Subjects and Topics in Basic
Medical Science
A Imhotep Virtual Medical School Primer
Compiled and Edited by Marc Imhotep C...
Contents
Articles
Anatomy 1
Embryology 3
Biochemistry 6
Histology 14
Epidemiology 20
Biostatistics 31
Molecular biology 34...
Medical sign 149
Physical examination 154
References
Article Sources and Contributors 157
Image Sources, Licenses and Cont...
Anatomy 1
Anatomy
Anatomy lesson carried out in Java, Dutch East
Indies, date unknown.
Anatomy (from the Greek ἀνατομία an...
Anatomy 2
An X-ray of a human chest.
Human heart and lungs, from an older
edition of Gray's Anatomy.
year at medical schoo...
Anatomy 3
(http://www.bium.parisdescartes.fr) see its digital library Medic@ (http://www.bium.univ-paris5.fr/
histmed/medi...
Embryology 4
History
Human embryo at six weeks
gestational age
Histological film 10 day mouse embryo
Beetle larvae
As rece...
Embryology 5
References
[1] Campbell et al. (p. 987)
[2] Massimo De Felici, Gregorio Siracus, The rise of embryology in It...
Biochemistry 6
Biochemistry
Biochemistry, sometimes called biological chemistry, is the study of chemical processes in liv...
Biochemistry 7
Today, there are three main types of biochemistry. Plant biochemistry involves the study of the biochemistr...
Biochemistry 8
Nucleic acids
The structure of deoxyribonucleic acid (DNA), the
picture shows the monomers being put togeth...
Biochemistry 9
occur, using a molecule of water to split up a disaccharide and break the glycosidic bond; this is termed h...
Biochemistry 10
Aerobic
In aerobic cells with sufficient oxygen, like most human cells, the pyruvate is further metabolize...
Biochemistry 11
In essence, proteins are chains of amino acids. An amino acid consists of a carbon atom bound to four grou...
Biochemistry 12
via the urea cycle.
Lipids
The term lipid comprises a diverse range of molecules and to some extent is a c...
Biochemistry 13
Relationship to other "molecular-scale" biological sciences
Schematic relationship between biochemistry, g...
Biochemistry 14
[5] Whiting, G.C. (1970), p.5
Further reading
• Hunter, Graeme K. (2000). Vital Forces: The Discovery of t...
Histology 15
Microscopic view of a histologic specimen of human lung tissue stained with
hematoxylin and eosin.
The traine...
Histology 16
the water. This is followed by a hydrophobic clearing agent (such as xylene) to remove the alcohol, and final...
Histology 17
Histology samples have often been examined by radioactive techniques. In historadiography, a slide (sometimes...
Histology 18
Table sourced from Michael H. Ross, Wojciech Pawlina, (2006). Histology: A Text and Atlas. Hagerstown, MD:
Li...
Histology 19
Related sciences
• Cell biology is the study of living cells, their DNA and RNA and the proteins they express...
Epidemiology 20
Epidemiology
Epidemiology is the study of health-event, health-characteristic, or health-determinant patte...
Epidemiology 21
Original map by John Snow showing the clusters of cholera cases in the London
epidemic of 1854
John Graunt...
Epidemiology 22
health/health protection service and are often at the forefront of investigating and combating disease out...
Epidemiology 23
4. Temporality: The effect has to occur after the cause (and if there is an expected delay between the cau...
Epidemiology 24
Population-based health management
Epidemiological practice and the results of epidemiological analysis ma...
Epidemiology 25
The latter type, more formally described as self-controlled case-series studies, divide individual patient...
Epidemiology 26
..... Case Non case Total
Exposed A B (A+B)
Unexposed C D (C+D)
As with the OR, a RR greater than 1 shows ...
Epidemiology 27
The validity of a study is dependent on the degree of systematic error. Validity is usually separated into...
Epidemiology 28
Journals
A list of journals:
[24]
General journals:
• American Journal of Epidemiology
• Canadian Journal ...
Epidemiology 29
References
Notes
[1] Nutter, Jr., F.W. (1999). "Understanding the interrelationships between botanical, hu...
Epidemiology 30
Bibliography
• Clayton, David and Michael Hills (1993) Statistical Models in Epidemiology Oxford Universit...
Subjects and Topics in Basic Medical Science-A Imhotep Virtual Medical School Primer
Subjects and Topics in Basic Medical Science-A Imhotep Virtual Medical School Primer
Subjects and Topics in Basic Medical Science-A Imhotep Virtual Medical School Primer
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Subjects and Topics in Basic Medical Science-A Imhotep Virtual Medical School Primer

  1. 1. Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer Compiled and Edited by Marc Imhotep Cray, M.D.
  2. 2. Contents Articles Anatomy 1 Embryology 3 Biochemistry 6 Histology 14 Epidemiology 20 Biostatistics 31 Molecular biology 34 Genetics 39 Cell biology 55 Endocrinology 60 General pathology 65 Immunology 67 Microbiology 71 Physiology 76 Pathophysiology 78 Pathology 80 Pathogenesis 85 Neuroscience 85 Pharmacology 93 Toxicology 98 Medicine 100 Medical history 114 Chief complaint 116 History of the present illness 117 Past medical history 119 Review of systems 121 Biological system 123 Family history (medicine) 124 List of childhood diseases and disorders 125 Social history (medicine) 127 Allergy 128 Doctor-patient relationship 142 Differential diagnosis 146 Symptom 148 Compiled and Edited by Marc Imhotep Cray , M.D.
  3. 3. Medical sign 149 Physical examination 154 References Article Sources and Contributors 157 Image Sources, Licenses and Contributors 163 Article Licenses License 165 Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  4. 4. Anatomy 1 Anatomy Anatomy lesson carried out in Java, Dutch East Indies, date unknown. Anatomy (from the Greek ἀνατομία anatomia, from ἀνατέμνειν ana: separate, apart from, and temnein, to cut up, cut open) is a branch of biology and medicine that is the consideration of the structure of living things. It is a general term that includes human anatomy, animal anatomy (zootomy) and plant anatomy (phytotomy). In some of its facets anatomy is closely related to embryology, comparative anatomy and comparative embryology, [1] through common roots in evolution. Anatomy is subdivided into gross anatomy (or macroscopic anatomy) and microscopic anatomy.[1] Gross anatomy (also called topographical anatomy, regional anatomy, or anthropotomy) is the study of anatomical structures that can be seen by unaided vision with the naked eye. [1] Microscopic anatomy is the study of minute anatomical structures assisted with microscopes, which includes histology (the study of the organization of tissues), [1] and cytology (the study of cells). The history of anatomy has been characterized, over time, by a continually developing understanding of the functions of organs and structures in the body. Methods have also improved dramatically, advancing from examination of animals through dissection of cadavers (dead human bodies) to technologically complex techniques developed in the 20th century including X-ray, ultrasound, and MRI imaging. Anatomy should not be confused with anatomical pathology (also called morbid anatomy or histopathology), which is the study of the gross and microscopic appearances of diseased organs. Superficial anatomy Superficial anatomy or surface anatomy is important in anatomy being the study of anatomical landmarks that can be readily seen from the contours or the surface of the body. [1] With knowledge of superficial anatomy, physicians or veterinary surgeons gauge the position and anatomy of the associated deeper structures. Superficial is a directional term that indicates one structure is located more externally than another, or closer to the surface of the body. Human anatomy Para-sagittal MRI scan of the head Human anatomy, including gross human anatomy and histology, is primarily the scientific study of the morphology of the adult human body. [1] Generally, students of certain biological sciences, paramedics, prosthetists and orthotists, physiotherapists, occupational therapy, nurses, and medical students learn gross anatomy and microscopic anatomy from anatomical models, skeletons, textbooks, diagrams, photographs, lectures and tutorials. The study of microscopic anatomy (or histology) can be aided by practical experience examining histological preparations (or slides) under a microscope; and in addition, medical students generally also learn gross anatomy with practical experience of dissection and inspection of cadavers (dead human bodies). Human anatomy, physiology and biochemistry are complementary basic medical sciences, which are generally taught to medical students in their first Compiled and Edited by Marc Imhotep Cray , M.D.
  5. 5. Anatomy 2 An X-ray of a human chest. Human heart and lungs, from an older edition of Gray's Anatomy. year at medical school. Human anatomy can be taught regionally or systemically; [1] that is, respectively, studying anatomy by bodily regions such as the head and chest, or studying by specific systems, such as the nervous or respiratory systems. The major anatomy textbook, Gray's Anatomy, has recently been reorganized from a systems format to a regional format,[2] [3] in line with modern teaching methods. A thorough working knowledge of anatomy is required by all medical doctors, especially surgeons, and doctors working in some diagnostic specialities, such as histopathology and radiology. Academic human anatomists are usually employed by universities, medical schools or teaching hospitals. They are often involved in teaching anatomy, and research into certain systems, organs, tissues or cells. Other branches • Comparative anatomy relates to the comparison of anatomical structures (both gross and microscopic) in different animals. [1] • Anthropological anatomy or physical anthropology relates to the comparison of the anatomy of different races of humans. • Artistic anatomy relates to anatomic studies for artistic reasons. Notes [1] "Introduction page, "Anatomy of the Human Body". Henry Gray. 20th edition. 1918" (http://www.bartleby.com/107/1.html). . Retrieved 19 March 2007. [2] "Publisher's page for Gray's Anatomy. 39th edition (UK). 2004. ISBN 0-443-07168-3" (http://web.archive.org/web/20071012104507/ http://intl.elsevierhealth.com/catalogue/title.cfm?ISBN=0443071683). Archived from the original (http://www.intl.elsevierhealth.com/ catalogue/title.cfm?ISBN=0443071683) on 2007-10-12. . Retrieved 19 March 2007. [3] "Publisher's page for Gray's Anatomy. 39th edition (US). 2004. ISBN 0-443-07168-3" (http://web.archive.org/web/20070209134753/ http://www.us.elsevierhealth.com/product.jsp?isbn=0443071683). Archived from the original (http://www.us.elsevierhealth.com/ product.jsp?isbn=0443071683) on 9 February 2007. . Retrieved 19 March 2007. References • "Anatomy of the Human Body". 20th edition. 1918. Henry Gray (http://www.bartleby.com/107/) External links • Anatomy Mnemonics (http://www.lifehugger.com/anatomy) Mnemonics in Anatomy. • Journal - Journal of Anatomy (http://onlinelibrary.wiley.com/journal/10.1111/(ISSN)1469-7580)* • Anatomy (http://www.bbc.co.uk/programmes/p005488j) on In Our Time at the BBC. ( listen now (http:// www.bbc.co.uk/iplayer/console/p005488j/In_Our_Time_Anatomy)) • Anatomia 1522–1867: Anatomical Plates from the Thomas Fisher Rare Book Library (http://link.library. utoronto.ca/anatomia/) • Anatomy of the Human Body (http://www.bartleby.com/107/) Gray, Henry. Philadelphia: Lea & Febiger, 1918 • High-Resolution Cytoarchitectural Primate Brain Atlases (http://brainmaps.org/) • Anatomy in the 16th century (http://www.bium.univ-paris5.fr/histmed/medica/anatomie.htm#vonseng) studies and digitized texts by the BIUM (Bibliothèque interuniversitaire de médecine et d'odontologie, Paris) Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  6. 6. Anatomy 3 (http://www.bium.parisdescartes.fr) see its digital library Medic@ (http://www.bium.univ-paris5.fr/ histmed/medica.htm). • 19th Century Anatomy Lesson (http://burkeandhare.com/bhlesson.htm) Animated dissection following Gray's Anatomy Embryology 1 - morula, 2 - blastula 1 - blastula, 2 - gastrula with blastopore; orange - ectoderm, red - endoderm. Embryology (from Greek ἔμβρυον, embryon, "unborn, embryo"; and -λογία, -logia) is a science which is about the development of an embryo from the fertilization of the ovum to the fetus stage. After cleavage, the dividing cells, or morula, becomes a hollow ball, or blastula, which develops a hole or pore at one end. In bilateral animals, the blastula develops in one of two ways that divides the whole animal kingdom into two halves (see: Embryological origins of the mouth and anus). If in the blastula the first pore (blastopore) becomes the mouth of the animal, it is a protostome; if the first pore becomes the anus then it is a deuterostome. The protostomes include most invertebrate animals, such as insects, worms and molluscs, while the deuterostomes include the vertebrates. In due course, the blastula changes into a more differentiated structure called the gastrula. The gastrula with its blastopore soon develops three distinct layers of cells (the germ layers) from which all the bodily organs and tissues then develop: • The innermost layer, or endoderm, gives rise to the digestive organs, lungs and bladder. • The middle layer, or mesoderm, gives rise to the muscles, skeleton and blood system. • The outer layer of cells, or ectoderm, gives rise to the nervous system and skin. In humans, the term embryo refers to the ball of dividing cells from the moment the zygote implants itself in the uterus wall until the end of the eighth week after conception. Beyond the eighth week, the developing human is then called a fetus. Embryos in many species often appear similar to one another in early developmental stages. The reason for this similarity is because species have a shared evolutionary history. These similarities among species are called homologous structures, which are structures that have the same or similar function and mechanism having evolved from a common ancestor. Compiled and Edited by Marc Imhotep Cray , M.D.
  7. 7. Embryology 4 History Human embryo at six weeks gestational age Histological film 10 day mouse embryo Beetle larvae As recently as the 18th century, the prevailing notion in human embryology was preformation: the idea that semen contains an embryo — a preformed, miniature infant, or "homunculus" — that simply becomes larger during development. The competing explanation of embryonic development was epigenesis, originally proposed 2,000 years earlier by Aristotle. According to epigenesis, the form of an animal emerges gradually from a relatively formless egg. As microscopy improved during the 19th century, biologists could see that embryos took shape in a series of progressive steps, and epigenesis displaced preformation as the favored explanation among embryologists. [1] Modern embryological pioneers include Karl Ernst von Baer, Charles Darwin, Ernst Haeckel, J.B.S. Haldane, and Joseph Needham, while much early embryology came from the work of Aristotle and the great Italian anatomists: Aldrovandi, Aranzio, Leonardo da Vinci, Marcello Malpighi, Gabriele Falloppio, Girolamo Cardano, Emilio Parisano, Fortunio Liceti, Stefano Lorenzini, Spallanzani, Enrico Sertoli, Mauro Rusconi, etc. [2] Other important contributors include William Harvey, Kaspar Friedrich Wolff, Heinz Christian Pander, August Weismann, Gavin de Beer, Ernest Everett Just, and Edward B. Lewis. After the 1950s, with the DNA helical structure being unravelled and the increasing knowledge in the field of molecular biology, developmental biology emerged as a field of study which attempts to correlate the genes with morphological change, and so tries to determine which genes are responsible for each morphological change that takes place in an embryo, and how these genes are regulated. Vertebrate and invertebrate embryology Many principles of embryology apply to both invertebrate animals as well as to vertebrates. [3] Therefore, the study of invertebrate embryology has advanced the study of vertebrate embryology. However, there are many differences as well. For example, numerous invertebrate species release a larva before development is complete; at the end of the larval period, an animal for the first time comes to resemble an adult similar to its parent or parents. Although invertebrate embryology is similar in some ways for different invertebrate animals, there are also countless variations. For instance, while spiders proceed directly from egg to adult form many insects develop through at least one larval stage Modern embryology research Currently, embryology has become an important research area for studying the genetic control of the development process (e.g. morphogens), its link to cell signalling, its importance for the study of certain diseases and mutations and in links to stem cell research. Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  8. 8. Embryology 5 References [1] Campbell et al. (p. 987) [2] Massimo De Felici, Gregorio Siracus, The rise of embryology in Italy: from the Renaissance to the early 20th Century, (http://www.ijdb. ehu.es/fullaccess/fulltext.0009/ft515.pdf) Int. J. Dev. Biol. 44: 515-521 (2000). [3] Parker, Sybil. "Invertebrate Embryology," McGraw-Hill Encyclopedia of Science & Technology (http://books.google.com/ books?vid=ISBN0079115047&id=CMC32Rmo9tYC&q="invertebrate+embryology"+and+"mcgraw-hill"&dq="invertebrate+ embryology"+and+"mcgraw-hill"&pgis=1) (McGraw-Hill 1997). Embryology - History of embryology as a science." Science Encyclopedia. Web. 06 Nov. 2009. <http://science.jrank.org/pages/2452/Embryology.html>. "Germ layer." Encyclopædia Britannica. 2009. Encyclopædia Britannica Online. 06 Nov. 2009 <http://www.britannica.com/EBchecked/topic/230597/germ-layer>. Further reading • Apostoli, Pietro; Catalani, Simona (2011). "Chapter 11. Metal Ions Affecting Reproduction and Development". In Astrid Sigel, Helmut Sigel and Roland K. O. Sigel. Metal Ions in Toxicology. Metal Ions in Life Sciences. 8. RSC Publishing. pp. 263-303. doi:10.1039/9781849732116-00263. • Scott F. Gilbert. Developmental Biology. Sinauer, 2003. ISBN 0-87893-258-5. • Lewis Wolpert. Principles of Development. Oxford University Press, 2006. ISBN 0-19-927536-X. External links • Indiana University's Human Embryology Animations (http://www.indiana.edu/~anat550/embryo_main/index. html) • What is a human admixed embryo? (http://www.cambridgenetwork.co.uk/views/biolines) • UNSW Embryology (http://embryology.med.unsw.edu.au/) | UNSW Embryology (http://php.med.unsw. edu.au/embryology/index.php?title=Main_Page) Large resource of information and media • Definition of embryo according to Webster (http://www2.merriam-webster.com/cgi-bin/ mwmednlm?book=Medical&va=embryo) Compiled and Edited by Marc Imhotep Cray , M.D.
  9. 9. Biochemistry 6 Biochemistry Biochemistry, sometimes called biological chemistry, is the study of chemical processes in living organisms, including, but not limited to, living matter. Biochemistry governs all living organisms and living processes. By controlling information flow through biochemical signalling and the flow of chemical energy through metabolism, biochemical processes give rise to the incredible complexity of life. Much of biochemistry deals with the structures and functions of cellular components such as proteins, carbohydrates, lipids, nucleic acids and other biomolecules although increasingly processes rather than individual molecules are the main focus. Over the last 40 years biochemistry has become so successful at explaining living processes that now almost all areas of the life sciences from botany to medicine are engaged in biochemical research. Today the main focus of pure biochemistry is in understanding how biological molecules give rise to the processes that occur within living cells which in turn relates greatly to the study and understanding of whole organisms. Among the vast number of different biomolecules, many are complex and large molecules (called biopolymers), which are composed of similar repeating subunits (called monomers). Each class of polymeric biomolecule has a different set of subunit types. [1] For example, a protein is a polymer whose subunits are selected from a set of 20 or more amino acids. Biochemistry studies the chemical properties of important biological molecules, like proteins, and in particular the chemistry of enzyme-catalyzed reactions. The biochemistry of cell metabolism and the endocrine system has been extensively described. Other areas of biochemistry include the genetic code (DNA, RNA), protein synthesis, cell membrane transport, and signal transduction. History It once was generally believed that life and its materials had some essential property or substance distinct from any found in non-living matter, and it was thought that only living beings could produce the molecules of life. Then, in 1828, Friedrich Wöhler published a paper on the synthesis of urea, proving that organic compounds can be created artificially. [2] [3] The dawn of biochemistry may have been the discovery of the first enzyme, diastase (today called amylase), in 1833 by Anselme Payen. Eduard Buchner contributed the first demonstration of a complex biochemical process outside of a cell in 1896: alcoholic fermentation in cell extracts of yeast. Although the term “biochemistry” seems to have been first used in 1882, it is generally accepted that the formal coinage of biochemistry occurred in 1903 by Carl Neuberg, a German chemist. Previously, this area would have been referred to as physiological chemistry. Since then, biochemistry has advanced, especially since the mid-20th century, with the development of new techniques such as chromatography, X-ray diffraction, dual polarisation interferometry, NMR spectroscopy, radioisotopic labeling, electron microscopy and molecular dynamics simulations. These techniques allowed for the discovery and detailed analysis of many molecules and metabolic pathways of the cell, such as glycolysis and the Krebs cycle (citric acid cycle). Another significant historic event in biochemistry is the discovery of the gene and its role in the transfer of information in the cell. This part of biochemistry is often called molecular biology. In the 1950s, James D. Watson, Francis Crick, Rosalind Franklin, and Maurice Wilkins were instrumental in solving DNA structure and suggesting its relationship with genetic transfer of information. In 1958, George Beadle and Edward Tatum received the Nobel Prize for work in fungi showing that one gene produces one enzyme. In 1988, Colin Pitchfork was the first person convicted of murder with DNA evidence, which led to growth of forensic science. More recently, Andrew Z. Fire and Craig C. Mello received the 2006 Nobel Prize for discovering the role of RNA interference (RNAi), in the silencing of gene expression. Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  10. 10. Biochemistry 7 Today, there are three main types of biochemistry. Plant biochemistry involves the study of the biochemistry of autotrophic organisms such as photosynthesis and other plant specific biochemical processes. General biochemistry encompasses both plant and animal biochemistry. Human/medical/medicinal biochemistry focuses on the biochemistry of humans and medical illnesses. Biomolecules The four main classes of molecules in biochemistry are carbohydrates, lipids, proteins, and nucleic acids. Many biological molecules are polymers: in this terminology, monomers are relatively small micromolecules that are linked together to create large macromolecules, which are known as polymers. When monomers are linked together to synthesize a biological polymer, they undergo a process called dehydration synthesis. Carbohydrates A molecule of sucrose (glucose + fructose), a disaccharide. Carbohydrates are made from monomers called monosaccharides. Some of these monosaccharides include glucose (C 6 H 12 O 6 ), fructose (C 6 H 12 O 6 ), and deoxyribose (C 5 H 10 O 4 ). When two monosaccharides undergo dehydration synthesis, water is produced, as two hydrogen atoms and one oxygen atom are lost from the two monosaccharides' hydroxyl group. Lipids A triglyceride with a glycerol molecule on the left and three fatty acids coming off it. Lipids are usually made from one molecule of glycerol combined with other molecules. In triglycerides, the main group of bulk lipids, there is one molecule of glycerol and three fatty acids. Fatty acids are considered the monomer in that case, and may be saturated (no double bonds in the carbon chain) or unsaturated (one or more double bonds in the carbon chain). Lipids, especially phospholipids, are also used in various pharmaceutical products, either as co-solubilisers (e.g. in parenteral infusions) or else as drug carrier components (e.g. in a liposome or transfersome). Proteins The general structure of an α-amino acid, with the amino group on the left and the carboxyl group on the right. Proteins are very large molecules – macro-biopolymers – made from monomers called amino acids. There are 20 standard amino acids, each containing a carboxyl group, an amino group, and a side chain (known as an "R" group). The "R" group is what makes each amino acid different, and the properties of the side chains greatly influence the overall three-dimensional conformation of a protein. When amino acids combine, they form a special bond called a peptide bond through dehydration synthesis, and become a polypeptide, or protein. To determine if two proteins are related or in other words to decide whether they are homologous or not, scientists use sequence-comparison methods. Methods like Sequence Alignments and Structural Alignments are powerful tools that help scientist identify homologies between related molecules. The relevance of finding homologies among proteins goes beyond forming an evolutionary pattern of protein families. By finding how similar two protein sequences are, we acquire knowledge about their structure and therefore their function. Compiled and Edited by Marc Imhotep Cray , M.D.
  11. 11. Biochemistry 8 Nucleic acids The structure of deoxyribonucleic acid (DNA), the picture shows the monomers being put together. Nucleic acids are the molecules that make up DNA, an extremely important substance which all cellular organisms use to store their genetic information. The most common nucleic acids are deoxyribonucleic acid and ribonucleic acid. Their monomers are called nucleotides. The most common nucleotides are Adenine, Cytosine, Guanine, Thymine, and Uracil. Adenine binds with thymine and uracil; Thymine only binds with Adenine; and Cytosine and Guanine can only bind with each other. Carbohydrates The function of carbohydrates includes energy storage and providing structure. Sugars are carbohydrates, but not all carbohydrates are sugars. There are more carbohydrates on Earth than any other known type of biomolecule; they are used to store energy and genetic information, as well as play important roles in cell to cell interactions and communications. Monosaccharides Glucose The simplest type of carbohydrate is a monosaccharide, which among other properties contains carbon, hydrogen, and oxygen, mostly in a ratio of 1:2:1 (generalized formula C n H 2n O n , where n is at least 3). Glucose, one of the most important carbohydrates, is an example of a monosaccharide. So is fructose, the sugar commonly associated with the sweet taste of fruits. [4] [a] Some carbohydrates (especially after condensation to oligo- and polysaccharides) contain less carbon relative to H and O, which still are present in 2:1 (H:O) ratio. Monosaccharides can be grouped into aldoses (having an aldehyde group at the end of the chain, e. g. glucose) and ketoses (having a keto group in their chain; e. g. fructose). Both aldoses and ketoses occur in an equilibrium (starting with chain lengths of C4) cyclic forms. These are generated by bond formation between one of the hydroxyl groups of the sugar chain with the carbon of the aldehyde or keto group to form a hemiacetal bond. This leads to saturated five-membered (in furanoses) or six-membered (in pyranoses) heterocyclic rings containing one O as heteroatom. Disaccharides Sucrose: ordinary table sugar and probably the most familiar carbohydrate. Two monosaccharides can be joined together using dehydration synthesis, in which a hydrogen atom is removed from the end of one molecule and a hydroxyl group (—OH) is removed from the other; the remaining residues are then attached at the sites from which the atoms were removed. The H—OH or H 2 O is then released as a molecule of water, hence the term dehydration. The new molecule, consisting of two monosaccharides, is called a disaccharide and is conjoined together by a glycosidic or ether bond. The reverse reaction can also Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  12. 12. Biochemistry 9 occur, using a molecule of water to split up a disaccharide and break the glycosidic bond; this is termed hydrolysis. The most well-known disaccharide is sucrose, ordinary sugar (in scientific contexts, called table sugar or cane sugar to differentiate it from other sugars). Sucrose consists of a glucose molecule and a fructose molecule joined together. Another important disaccharide is lactose, consisting of a glucose molecule and a galactose molecule. As most humans age, the production of lactase, the enzyme that hydrolyzes lactose back into glucose and galactose, typically decreases. This results in lactase deficiency, also called lactose intolerance. Sugar polymers are characterised by having reducing or non-reducing ends. A reducing end of a carbohydrate is a carbon atom which can be in equilibrium with the open-chain aldehyde or keto form. If the joining of monomers takes place at such a carbon atom, the free hydroxy group of the pyranose or furanose form is exchanged with an OH-side chain of another sugar, yielding a full acetal. This prevents opening of the chain to the aldehyde or keto form and renders the modified residue non-reducing. Lactose contains a reducing end at its glucose moiety, whereas the galactose moiety form a full acetal with the C4-OH group of glucose. Saccharose does not have a reducing end because of full acetal formation between the aldehyde carbon of glucose (C1) and the keto carbon of fructose (C2). Oligosaccharides and polysaccharides Cellulose as polymer of β-D-glucose When a few (around three to six) monosaccharides are joined together, it is called an oligosaccharide (oligo- meaning "few"). These molecules tend to be used as markers and signals, as well as having some other uses. Many monosaccharides joined together make a polysaccharide. They can be joined together in one long linear chain, or they may be branched. Two of the most common polysaccharides are cellulose and glycogen, both consisting of repeating glucose monomers. • Cellulose is made by plants and is an important structural component of their cell walls. Humans can neither manufacture nor digest it. • Glycogen, on the other hand, is an animal carbohydrate; humans and other animals use it as a form of energy storage. Use of carbohydrates as an energy source Glucose is the major energy source in most life forms. For instance, polysaccharides are broken down into their monomers (glycogen phosphorylase removes glucose residues from glycogen). Disaccharides like lactose or sucrose are cleaved into their two component monosaccharides. Glycolysis (anaerobic) Glucose is mainly metabolized by a very important ten-step pathway called glycolysis, the net result of which is to break down one molecule of glucose into two molecules of pyruvate; this also produces a net two molecules of ATP, the energy currency of cells, along with two reducing equivalents in the form of converting NAD + to NADH. This does not require oxygen; if no oxygen is available (or the cell cannot use oxygen), the NAD is restored by converting the pyruvate to lactate (lactic acid) (e. g. in humans) or to ethanol plus carbon dioxide (e. g. in yeast). Other monosaccharides like galactose and fructose can be converted into intermediates of the glycolytic pathway. Compiled and Edited by Marc Imhotep Cray , M.D.
  13. 13. Biochemistry 10 Aerobic In aerobic cells with sufficient oxygen, like most human cells, the pyruvate is further metabolized. It is irreversibly converted to acetyl-CoA, giving off one carbon atom as the waste product carbon dioxide, generating another reducing equivalent as NADH. The two molecules acetyl-CoA (from one molecule of glucose) then enter the citric acid cycle, producing two more molecules of ATP, six more NADH molecules and two reduced (ubi)quinones (via FADH 2 as enzyme-bound cofactor), and releasing the remaining carbon atoms as carbon dioxide. The produced NADH and quinol molecules then feed into the enzyme complexes of the respiratory chain, an electron transport system transferring the electrons ultimately to oxygen and conserving the released energy in the form of a proton gradient over a membrane (inner mitochondrial membrane in eukaryotes). Thereby, oxygen is reduced to water and the original electron acceptors NAD + and quinone are regenerated. This is why humans breathe in oxygen and breathe out carbon dioxide. The energy released from transferring the electrons from high-energy states in NADH and quinol is conserved first as proton gradient and converted to ATP via ATP synthase. This generates an additional 28 molecules of ATP (24 from the 8 NADH + 4 from the 2 quinols), totaling to 32 molecules of ATP conserved per degraded glucose (two from glycolysis + two from the citrate cycle). It is clear that using oxygen to completely oxidize glucose provides an organism with far more energy than any oxygen-independent metabolic feature, and this is thought to be the reason why complex life appeared only after Earth's atmosphere accumulated large amounts of oxygen. Gluconeogenesis In vertebrates, vigorously contracting skeletal muscles (during weightlifting or sprinting, for example) do not receive enough oxygen to meet the energy demand, and so they shift to anaerobic metabolism, converting glucose to lactate. The liver regenerates the glucose, using a process called gluconeogenesis. This process is not quite the opposite of glycolysis, and actually requires three times the amount of energy gained from glycolysis (six molecules of ATP are used, compared to the two gained in glycolysis). Analogous to the above reactions, the glucose produced can then undergo glycolysis in tissues that need energy, be stored as glycogen (or starch in plants), or be converted to other monosaccharides or joined into di- or oligosaccharides. The combined pathways of glycolysis during exercise, lactate's crossing via the bloodstream to the liver, subsequent gluconeogenesis and release of glucose into the bloodstream is called the Cori cycle. Proteins A schematic of hemoglobin. The red and blue ribbons represent the protein globin; the green structures are the heme groups. Like carbohydrates, some proteins perform largely structural roles. For instance, movements of the proteins actin and myosin ultimately are responsible for the contraction of skeletal muscle. One property many proteins have is that they specifically bind to a certain molecule or class of molecules—they may be extremely selective in what they bind. Antibodies are an example of proteins that attach to one specific type of molecule. In fact, the enzyme-linked immunosorbent assay (ELISA), which uses antibodies, is currently one of the most sensitive tests modern medicine uses to detect various biomolecules. Probably the most important proteins, however, are the enzymes. These molecules recognize specific reactant molecules called substrates; they then catalyze the reaction between them. By lowering the activation energy, the enzyme speeds up that reaction by a rate of 10 11 or more: a reaction that would normally take over 3,000 years to complete spontaneously might take less than a second with an enzyme. The enzyme itself is not used up in the process, and is free to catalyze the same reaction with a new set of substrates. Using various modifiers, the activity of the enzyme can be regulated, enabling control of the biochemistry of the cell as a whole. Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  14. 14. Biochemistry 11 In essence, proteins are chains of amino acids. An amino acid consists of a carbon atom bound to four groups. One is an amino group, —NH 2 , and one is a carboxylic acid group, —COOH (although these exist as —NH 3 + and —COO − under physiologic conditions). The third is a simple hydrogen atom. The fourth is commonly denoted "—R" and is different for each amino acid. There are twenty standard amino acids. Some of these have functions by themselves or in a modified form; for instance, glutamate functions as an important neurotransmitter. Generic amino acids (1) in neutral form, (2) as they exist physiologically, and (3) joined together as a dipeptide. Amino acids can be joined together via a peptide bond. In this dehydration synthesis, a water molecule is removed and the peptide bond connects the nitrogen of one amino acid's amino group to the carbon of the other's carboxylic acid group. The resulting molecule is called a dipeptide, and short stretches of amino acids (usually, fewer than thirty) are called peptides or polypeptides. Longer stretches merit the title proteins. As an example, the important blood serum protein albumin contains 585 amino acid residues. The structure of proteins is traditionally described in a hierarchy of four levels. The primary structure of a protein simply consists of its linear sequence of amino acids; for instance, "alanine-glycine-tryptophan-serine-glutamate-asparagine-glycine-lysine-…". Secondary structure is concerned with local morphology (morphology being the study of structure). Some combinations of amino acids will tend to curl up in a coil called an α-helix or into a sheet called a β-sheet; some α-helixes can be seen in the hemoglobin schematic above. Tertiary structure is the entire three-dimensional shape of the protein. This shape is determined by the sequence of amino acids. In fact, a single change can change the entire structure. The alpha chain of hemoglobin contains 146 amino acid residues; substitution of the glutamate residue at position 6 with a valine residue changes the behavior of hemoglobin so much that it results in sickle-cell disease. Finally quaternary structure is concerned with the structure of a protein with multiple peptide subunits, like hemoglobin with its four subunits. Not all proteins have more than one subunit. Ingested proteins are usually broken up into single amino acids or dipeptides in the small intestine, and then absorbed. They can then be joined together to make new proteins. Intermediate products of glycolysis, the citric acid cycle, and the pentose phosphate pathway can be used to make all twenty amino acids, and most bacteria and plants possess all the necessary enzymes to synthesize them. Humans and other mammals, however, can only synthesize half of them. They cannot synthesize isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. These are the essential amino acids, since it is essential to ingest them. Mammals do possess the enzymes to synthesize alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, and tyrosine, the nonessential amino acids. While they can synthesize arginine and histidine, they cannot produce it in sufficient amounts for young, growing animals, and so these are often considered essential amino acids. If the amino group is removed from an amino acid, it leaves behind a carbon skeleton called an α-keto acid. Enzymes called transaminases can easily transfer the amino group from one amino acid (making it an α-keto acid) to another α-keto acid (making it an amino acid). This is important in the biosynthesis of amino acids, as for many of the pathways, intermediates from other biochemical pathways are converted to the α-keto acid skeleton, and then an amino group is added, often via transamination. The amino acids may then be linked together to make a protein. A similar process is used to break down proteins. It is first hydrolyzed into its component amino acids. Free ammonia (NH 3 ), existing as the ammonium ion (NH 4 + ) in blood, is toxic to life forms. A suitable method for excreting it must therefore exist. Different strategies have evolved in different animals, depending on the animals' needs. Unicellular organisms, of course, simply release the ammonia into the environment. Similarly, bony fish can release the ammonia into the water where it is quickly diluted. In general, mammals convert the ammonia into urea, Compiled and Edited by Marc Imhotep Cray , M.D.
  15. 15. Biochemistry 12 via the urea cycle. Lipids The term lipid comprises a diverse range of molecules and to some extent is a catchall for relatively water-insoluble or nonpolar compounds of biological origin, including waxes, fatty acids, fatty-acid derived phospholipids, sphingolipids, glycolipids and terpenoids (e.g. retinoids and steroids). Some lipids are linear aliphatic molecules, while others have ring structures. Some are aromatic, while others are not. Some are flexible, while others are rigid. Most lipids have some polar character in addition to being largely nonpolar. Generally, the bulk of their structure is nonpolar or hydrophobic ("water-fearing"), meaning that it does not interact well with polar solvents like water. Another part of their structure is polar or hydrophilic ("water-loving") and will tend to associate with polar solvents like water. This makes them amphiphilic molecules (having both hydrophobic and hydrophilic portions). In the case of cholesterol, the polar group is a mere -OH (hydroxyl or alcohol). In the case of phospholipids, the polar groups are considerably larger and more polar, as described below. Lipids are an integral part of our daily diet. Most oils and milk products that we use for cooking and eating like butter, cheese, ghee etc., are composed of fats. Vegetable oils are rich in various polyunsaturated fatty acids (PUFA). Lipid-containing foods undergo digestion within the body and are broken into fatty acids and glycerol, which are the final degradation products of fats and lipids. Nucleic acids A nucleic acid is a complex, high-molecular-weight biochemical macromolecule composed of nucleotide chains that convey genetic information. The most common nucleic acids are deoxyribonucleic acid (DNA) and ribonucleic acid (RNA). Nucleic acids are found in all living cells and viruses. Aside from the genetic material of the cell, nucleic acids often play a role as second messengers, as well as forming the base molecule for adenosine triphosphate, the primary energy-carrier molecule found in all living organisms. Nucleic acid, so called because of its prevalence in cellular nuclei, is the generic name of the family of biopolymers. The monomers are called nucleotides, and each consists of three components: a nitrogenous heterocyclic base (either a purine or a pyrimidine), a pentose sugar, and a phosphate group. Different nucleic acid types differ in the specific sugar found in their chain (e.g. DNA or deoxyribonucleic acid contains 2-deoxyriboses). Also, the nitrogenous bases possible in the two nucleic acids are different: adenine, cytosine, and guanine occur in both RNA and DNA, while thymine occurs only in DNA and uracil occurs in RNA. Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  16. 16. Biochemistry 13 Relationship to other "molecular-scale" biological sciences Schematic relationship between biochemistry, genetics and molecular biology Researchers in biochemistry use specific techniques native to biochemistry, but increasingly combine these with techniques and ideas from genetics, molecular biology and biophysics. There has never been a hard-line between these disciplines in terms of content and technique. Today the terms molecular biology and biochemistry are nearly interchangeable. The following figure is a schematic that depicts one possible view of the relationship between the fields: • Biochemistry is the study of the chemical substances and vital processes occurring in living organisms. Biochemists focus heavily on the role, function, and structure of biomolecules. The study of the chemistry behind biological processes and the synthesis of biologically active molecules are examples of biochemistry. • Genetics is the study of the effect of genetic differences on organisms. Often this can be inferred by the absence of a normal component (e.g. one gene). The study of "mutants" – organisms with a changed gene that leads to the organism being different with respect to the so-called "wild type" or normal phenotype. Genetic interactions (epistasis) can often confound simple interpretations of such "knock-out" or "knock-in" studies. • Molecular biology is the study of molecular underpinnings of the process of replication, transcription and translation of the genetic material. The central dogma of molecular biology where genetic material is transcribed into RNA and then translated into protein, despite being an oversimplified picture of molecular biology, still provides a good starting point for understanding the field. This picture, however, is undergoing revision in light of emerging novel roles for RNA. • Chemical Biology seeks to develop new tools based on small molecules that allow minimal perturbation of biological systems while providing detailed information about their function. Further, chemical biology employs biological systems to create non-natural hybrids between biomolecules and synthetic devices (for example emptied viral capsids that can deliver gene therapy or drug molecules). Notes a.   It should be noted that fructose is not the only sugar found in fruits. Glucose and sucrose are also found in varying quantities in various fruits, and indeed sometimes exceed the fructose present. For example, 32 % of the edible portion of date is glucose, compared with 23.70 % fructose and 8.20 % sucrose. Conversely, peaches contain more sucrose (6.66 %) than they do fructose (0.93 %) or glucose (1.47 %). [5] References [1] Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life (http://www.phschool.com/el_marketing.html). Boston, Massachusetts: Pearson Prentice Hall. ISBN 0-13-250882-6. . [2] Wöhler, F. (1828). "Ueber künstliche Bildung des Harnstoffs". Ann. Phys. Chem. 12: 253–256. [3] Kauffman, G. B. and Chooljian, S.H. (2001). "Friedrich Wöhler (1800–1882), on the Bicentennial of His Birth". The Chemical Educator 6 (2): 121–133. doi:10.1007/s00897010444a. [4] Whiting, G.C (1970). "Sugars". In A.C. Hulme. The Biochemistry of Fruits and their Products. Volume 1. London & New York: Academic Press. pp. 1=31 Compiled and Edited by Marc Imhotep Cray , M.D.
  17. 17. Biochemistry 14 [5] Whiting, G.C. (1970), p.5 Further reading • Hunter, Graeme K. (2000). Vital Forces: The Discovery of the Molecular Basis of Life. San Diego: Academic Press. ISBN 0-12-361810-X. OCLC 162129355 191848148 44187710. External links • The Virtual Library of Biochemistry and Cell Biology (http://www.biochemweb.org/) • Biochemistry, 5th ed. (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=stryer. TOC&depth=2) Full text of Berg, Tymoczko, and Stryer, courtesy of NCBI. • Biochemistry, 2nd ed. (http://www.web.virginia.edu/Heidi/home.htm) Full text of Garrett and Grisham. • Biochemistry Animation (http://www.1lec.com/Biochemistry/) (Narrated Flash animations.) • SystemsX.ch - The Swiss Initiative in Systems Biology (http://www.systemsX.ch/) • Biochemistry Online Resources (http://www.icademic.org/97445/Biochemistry/) – Lists of Biochemistry departments, websites, journals, books and reviews, employment opportunities and events. biochemical families: prot · nucl · carb (glpr, alco, glys) · lipd (fata/i, phld, strd, gllp, eico) · amac/i · ncbs/i · ttpy/i Histology A stained histologic specimen, sandwiched between a glass microscope slide and coverslip, mounted on the stage of a light microscope. Histology (compound of the Greek words: ἱστός "tissue", and -λογία -logia) is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining a thin slice (section) of tissue under a light microscope or electron microscope. The ability to visualize or differentially identify microscopic structures is frequently enhanced through the use of histological stains. Histology is an essential tool of biology and medicine. Histopathology, the microscopic study of diseased tissue, is an important tool in anatomical pathology, since accurate diagnosis of cancer and other diseases usually requires histopathological examination of samples. Trained medical doctors, frequently board-certified as pathologists, are the personnel who perform histopathological examination and provide diagnostic information based on their observations. Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  18. 18. Histology 15 Microscopic view of a histologic specimen of human lung tissue stained with hematoxylin and eosin. The trained scientists who perform the preparation of histological sections are histotechnicians, histology technicians (HT), histology technologists (HTL), medical scientists, medical laboratory technicians, or biomedical scientists. Their field of study is called histotechnology. Histology Fixing Chemical fixation with formaldehyde or other chemicals Chemical fixatives are used to preserve tissue from degradation, and to maintain the structure of the cell and of sub-cellular components such as cell organelles (e.g., nucleus, endoplasmic reticulum, mitochondria). The most common fixative for light microscopy is 10% neutral buffered formalin (4% formaldehyde in phosphate buffered saline). For electron microscopy, the most commonly used fixative is glutaraldehyde, usually as a 2.5% solution in phosphate buffered saline. These fixatives preserve tissues or cells mainly by irreversibly cross-linking proteins. The main action of these aldehyde fixatives is to cross-link amino groups in proteins through the formation of CH 2 (methylene) linkage, in the case of formaldehyde, or by a C5H10 cross-links in the case of glutaraldehyde. This process, while preserving the structural integrity of the cells and tissue can damage the biological functionality of proteins, particularly enzymes, and can also denature them to a certain extent. This can be detrimental to certain histological techniques. Further fixatives are often used for electron microscopy such as osmium tetroxide or uranyl acetate Formalin fixation leads to degradation of mRNA, miRNA and DNA in tissues. However, extraction, amplification and analysis of these nucleic acids from formalin-fixed, paraffin-embedded tissues is possible using appropriate protocols.[1] Frozen section fixation Frozen section is a rapid way to fix and mount histology sections. It is used in surgical removal of tumors, and allow rapid determination of margin (that the tumor has been completely removed). It is done using a refrigeration device called a cryostat. The frozen tissue is sliced using a microtome, and the frozen slices are mounted on a glass slide and stained the same way as other methods. It is a necessary way to fix tissue for certain stain such as antibody linked immunofluorescence staining. It can also be used to determine if a tumour is malignant when it is found incidentally during surgery on a patient. Processing - dehydration, clearing, and infiltration The aim of Tissue Processing is to remove water from tissues and replace with a medium that solidifies to allow thin sections to be cut. Biological tissue must be supported in a hard matrix to allow sufficiently thin sections to be cut, typically 5 μm (micrometres; 1000 micrometres = 1 mm) thick for light microscopy and 80-100 nm (nanometre; 1,000,000 nanometres = 1 mm) thick for electron microscopy. For light microscopy, paraffin wax is most frequently used. Since it is immiscible with water, the main constituent of biological tissue, water must first be removed in the process of dehydration. Samples are transferred through baths of progressively more concentrated ethanol to remove Compiled and Edited by Marc Imhotep Cray , M.D.
  19. 19. Histology 16 the water. This is followed by a hydrophobic clearing agent (such as xylene) to remove the alcohol, and finally molten paraffin wax, the infiltration agent, which replaces the xylene. Paraffin wax does not provide a sufficiently hard matrix for cutting very thin sections for electron microscopy. Instead, resins are used. Epoxy resins are the most commonly employed embedding media, but acrylic resins are also used, particularly where immunohistochemistry is required. Thicker sections (0.35μm to 5μm) of resin-embedded tissue can also be cut for light microscopy. Again, the immiscibility of most epoxy and acrylic resins with water necessitates the use of dehydration, usually with ethanol. Embedding After the tissues have been dehydrated, cleared, and infiltrated with the embedding material, they are ready for external embedding. During this process the tissue samples are placed into molds along with liquid embedding material (such as agar, gelatine, or wax) which is then hardened. This is achieved by cooling in the case of paraffin wax and heating (curing) in the case of the epoxy resins. The acrylic resins are polymerised by heat, ultraviolet light, or chemical catalysts. The hardened blocks containing the tissue samples are then ready to be sectioned. Because Formalin-fixed, paraffin-embedded (FFPE) tissues may be stored indefinitely at room temperature, and nucleic acids (both DNA and RNA) may be recovered from them decades after fixation, FFPE tissues are an important resource for historical studies in medicine. Embedding can also be accomplished using frozen, non-fixed tissue in a water-based medium. Pre-frozen tissues are placed into molds with the liquid embedding material, usually a water-based glycol, OCT, TBS, Cryogel, or resin, which is then frozen to form hardened blocks. Sectioning Sectioning can be done in limited ways. Vertical sectioning perpendicular to the surface of the tissue is the usual method. Horizontal sectioning is often done in the evaluation of the hair follicles and pilosebaceous units. Tangential to horizontal sectioning is done in Mohs surgery and in methods of CCPDMA. For light microscopy, a steel knife mounted in a microtome is used to cut 10-micrometer-thick tissue sections which are mounted on a glass microscope slide. For transmission electron microscopy, a diamond knife mounted in an ultramicrotome is used to cut 50-nanometer-thick tissue sections which are mounted on a 3-millimeter-diameter copper grid. Then the mounted sections are treated with the appropriate stain. Frozen tissue embedded in a freezing medium is cut on a microtome in a cooled machine called a cryostat. Staining Biological tissue has little inherent contrast in either the light or electron microscope. Staining is employed to give both contrast to the tissue as well as highlighting particular features of interest. Where the underlying mechanistic chemistry of staining is understood, the term histochemistry is used. Hematoxylin and eosin (H&E stain) is the most commonly used light microscopical stain in histology and histopathology. Hematoxylin, a basic dye, stains nuclei blue due to an affinity to nucleic acids in the cell nucleus; eosin, an acidic dye, stains the cytoplasm pink. Uranyl acetate and lead citrate are commonly used to impart contrast to tissue in the electron microscope. Special staining: There are hundreds of various other techniques that have been used to selectively stain cells and cellular components. Other compounds used to color tissue sections include safranin, oil red o, Congo red, fast green FCF, silver salts, and numerous natural and artificial dyes that were usually originated from the development dyes for the textile industry. Histochemistry refers to the science of using chemical reactions between laboratory chemicals and components within tissue. A commonly performed histochemical technique is the Perls Prussian blue reaction, used to demonstrate iron deposits in diseases like hemochromatosis. Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  20. 20. Histology 17 Histology samples have often been examined by radioactive techniques. In historadiography, a slide (sometimes stained histochemically) is X-rayed. More commonly, autoradiography is used to visualize the locations to which a radioactive substance has been transported within the body, such as cells in S phase (undergoing DNA replication) which incorporate tritiated thymidine, or sites to which radiolabeled nucleic acid probes bind in in situ hybridization. For autoradiography on a microscopic level, the slide is typically dipped into liquid nuclear tract emulsion, which dries to form the exposure film. Individual silver grains in the film are visualized with dark field microscopy. Recently, antibodies have been used to specifically visualize proteins, carbohydrates, and lipids. This process is called immunohistochemistry, or when the stain is a fluorescent molecule, immunofluorescence. This technique has greatly increased the ability to identify categories of cells under a microscope. Other advanced techniques, such as nonradioactive in situ hybridization, can be combined with immunochemistry to identify specific DNA or RNA molecules with fluorescent probes or tags that can be used for immunofluorescence and enzyme-linked fluorescence amplification (especially alkaline phosphatase and tyramide signal amplification). Fluorescence microscopy and confocal microscopy are used to detect fluorescent signals with good intracellular detail. Digital cameras are increasingly used to capture histological and histopathological image Common laboratory stains Stain Common use Nucleus Cytoplasm Red blood cell (RBC) Collagen fibers Specifically stains Haematoxylin General staining when paired with eosin (i.e. H&E) Blue N/A N/A N/A Nucleic acids—blue ER (endoplasmic reticulum)—blue Eosin General staining when paired with haematoxylin (i.e. H&E) N/A Pink Orange/red Pink Elastic fibers—pink Collagen fibers—pink Reticular fibers—pink Toluidine blue General staining Blue Blue Blue Blue Mast cells granules—purple Masson's trichrome stain Connective tissue Black Red/pink Red Blue/green Cartilage—blue/green Muscle fibers—red Mallory's trichrome stain Connective tissue Red Pale red Orange Deep blue Keratin—orange Cartilage—blue Bone matrix—deep blue Muscle fibers—red Weigert's elastic stain Elastic fibers Blue/black N/A N/A N/A Elastic fibers—blue/black Heidenhain's AZAN trichrome stain Distinguishing cells from extracellular components Red/purple Pink Red Blue Muscle fibers—red Cartilage—blue Bone matrix—blue Silver stain Reticular fibers, nerve fibers, fungi N/A N/A N/A N/A Reticular fibers—brown/black Nerve fibers—brown/black Wright's stain Blood cells Bluish/purple Bluish/gray Red/pink N/A Neutrophil granules—purple/pink Eosinophil granules—bright red/orange Basophil granules—deep purple/violet Platelet granules—red/purple Orcein stain Elastic fibres Deep blue [or crazy red] N/A Bright red Pink Elastic fibres—dark brown Mast cells granules—purple Smooth muscle—light blue Periodic acid-Schiff stain (PAS) Basement membrane, localizing carbohydrates Blue N/A N/A Pink Glycogen and other carbohydrates—magenta Compiled and Edited by Marc Imhotep Cray , M.D.
  21. 21. Histology 18 Table sourced from Michael H. Ross, Wojciech Pawlina, (2006). Histology: A Text and Atlas. Hagerstown, MD: Lippincott Williams & Wilkins. ISBN 0-7817-5056-3. The Nissl method and Golgi's method are useful in identifying neurons. Alternative techniques Alternative techniques include cryosection. The tissue is frozen using a cryostat, and cut. Tissue staining methods are similar to those of wax sections. Plastic embedding is commonly used in the preparation of material for electron microscopy. Tissues are embedded in epoxy resin. Very thin sections (less than 0.1 micrometer) are cut using diamond or glass knives. The sections are stained with electron dense stains (uranium and lead) so that they can possibly be seen with the electron microscope. History In the 19th century, histology was an academic discipline in its own right. The 1906 Nobel Prize in Physiology or Medicine was awarded to histologists Camillo Golgi and Santiago Ramon y Cajal. They had dueling interpretations of the neural structure of the brain based in differing interpretations of the same images. Cajal won the prize for his correct theory and Golgi for the staining technique he invented to make it possible. Histological classification of animal tissues There are four basic types of tissues: muscle tissue, nervous tissue, connective tissue, and epithelial tissue. All tissue types are subtypes of these four basic tissue types (for example, blood cells are classified as connective tissue, since they generally originate inside bone marrow). • Epithelium: the lining of glands, bowel, skin, and some organs like the liver, lung, and kidney • Endothelium: the lining of blood and lymphatic vessels • Mesothelium: the lining of pleural and pericardial spaces • Mesenchyme: the cells filling the spaces between the organs, including fat, muscle, bone, cartilage, and tendon cells • Blood cells: the red and white blood cells, including those found in lymph nodes and spleen • Neurons: any of the conducting cells of the nervous system • Germ cells: reproductive cells (spermatozoa in men, oocytes in women) • Placenta: an organ characteristic of true mammals during pregnancy, joining mother and offspring, providing endocrine secretion and selective exchange of soluble, but not particulate, blood-borne substances through an apposition of uterine and trophoblastic vascularised parts • Stem cells: cells with the ability to develop into different cell types Note that tissues from plants, fungi, and microorganisms can also be examined histologically. Their structure is very different from animal tissues. Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  22. 22. Histology 19 Related sciences • Cell biology is the study of living cells, their DNA and RNA and the proteins they express. • Anatomy is the study of organs visible by the naked eye. • Morphology studies entire organisms. Artifacts Artifacts are structures or features in tissue that interfere with normal histological examination. These are not always present in normal tissue and can come from outside sources. Artifacts interfere with histology by changing the tissues appearance and hiding structures. These can be divided into two categories: Pre-histology These are features and structures that have being introduced prior to the collection of the tissues. A common example of these include: ink from tattoos and freckles (melanin) in skin samples. Post-histology Artifacts can result from tissue processing. Processing commonly leads to changes like shrinkage, washing out of particular cellular components, color changes in different tissues types and alterations of the structures in the tissue. Because these are caused in a laboratory the majority of post histology artifacts can be avoided or removed after being discovered. A common example is mercury pigment left behind after using Zenker's fixative to fix a section. Notes [1] Weiss AT, Delcour NM, Meyer A, Klopfleisch R. (2010). "Efficient and Cost-Effective Extraction of Genomic DNA From Formalin-Fixed and Paraffin-Embedded Tissues.". Veterinary Pathology 227. PMID 20817894. References 1. Merck Source (2002). Dorland's Medical Dictionary. Retrieved 2005-01-26. 2. Stedman's Medical Dictionaries (2005). Stedman's Online Medical Dictionary (http://stedmans.com/). Retrieved 2005-01-26. 3. 4,000‫ﻱ‬online histology images (2007). (http://histology-online.com) External links • Histology Protocols (http://www.ihcworld.com/protocol_database.htm) • Histoweb (http://www.kumc.edu/instruction/medicine/anatomy/histoweb) • SIU SOM Histology (http://www.siumed.edu/~dking2/index.htm) • Visual Histology Atlas (http://www.visualhistology.com/Visual_Histology_Atlas/) • Histology Glossary (http://www.histology-world.com/glossary/glossary1.htm) • Histology Group of Victoria Incorporated (http://www.hgv.org.au) • Histology Photomicrographs (http://www.histology-world.com/photoalbum/) • Virtual Slidebox (http://www.path.uiowa.edu/virtualslidebox) • Blue Histology (http://www.lab.anhb.uwa.edu.au/mb140/) Compiled and Edited by Marc Imhotep Cray , M.D.
  23. 23. Epidemiology 20 Epidemiology Epidemiology is the study of health-event, health-characteristic, or health-determinant patterns in a society. It is the cornerstone method of public health research, and helps inform policy decisions and evidence-based medicine by identifying risk factors for disease and targets for preventive medicine. Epidemiologists are involved in the design of studies, collection and statistical analysis of data, and interpretation and dissemination of results (including peer review and occasional systematic review). Major areas of epidemiologic work include outbreak investigation, disease surveillance and screening (medicine), biomonitoring, and comparisons of treatment effects such as in clinical trials. Epidemiologists rely on a number of other scientific disciplines such as biology (to better understand disease processes), biostatistics (to make efficient use of the data and draw appropriate conclusions), and exposure assessment and social science disciplines (to better understand proximate and distal risk factors, and their measurement). Etymology Epidemiology, literally meaning "the study of what is upon the people", is derived from Greek epi, meaning "upon, among", demos, meaning "people, district", and logos, meaning "study, word, discourse", suggesting that it applies only to human populations. However, the term is widely used in studies of zoological populations (veterinary epidemiology), although the term 'epizoology' is available, and it has also been applied to studies of plant populations (botanical epidemiology). [1] The distinction between 'epidemic' and 'endemic' was first drawn by Hippocrates, [2] to distinguish between diseases that are 'visited upon' a population (epidemic) from those that 'reside within' a population (endemic). [3] The term 'epidemiology' appears to have first been used to describe the study of epidemics in 1802 by the Spanish physician Villalba in Epidemiología Española. [3] Epidemiologists also study the interaction of diseases in a population, a condition known as a syndemic. The term epidemiology is now widely applied to cover the description and causation of not only epidemic disease, but of disease in general, and even many non-disease health-related conditions, such as high blood pressure and obesity. History The Greek physician Hippocrates has been called the father of epidemiology. [4] He is the first person known to have examined the relationships between the occurrence of disease and environmental influences. [5] He coined the terms endemic (for diseases usually found in some places but not in others) and epidemic (for disease that are seen at some times but not others). [6] Epidemiology is defined as the study of distribution and determinants of health related states in populations and use of this study to address health related problems. One of the earliest theories on the origin of disease was that it was primarily the fault of human luxury. This was expressed by philosophers such as Plato [7] and Rousseau, [8] and social critics like Jonathan Swift. [9] In the middle of the 16th century, a doctor from Verona named Girolamo Fracastoro was the first to propose a theory that these very small, unseeable, particles that cause disease were alive. They were considered to be able to spread by air, multiply by themselves and to be destroyable by fire. In this way he refuted Galen's miasma theory (poison gas in sick people). In 1543 he wrote a book De contagione et contagiosis morbis, in which he was the first to promote personal and environmental hygiene to prevent disease. The development of a sufficiently powerful microscope by Anton van Leeuwenhoek in 1675 provided visual evidence of living particles consistent with a germ theory of disease. Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  24. 24. Epidemiology 21 Original map by John Snow showing the clusters of cholera cases in the London epidemic of 1854 John Graunt, a professional haberdasher and serious amateur scientist, published Natural and Political Observations ... upon the Bills of Mortality in 1662. In it, he used analysis of the mortality rolls in London before the Great Plague to present one of the first life tables and report time trends for many diseases, new and old. He provided statistical evidence for many theories on disease, and also refuted many widespread ideas on them. Dr. John Snow is famous for his investigations into the causes of the 19th century cholera epidemics. He began with noticing the significantly higher death rates in two areas supplied by Southwark Company. His identification of the Broad Street pump as the cause of the Soho epidemic is considered the classic example of epidemiology. He used chlorine in an attempt to clean the water and had the handle removed, thus ending the outbreak. This has been perceived as a major event in the history of public health and can be regarded as the founding event of the science of epidemiology. Other pioneers include Danish physician Peter Anton Schleisner, who in 1849 related his work on the prevention of the epidemic of neonatal tetanus on the Vestmanna Islands in Iceland. [10] [11] Another important pioneer was Hungarian physician Ignaz Semmelweis, who in 1847 brought down infant mortality at a Vienna hospital by instituting a disinfection procedure. His findings were published in 1850, but his work was ill received by his colleagues, who discontinued the procedure. Disinfection did not become widely practiced until British surgeon Joseph Lister 'discovered' antiseptics in 1865 in light of the work of Louis Pasteur. In the early 20th century, mathematical methods were introduced into epidemiology by Ronald Ross, Anderson Gray McKendrick and others. Another breakthrough was the 1954 publication of the results of a British Doctors Study, led by Richard Doll and Austin Bradford Hill, which lent very strong statistical support to the suspicion that tobacco smoking was linked to lung cancer. • History of emerging infectious diseases The profession To date, few universities offer epidemiology as a course of study at the undergraduate level. Many epidemiologists are physicians, or hold graduate degrees such as a Master of Public Health (MPH), Master of Science or Epidemiology (MSc.). Doctorates include the Doctor of Public Health (DrPH), Doctor of Pharmacy (PharmD), Doctor of Philosophy (PhD), Doctor of Science (ScD), or for clinically trained physicians, Doctor of Medicine (MD) and Doctor of Veterinary Medicine (DVM) . In the United Kingdom, the title of 'doctor' is by long custom used to refer to general medical practitioners, whose professional degrees are usually those of Bachelor of Medicine and Surgery (MBBS or MBChB). As public health/health protection practitioners, epidemiologists work in a number of different settings. Some epidemiologists work 'in the field'; i.e., in the community, commonly in a public Compiled and Edited by Marc Imhotep Cray , M.D.
  25. 25. Epidemiology 22 health/health protection service and are often at the forefront of investigating and combating disease outbreaks. Others work for non-profit organizations, universities, hospitals and larger government entities such as the Centers for Disease Control and Prevention (CDC), the Health Protection Agency, The World Health Organization (WHO), or the Public Health Agency of Canada. Epidemiologists can also work in for-profit organizations such as pharmaceutical and medical device companies in groups such as market research or clinical development. The practice Epidemiologists employ a range of study designs from the observational to experimental and generally categorized as descriptive, analytic (aiming to further examine known associations or hypothesized relationships), and experimental (a term often equated with clinical or community trials of treatments and other interventions). Epidemiological studies are aimed, where possible, at revealing unbiased relationships between exposures such as alcohol or smoking, biological agents, stress, or chemicals to mortality or morbidity. The identification of causal relationships between these exposures and outcomes is an important aspect of epidemiology. Modern epidemiologists use informatics as a tool. The term 'epidemiologic triad' is used to describe the intersection of Host, Agent, and Environment in analyzing an outbreak. As causal inference Although epidemiology is sometimes viewed as a collection of statistical tools used to elucidate the associations of exposures to health outcomes, a deeper understanding of this science is that of discovering causal relationships. It is nearly impossible to say with perfect accuracy how even the most simple physical systems behave beyond the immediate future, much less the complex field of epidemiology, which draws on biology, sociology, mathematics, statistics, anthropology, psychology, and policy; "Correlation does not imply causation" is a common theme for much of the epidemiological literature. For epidemiologists, the key is in the term inference. Epidemiologists use gathered data and a broad range of biomedical and psychosocial theories in an iterative way to generate or expand theory, to test hypotheses, and to make educated, informed assertions about which relationships are causal, and about exactly how they are causal. Epidemiologists Rothman and Greenland emphasize that the "one cause - one effect" understanding is a simplistic mis-belief. Most outcomes, whether disease or death, are caused by a chain or web consisting of many component causes. Causes can be distinguished as necessary, sufficient or probabilistic conditions. If a necessary condition can be identified and controlled (e.g., antibodies to a disease agent), the harmful outcome can be avoided. Bradford-Hill criteria In 1965 Austin Bradford Hill detailed criteria for assessing evidence of causation. [12] These guidelines are sometimes referred to as the Bradford-Hill criteria, but this makes it seem like it is some sort of checklist. For example, Phillips and Goodman (2004) note that they are often taught or referenced as a checklist for assessing causality, despite this not being Hill's intention. [13] Hill himself said "None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required sine qua non". [12] 1. Strength: A small association does not mean that there is not a causal effect, though the larger the association, the more likely that it is causal. [12] 2. Consistency: Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect. [12] 3. Specificity: Causation is likely if a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship. [12] Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  26. 26. Epidemiology 23 4. Temporality: The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay). [12] 5. Biological gradient: Greater exposure should generally lead to greater incidence of the effect. However, in some cases, the mere presence of the factor can trigger the effect. In other cases, an inverse proportion is observed: greater exposure leads to lower incidence.[12] 6. Plausibility: A plausible mechanism between cause and effect is helpful (but Hill noted that knowledge of the mechanism is limited by current knowledge). [12] 7. Coherence: Coherence between epidemiological and laboratory findings increases the likelihood of an effect. However, Hill noted that "... lack of such [laboratory] evidence cannot nullify the epidemiological effect on associations". [12] 8. Experiment: "Occasionally it is possible to appeal to experimental evidence". [12] 9. Analogy: The effect of similar factors may be considered. [12] Legal interpretation Epidemiological studies can only go to prove that an agent could have caused, but not that it did cause, an effect in any particular case: "Epidemiology is concerned with the incidence of disease in populations and does not address the question of the cause of an individual's disease. This question, sometimes referred to as specific causation, is beyond the domain of the science of epidemiology. Epidemiology has its limits at the point where an inference is made that the relationship between an agent and a disease is causal (general causation) and where the magnitude of excess risk attributed to the agent has been determined; that is, epidemiology addresses whether an agent can cause a disease, not whether an agent did cause a specific plaintiff's disease." [14] In United States law, epidemiology alone cannot prove that a causal association does not exist in general. Conversely, it can be (and is in some circumstances) taken by US courts, in an individual case, to justify an inference that a causal association does exist, based upon a balance of probability. The subdiscipline of forensic epidemiology is directed at the investigation of specific causation of disease or injury in individuals or groups of individuals in instances in which causation is disputed or is unclear, for presentation in legal settings. Advocacy As a public health discipline, epidemiologic evidence is often used to advocate both personal measures like diet change and corporate measures like removal of junk food advertising, with study findings disseminated to the general public to help people to make informed decisions about their health. Often the uncertainties about these findings are not communicated well; news articles often prominently report the latest result of one study with little mention of its limitations, caveats, or context. Epidemiological tools have proved effective in establishing major causes of diseases like cholera and lung cancer, [12] but experience difficulty in regards to more subtle health issues where causation is not as clear. Notably, conclusions drawn from observational studies may be reconsidered as later data from randomized controlled trials becomes available, as was the case with the association between the use of hormone replacement therapy and cardiac risk. [15] Compiled and Edited by Marc Imhotep Cray , M.D.
  27. 27. Epidemiology 24 Population-based health management Epidemiological practice and the results of epidemiological analysis make a significant contribution to emerging population-based health management frameworks. Population-based health management encompasses the ability to: • Assess the health states and health needs of a target population; • Implement and evaluate interventions that are designed to improve the health of that population; and • Efficiently and effectively provide care for members of that population in a way that is consistent with the community's cultural, policy and health resource values. Modern population-based health management is complex, requiring a multiple set of skills (medical, political, technological, mathematical etc.) of which epidemiological practice and analysis is a core component, that is unified with management science to provide efficient and effective health care and health guidance to a population. This task requires the forward looking ability of modern risk management approaches that transform health risk factors, incidence, prevalence and mortality statistics (derived from epidemiological analysis) into management metrics that not only guide how a health system responds to current population health issues, but also how a health system can be managed to better respond to future potential population health issues. Examples of organizations that use population-based health management that leverage the work and results of epidemiological practice include Canadian Strategy for Cancer Control, Health Canada Tobacco Control Programs, Rick Hansen Foundation, Canadian Tobacco Control Research Initiative. [16] [17] [18] Each of these organizations use a population-based health management framework called Life at Risk that combines epidemiological quantitative analysis with demographics, health agency operational research and economics to perform: • Population Life Impacts Simulations: Measurement of the future potential impact of disease upon the population with respect to new disease cases, prevalence, premature death as well as potential years of life lost from disability and death; • Labour Force Life Impacts Simulations: Measurement of the future potential impact of disease upon the labour force with respect to new disease cases, prevalence, premature death and potential years of life lost from disability and death; • Economic Impacts of Disease Simulations: Measurement of the future potential impact of disease upon private sector disposable income impacts (wages, corporate profits, private health care costs) and public sector disposable income impacts (personal income tax, corporate income tax, consumption taxes, publicly funded health care costs). Types of studies Case series Case-series may refer to the qualititative study of the experience of a single patient, or small group of patients with a similar diagnosis, or to a statistical technique comparing periods during which patients are exposed to some factor with the potential to produce illness with periods when they are unexposed. The former type of study is purely descriptive and cannot be used to make inferences about the general population of patients with that disease. These types of studies, in which an astute clinician identifies an unusual feature of a disease or a patient's history, may lead to formulation of a new hypothesis. Using the data from the series, analytic studies could be done to investigate possible causal factors. These can include case control studies or prospective studies. A case control study would involve matching comparable controls without the disease to the cases in the series. A prospective study would involve following the case series over time to evaluate the disease's natural history. [19] Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  28. 28. Epidemiology 25 The latter type, more formally described as self-controlled case-series studies, divide individual patient follow-up time into exposed and unexposed periods and use fixed-effects Poisson regression processes to compare the incidence rate of a given outcome between exposed and unexposed periods. This technique has been extensively used in the study of adverse reactions to vaccination, and has been shown in some circumstances to provide statistical power comparable to that available in cohort studies. Case control studies Case control studies select subjects based on their disease status. A group of individuals that are disease positive (the "case" group) is compared with a group of disease negative individuals (the "control" group). The control group should ideally come from the same population that gave rise to the cases. The case control study looks back through time at potential exposures that both groups (cases and controls) may have encountered. A 2x2 table is constructed, displaying exposed cases (A), exposed controls (B), unexposed cases (C) and unexposed controls (D). The statistic generated to measure association is the odds ratio (OR), which is the ratio of the odds of exposure in the cases (A/C) to the odds of exposure in the controls (B/D), i.e. OR = (A/C) / (B/D) . ..... Cases Controls Exposed A B Unexposed C D If the OR is clearly greater than 1, then the conclusion is "those with the disease are more likely to have been exposed," whereas if it is close to 1 then the exposure and disease are not likely associated. If the OR is far less than one, then this suggests that the exposure is a protective factor in the causation of the disease. Case control studies are usually faster and more cost effective than cohort studies, but are sensitive to bias (such as recall bias and selection bias). The main challenge is to identify the appropriate control group; the distribution of exposure among the control group should be representative of the distribution in the population that gave rise to the cases. This can be achieved by drawing a random sample from the original population at risk. This has as a consequence that the control group can contain people with the disease under study when the disease has a high attack rate in a population. Cohort studies Cohort studies select subjects based on their exposure status. The study subjects should be at risk of the outcome under investigation at the beginning of the cohort study; this usually means that they should be disease free when the cohort study starts. The cohort is followed through time to assess their later outcome status. An example of a cohort study would be the investigation of a cohort of smokers and non-smokers over time to estimate the incidence of lung cancer. The same 2x2 table is constructed as with the case control study. However, the point estimate generated is the Relative Risk (RR), which is the probability of disease for a person in the exposed group, P e  = A / (A+B) over the probability of disease for a person in the unexposed group, P u  = C / (C+D), i.e. RR = P e  / P u . Compiled and Edited by Marc Imhotep Cray , M.D.
  29. 29. Epidemiology 26 ..... Case Non case Total Exposed A B (A+B) Unexposed C D (C+D) As with the OR, a RR greater than 1 shows association, where the conclusion can be read "those with the exposure were more likely to develop disease." Prospective studies have many benefits over case control studies. The RR is a more powerful effect measure than the OR, as the OR is just an estimation of the RR, since true incidence cannot be calculated in a case control study where subjects are selected based on disease status. Temporality can be established in a prospective study, and confounders are more easily controlled for. However, they are more costly, and there is a greater chance of losing subjects to follow-up based on the long time period over which the cohort is followed. Outbreak investigation For information on investigation of infectious disease outbreaks, please see outbreak investigation. Validity: precision and bias Random error Random error is the result of fluctuations around a true value because of sampling variability. Random error is just that: random. It can occur during data collection, coding, transfer, or analysis. Examples of random error include: poorly worded questions, a misunderstanding in interpreting an individual answer from a particular respondent, or a typographical error during coding. Random error affects measurement in a transient, inconsistent manner and it is impossible to correct for random error. There is random error in all sampling procedures. This is called sampling error. Precision in epidemiological variables is a measure of random error. Precision is also inversely related to random error, so that to reduce random error is to increase precision. Confidence intervals are computed to demonstrate the precision of relative risk estimates. The narrower the confidence interval, the more precise the relative risk estimate. There are two basic ways to reduce random error in an epidemiological study. The first is to increase the sample size of the study. In other words, add more subjects to your study. The second is to reduce the variability in measurement in the study. This might be accomplished by using a more precise measuring device or by increasing the number of measurements. Note, that if sample size or number of measurements are increased, or a more precise measuring tool is purchased, the costs of the study are usually increased. There is usually an uneasy balance between the need for adequate precision and the practical issue of study cost. Systematic error A systematic error or bias occurs when there is a difference between the true value (in the population) and the observed value (in the study) from any cause other than sampling variability. An example of systematic error is if, unbeknown to you, the pulse oximeter you are using is set incorrectly and adds two points to the true value each time a measurement is taken. The measuring device could be precise but not accurate. Because the error happens in every instance, it is systematic. Conclusions you draw based on that data will still be incorrect. But the error can be reproduced in the future (e.g., by using the same mis-set instrument). A mistake in coding that affects all responses for that particular question is another example of a systematic error. Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  30. 30. Epidemiology 27 The validity of a study is dependent on the degree of systematic error. Validity is usually separated into two components: • Internal validity is dependent on the amount of error in measurements, including exposure, disease, and the associations between these variables. Good internal validity implies a lack of error in measurement and suggests that inferences may be drawn at least as they pertain to the subjects under study. • External validity pertains to the process of generalizing the findings of the study to the population from which the sample was drawn (or even beyond that population to a more universal statement). This requires an understanding of which conditions are relevant (or irrelevant) to the generalization. Internal validity is clearly a prerequisite for external validity. Three types of bias Selection bias Selection bias is one of three types of bias that can threaten the validity of a study. Selection bias occurs when study subjects are selected or become part of the study as a result of a third, unmeasured variable which is associated with both the exposure and outcome of interest. [20] Examples of selection bias are volunteer bias (the opposite of which is non-response bias) [21] in which participants and non participants differ in terms of exposure and outcome. For instance, it has repeatedly been noted that cigarette smokers and non smokers tend to differ in their study participation rates. (Sackett D cites the example of Seltzer et al., in which 85% of non smokers and 67% of smokers returned mailed questionnaires)[21] It is important to note that such a difference in response will not lead to bias if it is not also associated with a systematic difference in outcome between the two response groups. Confounding Confounding has traditionally been defined as bias arising from the co-occurrence or mixing of effects of extraneous factors, referred to as confounders, with the main effect(s) of interest. [22] [23] A more recent definition of confounding invokes the notion of counterfactual effects. [23] According to this view, when one observes an outcome of interest, say Y=1 (as opposed to Y=0), in a given population A which is entirely exposed (i.e. exposure X=1 for every unit of the population) the risk of this event will be R A1 . The counterfactual or unobserved risk R A0 corresponds to the risk which would have been observed if these same individuals had been unexposed (i.e. X=0 for every unit of the population). The true effect of exposure therefore is: R A1 - R A0 (if one is interested in risk differences) or R A1 /R A0 (if one is interested in relative risk). Since the counterfactual risk R A0 is unobservable we approximate it using a second population B and we actually measure the following relations: R A1 - R B0 or R A1 /R B0 . In this situation, confounding occurs when R A0 ≠ R B0 . [23] (NB: Example assumes binary outcome and exposure variables.) Information bias Information bias is bias arising from systematic error in the assessment of a variable. [22] An example of this is recall bias. A typical example is again provided by Sackett in his discussion of a study examining the effect of specific exposures on fetal health: "in questioning mothers whose recent pregnancies had ended in fetal death or malformation (cases) and a matched group of mothers whose pregnancies ended normally (controls) it was found that 28%; of the former, but only 20%,; of the latter, reported exposure to drugs which could not be substantiated either in earlier prospective interviews or in other health records". [21] In this example, recall bias probably occurred as a result of women who had had miscarriages having an apparent tendency to better recall and therefore report previous exposures. Compiled and Edited by Marc Imhotep Cray , M.D.
  31. 31. Epidemiology 28 Journals A list of journals: [24] General journals: • American Journal of Epidemiology • Canadian Journal of Epidemiology and Biostatistics [25] • Epidemiologic Reviews [26] • Epidemiology • International Journal of Epidemiology • Annals of Epidemiology • Journal of Epidemiology and Community Health [27] • European Journal of Epidemiology • Emerging themes in epidemiology • Epidemiologic Perspectives and Innovations [28] • Eurosurveillance [29] Specialty journals: • Cancer Epidemiology Biomarkers and Prevention [30] • Genetic epidemiology • Journal of Clinical Epidemiology • Epidemiology and Infection • Paediatric Perinatal Epidemiology [31] • Pharmacoepidemiology and Drug Safety [32] • Preventive Medicine [33] Areas By physiology/disease: • Infectious disease epidemiology • Occupational Injury & Illness epidemiology • Cardiovascular disease epidemiology • Cancer epidemiology • Neuroepidemiology • Epidemiology of Aging • Oral/Dental epidemiology • Reproductive epidemiology • Obesity/diabetes epidemiology • Renal epidemiology • Intestinal epidemiology • Psychiatric epidemiology • Veterinary epidemiology • Epidemiology of zoonosis • Respiratory Epidemiology • Pediatric Epidemiology • Quantitative parasitology By methodological approach: • Environmental epidemiology • Economic epidemiology • Clinical epidemiology • Conflict epidemiology • Cognitive epidemiology • Genetic epidemiology • Molecular epidemiology • Nutritional epidemiology • Social epidemiology • Lifecourse epidemiology • Epi methods development / Biostatistics • Meta-analysis • Spatial epidemiology • Tele-epidemiology • Biomarker epidemiology • Pharmacoepidemiology • Primary care epidemiology • Infection control and hospital epidemiology • Public Health practice epidemiology • Surveillance epidemiology (Clinical surveillance) • Disease Informatics Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer
  32. 32. Epidemiology 29 References Notes [1] Nutter, Jr., F.W. (1999). "Understanding the interrelationships between botanical, human, and veterinary epidemiology: the Ys and Rs of it all". Ecosys Health 5 (3): 131–40. doi:10.1046/j.1526-0992.1999.09922.x. [2] Hippocrates. (~200BC). Airs, Waters, Places. [3] Carol Buck, Alvaro Llopis, Enrique Nájera, Milton Terris. (1998). The Challenge of Epidemiology: Issues and Selected Readings. Scientific Publication No. 505. Pan American Health Organization. Washington, DC. p3. [4] Alfredo Morabia (2004). A history of epidemiologic methods and concepts (http://books.google.com/books?id=E-OZbEmPSTkC& pg=PA93&dq&hl=en#v=onepage&q=&f=false). Birkhäuser. p. 93. ISBN 3764368187. . [5] Ray M. Merrill (2010). Introduction to Epidemiology (http://books.google.com/books?id=RMDBh6gw1_UC&pg=PA24&dq& hl=en#v=onepage&q=&f=false). Jones & Bartlett Learning. p. 24. ISBN 0763766224. . [6] "Changing Concepts: Background to Epidemiology" (http://www.duncan-associates.com/changing_concepts.pdf). Duncan & Associates. . Retrieved 2008-02-03. [7] Plato. "The Republic" (http://classics.mit.edu/Plato/republic.4.iii.html). The Internet Classic Archive. . Retrieved 2008-02-03. [8] "A Dissertation on the Origin and Foundation of the Inequality of Mankind" (http://www.constitution.org/jjr/ineq_03.htm). Constitution Society. . [9] Swift, Jonathan. "Gulliver's Travels: Part IV. A Voyage to the Country of the Houyhnhnms" (http://www.jaffebros.com/lee/gulliver/bk4/ chap4-7.html). . Retrieved 2008-02-03. [10] Ólöf Garðarsdóttir; Loftur Guttormsson (June 2008). "An isolated case of early medical intervention. The battle against neonatal tetanus in the island of Vestmannaeyjar (Iceland) during the 19th century" (http://ftp.ieg.csic.es/workshop/pdf/olofpaper.pdf). Instituto de Economía y Geografía. . Retrieved 2011-04-19. [11] Ólöf Garðarsdóttir; Loftur Guttormsson (25 August 2009). "Public health measures against neonatal tetanus on the island of Vestmannaeyjar (Iceland) during the 19th century". The History of the Family 14 (3): 266–79. doi:10.1016/j.hisfam.2009.08.004. [12] Hill, Austin Bradford (1965). "The environment and disease: association or causation?" (http://www.edwardtufte.com/tufte/hill). Proceedings of the Royal Society of Medicine 58: 295–300. PMC 1898525. PMID 14283879. . [13] Phillips, Carl V.; Karen J. Goodman (October 2004). "The missed lessons of Sir Austin Bradford Hill" (http://www.epi-perspectives.com/ content/1/1/3). Epidemiologic Perspectives and Innovations 1 (3): 3. doi:10.1186/1742-5573-1-3. PMC 524370. PMID 15507128. . [14] Green, Michael D.; D. Michal Freedman, and Leon Gordis (PDF). Reference Guide on Epidemiology (http://www.fjc.gov/public/pdf. nsf/lookup/sciman06.pdf/$file/sciman06.pdf). Federal Judicial Centre. . Retrieved 2008-02-03. [15] Gabriel Sanchez R, Sanchez Gomez LM, Carmona L, Roqué i Figuls M, Bonfill Cosp X. Hormone replacement therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD002229. DOI: 10.1002/14651858.CD002229.pub2 [16] Smetanin, P.; P. Kobak (October 2005). "Interdisciplinary Cancer Risk Management: Canadian Life and Economic Impacts". 1st International Cancer Control Congress (http://www.cancercontrol2005.com). [17] Smetanin, P.; P. Kobak (July 2006). "A Population-Based Risk Management Framework for Cancer Control" (http://www.riskanalytica. com/Library/Papers/Population Based Risk Management Framework for Cancer Control.pdf) (PDF). The International Union Against Cancer Conference (http://www.2006conferences.org/u-index.php). . [18] Smetanin, P.; P. Kobak (July 2005). "Selected Canadian Life and Economic Forecast Impacts of Lung Cancer" (http://www.riskanalytica. com/Library/Papers/Canadian Lung Cancer Abstract Jan 2005.pdf) (PDF). 11th World Conference on Lung Cancer. . [19] Hennekens, Charles H.; Julie E. Buring (1987). Mayrent, Sherry L. (Ed.). ed. Epidemiology in Medicine. Lippincott, Williams and Wilkins. ISBN 978-0316356367. [20] (http://journals.lww.com/epidem/Fulltext/2004/09000/A_Structural_Approach_to_Selection_Bias.20.aspx) 23 [21] (http://www.epidemiology.ch/history/PDF bg/Sackett DL 1979 bias in analytic research.pdf) 24 [22] Special:BookSources/0195135547 21 [23] (http://www.annualreviews.org/doi/full/10.1146/annurev.publhealth.22.1.189) 22 [24] "Epidemiologic Inquiry: Impact Factors of leading epidemiology journals" (http://www.epidemiologic.org/2006/10/ impact-factors-of-epidemiology-and.html). Epidemiologic.org. . Retrieved 2008-02-03. [25] http://www.cjeb.ca/ [26] http://epirev.oxfordjournals.org [27] http://jech.bmj.com [28] http://www.epi-perspectives.com [29] http://www.eurosurveillance.org [30] http://cebp.aacrjournals.org [31] http://www.blackwellpublishing.com/journal.asp?ref=0269-5022 [32] http://eu.wiley.com/WileyCDA/WileyTitle/productCd-PDS.html [33] http://www.elsevier.com/wps/find/journaldescription.cws_home/622934/description#description Compiled and Edited by Marc Imhotep Cray , M.D.
  33. 33. Epidemiology 30 Bibliography • Clayton, David and Michael Hills (1993) Statistical Models in Epidemiology Oxford University Press. ISBN 0-19-852221-5 • Last JM (2001). "A dictionary of epidemiology", 4th edn, Oxford: Oxford University Press. 5th. edn (2008), edited by Miquel Porta (http://www.oup.com/us/catalog/general/subject/Medicine/ EpidemiologyBiostatistics/?view=usa&ci=9780195314502) • Morabia, Alfredo. ed. (2004) A History of Epidemiologic Methods and Concepts. Basel, Birkhauser Verlag. Part I. (http://books.google.es/books?id=Hgnnhu1ym-8C&dq=Morabia,+Alfredo.+ed.+(2004)+A+History+ of+Epidemiologic+Methods&printsec=frontcover&source=bn&hl=es&ei=U4ARSvbaEJGUjAew8LnCBg& sa=X&oi=book_result&ct=result&resnum=4) (http://www.springer.com/public+health/book/ 978-3-7643-6818-0) • Smetanin P., Kobak P., Moyer C., Maley O (2005) "The Risk Management of Tobacco Control Research Policy Programs" The World Conference on Tobacco OR Health Conference, July 12–15, 2006 in Washington DC. • Szklo MM & Nieto FJ (2002). "Epidemiology: beyond the basics", Aspen Publishers, Inc. • Rothman, Kenneth, Sander Greenland and Timothy Lash (2008). "Modern Epidemiology", 3rd Edition, Lippincott Williams & Wilkins. ISBN 0781755646, ISBN 978-0781755641 • Rothman, Kenneth (2002). "Epidemiology. An introduction", Oxford University Press. ISBN 0195135547, ISBN 978-0195135541 External links • The Health Protection Agency (http://www.hpa.org.uk) • The Collection of Biostatistics Research Archive (http://www.biostatsresearch.com/repository/) • Statistical Applications in Genetics and Molecular Biology (http://www.bepress.com/sagmb/) • The International Journal of Biostatistics (http://www.bepress.com/ijb/) • European Epidemiological Federation (http://www.iea-europe.org/index.htm) • BMJ (http://bmj.bmjjournals.com/epidem/epid.html) - Epidemiology for the Uninitiated' (fourth edition), D. Coggon, G. Rose, D.J.P. Barker British Medical Journal • Epidem.com (http://www.epidem.com) - Epidemiology (peer reviewed scientific journal that publishes original research on epidemiologic topics) • NIH.gov (http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=mmed.chapter.631) - 'Epidemiology' (textbook chapter), Philip S. Brachman, Medical Microbiology (fourth edition), US National Center for Biotechnology Information • UTMB.edu (http://gsbs.utmb.edu/microbook/) - 'Epidemiology' (plain format chapter), Philip S. Brachman, Medical Microbiology • Monash Virtual Laboratory (http://vlab.infotech.monash.edu.au/simulations/cellular-automata/epidemic/) - Simulations of epidemic spread across a landscape • EMER (http://sist-emer.net/?lang=en)- Epizootic Diseases, Emerging and Re-emerging Diseases • Umeå Centre for Global Health Research • Epidemiology and Public Health Sciences, Umeå International School of Public Health (http://www8.umu.se/ phmed/epidemi/index.html/) • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (http:// dceg.cancer.gov/) • The Centre for Research on the Epidemiology of Disasters (CRED) at the Université catholique de Louvain (UCL) (http://www.cred.be) • People's Epidemiology Library (http://www.epidemiology.ch/history/betaversion.htm) Subjects and Topics in Basic Medical Science A Imhotep Virtual Medical School Primer

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