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ENDOCERVICAL ADENOCARCINOMA
MITOSES.
OUTPOUCHINGS.
PAPILLARY INFOLDINGS & cribriform patterns.
SAA
SAA (serum amyloid-associated) synthesized in the liver.
circulates in association with the HDL3 subclass of lipoproteins.
NEPHROGENIC FIBROSING DERMATOPATHY (NFD)
Nephrogenic fibrosing dermopathy (NFD) is a recently described condition, with the first reported diagnosis dating back to early 1997, and only 140 cases being reported. NFD is a chronic skin disease that causes indurated plaques that usually involve the skin of the extremities. The papules may coalesce and increase to the point of causing joint contractures with loss of flexion. All patients have chronic renal failure and most require dialysis. It affects both sexes equally, with no predilection for ethnic background. It has been reported in all age groups but is more common in middle-aged individuals.
THROMBOTIC MICROANGIOPATHY
RENAL OR SYSTEMIC THROMBI
HUS or TTP

7 causes.
TRANSPLANTATION
MITOMYCIN
CYCLOSPORINE
TACROLIMUS
QUININE
TICLOPIDINE
CLOPRIDOGREL
PREDOMINANTLY RENAL PLATELET-FIBRIN THROMBI
SHIGA TOXIN

DEFICIT IN PLASMA FACTOR H (familial or recurrent HUS).
MOST COMMON LIGHT CHAIN SUBGROUPS IN AL.
Lambda VI and Kappa I are the most common light-chain subgroups in patients with AL amyloidosis.
LAMBDA VI LIGHT CHAINS ACCOUNT FOR...
Lambda VI light chains account for less than 5 percent of normal immunoglobulin.
LAMBDA VI IN AL.
lAMBDA VI in large % of AL.
KAPPA I LIGHT CHAIN AMYLOID
Among the known kappa I LC amyloid sequences, most appear to be derived from one pair of kappa variable region germ-line genes
SOME GERM LINES OR ALLELIC VARIANTS...
Some germ-line genes or allelic variants may be more prone than others to mutations that give rise to amyloidogenic light chains.
WHAT IS THE ROLE OF THROMBOSIS AND FIBRINOLYSIS IN HUS?
The plasma of patients with HUS shows inhibition of fibrinolysis by increased activity of PAI-1 (plasminogen-activator-inhibitor1)
GOODPASTURE ANTIGEN
The alpha3(IV) NC1 domain.
This target must be present as a component of native alpha3.alpha4.alpha5(IV) network of selected basement membranes in order for pulmonary and renal disease to develop.
WHEN DOES MOST CHRONIC INTERSTITIAL FIBROSIS OCCUR IN RENAL TRANSPLANTS?
Substantial CIF occurred within 1 year after transplantation, comprising 70% of the total burden accumulated during the 10 yr study period (Nankivell).
HOW IS COLLAGEN IV ARRANGED?
Six genetically distinct chains are arranged into
triple helical protomers
that differ in their
chain composition.
WHAT MAKES AL DIFFICULT TO DETECT BY ANTI-LIGHT CHAIN ANTIBODIES?
AL-amyloid consists of the variable domain of kappa or lambda light chains as well as intact light chains. Because of sequence variability of this domain and alterations
in the structure of the pathological light chains in the amyloid, antibodies that have been raised against intact light chains might not
react to an amyloid fibril, but could be used to detect circulating intact light chains. The process of amyloid fibril formation also often
fragments the light chain, further preventing detection by commercially available antibodies.
Antibodies raised against intact light chains might not react to an amyloid fibril, but could be used to detect circulating intact light chains. Why?
SEQUENCE VARIABILITY
AL-A consists of variable domain of immunoglobulin K or L of LCs as well as intact light chains. Because of sequence variability of this domain and alterations in the structure of the pathological light chains in the amyloid, antibodies raised against intact light chains might not react to an amyloid fibril, but could be used to detect circulating intact light chains.
COLLAGEN

chains
protomers
Six genetically distinct chains are arranged into three triple helical protomers that differ in their chain composition
ISLET CELL AMYLOID
DM2. Derived from 37 aa peptide, islet amyloid polypeptide, which is released along with insulin by beta cells. Deposition of this amyloid is probably a consequence of increased secretory demand from peripheral insulin resistance, and not a cause for beta cell dysfunction, but as amyloid accumulates there is loss of beta cell mass.
AGONISTIC ANTI-AT ANTIBODIES
AGONISTIC ANTI-AT ANTIBODIES AND PRE-ECLAMPSIA
Angiotensin-receptor-agonistic antibodies may serve as the mechanism underlying preeclampsia. Need to determine the presence of receptors on multiple target organs and to track the timing and initiation of antibody production.
INHIBITING A (BETA) AMYLOIDOGENESIS
A (beta) amyloidogenesis involves A(beta) aggregation into spherical structures and then into fibrils. The fibrils appear to grow most
efficiently through the addition of monomeric A (beta). Small, bifunctional molecules such as chemically modified forms of Congo red
(synthetic ligand for forkhead binding protein [FKBP]–Congo red conjugate [SLF-CR]) can bind a fibril or its precursor and then recruit an endogenous nonamyloidogenic protein — in this case, FKBP — thus,
sterically hindering A (beta) amyloidogenesis. The right combination of a bifunctional small-molecule inhibitor and endogenous protein could
result in strong binders and prevent the aggregation of A beta in the brain.
AGONISTIC ANTIBODIES AND RENAL ALLOGRAFT REJECTION
Agonistic antibodies against angiotensin II receptor in renal allografts with severe vascular rejection and malignant hypertension do not have anti-HLA antibodies, no detectable donor-specific anti-HLA antibodies. No C4d.
SYSTEMIC PLATELET THROMBI
Failure to degrade unusually large multimers of Von Willebrand factor.
Thrombotic thrombocytopenic purpura.
GLYCOPROTEIN IB.
PLATELETS ADHERE TO UNUSUALLY LARGE VON WILLEBRAND FACTOR
LA DISPOSICION NO-COHESIVA
La disposición no-cohesiva de las células parece favorecer el dg de Linfoma de células grandes, aunque no se reconoce la célula característica ("hallmark" cell).
Molecular analysis of ...and...genes showed a ....
Molecular analysis of immunoglobulin (Ig) H and T-cell receptor genes showed a germline polyclonal configuration.
chains
...
...
chains

triple helical protomers

differ in chain composition
A(beta) how do your fibrils grow?
A (beta) amyloidogenesis involves A(beta) aggregation into spherical structures and then into fibrils. The fibrils grow by the addition of monomeric A(beta).
WHAT IS LAMBDA VI
Lambda VI
A light-chain subgroup.
WHAT IS KAPPA I,
Kappa I is a light-chain subgroup.
ISCHEMIA-REPERFUSION INJURY.
How?
When
I/R recruits leukocytes from whole blood under flow conditions.
I/R occurs in pathological conditions; myocardial infarction, stroke, and organ
transplantation.
In reperfusion phase, leukocytes recruited into tissues, where they can cause tissue damage and organ failure.
I/R & ADHESION MOLECULES
Adhesion molecules in I/R-mediated leukocyte recruitment. We found that leukocytes were recruited from whole blood under shear conditions to endothelial cells treated with
chemically induced I/R or H/R. In both models, mRNA for
intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin was upregulated.
---
Free Radic Biol Med. 2004 May 1;36(9):1102-11. Cassie S, Masterson MF, Polukoshko A, Viskovic MM, Tibbles LA.
...triple helical promoters
three triple helical protomers
I/R MODELS IN VITRO
I/R-mediated leukocyte recruitment in which leukocyte recruitment was examined using whole blood under shear conditions. Chemical treatments were used to mimic I/R in the first model, while sequential exposure to
hypoxia/reoxygenation (H/R) was used to mimic I/R in the second model.
I/R
mRNA FOR ADHESION MOLECULES
---
---
---
Leukocytes recruited from whole blood under shear conditions to endothelial cells treated with
chemically induced I/R or H/R. In both models, mRNA for
intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E-selectin was upregulated.
HUS
FIBRINOLYSIS
FIBRINOLYSIS
INHIBITION
HUS
PLASMINOGEN
PLASMINOGEN INHIBITED

FIBRIN UNINHIBITED
SLE CHRONICITY INDEX
Glomerular sclerosis
Fibrous crescents
Tubular atrophy
Interstitial fibrosis
q
a
ADHESION MOCELULES
ICAM-1.
VCAM-1.
E-selectin.
configuration
a germline polyclonal configuration.
ANTIBODY-MEDIATED REJECTION
1. subtle process, seen early, with edema, little inflammation, some tubular injury, and deposition of immunoglobulin and C4d in capillaries;
2. capillaritis and glomerulitis with immunoglobulin and C4d in
capillaries.
3. arteritis with deposits of immunoglobulin and C4d.
IAP IN DM2
From 37 amino acid peptide, islet amyloid polypeptide, which is released along with insulin by beta cells. The deposition of this amyloid is probably a consequence of increased secretory demand from peripheral insulin resistance, not a cause for beta cell dysfunction, but as amyloid accumulates there is loss of beta cell mass.
Germline polyclonal configuration.
Germline polyclonal configuration.
GOODPASTURE ANTIGEN SETTING
alpha3.alpha4.alpha5(IV) network
Each of the six chains of collagen IV has three domains:
Each of the six chains of collagen IV has three domains: there is a short 7S domain at the N-terminal; a long, collagenous domain occupies the midsection of the molecule; and a noncollagenous domain (NC1) is positioned at the C-terminal.
The six chains of collagen IV form only three sets of triple helical molecules called protomers
In spite of many potential permutations, the six chains of collagen IV apparently form only three sets of triple helical molecules called protomers, which are designated as {alpha}1.{alpha}1.{alpha}2(IV), {alpha}3.{alpha}4.{alpha}5(IV), {alpha}5.{alpha}5.{alpha}6(IV).
SEQUENCE VARIABILITY
SEQUENCE VARIABILITY
variable domain of K or L . Sequence variability of this domain.
Kappa V1
During the development of a B cell, the randomly chosen V gene segment (V3 in this case) is moved to lie precisely next to one of the J gene segments (J3 in this case).
WHY MIGHT AN ANTIBODY TO A LIGHT CHAIN FAIL TO DETECT THAT LIGHT CHAIN IN AMYLOID.
SEQUENCE VARIABILITY
AL-A consists of variable domain of immunoglobulin K or L of LCs. Because of sequence variability of this domain antibodies might not react to an amyloid fibril.
LUPUS VASCULOPATHY
LUPUS VASCULOPATHY (non-nectrotizing arteritis).
APA
TMA/HUS
Immunoglobulin microvascular casts (IMCs)
Immunoglobulin microvascular casts (IMCs) ("lupus vasculopathy") is the presence of Ig' deposition within the glomerular capillaries and small arterioles. The lesions were notable for the absence of endothelial or parietal vascular lesions and of fibrin, platelets, and leukocytes, which indicates that thrombosis is not involved in the vascular obstruction. According to our data immunoglobulin precipitation in the microvasculature seems to play a central role in the pathogenesis of this lesion. IMCs were associated with the most severe and active forms of diffuse proliferative lupus nephritis .The long-term outcome of patients with IMCs is not worse than that of other patients with class IV LN.
KAPPA I LC
Among k-I LC amyloid sequences, most derived from one pair of k-variable region germ-line genes, suggesting that some germ-line genes or allelic variants more prone than others to mutations that give rise to AL amyloid.
ISCHEMIA/REPERFUSION INJURY
Ischemia/reperfusion induces the recruitment of leukocytes from whole blood under flow conditions. Ischemia/reperfusion (I/R) occurs in a number of pathological conditions, including myocardial infarction, stroke, and organ
transplantation. During the reperfusion phase, leukocytes are recruited into affected tissues, where they can cause tissue damage and organ failure.
KERATIN PROFILE IN BREAST CA
CK 7 and CK20.
Figure 1.Micropapillary carcinoma.
Figure 1.Micropapillary carcinoma is composed of small papillary cell clusters surrounded by empty lacunar spaces. The papillae were lined by polygonal cells showing intermediate- to high-grade nuclei.Figure 2.Micropapillary carcinoma is a frequent component in lymph node metastasis.Figure 3. Immunohistochemical findings of micropapillary carcinoma component. A, The tumor cells are positive for p53. B, The tumor cells are strongly positive for cytokeratin 7. C, The tumor cells are negative for cytokeratin 20. D, The tumor cells are not reactive for cytokeratin 5 .
Germ line mutations of the... and mutation of the...
Germ line mutations of the E-cadherin gene can predispose to familial gastric carcinoma, and mutation of the gene and decreased E-cadherin
expression are present in a variable proportion of gastric cancers of the diffuse type.
DCIS

CK7
CK20
CK5
DCIS positive for CK7, but negative for CK20, CK5, epidermal growth factor receptor, or c-Kit.
ADENOCA LUNG
mucin, low molecular weight keratin (CK7), EMA, CEA, TTF1 (72%), surfactant apoprotein (50%),
ADENOCA LUNG -VE
Negative stains: CK20, vimentin (usually), keratin 5 (usually), P504S
SPINDLE CELLS
The cells displayed spindled, euchromatic nuclei, often with tapering ends.
HUS VS TTP
HUS is more frequently characterised by endothelial swelling than is TTP, and glomerular thrombi in HUS patients contain fibrin but little von Willebrand factor, also suggesting that von Willebrand factor is not involved in the evolution of the thromboses in STEC-associated HUS.
T Cell-Mediated Graft Rejection.
T Cell-Mediated Reactions.
T cell-mediated graft rejection is called cellular rejection, and it is induced by two mechanisms: destruction of graft cells by CD8+ CTLs and delayed hypersensitivity reactions triggered by activated CD4+ helper cells. The recipient's T cells recognize antigens in the graft ( or alloantigens) by
two pathways, called direct and indirect.
VEROCYTOTOXINS
The ... for ... is present on
the ... of ... cells and has been shown to be more prevalent in the renal cortex than in the medulla.
VEROCYTOTOXINS
The glycolipid receptor for verotoxins is present on
the membranes of endothelial cells and has been shown to be more prevalent in the renal cortex than in the medulla.
PLATELETS AND HUS/TMA
Because igher-molecular-weight polymers of VWF support platelet adhesion to the subendothelium and promote platelet aggregation, VWF was suspected of playing a pathogenetic role in
HUS/TTP. Patients with relapsing TTP have very large
circulating polymers of VWF during remissions, but not during relapses. A specific protease responsible for cleavage of VWF multimers was isolated from normal human plasma and was originally found to be deficient in patients with chronic relapsing TTP. These findings suggested that acquired as well as constitutional deficiency of the VWF-cleaving protease may predispose to TTP.
Proteinuria may develop in renal-transplant recipients who have converted from treatment with ... to treatment with ...
Proteinuria may develop in renal-transplant recipients who have converted from treatment with calcineurin inhibitors to treatment with SIROLIMUS.
Molecular mutational analysis.
Molecular mutational analysis, using multiple polymorphic markers associated with tumor suppressor genes, was performed on the ileocecal endometrioma and a benign glandular inclusion. Both lesions demonstrated no allelic imbalance in any of the markers tested, confirming their nonneoplastic nature
AMYLOID

CORRECTING.....
INHIBITING.....
CORRECTING PROTEIN MISFOLDING AND INHIBITING FIBRILLOGENESIS
Therapeutic strategies aimed at correcting protein misfolding and inhibiting fibrillogenesis are being developed.
THYROID FNA

MICROFOLLICLES
MACROFOLLICLES
Cases that were consistently classified as microfollicles were composed of fewer than 15 cells, were arranged in a circle with a lumen that was at least two-thirds complete , and were flat. Cases that were classified as macrofollicular had between 8 and 35 cells, were arranged in sheets composed of at least 15 cells or rows of 8 cells , and were flat. In contrast, cases that were indeterminate were composed of either 3-dimensional groups, flat groups of fewer than 10 cells, or single cells.
THYROID FNA

MICROFOLLICLES
Not all small groups of follicular cells are consistently classified as microfollicles, and some are more often classified as macrofollicles. The criteria described here for reproducible microfollicles (<15 cells, arranged in a circle that is at least two-thirds complete, and flat) may help improve the agreement in classification of microfollicles and lead to more consistent classification of thyroid fine-needle aspirates.
MICROFOLLICLES

MACROFOLLICLES
Cases that were consistently classified as microfollicles were composed of fewer than 15 cells, were arranged in a circle with a lumen that was at least two-thirds complete, and were flat. Cases that were classified as macrofollicular had between 8 and 35 cells, were arranged in sheets composed of at least 15 cells (or rows of 8 cells cases), and were flat. In contrast, cases that were indeterminate were composed of either 3-dimensional groups, flat groups of fewer than 10 cells, or single cells.
...mutations in the NF-2 gene predispose to the development of neurofibromatosis type 2. Patients with NF-2 deficiency develop benign bilateral schwannomas of the acoustic nerve. In addition, ... affecting both alleles of NF-2 have also been found in spo
Germ line mutations in the NF-2 gene predispose to the development of neurofibromatosis type 2. Patients with NF-2 deficiency develop benign bilateral schwannomas of the acoustic nerve. In addition, somatic mutations affecting both alleles of NF-2 have also been found in sporadic meningiomas and ependymomas.
Some... genes or ... may be more prone than others to mutations that give rise to amyloidogenic light chains.
Some germ-line genes or allelic variants may be more prone than others to mutations that give rise to amyloidogenic light chains.
Among the known --- --- amyloid sequences, most appear to be derived from one pair of --- --- region --- ---.
Among the known kappa I LC amyloid sequences, most appear to be derived from one pair of kappa variable region germ-line genes
ICELANDIC CEREBRAL AMYLOID ANGIOPATHY
ICELANDIC CEREBRAL AMYLOID ANGIOPATHY (HEREDITARY CYSTATIN C AMYLOID ANGIOPATHY)
Icelandic CAA, or hereditary cystatin C amyloid angiopathy, is inherited as an autosomal dominant trait. It is associated with brain hemorrhage in young adult or middle-aged patients. Hereditary cystatin C amyloid
angiopathy is characterized by vascular deposition of a mutant form of cystatin C γ trace (a cystein proteinase inhibitor), in which glutamine
is replaced by leucine as a result of a single nucleotide substitution.The amyloid implicated in this type of CAA is biochemically distinct from β-amyloid CAA.
DUTCH TYPE CEREBRAL AMYLOID ANGIOPATHY
DUTCH TYPE CEREBRAL AMYLOID ANGIOPATHY
Dutch CAA, or hereditary cerebral hemorrhage with amyloidosis (Dutch), is an autosomal dominant trait. In contrast to hereditary cystatin C amyloid angiopathy, it leads to brain hemorrhage
in middle-aged and older patients. The vascular amyloid is related to β-amyloid protein. The condition results from a mutation at codon 693 of the amyloid precursor protein.
Small, ... molecules such as chemically modified forms of ... (....) can bind a fibril or its precursor and then recruit an ... — in this case, ... — thus, sterically hindering A (beta) amyloidogenesis. The right combination of a bifunctional small-m
Small, bifunctional molecules such as chemically modified forms of Congo
red (synthetic ligand for forkhead binding protein [FKBP]–Congo red
conjugate [SLF-CR]) can bind a fibril or its precursor and then recruit an endogenous nonamyloidogenic protein — in this case, FKBP — thus, sterically hindering A (beta) amyloidogenesis. The right combination of a bifunctional small-molecule inhibitor and endogenous protein could result in strong binders and perhaps prevent the aggregation of A beta in the brain.
CAA WITH VASCULITIS VS CAA WITH NON-VASCULITIC INFLAMMATORY REACTION
CAA WITH VASCULITIS VS CAA WITH NON-VASCULITIC INFLAMMATORY REACTION
Early diagnosis is essential for the effective management of primary^ angiitis of the CNS (PACNS), but the presence of cerebrovascular amyloid^ angiopathy (CAA) may complicate the pathologic diagnosis since^ nonvasculitic inflammatory reactions can accompany CAA.
GIANT CELLS AND CAA
giant cells have frequently been reported in cases of cerebral amyloid angiopathy, and their presence has been attributed to either the coexistence of vasculitis and cerebral amyloid angiopathy or a giant-cell reaction to the amyloid deposits
FK506 (Tacrolimus)
FK506 (Tacrolimus)
FK506 inhibits T cell activation in vitro like cyclosporine effects on T cells are similar. Because of structural differences, FK506 binds a family of cytosolic proteins termed FK506-binding proteins (FKBP), which are different from the cyclosporine-binding cyclophilins. Both agents inhibit the phosphatase activity of calcineurin. Thus, although FK506 and cyclosporine have different structures, their immunosuppressive effects are mediated through a common final pathway. Both drugs block the induction of lymphokine mRNA, including IL-2, inhibit lymphokine production, and indirectly inhibit T cell proliferation. Toxicities of FK506 and cyclosporine are also very similar. In experimental studies, the combination of FK506 and cyclosporine show additive increases in toxicity
and in efficacy. Therefore, in clinical transplantation,
immunosuppressive protocols involving multiple drugs utilize either cyclosporine or FK506.
Another question is whether... differs substantially from other forms of...in the central nervous system, with respect to either its clinical features or its response to therapy.
Another question is whether vasculitis related to cerebral amyloid angiopathy differs substantially from other forms of vasculitis in the central nervous system, with respect to either its clinical features or its response to therapy. The literature suggests that this disorder is not markedly different from other forms of vasculitis and that it is reasonable for the neurologist to treat the disorder as if it were an idiopathic central nervous system vasculitis. Vasculitis related to cerebral amyloid angiopathy may provide biologic insight into the more common, nonvasculitic form of cerebral amyloid angiopathy, which is an important cause of hemorrhagic stroke in the elderly. is not a feature of these cases, several authors have noted perivascular inflammatory cells in the brains of patients with severe cerebral amyloid angiopathy, an inflammatory response to amyloid may contribute to the rupture of the vessel wall in patients with cerebral hemorrhage related to cerebral amyloid angiopathy.
Heredofamilial Amyloidosis.
Heredofamilial Amyloidosis. Most of them are rare and occur in limited geographic areas. The most common and best studied is an autosomal
recessive condition called familial Mediterranean fever. This is a febrile disorder of unknown cause characterized by attacks of fever accompanied by inflammation of serosal surfaces, including peritoneum, pleura, and synovial membrane. This disorder is encountered largely in individuals of Armenian, Sephardic Jewish, and Arabic origins. It is
associated with widespread tissue involvement indistinguishable from
reactive systemic amyloidosis. The amyloid fibril proteins are made up of AA proteins, suggesting that this form of amyloidosis is related to
the recurrent bouts of inflammation that characterize this disease. The gene for familial Mediterranean fever has been cloned, and its product is called pyrin (for its relation to fever). It has been suggested that pyrin is responsible for regulating acute inflammation, presumably by inhibiting the function of
neutrophils. The relationship of this mutation to the disease is not understood.
AMYLOID & AGEING
Amyloid of Aging. Senile systemic amyloidosis-systemic deposition of amyloid in elderly patients.Dominant involvement and related dysfunction of the heart, previously called senile cardiac amyloidosis. when symptomatic-restrictive cardiomyopathy and arrhythmias. TTR molecule. In addition to the sporadic senile systemic amyloidosis, another form, affecting predominantly the heart, that
results from the deposition of a mutant form of TTR has also been recognized. 4% blacks in US carrier of the mutant allele, and cardiomyopathy has been
identified in both homozygous and heterozygous patients.
AMYLOID
AMYLOID
X-ray crystallography and infrared spectroscopy demonstrate a characteristic cross-β-pleated sheet conformation. This conformation is
responsible for the distinctive staining and birefringence of Congo red stained amyloid.
PrPc
A prion protein can cause a “normal” folded protein of the same type (called PrPc for prion protein - cellular form) to assume a prion-like conformation. Misfolded prion-like proteins form filaments, and cause conformation changes in additional PrPc’s they come in contact with. This results in an amplifying cascade that leads to accumulation of prion protein fibers (“amyloid”) which cause progressive neuronal cell death.Transfer of prion proteins alone from a sick organism to a healthy one causes the propagation cascade to start anew.
Darwinain evolution is a logically unavoidable consequence of --- displaying --- variation in a --- environment.
When prions propagate, what gets replicated is not really a material entity. Non-pathogenetic, correctly folded PrPc proteins exist in a host before prion infection. Unlike all other infectious agents, prions do not make new forms of themselves by synthesizing anything. Like in the case of crystal formation, what gets replicated is a structure. In other words, prions are not replicating proteins, but replicating shapes in a protein substrate world. There is even evidence that the same prion may exist in alternative forms (“strains”) with different properties, which may potentially compete with each other for the available substrates (PrPc’s), in a sort of Darwinian competition between “immaterial” replicators. Now, this is not unexpected: Darwinain evolution is a logically unavoidable consequence of replicators displaying heritable variation in a selective environment.
QUININE

immune thrombocytopenia.
thrombotic microangiopathy
QUININE
In quinine-induced immune thrombocytopenia, patients produce antibodies against epitopes of platelet glycoprotein Ib/IX/V or IIb/IIIa complexes that have been antigenically altered by the attachment of quinine. In
some of these patients, thrombotic microangiopathy also develops, possibly because the antibodies cross-react with quinine- altered glycoprotein IIIa molecules on endothelial cell membranes.
TMA

drugs et al.
Thrombotic microangiopathy has been associated with
MITOMYCIN,
CYCLOSPORINE,
TACROLIMUS,
combinations of chemotherapeutic agents, and
total-body irradiation weeks or months after exposure to these agents.
TMA

& transplants
Thrombi may be predominantly renal or systemic and have been reported after allogeneic bone marrow, kidney, liver, heart, or lung transplantation. In the type of thrombotic microangiopathy that is associated with bone marrow transplantation, the activity of ADAMTS 13
in plasma is not usually reduced. The mechanism of these
microangiopathies is unknown.
TMA

ticlopidine
clopidogrel
pregnancy
Thrombotic thrombocytopenic purpura develops within a few
weeks after the initiation of therapy in a small fraction of patients with arterial thrombosis who receive ticlopidine, an inhibitor of one of the platelet adenosine diphosphate (ADP) receptors, and an even smaller fraction of those who receive the structurally similar agent
clopidogrel. The disorder also occurs occasionally during pregnancy (especially the last trimester) or in the postpartum period.
BETA 2 MICROGLOBULIN
β2-microglobulin, a component of the MHC class I molecules and a normal serum protein, has been identified as the amyloid fibril subunit (Aβ2m) in amyloidosis that complicates the course of
patients on long-term hemodialysis. Aβ2m fibers are structurally similar to normal β2m protein.
β-amyloid protein (Aβ)
β-amyloid protein (Aβ), not to be confused with Beta 2-microglobulin, is a 4000-dalton peptide that constitutes the core of cerebral plaques found in Alzheimer disease as well as the amyloid deposited in walls of cerebral blood vessels in patients with Alzheimer disease. The Aβ protein is derived from a much larger
transmembrane glycoprotein, called amyloid precursor protein.
PRION DISEASE
In a minority (?) of cases of prion disease in the central nervous system, the misfolded prion proteins aggregate in the extracellular space and acquire the structural and staining characterstics of amyloid protein. Therefore, prion diseases are sometimes considered examples of local amyloidosis.
NON-FIBRILLAR COMPONENTS OF AMYLOID
In addition, other minor components are always present in amyloid. These include serum amyloid P component, proteoglycans, and highly sulfated glycosaminoglycans. Serum amyloid P protein may contribute to amyloid
deposition by stabilizing the fibrils and decreasing their clearance.
Hemodialysis-Associated Amyloidosis.
Hemodialysis-Associated Amyloidosis. Patients on long-term hemodialysis
for renal failure develop amyloidosis owing to deposition of
β2-microglobulin. This protein is present in high concentrations in the
serum of patients with renal disease and is retained in circulation
because it cannot be filtered through the cuprophane dialysis membranes.
In some series, as many as 60% to 80% of the patients on long-term
dialysis developed amyloid deposits in the synovium, joints, and tendon
sheaths.
SPLENIC AMYLOID
One of two patterns of deposition is seen. In one,
the deposit is largely limited to the splenic follicles, producing tapioca-like granules on gross inspection, designated sago spleen.
Histologically the entire follicle may be replaced in advanced cases. In the other pattern, the amyloid appears to spare the follicles and
instead involves the walls of the splenic sinuses and connective tissue framework in the red pulp. Fusion of the early deposits gives rise to
large, maplike areas of amyloidosis, creating what has been designated the lardaceous spleen.
FMF
FMF autosomal recessive.
The gene for familial Mediterranean fever has been cloned, and its product is called PYRIN (for its relation to fever). Although its exact function is not known, it has been suggested that PYRIN IS RESPONSIBLE FOR REGULATING ACUTE INFLAMMATION, PRESUMABLY BY INHIBITING THE FUNCTION OF
NEUTROPHILS.
AUTOSOMAL DOMINANT AMYLOIDOPATHIES
In contrast to familial Mediterranean fever, a group of autosomal dominant familial disorders is characterized by deposition of amyloid
predominantly in the nerves-peripheral and autonomic. These familial
amyloidotic polyneuropathies have been described in different parts of the world. In all of these genetic Disorders, the fibrils are made up of mutant transthyretins (ATTR).
LOCALIZED AMYLOIDOSIS
Localized Amyloidosis. Sometimes, amyloid deposits are limited to a
single organ or tissue without involvement of any other site in the
body. The deposits may produce grossly detectable nodular masses or be
evident only on microscopic examination. Nodular (tumor-forming)
deposits of amyloid are most often encountered in the lung, larynx,
skin, urinary bladder, tongue, and the region about the eye. Frequently,
there are infiltrates of lymphocytes and plasma cells in the periphery
of these amyloid masses, raising the question of whether the mononuclear
infiltrate is a response to the deposition of amyloid or instead is
responsible for it. At least in some cases, the amyloid consists of AL
protein and may therefore represent a localized form of
immunocyte-derived amyloid.
ENDOCRINE AMYLOID
Endocrine Amyloid. Microscopic deposits of localized amyloid may be found in certain endocrine tumors, such as medullary carcinoma of the
thyroid gland, islet tumors of the pancreas, pheochromocytoma and undifferentiated carcinomas of the stomach, and in the islets of Langerhans in patients with type II diabetes mellitus. In these settings, the amyloidogenic proteins seem to be derived either from polypeptide hormones (e.g., medullary carcinoma) or from unique proteins (e.g., islet amyloid polypeptide).
IMAGING AMYLOID
Scintigraphy with radiolabeled serum amyloid P (SAP) component is a rapid and specific test, since SAP binds to the amyloid deposits and
reveals their presence. It also gives a measure of the extent of amyloidosis, and can be used to follow patients undergoing treatment.
SERPINS ARE THE PRINCIPLE PROTEASE INHIBITORS IN HUMAN PLASMA.
the serpins are the principle protease inhibitors in human plasma :
* antithrombin controls the proteolytic coagulation cascade;
* C1-inhibitor controls complement activation;
* the plasminogen activator inhibitors, PAI-1 and PAI-2, control fibrinolysis;
* and alpha-1-antitrypsin, also called alpha-1-proteinase inhibitor, modulates connective tissue restructuring.
COMMONALITIES IN THE SERPIN FAMILY
SERPIN
The serpins is an acronymic name given to a family of serine protease inhibitors that share a complex, but well conserved, tertiary structure. Members of the family are diversely present in eukaryotes, plants and viruses, and are evident in everyday life from the white of the egg - the non-inhibitory serpin Ovalbumin, to the foam protein of the beer - the barley Z protease inhibitor.
FNA PAP CA THYROID
3 FEATURES.
FNA THYROID
marked nuclear enlargement
pale chromatin
intranuclear inclusions
PAP CA THYROID
8 FEATURES NOT HELPFUL
staining
type of preparation
nuclear grooves
nuclear crowding
colloid
cellularity
nuclear pleomorphism
Hurthle cell change.
FNA PAP CA THYROID

nuclear enlargement
enlarged nuclei had a nuclear diameter at least twice the size of a red blood cell.
PAP CA THYROID

nuclear crowding
Nuclear crowding closely correlated with nuclear membrane contact and overlapping.
C1q NEPHROPATHY
C1q nephropathy
proteinuria that responds poorly to steroids.
Teenagers and young adults, blacks and males
renal failure
variable mesangial hypercellularity with increase in mesangial matrix; variable segmental glomerulopathy
IF: prominent mesangial C1q deposition; also IgG, IgM, IgA and C3
EM: mesangial immune complex deposits
lupus nephritis
QUATERNARY STRUCTURE
Quartenary structure is only present if there is more than one polypeptide chain. With multiple polypeptide chains, quartenary structure is their
interconnections and organization. This is an image of hemoglobin, a protein with four polypeptides-- two alpha-globins, and two
beta-globins. The red patches are heme groups (iron complexes bound to
the protein, which bind oxygen).
PAPILLARY CA THYROID
Papillary carcinoma: enlarged nuclei with irregular contours, nuclear
inclusions and grooves, pale chromatin, dense squamoid cytoplasm,
papillary architecture, psammoma bodies (don’t see ground glass nuclei
in cytologic preparations), presence of <20 cells with features of
papillary carcinoma is associated with a high rate of papillary
carcinoma at resection, usually classic type and > 1 cm, AJCP 2002;118:208
Strong CK19 staining of cell blocks can confirm diagnosis in equivocal
cases, Archives 2003;127:579
CELIAC
Increase in intraepithelial lymphocytes (initial, most sensitive marker, 40+ lymphs per 100 surface or upper crypt enterocytes; early-clustering of 12+ lymphocytes at tip of villi and extending evenly down the sides of the villus
IEL
Up to 2.5% of proximal small intestinal mucosal biopsies display
increased IELs (>25 IELs per 100 epithelial cells) in the absence of
villus architectural change.

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