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Thursday, February 8, 2007

Lead Poisoning


An 18th month old child of migrant farm workers was hospitalized because of weight loss, vomiting, and acute abdominal pain. it was noted that the child had mild muscular incoordination, weakness of the muscles of the feet, moderate hypertension, and possible edema of the optic nerve ends.
Microscopic examination of blood smear showed:

Reticulocyte count: moderate but distinct increase
RBC : 4 x 10 cells/mm
hematocrit : 37%
24 hour urine sample (collected in acid washed bottle) contained:
6.4 umol of aminolevulinic acid
1.8 umol of coproporphyrin III
Penicillamine therapy was started immediately, and the laboratory was requested to perform a quantitative lead analysis on the urine. the report of that test indicated the sample contained 1.1 umol (0.24 mg) of lead in the 24-hour sample. Xray examination of the patients long bones showed electron dense deposits at the epiphyses.


-present in the body in small amount
-normally the tissues contain 4-10 ppm
-both organic and inorganic compounds of lead are toxic.
-the serious effect occurs on the central and peripheral nervous system
-if greater that 0.5 ng of lead is aborbed per day, it will accumulate and produce toxic effect.
-it is absorbed in the gastrointestinal tract, may also be absorbed through lungs, as in chronic exposure to high concentrations of auto mobile exhaust fumes.
-ingested lead is taken up most avidly in the sternum and bones. The half life of lead in bone is 32 years and may act as reservoir for endogenous intoxication
lesser amount of lead is deposited in brain, kidneys,liver and lungs.
-normally absorbed lead is excreted in urine contains 19-70 nmol/24 hour.

*Accidental lead poisoning results from ingestion of excessive amount of lead, over a considerable amount of time. In this case it is likely that the child was eating of chewing on something in the home that contained lead, such as flakes of paint from woodwork, furnitures, toys or radiators.

Lead poisoning is seen in children who consume it in the form of paint (pica)

Acute manifestation of lead poisoning
CNS symptoms include encephalopathy, convulsions, stupor
GI symptomatously (such as colic)
Lead encephalopathy is accompanied with hematologic picture of increased reticulocytes and basophilic stippling of RBS's

Chronic Toxicity may be manifested by wide range of systemic effects:
general malaise
weight loss

-Organolead compounds such as tetraethyl and tetramethyl lead are lipid soluble and produce their major toxic effect on CNS.

-Lead appears to interact with thiol , carboxylic and phosphate groups to form stable complexes, enzymes and proteins.

-Lead is also known for heme synthesis because it blocks the action of - aminolevulinic acid(ALA) synthetase, -ALA dehydratase (ALAD), coproporphyrinnogen decarboxylase and ferro chelatase, producing anemia

Lead levels in serum may be determined directly using either atomic absorption spectroscopy or anode stripping voltammetry.

Sunday, February 4, 2007

Xeroderma Pigmentosum

A 45-year old woman, D.R., has lived her entire life on a farm. She has the skin manifestations of xeroderma pigmentosum (XP) without the fairly common neurologic abnormalities. She is heavily freckled and has a lengthy history of skin cancer. In the past 5 years she has had 35 clinically diagnosed neoplasms excised from sun exposed areas of her skin, and she recently developed ocular involvement requiring a corneal transplant.

Case discussion:

• XP is an autosomal recessive human skin disease characterized by sensitivity to sunlight, which causes multiple cutaneous neoplasm.
• It occurs in about one person in 250,000 of the general population, often in consanguineous matings, and is found worldwide in al races.
• The disease is detected by the effects it has on the exposed areas of the skin and eyes, it also can have systemic effects.
• It can cause a number of neurologic abnormalities, including progressive mental deficiency, deafness, ataxia, and retarded growth.
• The neurologic manifestation are characteristic of a variant form called De Sanctis–Cacchione syndrome.
• Treatment involves minimizing exposure to sunlight and the removal of the tumors when they appear, but there is no cure.
• The molecular defect in XP is associated with the repair of DNA damaged by exposure to UV light.
• The association of this defect with a strong predisposition to Cancer has attracted much attention to this otherwise rather obscure disease.
• The Tumors of XP patients are no different from those of other individuals without the disease; only their incidence in XP patients is greatly increased.
• Exposure to sunlight is well correlated to the incidence of the two most common skin cancers:
• Basal cell carcinoma
• Squamous cell carcinoma
• XP patients also develop malignant melanomas.
• Frecklings may be a manifestation of the mutagenic effects of ultraviolet light.
• Freckles, even in normal persons, are collections of large melanocyte with melanosome that are unusually large and dark.
• It is thought that each freckle represents a clone of melanocytes that arose from a single cell tha had undergone UV-induced mutation.
• XP patient also has a patches of hypopigmentation that could arise from mutations in pigment formation.
• Repair of UV-damaged DNA. A great deal is known about how UV light modifies bacterial DNA.
• The 5-6 double bond of cytosine can be hydrated, and DNA protein cross-links may form, but the most significant lesion is the cross-linking of adjacent pyrimidine residues in DNA.
• Adjacent thymine residues on the same DNA strand dimerize to yield the following product.
• Both bacterial and animal cells have evolved enzymes systems to cope with UV-induced thymine dimers.
• There are at least three different enzyme systems that neutralized the effects of thymine dimers.
• One, called excision repair, an endonuclease recognizes the damaged DNA and breaks the nucleotide chain close to and on 5’ side of the lesion.
• The damaged single strand peels off the DNA duplex, and a DNA polymerase catalyzes the synthesis of polynucleotide to replace the damaged segment.
• A 5’- exonuclease hydrolyzes away the damaged single-stranded segment, and a DNA ligase seals the break, yielding a complete DNA duplex.
• Another way to repair DNA strands is called postreplication repair.
• If the damaged DNA is in the process of being replicated, the DNA polymerase skips over the thymine dimer, leaving a slight gap in the newly synthesized strand.
• This gap can be later filled by enzymes that differ in some respects from those involved in excision repair.
• A third method for dealing with thymine dimers is called photoreactivation.
• First discovered in bacteria, the enzyme responsible for this kind of repair has just recently been found in human cells.
• The photoreacting enzyme simply converts thymine dimers to monomers before they can do any harm.
• The enzyme binds to thymine dimers in DNA and catalyzes the formation of the thymine monomers when exposed to light of wavelengths 300 to 600 nm.
• Genetic Variants. There is evidence for defects in all three of the DNA repair systems from cells of patients with XP.
• Because there are at least five different genetic forms of the disease as detected by cell hybridization studies, it is tempting to suppose that each might be concerned with the different enzymes in one of the three repair systems.
• This interpretations is probably correct, but it is still not known whether components of one repair system might be shared with another.
• This would explain why some patients appear to be defective in more than one repair systems.

• Alternatively, a defect in a gene that regulates an operon containing two or more repair systems would also explain the data.

Monday, January 29, 2007

Bone and CartilageHistologyFunctionsSpecialized connective tissue that provide the body with mechanical support and protectionBones are principal supports for the body provide a rigid structure for muscle attachment and constitute a system of levers that turn muscle contraction into purposeful movementsBones protect vital organs in the skull and thoracic cavityBone store large concentration of Ca ions and bone marrow (hematopoeisis)
Common FeaturesIn endochondral ossification, cartilage models are converted to boneMature gross bones in adult have a cartilage component on their articular surfacesComposed of cells, fibers and amorphous ground substance CartilagesLocationsArticular surfaces of long bonesTracheaBronchiNoseEarsLarynxIntervertebral disksGeneral CharacteristicsContains; Cells: fibroblasts, chondroblasts, chondrocytes Fibers: collagen, elastinAmorphous Ground Substance: chondroitin sulfate, hyaluronateDominated by acellular elementsDevoid of blood vessels and nerves
FunctionsExcellent skeletal tissue for the fetusSupport
TypesHyaline CartilageElastic CartilageFibrocartilage
Hyaline CartilageBluish, opalescent tissue widely distributed in the bodyMost abundant type of cartilage in the adultExists on the ventral ends of the ribs; larynx, trachea, and bronchi; and on the articular surfaces of bonesAlso exists on the epiphyseal plates in the bones of fetuses and growing children
appears as discrete mass of tissue surrounded by a dense irregular connective tissue layer called the perichondrium Perichondrium – a layer of fibroblasts that merges with the fibroblasts and extracellular matrix of the connective tissue immediately surrounding the cartilage - it has an inner layer of flattened chondroblasts especially evident in growing cartilages
Chondroblasts – differentiated cells that secrete cartilaginous extracellular matrixChondrocytes – chondroblasts surrounded by their secretionHyaline cartilage is avascular and lacks nerves
Extracellular MatrixAmorphousIntensely metachromatic (when stained with toluidine blue), caused by large concentration of proteoglycans Cartilage proteoglycans – molecular complex consisting of linker proteins attached to the GAGs GAGs include Hyaluronic acid, Chondroitin sulfate, keratan sulfateRich in collagen fibers composed predominantly of Type II CollagenChondrocytes are surrounded by a heterogenous extracellular matrix (territorial and intercellular)ChondrocytesSynthesize large amounts of protein and polysaccharide for secretion from the cellCytoplasm is intensely basophilic due to large amounts of RERContains large euchromatic nucleus, prominent nucleolus, numerous mitochondria and well-developed Golgi apparatus
Contains many cytoplasmic vacuoles that bud from the distal face of the golgi apparatusThese vacuoles contain fibrous materials (collagen precursors) and amorphous materials (cartilage proteoglycans and glycoproteins)Store large amounts of nutrients such as glycogen granules and large lipid vacuolesElastic CartilageExists in pinna (auricle) of the external ear, walls of the auditory (eustachean) tube, the epiglottis, and parts of the larynxUntreated elastic cartilage appears similar to hyaline cartilage By Verhoeff’s stain or Wegert’s stain reveals that elastic cartilage contains elastin and collagen fibersExtracellular matrix is metachromatic due to high concentration of GAGsElasticity ensures the patency of the lumina of the tubesFibrocartilageExists in the annulus fibrosus of intervertebral disks, the symphysis pubis, junctions between large tendons and articular cartilage in large jointsEspecially prominent where large tendons attach to bones
Quite distinct from hyaline and elastic cartilageConsists of many regularly arranged collagen fibersLooks intermediate to tendon and cartilage
Less cellular than hyaline and elastic cartilageChondrocytes aresparsely scattered among large arrays of collagen fibersExtracellular matrix ehibits less metachromatic than hyaline cartilage due to lesser GAGs and more collagen fibersIntervertebral DisksContains an outer layer of fibrocartilage called annulus fibrosus and a core of special liquid connective tissue called nucleus pulposus Both sides of annulus fibrosus are firmly attached to adjacent vertebral bodiesNucleus pulposus is a viscous liquid containing a few cells and a large concentration of hyaluronic acids that serves as shock absorber for intervertebral disksAnnulus fibrosus strength decreases with age
Dominated by acellular elementsDevoid of blood vessels and nervesBone
Diaphysis – middle tubular section of a long bone; composed of dense connective tissueMetaphysis – expanded portion of a long bone; includes a region where a compact bone forms a shell around a mass of spongy or cancellous boneEpiphysis – ends o long bones
Articular surfaces of have a thin layer of hyaline cartilage covering the epiphyseal compact bone; slippery in its normal stateEpiphyseal plate – the junction between the epiphysis and metaphysis In growing bones, it is a profilerative plate of hyaline cartilage This is also the region of bone that grows longer prior to puberty and during the pubertal growth spurt
Periosteum – dense irregular connective tissue with the ability to form new bone that covers all bone surfaces exceprt articular surfaces Inner layer is composed of the osteoblastsEndosteum- made up of thin layer of osteoblats that lines the marrow cavity and the surface of the spongy bone spiculesPeriosteum and endosteum- for growth in the diameter of the bonesShort bonesComposed of a core of cancellous bone and completely surrounded by the compact boneE.g. bones of the carpus and tarsusFlat bonesComposed of two layers of compact bonbes separtaed by a layer of cancellous bone (diploe)E.g. bones of the skull and the scapulae LamellaeExtracellular matrix arranged in platesContain small lacunae, small anstomosing network of a minute canaliculiLive osteocytes occupy lacunae, and delicate osteocytes processes fill the canaliculiThese mineralized matrix prevents free diddusion
In Compact Bones, Lamellae are arranged in thrre common patterns: 1. Circumferential Lamellae – parallel to to the free surfaces of the periosteum and endosteum 2. Haversian systems (Osteons) – parallel to the long axis of a compact bone; lamellar layers are concentrically arranged around a vascular space 3. Interstitial System - irregular arrays of lamellae, often roughly triangular and quadrangular
Compact Bone shave two kinds of Vascular Channels 1. Haversian Canals - - surrounded by concentriac;lly arranged lamellae; long axis of the lamellar cylinder is parallel to the long axis of the blood vessel 2. Volkmann’s canal – less common than haversian canals; blod vesels from the periosteum penetracte the compact bone and cross havresian system as trhey extyend into the bone; the long axis are perpendiicular to the hacversian systemlamellae Cancellous BoneComposed of small quantities of lamellaeLie close to blood vessels and the endosteumReceive nutrition by direct diffusionLamellae are not arranged into haversian systems PeriosteumThe osteoblast layer in growing bones is a cuboidal layer of cells loosely arranged in a sheetOsteoblasts are forming new bone by secreting uncalcified bone matrix When bones reaches its diameter, osteoblasts become quiscent and indistiguishable from the other densely packed fibroblasts in the periosteum

When needed, these cells again become osteoblasts and express their osteogenoic potentialShapey’s fibers – dense bundles of collagen fibers trapped in the bony matrix of growing bone, firmly anchor the periosteum to the underlying bone
EndosteumA layer of osteoblasts that covers all the free bony surfaces inside the boneOsteoblasts secrete osteoid tissue;Also form a boundary between the bone and the marrow cavityExtracellular matrixDominated by inorganic salts and also contain substantial quantities of organic matrixOrganic Componentsglycoproteins and glycosaminglycans (e.g. keratan sulfate, chondroitin sulfate, hyaluronic acidType I Collagen
Inorganic ComponentsCa phosphate similar to hydroxyapatiteCa carbonate, citrate, fluoride, magnesium and sodium ionsBone CellsOsteoprogenitorsOsteoblastsOsteocytesOsteoclasts
All stem from undifferentiated embryonic mesenchymeCapable of interconversion e.g. osteoprogenitor cells -> osteoblasts -> osteocytesOsteoclats are derived from the fusion of monocyte-like precursors; modified versions of MPSOsteoprogenitor cells and Osteoclasts precursors Osteoprogenitor CellsUndifferentiated cells similar to fibroblastsHighly proliferative or have latent mitotic potentialCommon in embryos during bone formation and comprise part of the periosteum in mature bones
Exists near all free surfaces of bone (periosteum, endosteum, and the lining of the haversian canals0 and on the trabeculae of cartilage that degenerates as the epiphyseal plate grows Poorly stained oval nucleus and acidophilic or faintly basophilic cytoplasm in the light microscope OsteoblastsSecrete bone extracellular matrix; similar to fibroiblats and chondroblatsCytoplasm is intensely basophilic due to numerous RERHave promient nucleus with alarge basophilic nucleolusand a well-developed Golgi ApparatusGolgi apparatus prepaaes collagenfor export, glycosylates colagen, produces GAGs and glycoproteinms for the xtracellular matrixOsteocytesSimilar to osteoblasts Less active in matrix secretionRER and Golgi Apparatus are less prominentRespond to parathormone athat help rehguilate blood calciumand can secrete new bone extracellular matrixOccupy lacunaein the solid matrix and are attache dto each other by the slender cellular processes that occupy canaliculi
Osteocyte processes are joined by gap junctions, which facilitate the exchange of small moleculkes and probably expedite the conduction of horminesfrom the vascular haversian canbals to osteocytes in distant lamellaeOsteoclastsSyncitial cells – large multinuclear cells formed from the fusion of of m,any mononuclear cel;ls Arise from stem cellsother than the undifferentiated mesenchymal cells that produce the odsteoprogenitor –osteoblast-osteocyte cell line
Considered to be part of the MPS because they are derived from monocytes and and are involved in bone matrix phagocytosis Have a conspicuous rufled, folded borderthat is closely applied to bone fragmentsas they are brokjen downSecret acid hydrolases (from lysosomes) and ions that disintegrate bone
Osteoclasts cytoplasm is acidophilic; stains intensely with eosinContains numerous mitochondria. Many prominent Golgi bodies, and numerous lysosomes and residual bodiesRespiond to parathormone and calcitonin to help regulate serum calcium levelsErode bone lamellae, create small pockets in the bone called Howship’s lacunae

Bone and Calcium HomeostasisOsteoclasts break down bone and release calcium into the blood, and osteoblasts remove calcium from the blood to make bone. Parathyroid hormones regulates blood levels by indirectly stimulating osteoclast activity, resulting in increased calcium release into the blood. Calcitonin plays a major role in in calcium maintenance by inhibiting the osteoclast activity


Wednesday, December 6, 2006

wanna know how indian people communicate without talking?

see the red dot on their forehead?