Special Tissues

Special Tissues Zharlah A. Gulmatico-Flores, MD, DPDS

Objectives •

To correlate the structural characteristics of the special body tissues to their biological functions in the body.

•

To identify diseases involved in the alteration of genes and enzymes of the special tissues.

•

To compare the specific characteristics of the different special body fluids with that of the blood plasma.

•

To describe the disease processes which resulted from the modification of body fluids.

SPECIAL TISSUES Extracellular Matrix • Structural proteins • Specialized proteins • Proteogylcan Bone Cartilage Skin Muscle Nervous Tissue Special Body Fluids

EXTRACELLULAR MATRIX provides a chemical and mechanical structure diverse characteristics include stiffness and composition plays an important role in development, in inflammatory states and in the spread of cancer cells

Most mammalian cells are located in tissues where they are surrounded by a complex ECM often referred to as "connective tissue. (CLICK) The ECM provides a chemical and mechanical structure, which is essential for development and for responses to (patho)-physiological signals.

Differentiation and cell fate decisions are controlled by their surrounding microenvironment of which the ECM is one of the main constituents. The diverse characteristics of the ECM, such as stiffness and composition, have been recognized as being responsible for the variation of cellular behavior involving an individual’s health.

The ECM has been found to be involved in many normal and pathologic processes—it plays important roles in development, in inflammatory states, and in the spread of cancer cells

EXTRACELLULAR MATRIX vThree major classes: • 1. Structural proteins • Collagen • Elastin • Fibrillin • 2. Specialized proteins • Fibronectin • Laminin • 3. Proteoglycans

The ECM contains three major classes of biomolecules: (1) structural proteins: collagen, elastin and fibrillin; (2) specialized proteins: fibrillin, fibronectin and laminin; (3) proteoglycans.

QUESTION

Structural Proteins Collagen ú Most abundant protein in all tissues ú Contains approximately 1000 amino acids. ú Each alpha chain is twisted into left-

handed helix of 3 residues per turn. Three of these alpha chains are then wound into right handed super helix.

It is the major component of most connective tissue, constitutes approximately 25% to 1/3 of the body protein. It provides an extracellular framework for all metazoan animals and exists in virtually every animal tissue.

All collagen molecules are long, stiff rods consisting of a triple helix of three polypeptide chains called alpha chains. . It contains approximately 1000 amino acid. Each alpha chain is twisted into a left-handed helix of 3 residues per turn. Three of these alpha chains are then wound into a right handed superhelix.

CASE NO. 1 ❀ A 27-year-old man presented with low back pain. ❀ Past medical history included a Colle’s fracture at age 8 and several digital fractures in childhood. ❀ He had an adequate calcium intake, and his past medical history was noncontributory. ❀ Family Medical History revealed that his father, who had been diagnosed with osteoporosis, had had more than a dozen fractures, including a hip fracture at age 54. His sister, age 30, also had osteoporosis. ❀ On examination, the patient was 177 cm tall and weighed 62 kg. He had blue-gray sclera and normal dentition. A murmur was heard over the left sternal border. Musculoskeletal examination demonstrated S-curved spine and bowed legs and arms. Other systems were intact.

CASE NO. 1 â?€ What is your clinical impression of the case?

A. Osteogenesis imperfecta B. Osteoarthritis C. Osteoporosis D. Osteopetrosis

Hydroxyproline helps to form water bridges that stabilize the triple helix at body temperature.

Proline and hydroxyproline confer the rigidity of collagen molecule.

Glycine at every third position of triple helical portion of the chain is a striking characteristic of collagen

The repeating triplet GLY-X-Y is an absolute requirement for the formation of the triple helix which is shown here. (CLICK) Glycine is the smallest amino acid, and its size permits the alpha chains to form a tight triple helix.. Glycine residues at every third position (CLICK) of triple helical portion of the alpha chain is a striking characteristic of collagen. Notice how the glycine forms a tiny elbow packed

inside the helix, and notice how the proline and hydroxyproline smoothly bend the chain back around the helix. In this structure, the researchers placed a larger alanine amino acid in the position normally occupied by glycine, showing that it crowds the neighboring chains. (CLICK) Proline and hydroxyproline confer the rigidity of collagen molecule. This helix is then stabilized by (CLICK) hydroxyproline which helps to form water bridges that stabilize the triple helix at body temperature. This tight helix also makes the collagen molecule a relatively stiff, unbending rod and this configuration is essential for the organization of collagen molecules into fibrils.

Collagen Type

Genes

Tissue

I

COLA1, COLA2

Most connective tissue, including bone

II

COL2A1

Cartilage, vitreous humor

III

COL3A1

Extensible connective tissues such as skin, lung and the vascular system

IV

COL4A1- COL4A6

Basement membrane

V

COL5A1- COL5A3

Minor component in tissues, containing collagen 1

VI

COL6A1- COL6A3

Most connective tissues

VII

COL7A1

Anchoring fibrils

VIII

COL8A1- COL8A2

Endothelium, other tissues

IX

COL9A1- COL9A3

Tissues containing collagen II

X

COL10A1

Hypertrophic cartilage

XI

COL11A1, COL11A2

Tissue containing collagen II

XII

COL12A1

Tissue containing collagen I

XIII

COL13A1

Many tissues

XIV

COL14A1

Tissue containing collagen I

XV

COL15A1

Many tissues

XVI

COL16A1

Many tissues

XVII

COL17A1

Skin hemidesomes

XVIII

COL18A1

Many tissues (eg. Liver, kidney)

XIX

COL19A1

Rhabdomyosarcoma cells

These are the different types of collagen and their tissue target.

Type IV collagen, is characterized by a collagen with discontinous triple helices. It is an important component of basement membrane. Â Type XVIII, endostatin, is an inhibitor of angiogenesis

Collagen Class Fibril-forming Network-like FACITs Beaded filaments Anchoring fibrils Transmembrane domain Others

Type I, II, III, and V IV, VIII, X IX, XII, XIV, XVI, XIX VI VII XIII, XVII XV, XVII

Classification of collagens based primarily on the structures that they form

Collagen Intracellular • 1. Cleavage of signal peptide.

• 2. Hydroxylation of prolyl residues and some lysyl residues.

• 3. Formation of intrachain and interchain S-S bonds in extension peptides.

• 4. Formation of triple helix.

Extracellular • 1. Cleavage of amino and carboxy terminal propeptides.

• 2. Assembly of collagen fibers in quarter-staggered alignment.

• 3. Oxidative deamination of amino groups of lysyl and hydroxylysyl residues to aldehydes.

• 4. Formation of intra-and interchain cross links via Schiff bases and aldol condensation products.

Order and Location of Processing of the Fibrillar Collagen Precursor Intracellular 1. Cleavage of signal peptide 2. Hydroxylation of prolyl residues and some lysyl residues; glycosylation of some hydroxylysyl residues 3. Formation of intrachain and interchain S–S bonds in extension peptides 4. Formation of triple helix Extracellular 1. Cleavage of amino and carboxyl terminal propeptides 2. Assembly of collagen fibers in quarter-staggered alignment 3. Oxidative deamination of -amino groups of lysyl and hydroxylysyl residues to aldehydes 4. Formation of intra- and interchain cross-links via Schiff bases and aldol condensation products

Collagen Diseases Gene or enzyme

Disease

COL1A1, COL1A2

Osteogenesis imperfecta, type 1 Osteoporosis, Ehlers Danlos syndrome VII

COL2A1

Severe chondrodysplasia, Osteoarthritis

COL3A1

Ehlers-Danlos syndrome IV

COL4A3-A6

Alport syndrome

COL7A1

Epidermolysis bullosa, dystrophic

COL10A1

Schmid metaphysial chondrodysplasia

Lysyl hydroxylase

Ehlers-Danlos syndrome VI

Procollagen proteinase Lysyl hydroxylase

N - Ehlers-Danlos syndrome VI Menke’s disease

Diseases caused by mutations in collagen genes or by deficiencies in the activities of posttranslational enzymes involved in the biosynthesis of collagen

Name that Collagen 1.

Osteoporosis

2.

Ehler Danlos

3.

Epidermolysis bullosa

4.

Severe chondrodysplasia

5.

Osteogenesis Imperfecta

CASE NO. 2 â?€ What is your clinical impression in this case?

A.

Cutis Laxa

B.

Scleroderma

C.

Ehler Danlos Syndrome

D.

Premature aging

Collagen VS Elastin Collagen

Elastin

1. Many different genetic types

One genetic type

2. Triple helix

NO triple helix; random coil conformations permitting stretching

3. (Gly-X-Y) repeating structure

NO (Gly-X-Y) repeating structure

4. Presence of hydroxylysine

NO hydroxylysine

5. Carbohydrate-containing

NO carbohydrate

6. Intramolecular aldol cross-links

Intramolecular desmosine crosslinks

7. Presence of extension peptides NO extension peptides present during biosynthesis during biosynthesis

CASE NO. 3 â?€ What is your clinical impression in this case?

A.

Cutis Laxa

B.

Scleroderma

C.

Marfan Syndrome

D.

Ehler Danlos Syndrome

Fibrillin â?€A large glycoprotein that is a structural component of microfibrils. â?€It is secreted into the ECM by fibroblasts and incorporated in the microfibrils. â?€It is found in lens, periosteum and aorta.

Both structural and specialized protein It is large glycoprotein that is a structural component of microfibrils. It is secreted into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibrils, which appear to provide scaffold for deposition of elastin. It is found in the zonular fibers lens, periosteum and associated with elastin fibers in the aorta.

Marfan Syndrome low fibrillin

Cytokine TGF

TGF

This results in (CLICK) abnormal fibrillin and/or lower amounts being deposited in the ECM. There is evidence that the (CLICK) cytokine TGF- normally binds to fibrillin-1, and if this binding is (CLICK) decreased (due to lower amounts of fibrillin-1), this can lead to an excess of the cytokine. The (CLICK) excess of TGF- may contribute to the pathology (eg, in the aorta and aortic valve) found in the syndrome.

Fibronectin â?€ major glycoprotein of the ECM â?€ plays an important roles in cell adhesion, migration, growth, and differentiation

Fibronectin (FN) mediates a wide variety of cellular interactions with the extracellular matrix (ECM) and plays important roles in cell adhesion, migration, growth and differentiation. FN is widely expressed by multiple cell types and is critically important in vertebrate development.

FN has a remarkably wide variety of functional activities besides binding to cell surfaces through integrins. It binds to a number of biologically important molecules that include heparin, collagen/gelatin, and fibrin.

CASE NO. 4 â?€ Major protein component of renal glomerulus.

A. Laminin B.

Type IV Collagen

C. Fibrillin D. Fibronectin

The four major components of BM are(CLICK) type IV collagen, (CLICK) laminin, (CLICK) nidogen/entactin, and (CLICK) perlecan or heparan sulfate (in renal basement membrane).

(CLICK) Nidogen, also known as entactin, accounts for 2%–3% of all BM proteins. It is the major cell attachment factor.

They are essential for the proper function of BM of certain organs postnatally, specifically for BM in the lung and the heart.

(CLICK) Perlecan is a heparan sulfate proteoglycan resembling (CLICK) “pearls on a string.” They are ubiquitously expressed in BM and are also key players in (CLICK) chrondogenesis.

The glomerular membrane allows small molecules, such as inulin, to pass through as easily as water. On the other hand, only a small amount of the protein albumin. In glomerulonephritis, alteration of these basal lamina component will result passage of massive amounts of albumin which known as (CLICK) albuminuria.

MATCHING TYPE 1.

Proteinuria

A. Collagen

2.

Scleroderma

3.

Ehler Danlos Syndrome

4.

Marfans Syndrome

B. Elastin

C. Fibronectin

D. Fibrillin

Proteoglycans and Glycosaminoglycans vProteins that contain covalently linked glycosaminoglycans. vGAG is an unbranched polysaccharide made up of repeating disaccharides. One of its component is always an amino sugar and repeating dissacharide.

• Galactosamine or Glucosamine • Glucuronic acid or Iduronic acid

Proteoglycans are proteins that contain covalently linked glycosaminoglycans. At least 30 have been characterized and given names such as syndecan, betaglycan, serglycin, perlecan, aggrecan, versican, decorin, biglycan, and fibromodulin. They vary in tissue distribution, nature of the core protein, attached glycosaminoglycans, and function. The proteins bound covalently to glycosaminoglycans are called "core proteins"; they have proved difficult to isolate and characterize, but the use of recombinant DNA technology is beginning to yield important information about their structures. The amount of carbohydrate in a proteoglycan is usually much greater than is found in a glycoprotein and may comprise up to 95% of its weight.

Proteoglycans (PGs) consist of a protein portion and long, unbranched polysaccharides (glycosaminoglycans or GAGs).

The latter have a high negative charge, owing to the presence of acidic sugar residues and/or modification by sulphate groups.

A GAG is an unbranched polysaccharide made up of repeating disaccharides, one component of which is always an amino sugar, either or glucosamine. The other component of the repeating disaccharide (except in the case of keratan sulfate) is a uronic acid, either L-glucuronic acid (GlcUA) or its 5'-epimer, L-iduronic acid (IdUA).

All the GAGs contain sulfate groups, either as O-esters or as N-sulfate (in heparin and heparan sulfate) except hyaluronic acid.

Glycosaminoglycans ❀ Classified according to the hexosamine unit.

• Glucosaminoglycans – heparin, heparan sulfate, and hyaluronic acid • Galactosaminoglycans – chondroitin sulfate and dermatan sulfate ❀ All GAGs contain sulfate groups except Hyaluronic acid.

GAGs; mucopolyssacharides are long, highly negatively charged, unbranched polymers of repeating dissacharide units.

They are classified according to the hexosamine units that alternate with uronic acid in the polymer.

Glycosaminoglycans

HA is found in synovial fluid, VH, LCT, CS in cartilage and cornea, bone KS 1 Cornea, KS II is found along with chondroitin sulfate and attached to HA in LCT, Heparin mast cells, fibroblast, aortic wall DS wide distribution

Glycosaminoglycans

This matrix is made up of a variety of sugars and proteins and helps to form the architectural framework of the body.

The matrix surrounds the cells of the body in an organized meshwork and functions as the glue that holds the cells of the body together. One of the parts of the extracellular matrix is a complex molecule called a proteoglycan. Like many components of the body, proteoglycans need to be broken down and replaced. When the body breaks down proteoglycans, one of the resulting products is mucopolysaccharides, otherwise known as GAG.

Name

Enzymatic defect

Urinary Metabolites

Mucopolysaccahridoses Hurler

£-L-Iduronidase

Dermatan sulfate, heparan sulfate

Hunter

Iduronate sulfatase

Dermatan sulfate, heparan sulfate

Sanfilippo A

Heparan sulfate N-sulfatase Heparan sulfate

Sanfilippo B

£-N-Acetylglucosamine

Heparan sulfate

Sanfilippo C

Acetyltransferase

Heparan sulfate

Sanfilippo D Morquio A

N - A c e t y l g l u c o s a m i n e 6 - Heparan sulfate sulfatase Galactosamine 6-sulfatase Keratan sulfate, chondroitin 6-sulfate

Morquio B

ß-Galactosidase

Maroteaux-Lamy

N-Acetylgalactosamine 4- Dermatan sulfate sulfatase ß-Glucuronidase Dermatan sulfate, heparin sulfate, chondroitin 4-sulfate, chondroitin 6sulfate

Sly

Keratan sulfate

Mucolipidoses Sialidosis

Sialidase

Glycoprotein fragments

I-cell disease

UDP-N-acetylglucosamine

Glycoprotein fragments

Pseudo-Hurler polydystrophy

UDP-N-acetylglucosamine

Glycoprotein fragments

Bone ❀Inorganic component: • • • • • •

Hydroxyapatite Sodium Magnesium Carbonate Fluoride Calcium

❀Organic component: • Collagen type 1 • Osteocalcin and sialoprotein

The composition of bone matrix has both organic and inorganic component.. Hydroxyapatite along with sodium, magnesium,

carbonate, and fluoride; approximately 99% of the body's calcium is contained in bone. Hydroxyapatite confers on bone the strength and resilience. Aside from its inorganic component, bone matrix is mainly composed of type I collagen molecules linked together by crosslinking molecules such as (CLICK) pyridinoline (Pyr) and deoxypyridinoline. Bone matrix also comprises several noncollagenous proteins, some of which are almost specific for bone tissue. These include osteocalcin and bone sialoprotein (BSP).

Bone

BONE IS A METABOLICALLY ACTIVE tissue and undergoes continuous remodelling, a process that largely relies on the activity of osteoclasts to remove bone and of osteoblasts to form bone. In normal conditions, bone resorption and formation are coupled to each other.

Bone

Here again is another illustration of osteoclast where they have an apical membrane in its (CLICK) ruffled border that plays in bone resorption. Lysosomal enzymes and hydrogen ions which are confined (CLICK) low ph microenvironment, an environment created by the attachment between bone matrix and the apical membrane of osteoclast. This (CLICK) space facilitates the dissolution of calcium phosphate from bone and a very favorable pH for the activity of lysosomal hydrolases. As the Bone matrix is removed, and the products of bone resorption are taken up into the cytoplasm of the osteoclast, and (CLICK) transferred into blood circulation thru capillaries

Bone �Approximately 4% of compact bone is renewed annually and 20% of trabecular bone is replaced. �Factors involved in the regulation of bone metabolism: • parathyroid hormone and 1, 25 dihydroxycholecalciferol, corticosteroid, calcitonin and estrogen

It is estimated that approximately 4% of compact bone is renewed yearly in the typical healthy human being, whereas approximately 20% of trabecular bone is replaced.

Many factors are involved in the regulation of bone metabolism. Some stimulate osteoblasts like parathyroid hormone and 1,25-dihydroxycholecalciferol and others inhibit them like corticosteroids. Parathyroid hormone and 1,25-dihydroxycholecalciferol also stimulate osteoclasts, whereas calcitonin and estrogens inhibit them.

CASE NO. 5 ❀ A 60-year-old postmenopausal woman has low back pain.

She has been in good general health for the past several years. She experienced menopause in her early 50s.

Although the patient has no personal history of fractures, her older sister experienced a hip fracture at age 44 years old. She is 5’5” and weighs 118 lbs. She smokes cigarettes, drinks several cups of coffee a day, and rarely exercises.

CASE NO. 5 â?€ In examining her low back pain, what diagnostic step should be done?

A. BMD testing B. TSH, T3 and T4 C. X-ray D. Complete blood count (CBC), comprehensive chemistry profile, and vitamin D25 levels E. 12 lead ECG

Osteoporosis

Osteoporosis

What happens in osteoporosis? The central point is that osteoporosis occurs when bone resorption (osteoclastic [OC]) activity) exceeds bone formation (osteoblastic [OB] activity).

The (CLICK) hormones have a variety of effects on bone. (CLICK) IGF-1 and IGF-2 have anabolic effects on bone, but may also stimulate turnover of bone. (CLICK) Cytokine is involved in communication between osteoblasts and osteoclasts; when it interacts with osteoclasts, it increases their activity. The other cytokines are made by osteoblasts. Their synthesis is increased or decreased by estrogen deficiency, with the overall effect of extending the life span of osteoclasts (by inhibiting apoptosis).

Bone Diseases Disease Dwarfism Rickets

Comments Often due to a deficiency of growth hormone.

Due to a deficiency of vitamin D during childhood.

Osteomalacia

Due to a deficiency of vitamin D during adulthood.

Hyperparathyroidism Osteogenesis imperfecta Osteoporosis

Excess parathormone causes bone resorption.

Mutations in the COL1A1 and COL1A2 Mutations in the COL1A1 and COL1A2 genes and possibly in the vitamin D receptor gene Osteoarthritis Mutations in the COL1A genes Several chondrodysplasias Due to mutations in COL10A1 genes Pfeiffer syndrome1 Mutations in the gene encoding FGFR1 Jackson-Weiss and Crouzon syndromes1

Mutations in the gene encoding FGFR2

Achondroplasia and thanatophoric dysplasia2

Mutations in the gene encoding FGFR3

Metabolic and Genetic Disorders in Bone

Dwarfism

This is often due to deficiency of growth hormone, but could other causes.

Rickets

In the vitamin D deficiency state, hypocalcemia develops, which stimulates excess parathyroid hormone, which stimulates renal phosphorus loss, further reducing deposition of calcium in the bone. Excess parathyroid hormone also produces changes in the bone similar to those occurring in hyperparathyroidism. Early in the course of rickets, the calcium concentration in the serum decreases. After the parathyroid response, the calcium concentration usually returns to the reference range, though phosphorus levels remain low. Alkaline phosphatase, which is produced by overactive osteoblast cells, leaks to the extracellular fluids so that its concentration rises to anywhere from moderate elevation to very high levels.

Cholecalciferol (ie, vitamin D-3) is formed in the skin from 5-dihydrotachysterol. This steroid undergoes hydroxylation in 2 steps. The first hydroxylation occurs at position 25 in the liver, producing calcidiol (25-hydroxycholecalciferol), which circulates in the plasma as the most abundant of the vitamin D metabolites and is thought to be a good indicator of overall vitamin D status. The second hydroxylation step occurs in the kidney at the 1 position, where it undergoes hydroxylation to the active metabolite calcitriol (1,25-dihydroxycholecalciferol). This cholecalciferol is not technically a vitamin but a hormone.

Calcitriol acts at 3 known sites to tightly regulate calcium metabolism. Calcitriol promotes absorption of calcium and phosphorus from the intestine, increases reabsorption of phosphate in the kidney, and acts on bone to release calcium and phosphate. Calcitriol may also directly facilitate calcification. These actions increase the concentrations of calcium and phosphorus in extracellular fluid. The increase of calcium and phosphorus in extracellular fluid, in turn, leads to the calcification of osteoid, primarily at the metaphyseal growing ends of bones but also throughout all osteoid in the skeleton. Parathyroid hormone facilitates the 1-hydroxylation step in vitamin D metabolism.

Osteomalacia

In osteomalacia, , the amount of bone density or mass may be normal, but there is little mineral in bone. while there are usually symptoms with osteomalacia like aches and pain in lumbar (lower back) regions and thighs, spreading later to arms and ribs.

In osteomalacia, the bones get weak and soft from loss of calcium and phosphorous. The volume of bone matrix does not change. Osteomalacia is specifically a defect in mineralization of the protein framework known as osteoid. This defective mineralization is mainly caused due to lack of vitamin D. Osteomalacia is a disease occurring mostly in adult women who have a deficiency of vitamin D and calcium and is characterized by softening of bones with accompanying pain and weakness.

Osteomalacia Definition

Bone density maybe normal

Osteoporosis Abnormal to loss of bone density

Age of Onset Any age

Elderly

Etiology

Vitamin D def.

Calcium def.

Site

Appendicular

Axial skeleton

Osteoporosis:Bone mass reduced, mineralisation normal Osteomalacia:Bone mass variable, Mineralisation decreases Age at onset Osteoporosis Generally elderly and postmenopausal Osteomalacia Any age Etiology OsteoporosisIdiopathic, Endocrine abn., inactivity,disuse,alcoholism,calcium deficiency Osteomalacia Vitamin D deficiency, abnormality of vit D pathway, hypophosphatasia syndromes, renal tubular acidosis Symptoms Osteoporosis Pain referable to site Osteomalacia Generalised bone pain Signs OsteoporosisTenderness at fracture site OsteomalaciaTenderness at fracture site and generalised tenderness Radiographic features Osteoporosis Mainly axial skeleton fracture Osteomalacia Often symmetric pseudofractures or completed fracture in appendicular skeleton

Pfeiffer Syndrome

FGFR 1

Note the acrocephalic skull shape and prominent eyes.

There’s a broad and deviated great toes.

A clover leaf shape skull is not infrequently seen as part of the syndrome.

Crouzon syndrome

FGFR 2

Crouzon is usually distinguished from other similar FGFR disorders involving craniosynostosis (Pfeiffer, Jackson-Weiss, Apert) by lack of hand or foot anomalies.

Mutation on FGFR 2 prominent forehead, proptosis, hypertelorism, hooked nose and small jaw

Cartilage vPrincipal protein is Type II collagen vCollagen type IX cross-links to collagen type II. vAggrecan is the major proteoglycan • HA, CS and KS vAn avascular tissue vChondronectin and Anchorin C II binds type II collagen to surface to chondrocyte.

The principal proteins of hyaline cartilage is Type II. Cartilage contains a number of proteoglycans which play an important role in its compressibility. Aggrecan is the major proteoglycan. it has a very complex structure, containing several GAGs (hyaluronic acid, chondroitin sulfate, and keratan sulfate) and both link and core proteins.

Cartilage is an avascular tissue and obtains most of its nutrients from synovial fluid.

Cartilage

This is a table where you can see the proteins which are contained in the cartilage. contains a number of proteoglycans, Aggrecan. is the major proteoglycan. CS-PG (chondroitin sulfate-proteoglycan) DS-PG(dermatan sulfate –proteoglycan)

CASE NO. 6 A 8 month-old girl was brought by her parents at the emergency because of difficulty to breathing and failure to thrive. she has been hospitalized for severe pneumonia more than 5 times for the past several months. Her brother who is 2 year-old also showed the same signs and symptoms.

QUESTION An electrolyte/s that is/are expected to be increased in Sweat test?! ! A. Sodium ! B. Potassium ! C. Chloride ! D. Both A and B E. Both A and C !

SWEAT Eccrine Clear, odor-free, colorless, slightly acidic fluid that is almost full water.

It also consist of NaCl, K and HCO3 and some other molecule.

Raised levels of NaCl in sweat are a reliable diagnostic feature of cystic fibrosis.

Apocrine Thicker, more viscous and with milky consistency.

Found in puberty, located in the groin, anal region, axilla, areola of the breast, and beard.

Control of these nerves resides in so-called ‘sweat centers’ in the hypothalamus of the brain. Sweating rate is directly proportional to skin temperature and is markedly reduced at temperatures below 30 uC. While sweating can be induced by direct heating alone (39 to 46 uC), generally physiologic sweating is due to a nervous reflex that can arise from sweat centers in the brain cortex (emotional), hypotha- lamus (thermoregulation), and medulla (gustatory).

CASE NO. 7 A regular alcoholic beverage 40-year-old male drinker complained of agonizing pain on his right toe.

QUESTION What is the most likely diagnosis for this case?

Support your answer. ! A. Pseudogout ! B. Osteoarthritis C. Gout ! D. Big toe trauma

Synovial Fluid Clear viscous ultra filtrate of plasma Glucose and uric acid is equivalent to plasma Protein is lower than plasma Hyaluronate protein complex containing mucin Moistens and lubricates joints Most frequently requested test is the glucose determination because markedly decreased values are indicative of inflammatory or septic disorders

Because synovial fluid is biochemically an ultrafiltrate of plasma, biochemistry test values are approximately the same of serum values

GOUT vs. PSEUDOGOUT GOUT

PSEUDOGOUT

Monosodium urate crystals

Calcium pyrophosphate

Intracellular (acute stages) and extracellular

Intracellular and extracellular

Polarized light: strongly birefringent

Polarized light: weakly birefringent

Compensated polarized light: yellow Compensated polarized light: blue when parallel, blue when when parallel (yellow when perpendicular perpendicular) Needle shaped

Blunt rods or rhombic shape

CASE NO. 8 55-year-old woman presented with chief complaints of foreign body sensation and dryness of eyes for 3-4 years, which worsened during nights. Schirmer’s test showed wetting of less than 6 mm per 5 minutes, suggestive of severe dry eyes. Based on these findings and previous medical records, the diagnosis of Sjögren’s syndrome was made.

Tears The lacrimal fluid contains Sodium - 128.7 Potassium - 17 Chloride - 141.3 Bicarbonate - 12.4

The osmolarity of the lacrimal fluid is about 300 mosM and contains Na+ (128.7 mM), K+ (17 mM), Cl– (141.3 mM), and bicarbonate (HCO3–; 12.4 mM) (12). This fluid has about the same osmolarity as plasma but has lower Na+ (140 mM plasma) and higher K+ (4 mM plasma) and much higher Cl– (100 mM plasma). A

Cerebrospinal Fluid Functions: ! a. provides physical support for the brain ! b. protects against acute changes in! !

arterial and venous blood pressure.

! c. a route of waste excretion ! d. maintain the ionic homeostasis of the !

CNS

CSF and Plasma CSF proteins are less than 1% that of plasma CSF calcium levels are less than 50% that of plasma CSF glucose levels are less than 60% that of plasma CSF chloride and magnesium levels are higher than plasma CO2 diffuses rapidly and HCO3 slowly, from the plasma into the CSF.

SEMEN § 5% of it, is made up of secretions from the Cowper (bulbourethral) and Littre glands. § 15% to 30% - prostrate gland. § 50 to 60% - seminal vesicles

Human semen is a mixture of components produced by sev- eral different glands. These components are incompletely mixed during ejaculation and, hence, the initial ejaculate is not an en- tirely homogeneous mixture. The first portion of the ejaculate, about 5% of it, is made up of secretions from the Cowper (bul- bourethral) and Littre glands. The second portion derives from the prostate and contributes from 15% to 30% to the ejaculate. There follow small contributions of the ampulla and epididymis and, finally, of the seminal vesicles, which contribute the re- mainder, and majority, of the ejaculate (

SEMEN and PLASMA H i g h e r co n ce nt rat i o n o f ca lc i u m a n d magnesium in plasma than in whole semen For sodium, the concentration in whole semen was greater than in plasma.

CASE NO. 9 A 42 year-old patient came into emergency room with severe eye pain which is of sudden onset. The pain is accompanied by blurring of vision and non projectile vomiting.

PE showed hazy cornea and posterior synechiae (iris adherent to anterior lens surface), intraocular pressure is 65mmHg.

QUESTION Your most likely impression on this case:

A. B. C. D.

Error of refraction Viral conjunctivitis Glaucoma Dislocation of lens

Acqueous Humor Aqueous humor is formed in the eye at an average rate of 2 to 3 microliters each minute. Essentially all of it is secreted by the ciliary processes, which are linear folds projecting from the ciliary body into the space behind the iris where the lens ligaments and ciliary muscle attach to the eyeball.

Acqueous humor After aqueous humor is formed by the ciliary processes, it first flows, through the pupil into the anterior chamber of the eye. From here, the fluid flows anterior to the lens and into the angle between the cornea and the iris, then through a meshwork of trabeculae, finally entering the canal of Schlemm, which empties into extraocular veins.

CASE No. 10 Pathophysiology of atopic dermatitis would include: ! A.

Disturbance in the TGase-mediated cross linking

of structural proteins and lipids. ! B. ! Topical application of solvents to the skin will ! ! remove lipids from S. corneum and increases TEWL. ! C.! Atopic dermatitis is associated with ceramide-! ! dominance. ! D. ! All of the statements are true.

Skin ² extends to approximately 2 m2 in area. ² 2.5 mm thick on average ² provide for a 5–6 kg mass value for skin or 6% of our total body weight

Tobin. Biochemistry of human skin—our brain on the outside.

Aug 2005. Chemical Society Reviews

Skin Layers of the skin: 1. Epidermis Stratified, non, vascularized, epithelium of between 75 and 150 Îźm.

2. Dermis Consist of mixture of fibroblasts 3. Subcutis Fatty connective tissue that connects the dermis to underlying skeletal components.

Tobin. Biochemistry of human skin—our brain on the outside.

Aug 2005. Chemical Society Reviews

Epidermis

Skin

Stratum corneum Stratum lucidum Stratum granulosum Stratum spinosum Stratum basale

Epidermal permeability barrier Barrier function of the stratum corneum is to consider as a brick wall. It depends on transglutaminase-mediated cross-linking of structural proteins (Tgase) and lipids during the terminal stages of keratinocytes differentiation.

The corneocytes (made of tough protein) form the bricks and between these a double layer of lipids (fatty materials) and water make up the mortar.

Tobin. Biochemistry of human skin—our brain on the outside.

Aug 2005. Chemical Society Reviews

Epidermis The quality of the S. corneum barrier depends on the presence of equimolar amounts of ceramides, cholesterol and free fatty acids.

Aged and photo-aged skin exhibit a cholesteroldominant barrier, while atopic dermatitis is associate d w ith cerami de- do minance an d a dominance of free fatty acids is associated with psoriasis.

Tobin. Biochemistry of human skin—our brain on the outside.

Aug 2005. Chemical Society Reviews

Dermis and ECM Collagen – 90% of the total dermal protein. ! Type I > Type III > Type V > Type VII Elastin : ! Oxytalan fibers, elaunin fibers and elastic fibers Extrafibrillar matrix : Most important proteoglycan is the versican.

Tobin. Biochemistry of human skin—our brain on the outside.

Aug 2005. Chemical Society Reviews

The most important proteoglycan in skin is versican, produced by fibroblasts, smooth muscle cells and epithelial cells, and versican is associated with elastic fibres and hyaluronic acid to provide tautness to the skin.

Signs of Internal Aging Fine wrinkles Thin and transparent skin Loss of underlying fat Sagging skin Dry skin

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