Nobel laureate Harold Varmus discusses the intersection of cancer biology and cancer medicine. Varmus, president of Memorial Sloan-Kettering Cancer Center in New York, earned his Nobel Prize for discovering retroviral oncogenes that can cause cancer. That work changed the way people thought about cancer: Rather than being a disease caused by environmental exposure, it could result from mutations in specific genes. Now, much cancer research and the search for therapeutics focus on genetic changes in cancer.
Menstrual cycle is a recurring cycle of physiologic changes that occurs in reproductive-age females. Overt menstruation (where there is blood-flow from the vagina) occurs primarily in humans and close evolutionary relatives such as chimpanzees. The females of other species of placental mammal have estrous cycles, in which the endometrium is completely reabsorbed by the animal (covert menstruation) at the end of its reproductive cycle.
The menstrual cycle is under the control of the hormone system and is necessary for reproduction. Menstrual cycles are counted from the first day of menstrual flow, because the onset of menstruation corresponds closely with the hormonal cycle. The menstrual cycle may be divided into several phases, and the length of each phase varies from woman to woman and cycle to cycle.
During the follicular phase the lining of the uterus thickens, stimulated by gradually increasing amounts of estrogen. Follicles in the ovary begin developing under the influence of a complex interplay of hormones, and after several days one or occasionally two follicles become dominant (non-dominant follicles atrophy and die). The dominant follicle releases an ovum or egg in an event called ovulation. (An egg that is fertilized by a spermatozoon will become a zygote, taking one to two weeks to travel down the fallopian tubes to the uterus. If the egg is not fertilized within about a day of ovulation, it will die and be absorbed by the woman's body.) After ovulation the remains of the dominant follicle in the ovary become a corpus luteum; this body has a primary function of producing large amounts of progesterone. Under the influence of progesterone, the endometrium (uterine lining) changes to prepare for potential implantation of an embryo to establish a pregnancy. If implantation does not occur within approximately two weeks, the corpus luteum will die, causing sharp drops in levels of both progesterone and estrogen. These hormone drops cause the uterus to shed its lining in a process termed menstruation.
Phases of the menstrual cycleMenstruation
Menstruation is also called menstrual bleeding, menses, a period or catamenia. The flow of menses normally serves as a sign that a woman has not become pregnant. (However, this cannot be taken as certainty, as sometimes there is some flow of blood in early pregnancy.) During the reproductive years, failure to menstruate may provide the first indication to a woman that she may have become pregnant.
Eumenorrhea denotes normal, regular menstruation that lasts for a few days (usually 3 to 5 days, but anywhere from 2 to 7 days is considered normal).The average blood loss during menstruation is 35 millilitres with 10–80 ml considered normal; many women also notice shedding of the endometrium lining that appears as tissue mixed with the blood. An enzyme called plasmin — contained in the endometrium — tends to inhibit the blood from clotting. Because of this blood loss, women have higher dietary requirements for iron than do males to prevent iron deficiency. Many women experience uterine cramps during this time (severe cramps or other symptoms are called dysmenorrhea), as well as other premenstrual syndrome symptoms. A vast industry of sanitary products is marketed to women for use during their menstruation.
Follicular phase
Through the influence of a rise in follicle stimulating hormone (FSH), five to seven tertiary-stage ovarian follicles are recruited for entry into the next menstrual cycle. These follicles, that have been growing for the better part of a year in a process known as folliculogenesis, compete with each other for dominance. Under the influence of several hormones, all but one of these follicles will undergo atresia, while one (or occasionally two) dominant follicles will continue to maturity. As they mature, the follicles secrete increasing amounts of estradiol, an estrogen.
The estrogens that follicles secrete initiate the formation of a new layer of endometrium in the uterus, histologically identified as the proliferative endometrium. The estrogen also stimulates crypts in the cervix to produce fertile cervical mucus, which may be noticed by women practicing fertility awareness.
Ovulation
When the egg has matured, it secretes enough estradiol to trigger the acute release of luteinizing hormone (LH). In the average cycle this LH surge starts around cycle day 12 and may last 48 hours. The release of LH matures the egg and weakens the wall of the follicle in the ovary. This process leads to ovulation: the release of the now mature ovum, the largest cell of the body (with a diameter of about 0.5 mm). Which of the two ovaries — left or right — ovulates appears essentially random; no known left/right co-ordination exists. The egg is swept into the fallopian tube by the fimbria - a fringe of tissue at the end of each fallopian tube. If fertilization occurs, it will happen in the fallopian tube.
In some women, ovulation features a characteristic pain called mittelschmerz (German term meaning 'middle pain') which may last a few hours. The sudden change in hormones at the time of ovulation also causes light mid-cycle blood flow from the vagina of some women. An unfertilized egg will eventually disintegrate or dissolve.
Luteal phase
The corpus luteum is the solid body formed in the ovaries after the egg has been released into the fallopian tube which continues to grow and divide for a while. After ovulation, the residual follicle transforms into the corpus luteum under the support of the pituitary hormones. This corpus luteum will produce progesterone in addition to estrogens for approximately the next 2 weeks. Progesterone plays a vital role in converting the proliferative endometrium into a secretory lining receptive for implantation and supportive of the early pregnancy. It raises the body temperature by 0.25 °C to 0.5 °C (0.5 °F to 1.0 °F), thus women who record their basal body temperature on a daily basis will notice that they have entered the luteal phase. If fertilization of an egg has occurred, it will travel as an early blastocyst through the fallopian tube to the uterine cavity and implant itself 6 to 12 days after ovulation. Shortly after implantation, the growing embryo will signal its existence to the maternal system. One very early signal consists of human chorionic gonadotropin (hCG), a hormone that pregnancy tests can measure. This signal has an important role in maintaining the corpus luteum and enabling it to continue to produce progesterone. In the absence of a pregnancy and without hCG, the corpus luteum demises and inhibin and progesterone levels fall. This will set the stage for the next cycle. Progesterone withdrawal leads to menstrual shedding (progesterone withdrawal bleeding), and falling inhibin levels allow FSH levels to rise to raise a new crop of follicles.
Fertile window
The length of the follicular phase — and consequently the length of the menstrual cycle — may vary widely. The luteal phase, however, almost always takes the same number of days for each woman: Some women have a luteal phase of 10 days, others 16 days, while the average is 14 days. Normal sperm life inside a woman ranges from 1-5 days, though a pregnancy resulting from sperm life of 8 days has been documented. The most fertile period (the time with the highest likelihood of pregnancy resulting from sexual intercourse) covers the time from some 5 days before ovulation until 1–2 days after ovulation. In an average 28 day cycle with a 14-day luteal phase, this corresponds to the second and the beginning of the third week of the cycle. Fertility awareness methods of birth control attempt to determine the precise time of ovulation in order to find the relatively fertile and the relatively infertile days in the cycle.
People who have heard about the menstrual cycle and ovulation often mistakenly assume, for contraceptive purposes, that menstrual cycles regularly take 28 days, and that ovulation always occurs 14 days after beginning of the menses. This assumption may lead to unintended pregnancies. Note too that not every event of blood flow counts as a menstruation, and this can mislead people in their calculation of the fertile window.
If a woman wants to conceive, the most fertile time occurs between 19 and 10 days prior to the expected menses. Many women use ovulation detection kits that detect the presence of the LH surge in the urine to indicate the most fertile time. Other ovulation detection systems rely on observation of one or more of the three primary fertility signs (basal body temperature, cervical fluid, and cervical position).
Potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes. Furthermore potassium channels are found in most cell types and control a wide variety of cell functions.
Functions
In excitable cells such as neurons, they shape action potentials and set the resting membrane potential.
By contributing to the regulation of the action potential duration in cardiac muscle, malfunction of potassium channels may cause life-threatening arrhythmias.
They also regulate cellular processes such as the secretion of hormones (e.g., insulin release from beta-cells in the pancreas) so their malfunction can lead to diseases (such as diabetes).
Types There are four major classes of potassium channels:
Calcium-activated potassium channel - open in response to the presence of calcium ions or other signalling molecules.
Inwardly rectifying potassium channel - passes current (positive charge) more easily in the inward direction (into the cell).
Tandem pore domain potassium channel - are constitutively open or possess high basal activation, such as the "resting potassium channels" or "leak channels" that set the negative membrane potential of neurons. When open, they allow potassium ions to cross the membrane at a rate which is nearly as fast as their diffusion through bulk water.
Voltage-gated potassium channel - are voltage-gated ion channels that open or close in response to changes in the transmembrane voltage.
Structure
Potassium channels have a tetrameric structure in which four identical protein subunits associate to form a four fold symmetric (C4) complex arranged around a central ion conducting pore (i.e., a homotetramer). Alternatively four related but not identical protein subunits may associate to form heterotetrameric complexes with pseudo C4 symmetry. All potassium channel subunits have a distinctive pore-loop structure that lines the top of the pore and is responsible for potassium selective permeability.
There are over 80 mammalian genes that encode potassium channel subunits. However potassium channels found in bacteria are amongst the most studied of ion channels, in terms of their molecular structure. Using X-ray crystallography,[6][7] profound insights have been gained into how potassium ions pass through these channels and why (smaller) sodium ions do not (since sodium ions have greater charge density, they have a larger shell of water molecules surrounding them and thus are more bulky).[8] The 2003 Nobel Prize for Chemistry was awarded to Rod MacKinnon for his pioneering work in this area.
Selectivity filter
Potassium ion channels remove the hydration shell from the ion when it enters the selectivity filter. The selectivity filter is formed by five residues (TVGYG-in prokaryotic species) in the P loop from each subunit which have their electro-negative carbonyl oxygen atoms aligned towards the centre of the filter pore and form an anti-prism similar to a water solvating shell around each potassium binding site. The distance between the carbonyl oxygens and potassium ions in the binding sites of the selectivity filter is the same as between water oxygens in the first hydration shell and a potassium ion in water solution. Passage of sodium ions would be energetically unfavorable since the strong interactions between the filter and pore helix would prevent the channel from collapsing to the smaller sodium ion size. The selectivity filter opens towards the extracellular solution, exposing four carbonyl oxygens in a glycine residue (Gly79 in KcsA). The next residue towards the extracellular side of the protein is the negatively charged Asp80 (KcsA). This residue together with the five filter residues form the pore that connects the water filled cavity in the centre of the protein with the extracellular solution.[11]
The carbonyl oxygens are strongly electro-negative and cation attractive. The filter can accommodate potassium ions at 4 sites usually labelled S1 to S4 starting at the extracellular side. In addition one ion can bind in the cavity at a site called SC or one or more ions at the extracellular side at more or less well defined sites called S0 or Sext. Several different occupancies of these sites are possible. Since the X-ray structures are averages over many molecules, it is, however, not possible to deduce the actual occupancies directly from such a structure. In general, there is some disadvantage due to electrostatic repulsion to have two neighbouring sites occupied by ions. The mechanism for ion translocation in KcsA has been studied extensively by simulation techniques. A complete map of the free energies of the 24=16 states (characterised by the occupancy of the S1, S2, S3 and S4 sites) has been calculated with molecular dynamics simulations resulting in the prediction of an ion conduction mechanism in which the two doubly occupied states (S1, S3) and (S2, S4) play an essential role. The two extracellular states, Sext and S0, were found in a better resolved structure of KcsA at high potassium concentration. In free energy calculations the entire ionic pathway from the cavity, through the four filter sites out to S0 and Sext was covered in MD simulations. The amino acids sequence of the selectivity filter of potassium ion channels is conserved with the exception that an isoleucine residue in eukaryotic potassium ion channels often is substituted with a valine residue in prokaryotic channels.
TATA binding protein (TBP) is a transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 25-30 base pairs upstream of the transcription start site in some eukaryotic gene promoters. TBP, along with a variety of TBP-associated factors, make up the TFIID, a general transcription factor that in turn makes up part of the RNA polymerase II preinitiation complex. As one of the few proteins in the preinitation complex that binds DNA in a sequence-specific manner, it helps position RNA polymerase II over the transcription start site of the gene. However, it is estimated that only 10-20% of human promoters have TATA boxes. Therefore, TBP is probably not the only protein involved in positioning RNA polymerase II.
Role as Transcription Factor Subunit
TBP is a subunit of the eukaryotic transcription factor TFIID. TFIID is the first protein to bind to DNA during the formation of the pre-initiation transcription complex of RNA polymerase II (RNA Pol II). Binding of TFIID to the TATA box in the promoter region of the gene initiates the recruitment of other factors required for RNA Pol II to begin transcription. Some of the other recruited transcription factors include TFIIA, TFIIB and TFIIF. Each of these transcription factors are formed from the interaction of many protein subunits, indicating that transcription is a heavily regulated process.
TBP is also a necessary component of RNA polymerase I and RNA polymerase III, and is perhaps the only common subunit required by all three of the RNA polymerases.
DNA-Protein Interactions
When TBP binds to a TATA box within the DNA, it distorts the DNA by inserting amino acid side chains between base pairs, partially unwinding the helix, and doubly kinking it. The distortion is accomplished through a great amount of surface contact between the protein and DNA. TBP binds with the negatively charged phosphates in the DNA backbone through positively charged lysine and arginine amino acid residues. The sharp bend in the DNA is produced through projection of four bulky phenylalanine residues into the minor groove. As the DNA bends, its contact with TBP increases, thus enhancing the DNA-protein interaction.
The strain imposed on the DNA through this interaction initiates melting, or separation, of the strands. Because this region of DNA is rich in adenine and thymine residues, which base pair through only two hydrogen bonds, the DNA strands are more easily separated. Separation of the two strands exposes the bases and allows RNA polymerase II to begin transcription of the gene.
For information on the use of TBP in cells see: RNA polymerase I, RNA polymerase II and RNA polymerase III.
TBP is involved in DNA melting (double strand separation) by bending the DNA by 80° (the AT-rich sequence to which it binds facilitates easy melting). The TBP is an unusual protein in that it binds the minor groove using a β sheet.
Another distinctive feature of TBP is a long string of glutamines in the N-terminus of the protein. This region modulates the DNA binding activity of the C-terminus, and modulation of DNA binding affects the rate of transcription complex formation and initiation of transcription. Mutations that expand the number of CAG repeats encoding this polyglutamine tract, and thus increase the length of the polyglutamine string, are associated with spinocerebellar ataxia 17, a neurodegenerative disorder classified as a polyglutamine disease.
A tonsillectomy is a surgical procedure in which the tonsils are removed. Sometimes the adenoids are removed at the same time.
Tonsillectomy may be performed when the patient:
Experiences frequent bouts of acute tonsillitis. The number requiring tonsillectomy varies with the severity of the episodes. One case, even severe, is generally not enough for most surgeons to decide tonsillectomy is necessary.
Has chronic tonsillitis, consisting of persistent, moderate-to-severe throat pain.
Has multiple bouts of peritonsillar abscess.
Has sleep apnea (stopping or obstructing breathing at night due to enlarged tonsils or adenoids)
Difficulty eating or swallowing due to enlarged tonsils (very unusual reason for tonsillectomy)
* Produces tonsilloliths in the back of their mouth.
Methods of tonsil removal
The first report of tonsillectomy was made by the Roman encyclopedist Celsus in 30 AD. He described scraping the tonsils and tearing them out or picking them up with a hook and excising them with a scalpel. Today, the scalpel is still the preferred surgical instrument of many ear, nose, and throat specialists. However, there are other procedures available – the choice may be dictated by the extent of the procedure (complete tonsil removal versus partial tonsillectomy) and other considerations such as pain and post-operative bleeding. A quick review of each procedure follows:
Dissection and snare method: Removal of the tonsils by use of a forceps and scissors with wire loop called 'snare' is the most common method practiced by otolaryngologists today. The procedure requires the patient to undergo general anesthesia; the tonsils are completely removed with minimal post-operative bleeding.
Electrocautery: Electrocautery burns the tonsillar tissue and assists in reducing blood loss through cauterization. Research has shown that the heat of electrocautery (400°C) results in thermal injury to surrounding tissue. This may result in more discomfort during the postoperative period.
Harmonic scalpel: This medical device uses ultrasonic energy to vibrate its blade at 55,000 cycles per second. Invisible to the naked eye, the vibration transfers energy to the tissue, providing simultaneous cutting and coagulation. The temperature of the surrounding tissue reaches 80°C. Proponents of this procedure assert that the end result is precise cutting with minimal thermal damage.
Radiofrequency ablation: Monopolar radiofrequency thermal ablation transfers radiofrequency energy to the tonsil tissue through probes inserted in the tonsil. The procedure can be performed in an office setting under light sedation or local anesthesia. After the treatment is performed, scarring occurs within the tonsil causing it to decrease in size over a period of several weeks. The treatment can be performed several times. The advantages of this technique are minimal discomfort, ease of operations, and immediate return to work or school. Tonsillar tissue remains after the procedure but is less prominent. This procedure is recommended for treating enlarged tonsils and not chronic or recurrent tonsillitis.
Thermal Welding: A new technology which uses pure thermal energy to seal and divide the tissue. The resulting absence of thermal spread means that the temperature of surrounding tissue is only 2-3 °C higher than normal body temperature. Clinical papers show patients with minimal post-operative pain (no requirement for narcotic pain-killers), zero edema (swelling) plus almost no incidence of bleeding. Hospitals in the US are advertising this procedure as "Painless Tonsillectomy". Also known as Tissue Welding.
Carbon dioxide laser: Laser tonsil ablation (LTA) finds the otolaryngologist employing a hand-held CO2 or KTP laser to vaporize and remove tonsil tissue. This technique reduces tonsil volume and eliminates recesses in the tonsils that collect chronic and recurrent infections. This procedure is recommended for chronic recurrent tonsillitis, chronic sore throats, severe halitosis, or airway obstruction caused by enlarged tonsils.
The LTA is performed in 15 to 20 minutes in an office setting under local anesthesia. The patient leaves the office with minimal discomfort and returns to school or work the next day. Post-tonsillectomy bleeding may occur in two to five percent of patients. Previous research studies state that laser technology provides significantly less pain during the post-operative recovery of children, resulting in less sleep disturbance, decreased morbidity, and less need for medications. On the other hand, some believe that children are adverse to outpatient procedures without sedation.
Microdebrider: The microdebrider is a powered rotary shaving device with continuous suction often used during sinus surgery. It is made up of a cannula or tube, connected to a hand piece, which in turn is connected to a motor with foot control and a suction device.
The endoscopic microdebrider is used in performing a partial tonsillectomy, by partially shaving the tonsils. This procedure entails eliminating the obstructive portion of the tonsil while preserving the tonsillar capsule. A natural biologic dressing is left in place over the pharyngeal muscles, preventing injury, inflammation, and infection. The procedure results in less post-operative pain, a more rapid recovery, and perhaps fewer delayed complications. However, the partial tonsillectomy is suggested for enlarged tonsils – not those that incur repeated infections.
Bipolar Radiofrequency Ablation (Coblation): This procedure produces an ionized saline layer that disrupts molecular bonds without using heat. As the energy is transferred to the tissue, ionic dissociation occurs. This mechanism can be used to remove all or only part of the tonsil. It is done under general anesthesia in the operating room and can be used for enlarged tonsils and chronic or recurrent infections. This causes removal of tissue with a thermal effect of 45-85 C. It has been claimed that this technique results in less pain, faster healing, and less post operative care . However, review of 21 studies gives conflicting results about levels of pain, and its comparative safety has yet to be confirmed .
A prion combination of the first two syllables of the words proteinaceous and infectious It is a poorly-understood hypothetical infectious agent that, according to the "protein only" hypothesis, is composed entirely of proteins. Prions are thought to cause a number of diseases in a variety of mammals, including bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle and Creutzfeldt-Jakob disease (CJD) in humans. All thus-far hypothesized prion diseases affect the structure of the brain or other neural tissue, and all are currently untreatable and thought to be fatal. In general usage, prion can refer to both the theoretical unit of infection or the specific protein (e.g. PrP) that is thought to be the infective agent, whether or not it is in an infective state. Subscribe in a reader
Prions are hypothesized to infect and propagate by refolding abnormally into a structure which is able to convert normal molecules of the protein into the abnormally structured form. All known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. This altered structure is extremely stable and accumulates in infected tissue, causing cell death and tissue damage. This stability means that prions are resistant to denaturation by chemical and physical agents, making disposal and containment of these particles difficult. Structure Isoforms
The protein that prions are made of is found throughout the body, even in healthy people and animals. However, the prion protein found in infectious material has a different folding pattern and is resistant to proteases, the enzymes in the body that can normally break down proteins. The normal form of the protein is called PrPC, while the infectious form is called PrPSc — the C refers to 'cellular' or 'common' PrP, while the Sc refers to 'scrapie', a prion disease occurring in sheep. While PrPC is structurally well-defined, PrPSc is certainly polydisperse and defined at a relatively poor level. PrP can be induced to fold into other more-or-less well-defined isoforms in vitro, and their relationship to the form(s) that are pathogenic in vivo is not yet clear.
PrPC
PrPC is a normal protein found on the membranes of cells. It has 209 amino acids (in humans), one disulfide bond, a molecular weight of 35-36kDa and a mainly alpha-helical structure. Several topological forms exist; one cell surface form anchored via glycolipid and two transmembrane forms. Its function has not been fully resolved. PrPC binds copper (II) ions with high affinity. The significance of this is not clear, but it presumably relates to PrP structure or function. PrPC is readily digested by proteinase K and can be liberated from the cell surface in vitro by the enzyme phosphoinositide phospholipase C (PI-PLC), which cleaves the glycophosphatidylinositol (GPI) glycolipid anchor.
PrPSc The infectious isoform of PrPC, known as PrPSc, is able to convert normal PrPC proteins into the infectious isoform by changing their conformation. Although the exact 3D structure of PrPSc is not known, there is increased β-sheet content in the diseased form of the molecule, replacing normal areas of α-helix. Aggregations of these abnormal isoforms may form highly structured amyloid fibers. The end of a fiber acts as a template for the free protein molecules, causing the fiber to grow. Small differences in the amino acid sequence of prion-forming regions lead to distinct structural features on the surface of prion fibers. As a result, only free protein molecules that are identical in amino acid sequence to the prion protein can be recruited into the growing fiber. Function
It has now been conclusively proven that the prion protein's normal cellular role is as a copper dependent antioxidant. While a small number of researchers in the field pursue other possibilities, the majority of evidence from many researcher supports this finding. PrP and long-term memory
There is evidence that PrP may have a normal function in maintenance of long term memory.Maglio and colleagues have shown that mice without the genes for normal cellular PrP protein have altered hippocampal LTP. PrP and stem cell renewal
A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is necessary for an organism's self-renewal of bone marrow. The study showed that all long-term hematopoietic stem cells expressed PrP on their cell membrane and that hematopoietic tissues with such PrP-null stem cells exhibited increased sensitivity to cell depletion. Prion disease
Prions cause neurodegenerative disease by aggregating extracellularly within the central nervous system to form plaques known as amyloids, which disrupt the normal tissue structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the vacuole formation in the neurons.Other histological changes include astrogliosis and the absence of an inflammatory reaction. While the incubation period for prion diseases is generally quite long, once symptoms appear the disease progresses rapidly, leading to brain damage and death. Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes. All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal. However, a vaccine has been developed in mice that may provide insight into providing a vaccine in humans to resist prion infections. Additionally, in 2006 scientists announced that they had genetically engineered cattle lacking a necessary gene for prion production - thus theoretically making them immune to BSE, building on research indicating that mice lacking normally-occurring prion protein are resistant to infection by scrapie prion protein. Many different mammalian species can be affected by prion diseases, as the prion protein (PrP) is very similar in all mammals. Due to small differences in PrP between different species, it is unusual for a prion disease to be transmitted from one species to another. However, the human prion disease variant Creutzfeldt-Jakob disease is believed to be caused by a prion which typically infects cattle and is transmitted through infected meat.
An osteoclast (from the Greek words for "bone" and "broken") is a type of bone cell that removes bone tissue by removing its mineralized matrix. This process is known as bone resorption. Osteoclasts and osteoblasts are instrumental in controlling the amount of bone tissue: osteoblasts form bone, osteoclasts resorb bone. Osteoclasts are formed by the fusion of cells of the monocyte-macrophage cell line. Osteoclasts are characterized by high expression of tartrate resistant acid phosphatase (TRAP) and cathepsin K.
Morphology
An osteoclast is a large cell that is characterized by multiple nuclei and a cytoplasm with a homogeneous, "foamy" appearance. This appearance is due to a high concentration of vesicles and vacuoles. At a site of active bone resorption, the osteoclast forms a specialized cell membrane, the "ruffled border", which touches the surface of the bone tissue.
The ruffled border, which facilitates removal of the bony matrix, is a morphologic characteristic of an osteoclast that is actively resorbing bone. The ruffled border increases surface area interface for bone resorption. The mineral portion of the matrix (called hydroxyapatite) includes calcium and phosphate ions. These ions are absorbed into small vesicles (see endocytosis) which move across the cell and eventually are released into the extracellular fluid, thus increasing levels of the ions in the blood.
Formation
Osteoclasts formation requires the presence of RANK ligand (receptor activator of nuclear factor κβ) and M-CSF (Macrophage colony-stimulating factor). These membrane bound proteins are produced by neighbouring stromal cells and osteoblasts; thus requiring direct contact between these cells and osteoclast precursors.
M-CSF acts through its receptor on the osteoclast, c-fms (colony stimulating factor 1 receptor), a transmembrane tyrosine kinase-receptor, leading to secondary messenger activation of tyrosine kinase Src. Both of these molecules are necessary for osteoclastogenesis and are widely involved in the differentiation of monocyte/macrophage derived cells.
RANKL is a member of the tumour necrosis family (TNF), and is essential in osteoclastogenesis. RANKL knockout mice exhibit a phenotype of osteopetrosis and defects of tooth eruption, along with an absence or deficiency of osteoclasts. RANKL activates NF-κβ (nuclear factor-κβ) and NFATc1 (nuclear factor of activated t cells, cytoplasmic, calcineurin-dependent 1) through RANK. NF-κβ activation is stimulated almost immediately after RANKL-RANK interaction occurs, and is not upregulated. NFATc1 stimulation, however, begins ~24-48 hours after binding occurs and its expression has been shown to be RANKL dependent.
Osteoclast differentiation is inhibited by osteoprotegerin (OPG), which binds to RANKL thereby preventing interaction with RANK.
Function
Once activated, they move to areas of microfracture in the bone by chemotaxis. Osteoclasts lie in a small cavity called Howship's lacuna, formed from the digestion of the underlying bone. The sealing zone is the attachment of the osteoclast's plasmalemma to the underlying bone. Sealing zones are bounded by belts of specialized adhesion structures called podosomes. Attachment to the bone matrix is facilitated by integrin receptors, such as αvβ3, via the specific amino acid motif Arg-Gly-Asp in bone matrix proteins, such as osteopontin. The osteoclast releases hydrogen ions (H2O + CO2 → HCO3- + H+) through the ruffled border into the cavity, acidifying and dissolving the mineralized bone matrix into Ca2+, H3PO4, H2CO3 and water. Hydrogen ions are pumped against a high concentration gradient by proton pumps, specifically a unique vacuolar-ATPase. This enzyme has been targeted in the prevention of osteoporosis. In addition, several hydrolytic enzymes, such as members of the cathepsin and matrix metalloprotease(MMP) groups , are released to digest the organic components of the matrix. These enzymes are released into the compartment by lysosomes. Of these hydrolytic enzymes, cathepsin K is of most importance.
Cathepsin K and other cathepsins
Cathepsin K is a collagenolytic, papain-like, cysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Mutations in the cathepsin K gene are associated with pycnodysostosis, a hereditary osteopetrotic disease, characterised by lack of functional cathepsin K expression. Knockout studies of cathepsin K in mice lead to an osteopetrotic phenotype, which, is partially compensated by increased expression of proteases other that cathepsin K and enhanced osteoclastogenesis.
Cathepsin K has an optimal enzymatic activity in acidic conditions. It is synthesized as a proenzyme with a molecular weight of 37kDa, and upon activation by autocatalytic cleavage, is transformed into the mature, active form with a molecular weight of ~27kDa.
In the osteoclast, cathepsin K functions in the resorptive process. Upon polarization of the osteoclast over the site of resorption, cathepsin K is secreted from the ruffled border into the resorptive pit. Here, it is the major protease involved in the degradation of type I collagen and other noncollagenous proteins, which have been demineralized by the acidic environment of the resorptive pit. From the resorptive pit, cathepsin K transmigrates across the ruffled border, through the osteoclast via intercellular vesicles and is then released by the functional secretory domain. Within these intercellular vesicles, cathepsin K, along with ROS generation by TRAP further degrades bone resorption products.
Numerous other cathepsins are expressed in osteoclasts. These include cathepsin B, C, D, E, G, and L. The function of these cysteine and aspartic proteases is generally unknown within bone, and they are expressed at much lower levels that cathepsin K.
Studies on cathepsin L knockout mice have been mixed, with a report of reduced trabecular bone in homozygous and heterozygous cathepsin L knockout mice compared to wild-type and another report finding no skeletal abnormalities.
Matrix metalloproteinases
The matrix metalloproteinases (MMPs) comprise a family of more that 20 zinc-dependent endopeptidases. The role of matrix metalloproteinases (MMPs) in osteoclast biology is ill-defined, but in other tissue they have been linked with tumor promoting activities, such as activation of growth factors and are required for tumor metastasis and angiogenesis.
MMP-9 is associated with the bone microenvironment. It is expressed by osteoclasts, and is known to be required for osteoclast migration and is a powerful gelatinase. Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis, and fracture repair.
MMP-13 is believed to be involved in bone resorption and in osteoclast differentiation, as knockout mice revealed decreased osteoclast numbers, osteopetrosis, and decreased bone resorption.
MMPs expressed by the osteoclast include MMP-9, -10, -12, and -14. apart from MMP-9, little is know about their relevance to the osteoclast, however, high levels of MMP-14 are found at the sealing zone.
Regulation
Osteoclasts are regulated by several hormones, including parathyroid hormone (PTH) from the parathyroid gland, calcitonin from the thyroid gland, and growth factor interleukin 6 (IL-6). This last hormone, IL-6, is one of the factors in the disease osteoporosis, which is an imbalance between bone resorption and bone formation. Osteoclast activity is also mediated by the interaction of two molecules produced by osteoblasts, namely osteoprotegerin and RANK ligand. Note that these molecules also regulate differentiation of the osteoclast.
Programmed cell-death (PCD) is death of a cell in any form, mediated by an intracellular program. In contrast to necrosis, which is a form of cell-death that results from acute tissue injury and provokes an inflammatory response, PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle. PCD serves fundamental functions during both plant and metazoa (multicellular animals) tissue development.
Autophagic or Type II cell-death ( cytoplasmic: characterized by the formation of large vacuoles which eat away organelles in a specific sequence prior to the nucleus being destroyed.)
Besides these two types of PCD, other pathways have been discovered. Called "non-apoptotic programmed cell-death" (or "caspase-independent programmed cell-death" or "necrosis-like programmed cell-death") these alternative routes to death are as efficient as apoptosis and can function as either backup mechanisms or the main type of PCD.
Other forms of programmed cell death include anolkis, almost identical to apoptosis except in its induction; cornification, a form of cell death exlusive to the eyes; excitotoxicity and Wallerian degeneration.
Plant cells undergo particular processes of PCD which are similar to autophagic cell death. However, some common features of PCD are highly conserved in both plants and metazoa.
The concept of "programmed cell-death" was used by Lockshin & Williams in 1964 in relation to insect tissue development, around eight years before "apoptosis" was coined. Since then, PCD has become the more general of these two terms.
Information entering the brain along the sensory nerve pathway passes to the sensory cortex. However, nerve branches from the pathway first send impulses to the ascending reticular-activating system or RAS, which stimulates activity and attentiveness throughout the entire cortex. The resultant outgoing information leaves the brain from the motor cortex through the motor pathway and then into the spinal cord.
Signaling Pathway of Ras. Binding of growth factors to receptor tyrosine kinases stimulates the autophosphorylation of specific tyrosines on the receptors. The phosphorylated receptor then binds to an adaptor protein called GRB2 which, in turn, recuits SOS (son of sevenless) to the plasma membrane. SOS is a guanine nucleotide exchange factor which displaces GDP from Ras, subsequently allowing the binding of GTP (Ras is already anchored to the plasma membrane by post-translationally added lipids, shown as a red line). GTP-bound Ras recruits and activates Raf. Raf initates a cascade of protein phosphorylation by first phophorylating MEK. Phosphorylated MEK in turn phosphorylates ERK. Phosphorylated ERK moves from the cytoplasm into the nucleus where it subsequently phosphorylates a number of transcription factors, including the specific transcription factor called Elk-1. Phosphorylated transcription factors turn on transcription (gene expression) of specific sets of target genes. The activity of Ras is limited by the hydrolysis of GTP back to GDP by GTPase activating proteins (GAP). Other abbreviations are: MEK = MAPK/ERK kinase, ERK = extracellular receptor-stimulated kinase, MAPK = mitogen-activated protein kinase. Kinases are enzymes that add phosphates to molecules using ATP. Mitogens are factors (such as growth factors) that stimulate cell division.
All apes apart from man have 24 pairs of chromosomes. There is therefore a hypothesis that the common ancestor of all great apes had 24 pairs of chromosomes and that the fusion of two of the ancestor's chromosomes created chromosome 2 in humans. The evidence for this hypothesis is very strong.
The Evidence
Evidence for fusing of two ancestral chromosomes to create human chromosome 2 and where there has been no fusion in other Great Apes is:
1) The analogous chromosomes (2p and 2q) in the non-human great apes can be shown, when laid end to end, to create an identical banding structure to the human chromosome 2.
2) The remains of the sequence that the chromosome has on its ends (the telomere) is found in the middle of human chromosome 2 where the ancestral chromosomes fused.
3) the detail of this region (pre-telomeric sequence, telomeric sequence, reversed telomeric sequence, pre-telomeric sequence) is exactly what we would expect from a fusion.
4) this telomeric region is exactly where one would expect to find it if a fusion had occurred in the middle of human chromosome 2.
5) the centromere of human chromosome 2 lines up with the chimp chromosome 2p chromosomal centromere.
6) At the place where we would expect it on the human chromosome we find the remnants of the chimp 2q centromere .
Not only is this strong evidence for a fusion event, but it is also strong evidence for common ancestry; in fact, it is hard to explain by any other mechanism.
Centromere evidence
Let us re-iterate what we find on human chromosome 2. Its centromere is at the same place as the chimpanzee chromosome 2p as determined by sequence similarity. Even more telling is the fact that on the 2q arm of the human chromosome 2 is the unmistakable remains of the original chromosome centromere of the common ancestor of human and chimp 2q chromosome, at the same position as the chimp 2q centromere (this structure in humans no longer acts as a centromere for chromosome 2.
LASIK (laser-assisted in situ keratomileusis) is a type of refractive laser eye surgery performed by ophthalmologists for correcting myopia, hyperopia, and astigmatism.[1] The procedure is generally preferred to photorefractive keratectomy, PRK, (also called ASA, Advanced Surface Ablation) because it requires less time for the patient's recovery, and the patient feels less pain, overall; however, there are instances where PRK/ASA is medically indicated as a better alternative to LASIK.
The LASIK technique was made possible by the Colombian-based Spanish ophthalmologist Jose Barraquer, who, around 1950 in his clinic in Bogotá, Colombia, developed the first microkeratome, used to cut thin flaps in the cornea and alter its shape, in a procedure called keratomileusis. Stephan Schaller assisted. Barraquer also provided the knowledge about how much of the cornea had to be left unaltered to provide stable long-term results.
Later technical and procedural developments included the RK (radial keratotomy), started in the '70s in Russia by Svyatoslav Fyodorov , and the development of PRK (photorefractive keratectomy) in the '80s in Germany by Theo Seiler. RK is a procedure where radial corneal cuts are made typically using a micrometer diamond knife, and has nothing to do with LASIK
In 1968, at the Northrup Corporation Research and Technology Center of the University of California, Mani Lal Bhaumik and a group of other scientists, while working on the development of a carbon-dioxide laser, developed the Excimer laser, where molecules that do not normally exist come into being when xenon, argon or krypton gases are excited. This formed the cornerstone for LASIK eye surgery. Dr. Bhaumik announced his discovery in May of 1973 at a meeting of the Denver Optical Society of America in Denver, Colorado. He would later patent it.
The introduction of Laser in this refractive procedure started with the developments in Laser technology by Rangaswamy Srinivasan. In 1980, Srinivasan, working at IBM Research Lab, discovered that an ultraviolet excimer laser could etch living tissue in a precise manner with no thermal damage to the surrounding area. He named the phenomenon Ablative Photodecomposition (APD). Dr. Stephen Trokel published a paper in the American Journal of Ophthalmology in 1983, outlining the potential of using the excimer laser in refractive surgeries.
The first patent for LASIK was granted by the US Patent Office to Gholam A. Peyman, MD on June 20, 1989, US Patent #4,840,175, "METHOD FOR MODIFYING CORNEAL CURVATURE", describing the surgical procedure in which a flap is cut in the cornea and pulled back to expose the corneal bed. This exposed surface is then ablated to the desired shape with an excimer laser, following which the flap is replaced.
Using these advances in laser technology and the technical and theoretical developments in refractive surgery made since the 50's, LASIK surgery was developed in 1990 by Lucio Buratto (Italy) and Ioannis Pallikaris (Greece) as a melding of two prior techniques, keratomileusis and photorefractive keratectomy. It quickly became popular because of its greater precision and lower frequency of complications in comparison with these former two techniques.
Today, faster lasers, larger spot areas, bladeless flap incision, and wavefront-optimized and -guided techniques have significantly improved the reliability of the procedure compared to that of 1991. Nonetheless, the fundamental limitations of excimer lasers and undesirable destruction of the eye's nerves have spawned research into many alternatives to "plain" LASIK, including all-femtosecond correction (Femtosecond Lenticule EXtraction, FLIVC), LASEK, Epi-LASIK, sub-Bowman’s Keratomileusis aka thin-flap LASIK, wavefront-guided PRK, and modern intraocular lenses.
Procedure
There are several necessary preparations in the preoperative period. The operation itself is made by creating a thin flap on the eye, folding it to enable remodeling of the tissue underneath with laser. The flap is repositioned and the eye is left to heal in the postoperative period.
Preoperative
Patients wearing soft contact lenses are usually instructed to stop wearing them approximately 5 to 7 days before surgery. One industry body recommends that patients wearing hard contact lenses should stop wearing them for a minimum of six weeks plus another six weeks for every three years the hard contacts have been worn. Before the surgery, the patient's corneas are examined with a pachymeter to determine their thickness, and with a topographer to measure their surface contour. Using low-power lasers, a topographer creates a topographic map of the cornea. This process also detects astigmatism and other irregularities in the shape of the cornea. Using this information, the surgeon calculates the amount and locations of corneal tissue to be removed during the operation. The patient typically is prescribed an antibiotic to start taking beforehand, to minimize the risk of infection after the procedure.
Operation
The operation is performed with the patient awake and mobile; however, the patient is given a mild sedative (such as Valium) and anesthetic eye drops.
LASIK is performed in three steps. The first step is to create a flap of corneal tissue. The second step is remodeling of the cornea underneath the flap with the laser. Finally, the flap is repositioned.
Flap creation
A corneal suction ring is applied to the eye, holding the eye in place. This step in the procedure can sometimes cause small blood vessels to burst, resulting in bleeding or subconjunctival hemorrhage into the white (sclera) of the eye, a harmless side effect that resolves within several weeks. Increased suction typically causes a transient dimming of vision in the treated eye. Once the eye is immobilized, the flap is created. This process is achieved with a mechanical microkeratome using a metal blade, or a femtosecond laser microkeratome (procedure known as IntraLASIK) that creates a series of tiny closely arranged bubbles within the cornea. A hinge is left at one end of this flap. The flap is folded back, revealing the stroma, the middle section of the cornea. The process of lifting and folding back the flap can be uncomfortable.
Laser remodeling
The second step of the procedure is to use an excimer laser (193 nm) to remodel the corneal stroma. The laser vaporizes tissue in a finely controlled manner without damaging adjacent stroma. No burning with heat or actual cutting is required to ablate the tissue. The layers of tissue removed are tens of micrometers thick. Performing the laser ablation in the deeper corneal stroma typically provides for more rapid visual recovery and less pain, than the earlier technique photorefractive keratectomy (PRK).
During the second step, the patient's vision will become very blurry once the flap is lifted. He/she will be able to see only white light surrounding the orange light of the laser. This can be disorienting.
Currently manufactured excimer lasers use an eye tracking system that follows the patient's eye position up to 4,000 times per second, redirecting laser pulses for precise placement within the treatment zone. Typical pulses are around 1 mJ of pulse energy in 10 to 20 nanoseconds.
Reposition of flap
After the laser has reshaped the stromal layer, the LASIK flap is carefully repositioned over the treatment area by the surgeon and checked for the presence of air bubbles, debris, and proper fit on the eye. The flap remains in position by natural adhesion until healing is completed.
Postoperative
Patients are usually given a course of antibiotic and anti-inflammatory eye drops. These are continued in the weeks following surgery. Patients are usually told to sleep much more and are also given a darkened pair of shields to protect their eyes from bright lights and protective goggles to prevent rubbing of the eyes when asleep and to reduce dry eyes. They also have to moisturize the eyes with preservative free tears and follow directions for prescription drops. Patients should be adequately informed by their surgeons of the importance of proper post-operative care to minimize the risk of post-surgical complications.
Respiratory system consists of the airways, the lungs, and the respiratory muscles that mediate the movement of air into and out of the body. Within the alveolar system of the lungs, molecules of oxygen and carbon dioxide are passively exchanged, by diffusion, between the gaseous environment and the blood. Thus, the respiratory system facilitates oxygenation of the blood with a concomitant removal of carbon dioxide and other gaseous metabolic wastes from the circulation. The system also helps to maintain the acid-base balance of the body through the efficient removal of carbon dioxide from the blood.
Ventilation
Ventilation of the lungs is carried out by the muscles of respiration.
Control
Ventilation occurs under the control of the autonomic nervous system from parts of the brain stem, the medulla oblongata and the pons. This area of the brain forms the respiration regulatory center, a series of interconnected brain cells within the lower and middle brain stem which coordinate respiratory movements. The sections are the pneumotaxic center, the apneustic center, and the dorsal and ventral respiratory groups. This section is especially sensitive during infancy, and the neurons can be destroyed if the infant is dropped and/or shaken violently. The result can be death due to "shaken baby syndrome."
Inhalation is initiated by the diaphragm and supported by the external intercostal muscles. Normal resting respirations are 10 to 18 breaths per minute. Its time period is 2 seconds. During vigorous inhalation (at rates exceeding 35 breaths per minute), or in approaching respiratory failure, accessory muscles of respiration are recruited for support. These consist of sternocleidomastoid, platysma, and the strap muscles of the neck.
Inhalation is driven primarily by the diaphragm. When the diaphragm contracts, the ribcage expands and the contents of the abdomen are moved downward. This results in a larger thoracic volume, which in turn causes a decrease in intrathoracic pressure. As the pressure in the chest falls, air moves into the conducting zone. Here, the air is filtered, warmed, and humidified as it flows to the lungs.
During forced inhalation, as when taking a deep breath, the external intercostal muscles and accessory muscles further expand the thoracic cavity.
Exhalation
Exhalation is generally a passive process; however, active or forced exhalation is achieved by the abdominal and the internal intercostal muscles. During this process air is forced or exhaled out.
The lungs have a natural elasticity; as they recoil from the stretch of inhalation, air flows back out until the pressures in the chest and the atmosphere reach equilibrium.
During forced exhalation, as when blowing out a candle, expiratory muscles including the abdominal muscles and internal intercostal muscles, generate abdominal and thoracic pressure, which forces air out of the lungs.
Circulation
The right side of the heart pumps blood from the right ventricle through the pulmonary semilunar valve into the pulmonary trunk. The trunk branches into right and left pulmonary arteries to the pulmonary blood vessels. The vessels generally accompany the airways and also undergo numerous branchings. Once the gas exchange process is complete in the pulmonary capillaries, blood is returned to the left side of the heart through four pulmonary veins, two from each side. The pulmonary circulation has a very low resistance, due to the short distance within the lungs, compared to the systemic circulation, and for this reason, all the pressures within the pulmonary blood vessels are normally low as compared to the pressure of the systemic circulation loop.
Virtually all the body's blood travels through the lungs every minute. The lungs add and remove many chemical messengers from the blood as it flows through pulmonary capillary bed. The fine capillaries also trap blood clots that have formed in systemic veins.
Gas exchange
The major function of the respiratory system is gas exchange. As gas exchange occurs, the acid-base balance of the body is maintained as part of homeostasis. If proper ventilation is not maintained, two opposing conditions could occur: 1) respiratory acidosis, a life threatening condition, and 2) respiratory alkalosis.
Upon inhalation, gas exchange occurs at the alveoli, the tiny sacs which are the basic functional component of the lungs. The alveolar walls are extremely thin (approx. 0.2 micrometres), and are permeable to gases. The alveoli are lined with pulmonary capillaries, the walls of which are also thin enough to permit gas exchange.
Development
The respiratory system lies dormant in the human fetus during pregnancy. At birth, the respiratory system has under-developed lungs. This is due to the incomplete development of the alveoli type II cells in the lungs, necessary for the production of surfactant. The infant lungs do not function due to collapse of alveoli caused by surface tension of water remaining in the lungs, which in normal cases would be prohibited by the presence of surfactant. This condition may be avoided by giving the mother a series of steroid shots in the final week prior to delivery, which will have weard the development of type II alveolar cells.
The blood differential test measures the percentage of each type of white blood cell (WBC) that you have in your blood. It also reveals if there are any abnormal or immature cells.The health care provider will take blood from your vein. The blood collects into an airtight container.In infants or a young child, blood will be taken from a heel stick or finger stick. The blood is collected in a small glass tube or onto a slide or test strip.
A laboratory specialist takes a drop of blood from your sample and smears it onto a glass slide. The smear is stained with a special dye, which helps tell the difference between various types of white blood cells.
Five types of white blood cells, also called leukocytes, normally appear in the blood:
Neutrophils
Lymphocytes (B cells and T cells)
Monocytes
Eosinophils
Basophils
A computer or the health care provider counts the number of each type of cell. The test shows if the number of cells are in proper proportion with one another, and if there is more or less of one cell type.
How to prepare for the test
No special preparation is necessary.
How the test will feel
When the needle is inserted to draw blood, some people feel moderate pain, while others feel only a prick or stinging sensation. Afterward, there may be some throbbing.
Why the test is performed
This test is done to diagnose an infection, anemia, and leukemia. It may also be used to see if treatment for any of these conditions is working.
Normal Values
Neutrophils: 40% to 60%
Lymphocytes: 20% to 40%
Monocytes: 2% to 8%
Eosinophils: 1% to 4%
Basophils: 0.5% to 1%
Band: 0% to 3%
What abnormal results mean
Any infection or acute stress increases your number of white blood cells. High white blood cell counts may be due to inflammation, an immune response, or blood diseases such as leukemia.
It is important to realize that an abnormal increase in one type of white blood cell can cause a decrease in the percentage of other types of white blood cells.
An increased percentage of neutrophils may be due to:
Acute infection
Eclampsia
Gout
Myelocytic leukemia
Rheumatoid arthritis
Rheumatic fever
Acute stress
Thyroiditis
Trauma
A decreased percentage of neutrophils may be due to:
Aplastic anemia
Chemotherapy
Influenza
Widespread bacterial infection
Radiation therapy
An increased percentage of lymphocytes may be due to:
Chronic bacterial infection
Infectious hepatitis
Infectious mononucleosis
Lymphocytic leukemia
Multiple myeloma
Viral infection (such as infectious mononucleosis, mumps, measles)
Recovery from a bacterial infection
A decreased percentage of lymphocytes may be due to:
Chemotherapy
HIV infection
Leukemia
Radiation therapy
Sepsis
An increased percentage of monocytes may be due to:
Chronic inflammatory disease
Parasitic infection
Tuberculosis
Viral infection (for example, infectious mononucleosis, mumps, measles)
An increased percentage of eosinophils may be due to:
Allergic reaction
Parasitic infection
Hodgkin's disease
A decreased percentage of basophils may be due to:
Acute allergic reaction
What the risks are
Excessive bleeding
Fainting or feeling light-headed
Hematoma (blood accumulating under the skin)
Infection (a slight risk any time the skin is broken)
Multiple punctures to locate veins
Special considerations
Veins and arteries vary in size from one patient to another, and from one side of the body to the other. Obtaining a blood sample from some people may be more difficult than from others.
Stem cells: Sorting through the hype and hope
You've heard about stem cells in the news and perhaps you've wondered if they might help you or a loved one with a serious disease. Like many others, you may struggle with understanding what exactly stem cells are, how they're actually being used now to treat disease and injury, and why they're the subject of such passionate debate.
Here, you can sort through the hype and the hope and get answers to frequently asked questions about stem cells.
Why is there high interest in stem cells?
Researchers are interested in stem cells for two main reasons:
Knowledge. By studying how stem cells mature into cells that eventually become bones, organs and other tissue, researchers hope to learn more about the function of stem cells and what can go wrong in development. This knowledge may shed new light on how a variety of diseases and conditions develop, such as cancer and birth defects.
Therapy. Researchers hope they can manipulate stem cells into becoming specific types of cells. If this is done successfully, stem cells could be used to treat diseases and conditions such as diabetes, Parkinson's disease, inherited genetic diseases or spinal cord injuries. Stem cells could also be grown to become organs to use in transplants, since donor organs are notoriously in short supply. Stem cells may also one day be used to test experimental medications before human clinical trials.
What exactly are stem cells?
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Stem cells: The body's master cells
Stem cells are master cells of the body, from which all other cells with specialized functions are created. Under the right conditions in the body or a laboratory, stem cells divide to form more cells, called daughter cells. These daughter cells either become new stem cells (self-renewal) or become specialized cells (differentiation) with a more specific function, such as blood cells, brain cells or bone cells. Besides the stem cell, no other cell in the body has the ability to self-renew or to differentiate.
If stem cells are master cells, where do they come from?
There are four sources of stem cells:
Embryonic stem cells. These stem cells come from human embryos that are four to five days old. At this stage, an embryo is called a blastocyst and has about 50 to 150 cells. Some of these cells are pluripotent (ploo-RIP-o-tunt) stem cells, meaning they can divide into more stem cells or they can specialize and become any type of body cell. These are the stem cells that researchers have focused on and that have become a matter of controversy.
Adult stem cells. These stem cells are found in small numbers in most adult tissues, such as bone marrow. Adult stem cells are also found in children and in placentas and umbilical cords. Because of that, a more precise term for these cells is somatic stem cell, meaning "of the body." Until recently, it appeared that adult stem cells could only create similar types of cells. For instance, it was thought that stem cells in the bone marrow could give rise only to blood cells. However, a new — but controversial — theory suggests that adult stem cells may be more versatile than previously thought and able to create unrelated types of cells after all. For instance, bone marrow stem cells may be able to create kidney cells. But that research is only in very early stages.
Embryonic germ cells. These are stem cells that come from areas within an embryo or fetus that are destined to become either the testicles or ovaries. Like embryonic stem cells, embryonic germ cells can become any type of cell. Less research has been done on embryonic germ cells because the embryos used to obtain them must be deliberately aborted. In addition, these cells tend to differentiate spontaneously, so they may be more difficult to use in a controlled manner.
Amniotic fluid stem cells. A study released in early 2007 identified amniotic fluid as an additional source of stem cells. Amniotic fluid fills the sac that surrounds and protects a developing fetus in its mother's uterus. Researchers identified stem cells in samples of amniotic fluid drawn from pregnant women during a procedure called amniocentesis. During this test, a doctor inserts a long, thin needle into a pregnant woman's abdomen to collect amniotic fluid. The test screens for abnormalities, such as Down syndrome, and is generally considered safe for the developing fetus and the mother. Researchers were able to use discarded amniocentesis samples to identify stem cells that could develop into several other types of cells. More study of amniotic fluid stem cells is needed to understand their potential.
Why is there a controversy about using embryonic stem cells?
Embryonic stem cells are derived from early-stage embryos — a group of cells that forms when a woman's egg is fertilized with a man's sperm. Extracting stem cells from the embryos destroys the embryos. Some people view this as taking a human life, which raises moral and ethical considerations.
Where do these embryos come from?
The embryos being used in embryonic stem cell research come from eggs that were fertilized at in vitro fertilization clinics but never implanted in a woman's uterus because they were no longer wanted or needed. The excess embryos were frozen and later voluntarily donated for research purposes. The stem cells live and grow in cultures, or special solutions in test tubes or petri dishes in laboratories.
Why can't researchers use adult stem cells instead?
Researchers believe that adult stem cells may not be as versatile, durable or healthy as embryonic stem cells are. The problems with adult stem cells are that they may not be able to be manipulated to produce all cell types, which limits how they can be used to treat diseases, and they don't seem to have the same ability to multiply that embryonic stem cells do. They're also more likely to contain abnormalities due to exposure to environmental hazards, such as toxins, or from errors introduced into cells during replication.
What is a stem cell line and why do researchers want to use them?
A stem cell line is a group of cells that all descend from an original stem cell. Cells in a stem cell line keep dividing but don't differentiate into specialized cells. Ideally, they remain free of genetic defects and continue to create more stem cells. Clusters of cells can be taken from a stem cell line and frozen for storage or distributed to other researchers. This way, researchers don't have to get stem cells from an embryo itself.
Why do researchers want to create more embryonic stem cell lines?
Researchers who receive federal funding to support their experiments — as most academic researchers do — are limited by law to working with about 20 stem cell lines. These stem cell lines, sometimes called the presidential lines, date back to the late 1990s, and some researchers contend that they pose several problems:
The limited number of lines limits the genetic diversity available, so cells may be useful only for certain diseases or people.
The lines are old, so cells don't grow as well as new ones.
The lines may have been contaminated by nonhuman cells in the growth cultures, compromising their safety.
The DNA in some of the cells may subtly change over time, causing genetic flaws that could be passed along to daughter cells or to humans.
How can additional stem cell lines be made available more quickly to U.S. researchers?
It will take a presidential order or an act of Congress signed by the president to make federal funding available for research on more stem cell lines, not just the presidential lines. This would speed the development of embryonic stem cell lines in the United States.
Until public funding is available, some researchers have turned to private funding to finance their embryonic stem cell studies and have created their own stem cell lines. Also, individual states can pass their own laws allowing funding of embryonic stem cell research with state money.
What is stem cell therapy and how does it work?
Stem cell therapy is the replacement of diseased, dysfunctional or injured cells with either adult or embryonic stem cells. It's somewhat similar to the organ transplant process but uses cells instead of organs.
Researchers grow stem cells in the lab. These stem cells are manipulated to make them specialize into specific types of cells, such as heart muscle cells, blood cells or nerve cells. This manipulation may involve changing the material in which the stem cells are grown or even injecting genes into the cells. The specialized cells are then implanted into a person. If the person has heart disease, the cells would be injected into the heart muscle. The normally functioning implanted heart cells, in theory, would replace the defective heart cells.
Have stem cells already been used to treat diseases?
Yes, stem cell transplants, also known as bone marrow transplants, have been performed in the United States since the late 1960s. These transplants have proved highly successful in treating a number of cancerous diseases, such as leukemia, and noncancerous diseases, such as aplastic anemia.
Stem cell transplants use cells harvested from a donor's or person's own bone marrow, circulating blood or umbilical cord blood. These are all adult stem cells — not stem cells derived from embryos. In addition, adult stem cells have also been used in human experiments involving the treatment of diabetes, heart disease and other conditions.
Embryonic stem cell treatment, on the other hand, has been purely experimental, involving animal studies only.
What are the problems with using embryonic stem cells in humans?
To be useful in people, researchers must be certain that embryonic stem cells will differentiate into the specific cell types desired. Because research on embryonic stem cells is still in early stages, that hasn't happened reliably enough in animal experiments to try in people. Researchers, for instance, don't want to transplant a stem cell into a person hoping it'll become a heart cell only to learn that it's become a bone cell, with potentially dangerous consequences.
Embryonic stem cells may also have other unpleasant surprises if used in people before the science is ready. They could become tumor cells — something that's happened in animal experiments — or travel to a part of the body where they're not intended to go. They also might trigger an immune response in which the recipient's body attacks the stem cells as foreign invaders, or simply fail to function normally, with unknown consequences.
What is therapeutic cloning and what benefits might it offer?
Therapeutic cloning is a technique to create embryonic stem cells without using fertilized eggs. In this technique, the nucleus is removed from a cell in a woman's egg. The nucleus is also removed from a somatic cell of a donor — a person with a disease or injury, such as type 1 diabetes. This donor nucleus is then injected into the egg, replacing the nucleus that was removed, a process called nuclear transfer. The egg is allowed to divide and soon forms a blastocyst. This creates a line of embryonic stem cells that is genetically identical to the donor — in essence, a clone. This technique is also called somatic cell nuclear transfer.
Some researchers believe that embryonic stem cells derived from therapeutic cloning may offer benefits over those from fertilized eggs because they're less likely to be rejected once transplanted back into the donor, and they allow researchers to see exactly how a disease develops from the beginning.
In addition, some researchers consider therapeutic cloning a good alternative to creating embryonic stem cell lines from fertility treatments, since they come from cells that were never fertilized. However, this technique is not without opponents. Critics contend therapeutic cloning can be perceived as destruction of a human life or potential human life.
Has therapeutic cloning in people been successful?
So far, human therapeutic cloning has worked only in theory. Researchers haven't been able to successfully perform therapeutic cloning of people. In 2005, South Korean researchers reported creation of human embryonic stem cells this way, but their claims were ultimately revealed to be untrue.
What does the future hold for stem cell therapy?
Researchers say the field has promise. Stem cell transplants using adult stem cells continue to be refined and improved. And researchers are discovering that adult stem cells may be somewhat more versatile than originally thought, which means they eventually may be able to treat a wider variety of diseases.
However, advances in embryonic stem cell research have been hindered by the limits of scientific knowledge, funding restrictions, politics and ethical debates. So for now, research on embryonic stem cells remains confined to laboratory animals.
Cholesterol is a lipid found in the cell membranes of all animal tissues, and it is transported in the blood plasma of all animals. Cholesterol is also a sterol (a combination steroid and alcohol). Because cholesterol is synthesized by all eukaryotes, trace amounts of cholesterol are also found in membranes of plants and fungi.
The name originates from the Greek chole- (bile) and stereos (solid), and the chemical suffix -ol for an alcohol, as researchers first identified cholesterol in solid form in gallstones by François Poulletier de la Salle in 1769. However, it is only in 1815 that chemist Eugène Chevreul named the compound "cholesterine".
Most of the cholesterol in the body is synthesized by the body and some has dietary origin. Cholesterol is more abundant in tissues which either synthesize more or have more abundant densely-packed membranes, for example, the liver, spinal cord and brain. It plays a central role in many biochemical processes, such as the composition of cell membranes and the synthesis of steroid hormones.
Since cholesterol is insoluble in blood, it is transported in the circulatory system within lipoproteins, complex spherical particles which have an exterior composed mainly of water-soluble proteins; fats and cholesterol are carried internally. There is a large range of lipoproteins within blood, generally called, from larger to smaller size: chylomicrons, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL). The cholesterol within all the various lipoproteins is identical.
According to the lipid hypothesis, abnormally high cholesterol levels (hypercholesterolemia), or, more correctly, higher concentrations of LDL and lower concentrations of functional HDL are strongly associated with cardiovascular disease because these promote atheroma development in arteries (atherosclerosis). This disease process leads to myocardial infarction (heart attack), stroke and peripheral vascular disease. Since higher blood LDL, especially higher LDL particle concentrations and smaller LDL particle size, contribute to this process more than the cholesterol content of the LDL particles , LDL particles are often termed "bad cholesterol" because they have been linked to atheroma formation. On the other hand, high concentrations of functional HDL, which can remove cholesterol from cells and atheroma, offer protection. These balances are mostly genetically determined but can be changed by body build, medications, food choices and other factors.
Carbohydrates (from 'hydrates of carbon') or saccharides the most abundant of the four major classes of biomolecules, which also include proteins, lipids and nucleic acids. They fill numerous roles in living things, such as the storage and transport of energy (starch, glycogen) and structural components (cellulose in plants, chitin in animals). Additionally, carbohydrates and their derivatives play major roles in the working process of the immune system, fertilization, pathogenesis, blood clotting, and development.
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Part 2
Chemically, carbohydrates are simple organic compounds that are aldehydes or ketones with many hydroxyl groups added, usually one on each carbon atom that is not part of the aldehyde or ketone functional group. The basic carbohydrate units are called monosaccharides, such as glucose, galactose, and fructose. The general stoichiometric formula of an unmodified monosaccharide is (C·H2O)n, where n is any number of three or greater; however, the use of this word does not follow this exact definition and many molecules with formulae that differ slightly from this are still called carbohydrates, and others that possess formulae agreeing with this general rule are not called carbohydrates (eg formaldehyde).
Monosaccharides can be linked together into polysaccharides in almost limitless ways. Many carbohydrates contain one or more modified monosaccharide units that have had one or more groups replaced or removed. For example, deoxyribose, a component of DNA, is a modified version of ribose; chitin is composed of repeating units of N-acetylglucosamine, a nitrogen-containing form of glucose. The names of carbohydrates often end in the suffix -ose.
