in blacks in US
* Women under age 40
* Irish, African, Afro-Caribbean.
* Presence inversely proportional to the incidence of TB and/or Leprosy.
* Etiology unknown
* HLA-A1 – Lofgren’s syndrome
* HLA-B13 – Chronic & Persistent form
* HLA-B8
* HLA-DR3
* Final common pathway is granuloma formation
“NAKED” GRANULOMAS
“NAKED” meanse a sparse rather than a dense infiltrate. Lymphocytes, macrophages & fibroblasts may occur
Sarcoid Skin Involvement
Sarcoid – like syphillis, mimics many other dz’s
Papular Sarcoid
Annular Sarcoidosis
Hypopigmented Sarcoid
Lupus
Pernio
Punched-Out Lytic lesions, Bone Cysts
Ulcerative Sarcoidosis
Lupus Pernio
Darier-Roussy Sarcoid
Scar Sarcoid
Erythrodermic Sarcoid
Ichthyosiform Sarcoid
Alopecia
Morpheaform Sarcoid
Mucosal Sarcoid
Erythema Nodosum in Sarcoid
Systemic Sarcoidosis
Heerfort’s Syndrome
Mikulicz’s Syndrome
CXR- Hilar Adenopathy
Sarcoidosis in Fingers
Candle-wax drippings – granulomatous uveitis
Sarcoid - Treatment
Non-X Histocytoses
* Juvenile Xanthogranuloma
* Benign Cephalic Histiocytosis
* Solitary/Multicentric Reticulohistiocytosis
* Generalized Eruptive Histiocytoma
* Necrobiotic Xanthogranuloma
* Xanthoma Disseminatum
* Papular Xanthoma
* Indeterminate Cell Histiocytosis
* Progressive Nodular Histiocytoma
* Hereditary Progressive Mucinous Histiocytosis
* Rosai-Dorfman Disease
* Sea-Blue Histiocytosis
Juvenile Xanthogranuloma (JXG)
JXG Histopathology
Reticulohistiocytosis
Reticulohistiocytic Granuloma
Multicentric Reticulohistiocytosis
“Coral Bead” Paronychia
Tx: Multicentric Reticulohisticytosis
Generalized Eruptive Histiocytoma
Necrobiotic Xanthogranuloma (NXG)
NXG and Malignancy
Xanthoma Disseminatum
XD - Pathology
Papular Xanthoma
Indeterminate Cell Histiocytosis
Progressive Nodular Histiocytosis
Hereditary Progressive Mucinous Histiocytosis in Women
Rosai-Dorfman Disease
Rosai-Dorfman Disease – LN Biopsy
RDD - Emperipolesis – Histiocytes engulf plasma cells and lymphocytes
RDD - Treatment
Sea-Blue Histiocytosis
Sea-Blue Histiocytosis – Bone Marrow
X-type Histiocytoses
Hashimoto-Pritzker
Hashimoto-Pritzker Before and After
H-P MANAGEMENT
Histiocytosis X
Histiocytosis X - TX

Monocyte / Macrophage Disorders.ppt

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30 April 2010

The BioArtificial Liver



The BioArtificial Liver
By:Susana Candia
Jahi Gist
Hashim Mehter
Priya Sateesha
Roxanne Wadia

Biology of the Liver
Left lobe
Right lobe
Kidneys
Gallbladder
Falciform Ligament
Inferior Vena Cava
Abdominal Aorta

What does the Liver do?
Among the most important liver functions are:
* Removing and excreting body wastes and hormones as well as drugs and other foreign substances
* Synthesizing plasma proteins, including those necessary for blood clotting
* Producing immune factors and removing bacteria, helping the body fight infection

Other important but less immediate functions include:
* Producing bile to aid in digestion
* Excretion of bilirubin
* Storing certain vitamins, minerals, and sugars
* Processing nutrients absorbed from digestive tract

Why would someone need a BioArtificial Liver?
Liver Transplantation Now
* Patients are in waiting list ranked according to severity of disease and life expectancy among other variables.
* Can be from a cadaveric donor or from a live donor.
* Involves heavy use of immunosuppressants during and after surgery.
* The risk of rejecion is always present.

What does a BioArtificial Liver need to do?
* Cellular components must be purified and every component in it must be clearly identified.
* The cellular preparation must be clearly shown to not transmit any infectious diseases of any kind.
* The cellular component must stay viable and active
* The synthetic component must be fully biocompatible, integrity of the material and parts must also be demonstrated
* The device must be able to introduce the therapeutic and regulatory molecules that a healthy liver provides, and it must also filter substances from the blood the way that the normal liver does.
* Must be immunocompatible.
* Blood must perfuse properly through system

Enabling Technologies
* Hemodialysis/hemofiltration hollow fibers- controlled interaction of cells and circulating fluids
* Maintenance and creation of a cell line
* Immortalizing cells
* Encapsulation-envelopment of hepatocytes in a polymeric matrix.
* Microcarriers- polymeric particles containing cells

Works in Progress: Points to Consider
Bioreactor designs/Membrane configurations
Cellular vs. Acellular system
Porcine vs. Human hepatocytes
Point in Development
Liver Dialysis Unit
* FDA approved in 1994
* Plate dialyzer with blood on one side, dialysate is a mixture of sorbents, activated charcoal being the essential component.
* For a substance to be removed, must be dialyzable and able to bind to charcoal.
* “Bridge to recovery” for treat acute hepatic encephalopathy and overdoses of drugs
* Post-market trials have shown the LDU to be effective in improving physiological and neurological status.

MARS®
* Limited to investigational use in US.
* Hollow fiber membrane hemodialyzer.
* Blood on one side, human albumin on other.
* Albumin recycled through circuit containing another dialyzer and carbon and anion exchanger adsorption columns.
* Removes both water-soluble and protein bound substances
* Keep valuable proteins
* Trial have found it safe and associated with clinical improvement

ELAD®
* Uses cultured human hepatocytes express normal liver-specific metabolic pathways. hollow fiber dialyzer.
* Dialyzer cartridge connected to continuous hemodialysis machines, like those used for renal therapy.
* Blood separated into a cellular component and a plasma component.
* Plasma through dialyzer, hepatocytes on outside of hollow fibers.
* Currently involved in a phase 2 clinical trial to evaluate the safety and efficiency.
BLSS
* Extracorporeal hemofiltration hollow fiber membrane bioreactor with 100 grams of primary porcine hepatocytes
* Whole blood is filtered
* Contains blood pump, heat exchanger, oxygenator to control oxygenation and pH, and hollow fiber bioreactor
* Currently undergoing phase I/II clinical trials
* Patients show some improvement

HepAssist 2000 System
* Four components: a hollow fiber bioreactor containing porcine hepatocytes, two charcoal filters, a membrane oxygenator, and a pump.
* Must be used in conjunction with a commercially available plasma separation machine
* Blood separated; plasma processed through charcoal filters to remove particulates, bacteria, then enters bioreactor
* Hepatocytes must be heated and oxygenated
* FDA mandated full Phase III trials
LIVERx2000
* Hollow fiber cartridge
* Primary porcine hepatocytes suspended in a cold collagen solution and injected inside fibers
* Blood circulates outside the hollow fibers
* Designed to treat both acute and chronic liver failure
* Phase I/II clinical trials are underway to test the safety of efficacy of this device
* Anyone treated with the LIVERx2000 will be monitored for PERV
MELS
* Parallel plate design
* Human hepatocytes attached to semipermeable membranes on parallel plate
* Plasma separator, then plasma passes into the bioreactor
* In the bioreactor, the plasma flows over the semipermeable membrane where the hepatocytes are adhered.
* Current trials in Europe show promise

Demographics and Cost
* Market for liver support is estimated to be substantial: $700 million in the United States and $1.4 billion worldwide.
* Liver transplants have more than doubled in the past ten years, with the transplant waitlist growing in a similar fashion

Current and Future Challenges
* GOAL: To produce a fully implantable bioartificial liver.

Problems:
Cell viability
Fibrosis around implanted capsules
Proteins greater than pore size cannot be released

To achieve density of cells needed to replace liver, an estimated 1000m of hollow fibers would be needed

The BioArtificial Liver.ppt

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Renal Replacement Therapy



Renal Replacement Therapy

* What is it?
* How does it work?
Where did it come from?
History of Pediatric Hemofiltration
Mechanisms of Action: Convection
* Hydrostatic pressure pushes solvent across a semi-permeable membrane
* Solute is carried along with solvent by a process known as “solvent drag”
* Membrane pore size limits molecular transfer
* Efficient at removal of larger molecules compared with diffusion
* Solvent moves up a concentration gradient
* Solute diffuses down an concentration gradient

Mechanisms of Action: Diffusion
Semi-permeable Membranes
o Urea
o Creatinine
o Uric acid
o Sodium
o Potassium
o Ionized calcium
o Phosphate
o Almost all drugs not bound to plasma proteins
* Allow easy transfer of solutes less than 100 Daltons
o Bicarbonate
o Interleukin-1
o Interleukin-6
o Endotoxin
o Vancomycin
o Heparin
o Pesticides
o Ammonia
* Sieving Coefficient
* Sieving Coefficient is “1” for molecules that easily pass through the membrane and “0” for those that do not
* Continuous hemofiltration membranes consist of relatively straight channels of ever-increasing diameter that offer little resistance to fluid flow
* Intermittent hemodialysis membranes contain long, tortuous inter-connecting channels that result in high resistance to fluid flow

How is it done?
* Peritoneal Dialysis
* Hemodialysis
* Hemofiltration
* The choice of which modality to use depends on
o Patient’s clinical status
o Resources available

Peritoneal Dialysis
* Fluid placed into peritoneal cavity by catheter
* Glucose provides solvent gradient for fluid removal from body
* Can vary concentration of electrolytes to control hyperkalemia
* Can remove urea and metabolic products
* Can be intermittent or continuously cycled
* Simple to set up & perform
* Easy to use in infants
* Hemodynamic stability
* No anti-coagulation
* Bedside peritoneal access
* Treat severe hypothermia or hyperthermia
* Unreliable ultrafiltration
* Slow fluid & solute removal
* Drainage failure & leakage
* Catheter obstruction
* Respiratory compromise
* Hyperglycemia
* Peritonitis
* Not good for hyperammonemia or intoxication with dialyzable poisons

Intermittent Hemodialysis
* Maximum solute clearance of 3 modalities
* Best therapy for severe hyperkalemia
* Limited anti-coagulation time
* Bedside vascular access can be used
* Hemodynamic instability
* Hypoxemia
* Rapid fluid and electrolyte shifts
* Complex equipment
* Specialized personnel
* Difficult in small infants

Continuous Hemofiltration
* Easy to use in PICU
* Rapid electrolyte correction
* Excellent solute clearances
* Rapid acid/base correction
* Controllable fluid balance
* Tolerated by unstable patients
* Early use of TPN
* Bedside vascular access routine
* Systemic anticoagulation (except citrate)
* Frequent filter clotting
* Vascular access in infants

SCUF:Slow Continuous Ultrafiltration
* Pros
* Cons
Continuous Venovenous Hemofiltration
Dialysis Fluid
Continuous Venovenous Hemodialysis
Continuous Venovenous Hemodialysis with Ultrafiltration
Is there a “Best” Method?
Indications for Renal Replacement Therapy
Indicators of Circuit Function
Filtration Fraction
QP: the filter plasma flow rate in ml/min
Blood Flow Rate & Clearance
Pediatric CRRT Vascular Access: Performance = Blood Flow!!!
Urea Clearance
Solute Molecular Weight and Clearance
Cytokines (large) adsorbed minimal clearance
Replacement Fluids
Physiologic Replacement Fluid
Anticoagulation
Mechanisms of Filter Thrombosis
Heparin - Problems
Sites of Action of Citrate
Anticoagulation: Citrate
What are the targets?
Unknowns of Hemofiltration for Sepsis
Pediatric CRRT in the PICU
Renal Replacement Therapy in the PICU Pediatric Literature

Renal Replacement Therapy.ppt

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