Histology & Molecular

·         SIMPLE SQUAMOUS--lung alveoli,blood vessels,descending limb of loop of henle,parietal layer of bowman's membrane..

·         SIMPLE CUBOIDAL-->duct of many glands,germinal layer of ovary,thyroid follicles

·         SIMPLE COLOUMNAR--gallbladder,stomach,small intestine..most of large intestine

·         SIMPLE COLOUMNAR CILIATED--uterus and uterine tube,ependyma of spinal cord,small bronchi and bronchiole

·         PSEUDOSTRATIFIED CILIATED COLOUMNAR--trachea,bronchi,nasopharynx

·         STRATIFIED SQUAMOUS NONKERATINIZED-lining of mouth,tongue,tonsil,pharynx,esophagus,epiglottis,cornea,vagina and KERATINIZED--skin

·         TRANSITONAL EPITHELIUM-major and minor calyx,pelvis renal,ureter,bladder,proximal part of urethra..

·         STRATIFIED CUBOIDAL--pancreas,sweat gland,salivary gland

·         EPIPHYSIS

1. Pressure epiphysis : which transmits weight from one bone to another. Eg: Head of femur, Condyles of tibia, Lower end radius.

2. Traction epiphysis or apophysis : situated at the point of attachment of

muscles or tendons. Eg : Trochanters of femur, Tubercles of Humerus, Mastoid process

3. Atavistic epiphysis : which represents a part of the skeleton which has lost its

original function. Eg: Coracoid process of scapula, Post. tubercle of talus, Ostrigonum

4. Aberrant Epiphysis : Not always present. Eg: Head of 1st MC, Base of Other MC.

PRIMARY EPIPHYSIS

1. Vertebral body: Calve

2. Carpal scaphoid: Preiser

3. Lunate, adult: Kienbock

4. Patella: Kohler

5. Talus: Mouchet

6. Tarsal scaphoid: Kohler

7. Medial Cuneiform: Buscke

8. Femoral trochanter: Monde Felix

9. Patella: Sinding-Larsen

10. Tibial head: Ritter

11. Tibial tubercle: Osgood-Schlatter

12. Os calcis: Sever

13. Metatarsal head: Freiberg

SECONDARY EPIPHYSIS

1. Vertebral epiphysis: Scheuermann’s

2. Sternal end clavicle: Friedrich

3. Humeral head: Hass

4. Humeral capitellum: Panner

5. Radial head: Brailsford

6. Distal ulna: Burns

7. Metacarpal heads: Mauclaire

8. Iliac crest: Buchman

9. Pubic symphysis: Van Neck

10. Ischiopubic region: Oldberg

11. Femoral head: Legg-Calve - Perthes

·         There are differences in the way that intermediate filaments interact with microtubules and microfilaments within the cytoplasm; however, their ropelike arrangement is well suited to providing mechanical stability to the cell and resisting stretch, allowing the cell to respond to tension.

The different types of intermediate filaments all have a similar structural pattern: nonhelical head and tail segments with a helical arrangement in the center of the intermediate filament structure.

Intermediate filaments that are “intermediate” in diameter (8 to 10 nm) between thin and thick filaments are of five different types. Type I and type II are the acidic and basic keratins (cytokeratins) respectively and are found specifically in epithelial cells. Type III intermediate filaments are composed of vimentin, desmin, and glial fibrillary acidic protein (GFAP). Vimentin is found in cells of mesenchymal origin, desmin in muscle cells, and glial fibrillary acidic protein in astrocytes. Type IV intermediate filaments are neurofilament proteins found in neurons. Type V intermediate filaments include the nuclear lamins A, B, and C and are associated with nuclear lamina of all cells.

Movement is generated by motor proteins such as myosin, dynein, and kinesin. There is a good mnemonic device for remembering the direction of movement directed by kinesin and dynein. Kinesin kicks the molecules out; dynein drags them in; also, the plus end of the microtubule is oriented toward the plasma membrane, so minus end toward nucleus. This works for fibroblasts as well as neurons.

Nucleation of microtubules is conducted by centrosomes.

 Microtubule-associated proteins (MAPs) stabilize or destabilize microtubules. Microtubules function in organellar transport (e.g., axonal transport).

COP-I (COat Protein-I) coats vesicles involved in retrograde transport from Golgi→RER. COP-II is the coat protein for vesicles transported in an anterograde direction from the RER→Golgi

·         The integrins are transmembrane heterodimers that act as membrane receptors for extracellular matrix components.

The best examples are the fibronectin receptor and the laminin receptor. The receptor structure includes an intracytosolic portion that binds to the actin cytoskeleton through the attachment proteins talin or ALPHA-actinin. The extracellular portion has specificity for extracellular matrix molecules.

Fibronectin is an adhesive glycoprotein that is important for cell attachment. It is important for modulation of cell migration in the adult and during development. Neural crest and other cells appear to be guided along fibronectin-coated pathways in the embryo.

Fibronectin is found in three forms:

1. a plasma form that is involved in blood clotting;
2. a cell surface form, which binds to the cell surface transiently;
3. a matrix form, which is fibrillar in arrangement.

Fibronectin contains a cell-binding domain (RGD sequence), a collagen-binding domain, and a heparin-binding domain. Type IV collagen is responsible for providing support.

Collagen fibrils are connected to other extracellular matrix molecules by the FACIT (fibril-associated collagens with interrupted triple helices = collagen 9-13) collagens.

Type I collagen is found in dentin.

·         The primary function of entactin (nidogen) is to cross-link laminin to type IV collagen. The basal lamina is formed by interactions between type IV collagen, laminin, entactin, and the proteoglycan perlecan.

·         In Ehlers-Danlos disorder type IV there is improperly formed type III collagen, which is responsible for the elasticity of the intestinal and aortic walls. In this form of the disorder there are errors in the transcription of type III collagen mRNA or in translation of this mRNA.

Hyperextensible skin occurs in Ehlers-Danlos type VI disorder in which problems with the hydroxylation of the amino acid lysine and subsequent cross-linking result in enhanced elasticity.

Type VII Ehlers-Danlos disorder involves a specific deficiency in an amino terminal procollagen peptidase. This results from a genetic mutation that alters the propeptide sequence in such a way that the molecular orientation and cross-linking are adversely affected. The result is hypermobility of synovial joints. Increased degradation of proteoglycans occurs in osteoarthritis.

·         The cell cortex is an area of the cell immediately underneath the plasma membrane and is rich in actin, which is required for cytokinesis. This region is important in maintaining the mechanical strength of the cytoplasm of the cell. It is also essential for cellular functions that require surface motility. These functions include phagocytosis, cytokinesis, and cell locomotion. Although movement of vesicles along filaments is regulated by minimyosins (myosin I), movement of vesicles and organelles is predominantly a function of microtubules under the influence of the unidirectional motors kinesin and dynein. The movements of cilia and flagella are driven by dynein and chromosomal movements occur through microtubular kinetics.

·         Endothelial cells synthesize a number of antithrombogenic factors including plasminogen activator and prostacyclin. Prostacyclin functions through cyclic AMP to inhibit thromboxane production by platelets.

Endothelial cells synthesize the basal lamina including types IV, V, and VIII collagens, fibronectin, and laminin. Secretion of A and B blood group antigens also occurs in endothelial cells.

Angiotensin converting enzyme on the endothelial cell surface converts angiotensin I to angiotensin II (a potent vasoconstrictor), but also serves as an inactivation enzyme (bradykininase) for bradykinin, a vasodilator.

The endothelium produces nitric oxide, also known as endothelium–derived relaxing factor (EDRF), and endothelin, the most potent vasoconstrictor in the body.

Endothelial cells also synthesize plasminogen inhibitor, a coagulant and von Willebrand factor (factor VIII) which is found in Weibel-Palade granules in endothelial cells of vessels larger than capillaries. A deficiency of factor VIII leads to decreased platelet aggregation and hemophilia.

·         The sebaceous glands are holocrine (i.e., they shed the cell along with the secretory product). Sebum is a lipid product released into a duct that terminates in a hair follicle. The photomicrograph represents a microscopic section obtained from thin skin. The presence of sebaceous glands identifies the section as thin skin. Sebaceous glands and hair follicles are not found in thick skin. Another difference between thick and thin skin is the virtual absence of the stratum lucidum in thin skin.

The sweat glands are of two different types: merocrine glands and apocrine glands.

The merocrine glands release their secretion through exocytosis with conservation of membrane.

In the anal, areolar, and axillary regions, the sweat glands are of the apocrine type and empty into the hair follicles. In apocrine glands, the apical part of the cell is released with the secretion.

·         The epididymis functions in the storage, maturation, and phagocytosis of sperm and residual bodies. In addition, the epididymis is involved in the absorption of testicular fluid and the secretion of glycoproteins. These glycoproteins may be involved in the inhibition of capacitation. The epithelium of the epididymis is pseudostratified with stereocilia (modified microvilli for absorption), and the wall contains extensive connective tissue.

·         The glomerular filtration barrier is a physical and charge barrier that exhibits selectivity based on molecular size and charge.

The barrier is formed by three components:

 (1) glomerular capillary endothelial cells,

(2) glomerular basement membrane: The presence of collagen type IV in the lamina densa of the basement membrane presents a physical barrier to the passage of large proteins from the blood to the urinary space. Glycosaminoglycans, particularly heparan sulfate, produce a polyanionic charge that binds cationic molecules

(3) podocyte layer. Filtration slits are found between adjacent podocyte foot processes and provide a gap of approximately 50 micron. The foot processes are coated with a glycoprotein called podocalyxin, which is rich in sialic acid and provides mutual repulsion to maintain the structure of the filtration slits. It also possesses a large polyanionic charge for repulsion of large anionic proteins.

·         GOLGI ORGAN:

 cis: hydroxylated and phosphorylated protein

Medial: Glycosylation site

Trans: sorting

2 diseases: I cell disease (mucolipoidosis II, def of NAG phosphotransferases) & hyperproinsulinemia( s/s similar to NIDDM )

The discoid stacks (CGN, cis, medial, trans, and TGN as one moves from the RER-side to the secretory vesicle-side) of the Golgi apparatus are involved in packaging and routing proteins for export or delivery to other organelles, including lysosomes and peroxisomes.

Secretory granules leave the TGN to dock with the plasma membrane. In that process, v-SNARE on the vesicle docks with t-SNARE on the cell membrane and requires Rab GTPase-activity, linking to tethering proteins, and eventually to a receptor protein in the cell membrane.

·         Four most common disorders of peroxisomes are:

.Zellweger (cerebrohepatorenal) syndrome ( EMPTY PEROXISOMES IN EM)

.Neonatal adrenoleukodystrophy

.Infantile Refsum disease

.Hyperpipecolatemia

·         Liver Zones:

Zone I: periportal zone–most sensitive to toxic injury, affected first by viral hepatitis

Zone II: intermediate zone

Zone III: pericentral vein zone, contains P-450 system, affected first by ischemia, alcoholic hepatitis

·         PTH stimulation of osteoblasts releases macrophage colony-stimulating factor (M-CSF) and RANK-L. M-CSF stimulates differentiation of monocytes into osteoclasts. RANK-L is found in both membrane and soluble forms and binds to RANK (receptor for activation of nuclear factor kappa B) on osteoclasts and osteoclast precursors stimulating osteoclastic activation/ ruffled border formation. Osteoprotegerin (OPG) is a decoy receptor for RANK-L, binds RANK-L, and leads to inhibition of osteoclastic activity. Those molecules create the link between osteoblasts and osteoclasts known as the ARF (activation-resorption-formation) cycle in which activation of osteoclasts is inextricably linked to osteoblasts. This has been one of the problems in treating osteoporosis in which osteoclastic activity dominates osteoblastic activity.

Osteoprotegerin inhibits osteoclastic activity.

·         The polyanionic charge of the membrane is produced by the sugar side chains on the glycoproteins and glycolipids. Glycoproteins often terminate in sialic acid side chains, which impart a negative (polyanionic) charge to the membrane. Similarly, the glycolipids (also called glycosphingolipids), particularly the gangliosides, terminate in sialic acid residues with a strong negative charge.

·         Freeze fracture is a procedure in which the tissue is rapidly frozen and fractured with a knife. The fracture plane occurs through the hydrophobic central plane of membranes, which is the plane of least resistance to the cleavage force. The two faces are essentially the two interior faces of the membrane. They are described as the extracellular face (E face) and the protoplasmic face (P face). The cytoplasm is the backing for the P face, which in general contains numerous intramembranous particles (mostly protein). The E face is backed by the extracellular space and in general contains a paucity of intramembranous particles compared with the P face.

·         In its anion exchanger role, band 3 protein exchanges bicarbonate ion for chloride ion. Bicarbonate is transported by band 3 out of the RBC in exchange for chloride, permitting the highly efficient transport of CO2 to the lungs as bicarbonate. In the absence of band 3 protein, the bicarbonate buffering of the blood is reduced, leading to acidosis or lowering of blood pH. The result is reduced capacity to carry CO2. In addition to its functional, bidirectional anion exchanger role, band 3 plays a key membrane structural role, since the cytoplasmic domain of the protein interacts with spectrin through an ankyrin bridge. Spectrin exists as dimers and trimers; the trimers are bound together by actin, thus providing a connection to the cytoskeleton maintaining the shape and stability of the RBC. The result of a null mutation in band 3 is the formation of erythrocytes that are small and round instead of biconcave (spherocytosis).

·         Asymmetry of the lipid bilayer is established during membrane synthesis in the endoplasmic reticulum before reaching the Golgi apparatus

·         Desmin is found in striated and most smooth muscle, except vascular smooth muscle.

Glial fibrillary acidic protein, GFAP, is specific for astrocytes, not microglia or oligodendrocytes.

·         The stability, arrangement, and functions of actin filaments depend on the actin-binding proteins. The fundamental structure of the actin molecule is the same no matter what the function or arrangement in a cell. Actin-binding proteins have a variety of functions: (1) tropomyosin strengthens actin filaments, (2) fibrin and villin are actin-bundling proteins, (3) filamin and gelsolin regulate transformation from the sol to the gel state, (4) members of the myosin II family are responsible for sliding filaments, (5) myosin I (minimyosin) is responsible for movement of vesicles on filaments, and (6) spectrin cross-links the sides of actin filaments to the plasma membrane.

·         Nucleation of microtubules is conducted by centrosomes.

·         Batten’s disease, neuronal ceroid lipofuscinoses, in which there is a build-up of lipofuscin because of the absence of specific lysosomal enzymes.

The child has shown a failure to thrive, is microcephalic, exhibits myoclonic jerks, delayed psychomotor development, visual disturbance and seizures. Analysis of fibroblasts from the skin by electron microscopy confirms the presence of fingerprint inclusion bodies. Elevated levels of dolichol are found in the urine.

Dolichol is normally associated with N-linked glycosylation in the rough endoplasmic reticulum (RER) an en bloc method in which dolichol is added to the protein. O-linked glycosylation occurs in the Golgi, by a mechanism involving oligosaccharide (glycosyl) transferases rather than en bloc with dolichol. N-linked oligosaccharides are the most common oligosaccharides found in glycoproteins and contain sugar residues linked to the NH2 amide nitrogen of asparagine. O-linked oligosaccharides have sugar residues linked to hydroxyl groups on the side chains of serine and threonine. The diversity in oligosaccharides is produced by selective removal of glucose and mannose from the core oligosaccharide. This trimming process begins in the RER before reaching the Golgi, where the final mannose-residue trimming occurs. Sulfation and protein sorting are carried out in the Golgi apparatus, but do not involve dolichol.

·         Zellweger syndrome, in which peroxisomes are empty.

A boy is born with epicanthal folds, a high forehead, hypoplastic supraorbital ridges, and upslanting palpebral fissures. He shows growth retardation following birth, he feels like a rag doll when held, and he exhibits neonatal seizures. He also has a ventricular septal defect, glaucoma, cataracts, elevated iron and copper levels in his blood, and hepatomegaly. A liver biopsy is prepared for electron microscopy and shows the presence of empty peroxisomes. The pathologist describes them as peroxisome “ghosts.”

Peroxisomes are the sole site of plasmalogen synthesis. Plasmalogen is a group of glycerol-based phospholipids in which the aliphatic side chains are not attached by ester linkages. They have a widespread distribution with highest concentrations in the brain, spinal cord, liver, and kidney. Energy production, exocytosis, detoxification, and the synthesis of lysosomal enzymes would not be affected in that disease. In Zellweger syndrome, peroxisomes are empty because of the failure of the signal system that sorts protein to the peroxisome. Because the peroxisome lacks a genome (DNA) or synthetic machinery (ribosomes), it must import all proteins. The defect appears to be in the peroxisomal membrane (peroxins), but errors or absence of the peroxisomal signal sequence would result in the same symptoms. Peroxisomes have only a single membrane around them and contain catalase. Peroxisomes carry out oxidation reactions to protect the cell. Those oxidation reactions remove hydrogen atoms from molecules like alcohol and phenols to form hydrogen peroxide. In the peroxidative reaction, catalase breaks down hydrogen peroxide to water and oxygen. Most of the alcohol humans consume is broken down by the ADH (alcohol dehydrogenase) and MEOS (microsomal ethanol-oxidizing system, that is, P450 cytochrome) pathways in the hepatocyte (liver cell) cytoplasm; the remaining small percentage is broken down by oxidation in the peroxisomes of hepatocytes using catalase.

·         Cytochalasins are potent inhibitors of cell motility and other cellular events that depend on actin assembly: cytokinesis, which is conducted by the actin-containing contractile ring; phagocytosis; and formation of lamellipodia. Cytochalasins bind to the plus end of actin filaments and prevent further polymerization. The movement of chromosomes in anaphase of the cell cycle depends on disassembly of microtubules at the kinetochore in anaphase A and addition at the plus end of the polar microtubules in anaphase B.

·         Chloroquine neutralizes acidic compartments such as the secretory vesicles. Chloroquine treatment inhibits the conversion of proinsulin to insulin, resulting in decreased formation of insulin within secretory vesicles.

·         Leigh’s Disease (Subacute Necrotizing Encephalomyelopathy), a generalized (systemic) form of Cytochrome C oxidase (COX) Deficiency, characterized by progressive degeneration of the brain and dysfunction of the heart, kidneys, muscles, and liver. Symptoms include loss of acquired motor skills and loss of appetite, vomiting, irritability, and/or seizure activity. As Leigh’s Disease progresses, symptoms include generalized weakness; loss of muscle tone (hypotonia); and/or episodes of lactic acidosis with lactate higher in the CSF than the blood.

·         Within the ER there are protein chaperones and mechanisms to prevent aberrant protein folding and to catalyze isomerization of correct covalent bonds. Frequently, changes in the extracellular environment result in aberrant protein folding in the ER as occurs in Alzheimer disease.

·         Signal hypothesis & function of the signal recognition particle (SRP):

The SRP prevents degradation of newly synthesized peptides because translocation across the ER membrane protects the nascent peptide from proteases. The signal hypothesis is the basis of the targeting of transmembrane, lysosomal, and exportable proteins across the ER membrane. It is the key event in the segregation of noncytosolic proteins in the ER cisternae. The result of SRP activity is attachment of ribosomes translating the secretory protein to the ER membrane and the translocation of the protein across the ER membrane. The SRP binds to the N terminus of the signal peptide as the peptide emerges from the ribosome and induces an immediate delay in translation until the ribosome interacts with a docking protein, also known as an SRP receptor, in the ER membrane. In the function of the RER, a presequence on the 3’-end of the AUG initiation codon is translated as an N-(amino)-terminal presequence [amino-terminal signal leader (prepeptide) sequence] that recognizes the ER membrane and leads to the translocation of the peptide across the ER membrane. This recognition is accomplished through the SRP, which cycles between the ER membrane and the cytosol. After the SRP-bound ribosome attaches to the ER membrane via the docking protein, translation continues with displacement of the SRP for subsequent recycling and translocation of the peptide across the ER membrane. Enzymatic cleavage (answer e) of the signal sequence releases the newly synthesized peptide.

·         Inclusion (I)–cell disease: There is an absence or deficiency of N-acetylglucosamine phosphotransferase and an absence of mannose-6-phosphate (M6P) on the lysosomal enzymes. The failure to add M6P in the cis-Golgi results in inappropriate vesicular segregation by M6P receptors in the trans–Golgi network (TGN). The default pathway is transport to the cell membrane and secretion from the cell by exocytosis for proteins lacking M6P. Lysosomal enzymes are secreted into the bloodstream, and undigested substrates build up within the cells. There is no missorting back to the Golgi.

Peroxisomal enzymes, which are sorted by the presence of three specific amino acids located at the C-terminus: Ser–Lys–Leu–COO−, are not affected.

KDEL  is the signal used for retrieval of proteins from the Golgi back to the endoplasmic reticulum.

SNAREs [soluble-N-ethylemalemide sensitive factor (NSF) attachment protein receptors] are the receptors for SNAPs [soluble-N-ethylemalemide sensitive factor (NSF) attachment proteins] and bind vesicles to membranes. Trafficking to other structures, such as the nucleus and mitochondria, is regulated by nuclear localization signals (NLSs) or an N-terminal signal peptide, respectively.

·         The TCOF1 gene encodes treacle. Expression of treacle is critical during early embryonic development in structures that form bones and other facial structures. Treacle is active in the nucleolus. The nucleolus is the site of ribosomal protein transcription and treacle regulates ribosomal DNA transcription and therefore ribosomal RNA (rRNA) synthesis. The nucleolus is a highly organized, heterogeneous structure within the nucleus, with distinct regions visible by electron microscopy: (1) fibrillar centers, which represent the nucleolar organizer regions where DNA is not being actively transcribed; (2) dense fibrillar components (pars fibrosa) where RNA molecules are being transcribed; and (3) a granular component (pars granulosa) where ribosomal subunits undergo maturation. The nucleolar organizer contains clusters of rRNA genes (DNA). The size and number of nucleoli differ with the metabolic activity of cells.

·         Meiosis is the mechanism used by the reproductive organs to generate gametes—cells with the haploid number of chromosomes. DNA synthesis occurs before meiotic prophase I begins and is followed by a G2 phase. Cells then enter meiotic prophase I. During meiotic prophase I, maternal and paternal chromosomes are precisely paired, and recombination occurs in each pair of homologous chromosomes. The first meiotic prophase consists of five substages: leptotene, zygotene, pachytene, diplotene, and diakinesis. During metaphase I, there is random segregation of maternal and paternal chromosomes. Homologous chromosomes are aligned on the metaphase plate of the meiotic spindle in metaphase I. The second meiotic division is responsible for the reduction in the chromosome content of the cell by 50%. In meiotic division II, metaphase consists of daughter chromatids of single homologous chromosomes aligned on a metaphase plate (metaphase II). Condensation of the chromatids occurs in leptotene. In zygotene, the synaptonemal complex begins to form, which initiates the close association between chromosomes known as synapsis. The bivalent is formed between the two sets of homologous chromosomes (one set maternal and one set paternal equals a pair of maternal chromatids and a pair of paternal chromatids). The four chromatids form a tetrad (bivalent). Pachytene begins as soon as the synapsis is complete and includes the period of crossover. The fully formed synaptonemal complex is present during the pachytene stage. At each point where crossover has occurred between two chromatids of the homologous chromosomes, an attachment point known as a chiasma forms.  The formation of chiasmata and desynapsing (separation of the axes of the synaptonemal complex) occurs in the diplotene stage. Diakinesis is an intermediate phase between diplotene and metaphase of the first meiotic division.

·         In Hutchinson-Gilford progerial syndrome (HGPS) an abnormal protein, progerin, is generated and has a “dominant negative” effect on the function of lamins. The lamins are intermediate filament proteins that regulate the nuclear envelope, maintain its stability, and are phosphorylated (prometaphase) and dephosphorylated (telophase) during the cell cycle. In HGPS the results are dramatic abnormalities in the architecture of the nucleus, changes in nuclear shape, loss of heterochromatin (unable to attach to lamins), and an altered distribution of nuclear proteins.

·         Triple A syndrome is an autosomal recessive neuroendocrinological disease caused by mutations in a gene that encodes the nucleoporin ALADIN, a component of the nuclear pore complex labeled with the arrows in the electron micrograph. The immediate effect of mutations in the nucleoporins is decreased import of macromolecules from the cytoplasm. Patients with triple A syndrome have adrenocorticotrophic (ACTH)-resistant adrenal failure, achalasia (abnormal esophageal motility most often due to inability of the esophageal sphincter to relax), and alacramia (reduced ability to produce tears). They also demonstrate neurological symptoms affecting the cranial nerves, autonomic nervous system (Horner’s syndrome and orthostatic hypotension).

·         Microvillous inclusion disease (MID) which results in the absence of microvilli in the small intestinal absorptive cell (enterocyte) brush border (apical structure labeled between the arrows in the photomicrograph). MID is associated with an inability to absorb even simple nutrients; the disease presents as refractory diarrhea in the newborn period with chronic dependency on total parenteral nutrition. In MID, microvilli are found as inclusions in the apical enterocyte.(Microvilli increase surface area for specialized uptake of molecules by pinocytosis, receptor-mediated endocytosis, and phagocytosis. The microvilli also contain the brush border enzymes such as lactase and alkaline phosphatase.)

·         Alterations in connexin density or distribution may be differentially affected during the development of hypertrophy, thereby increasing the risk of reentrant or nonsustained ventricular tachycardia seen in African-American males.

·         Distal tubule cells of the kidney and striated duct cells of the submandibular glands possess prominent basal infoldings that are observed at the light microscopic level as basal striations. Basal folds are modifications of the basal region of the cell. These deep infoldings of the basal plasma membrane increase surface area and compartmentalize numerous mitochondria that provide energy for ionic and water transport.

·         Nexin, the radial spokes, and the basal body all play a role in restricting the sliding motion and converting it to the bending of the axoneme in relation to the basal body. Dynein is a high-molecular-weight ATPase. When dynein is activated, it produces the sliding motion of the microtubules as it walks along the adjacent doublet. The basal body anchors the microtubules and also plays an essential role in converting the sliding of the outer microtubules into the bending of the cilium. The basal bodies resist the sliding movement generated by dynein activation. Nexin links the outer microtubular doublets, creating a strap-like arrangement of paired microtubules around the central microtubule doublet. The radial spokes hold the microtubule doublets in place, and sliding is limited lengthwise. The radial spokes are rigid and do not slide against nexin.

·         The centriole consists of nine microtubule triplets arranged together by linking proteins to form a cartwheel arrangement. Microtubules are found in different structural patterns within the cell. The basal body is a centriole-like structure associated with the ciliary axoneme. It too has a nine-triplet arrangement of microtubules. Cytoplasmic microtubules are found in the singlet form and undergo constant association and dissociation of tubulin at their plus ends and minus ends, respectively. Flagella have the same “9+2” arrangement as cilia, but are limited to one per cell and in adult humans are found only in sperm. The axoneme has the classic “9+2” arrangement of microtubules. Stereocilia are large, modified microvilli, found in the epididymis and on hair cells in the organ of Corti, therefore, they are not composed of microtubules.

·         Growth in the length of long bones after birth (postnatally) occurs through cell proliferation of chondroblasts (immature chandrocytes) in the secondary ossification centers of the epiphyses. The primary ossification centers “close” soon after birth.

Growth in the width of the long bone occurs by the addition of osteoblasts from the periosteum and deposition of a periosteal collar

The action of osteoblasts is to deposit bone matrix and secrete alkaline phosphatase; they do not proliferate in either the primary or the secondary ossification centers.

·         Type II autosomal dominant osteopetrosis (type II ADO), also known as Albers-Schönberg disease with a characteristic radiological image of “sandwich vertebrae.” The targets in this disease are the osteoclasts which are indicated in the micrographs. Osteoclast function is altered in osteopetrosis. Osteoclasts function by release of lytic enzymes and protons (derived from carbonic acid) into the calcified matrix beneath the ruffled border and not through a grinding action. The bone compartment around the ruffled border of the osteoclast is, therefore, analogous to a secondary lysosome in function, albeit extracellular. Osteoclasts use protons derived from carbonic acid, catalyzed by carbonic anydrase, in similar fashion to parietal cells of the stomach.

·         Downregulation of the anti-angiogenic peptides, angiostatin and endostain, would enhance tumor growth. Angiostatin is a cleavage product of plasminogen; endostatin is a cleavage product of type XVIII collagen.

The angiopoietins (Ang) 1 and 2 bind their receptor, Tie2, a receptor tyrosine kinase which regulates endothelial cell proliterative status. Ang 1 binds Tie2 leading to periendothelial cell recruitment and therefore vascular maturation.

Ang 2 is found in organs of the female reproductive tract and blocks Ang 1 effects when VEGF is absent. The result is regression of the blood vessel. Ang 2 in the presence of VEGF leads to loosening of the surrounding cells permitting multiplication of endothelial cells and angiogenesis.

·         In multiple sclerosis (MS), a demyelinating disease in which both CD4+ and CD8+-T cells as well as autoantibodies are targeted to oligodendrocytes. MS is twice as prevalent in women as in men and demyelination is most commonly found in the anterior corpus callosum.

·         Xenotransplantation induces hyperacute graft rejection since human preformed antibodies recognize [alpha]Gal(1–3)[beta]Gal terminal carbohydrates present on animal endothelial cells in the graft. Interestingly, Old World monkeys and humans do not express that xenoantigen on their endothelial cells.

·         Passage from the blood to the lymphoid compartment involves specific homing receptors on lymphocytes, which are complementary to addressins on the postcapillary high endothelial venules (HEVs) and explains the specificity of lymphocyte homing. The cells that line the HEVs permit the selective passage of lymphocytes by diapedesis through the intercellular junctions. Lymphocytes have specific homing receptors on their cell surfaces that provide entry for mucosal (versus lymph node) seeding. High endothelial venules (HEVs) provide a mechanism for lymphocytes to leave the bloodstream and enter specific areas of the lymph nodes. HEVs are also found in Peyer’s patches and during inflammation of tissues (e.g., the synovium in rheumatoid arthritis). Under normal conditions, HEVs are found in the T-dependent areas, that is, the deep cortex (paracortex) of the lymph nodes and the interfollicular regions of the Peyer’s patches. T cells home to T-dependent areas of the lymph nodes, spleen, and Peyer’s patches. The circulation and recirculation of lymphocytes is a constant process that allows lymphocytes to continuously monitor the presence of antigen. The circulation process also allows augmentation of the immune response to infection.

·         Type II dentinogenesis imperfecta, an autosomal dominant disorder caused by mutation in the DSPP gene. The result is defective dentin, discoloration of the translucent teeth (blue-gray or yellow-brown color). Those teeth are weaker than normal, making them prone to rapid decay, wear, breakage, and loss. Type II dentinogenesis imperfecta occurs about 1 in 6000–8000 births. Type I occurs in conjunction with osteogenesis imperfecta with mutations in type I collagen; children with type I have typical blue sclerae with defects in bone and dentin.

·         Glycation results in the production of advanced glycation end-products (AGE), which alters the properties of the glomerular basement membrane. The cellular receptor for AGE is called RAGE and is a multiligand member of the immunoglobulin superfamily of cell surface molecules. In addition, to its role in diabetes, RAGE interacts with molecular pathways that regulate homeostasis, development, and inflammation and plays a role in pathological conditions such as Alzheimer’s disease and diabetes mellitus. Binding of a ligand to RAGE activates key cell signaling pathways, such as p21 (ras), MAP kinases, and NFkappa-B (NFκB), thereby reprogramming cellular characteristics. The interactions and terminology are further complicated by the presence of ENRAGE (extracellular newly identified RAGE-binding protein) that interacts with cellular RAGE on endothelial cells, macrophages, lymphocytes, and other cells to activate proinflammatory mediators. Interactions between AGE, RAGE, and ENRAGE may explain many diabetic complications including delayed wound healing. AGE derivatization is probably nonspecific and involves not only basal lamina-specific molecules, but also a vast array of extracellular and intracellular proteins (transcription factors, structural proteins, and membrane transporters). Hence, cellular coordination/communication becomes slowly but progressively hampered in the kidney and other organs.