RRD #1 Intro, Genetics, Intracellular functions PDF

1 Nursing 3366 Pathologic Processes: Implications for Nursing (ONLINE COURSE) REQUIRED READING DOCUMENT #1 Basic Concepts, Genetic Influence in Disease, and Intracellular Function and Disorders Instructions: 1. Read this entire RRD (Required R...

1 Nursing 3366 Pathologic Processes: Implications for Nursing (ONLINE COURSE) REQUIRED READING DOCUMENT #1 Basic Concepts, Genetic Influence in Disease, and Intracellular Function and Disorders Instructions: 1. Read this entire RRD (Required Reading Document) and other documents mentioned. 2. Work on Assignment #1 and submit by designated deadline. Note about objectives /outcomes and studying for this course: For ALL content in this course, the student will be able to DESCRIBE/DISCUSS/IDENTIFY correlations (links) between pathophysiology of the disease and its clinical manifestations. In other words, #1: how does the pathophysiology of a particular disease cause the signs and symptoms, and #2: if a patient presents the signs and symptoms of a disease, be able to use critical thinking to figure out the disease process that is most likely in that context. Basic Concepts of Pathophysiology & Implications for Nursing Objectives /outcomes DESCRIBE/DISCUSS/IDENTIFY: 1. Concepts underlying the nomenclature of physiology and pathophysiology. 2. Appropriate, general application of those concepts to disease processes and situations. Re: sidebar & other boxed info in all your notes: Outline for Lecture: a. Information in a sidebar box is added knowledge for you, or a review of I. Overview previous info or sometimes some A&P info, etc b. If the info in the box is prefaced by “FYI,” you won’t be responsible A. Physiology for it on a test. B. Pathophysiology c. If there is no “FYI” preface, the information IS eligible for test C. Examples material. DO NOT FORGET TO STUDY THESE SIDEBAR NOTES! II. Some basic physiologic concepts. Some standard language usage A. Homeostasis clarifications: B. Compensation and decompensation o “AKA” means “also known as.” o “IE” or “ie” means “in other III. Pathophysiologic concepts & terminology words.” A. Disease vs disorder vs syndrome o “eg” means “for example.” B. Terms relating to elements leading up to a disease o this sign before a word means C. Terms relating to causes of a disease “approximately:” ~ D. Terms relating to course of a disease E. Sequela: aftermath of a disease ________________________________ I. Overview A. Physiology-- study of functions & processes that occur in body, mostly the NORMAL processes B. Pathophysiology -- the study of the underlying changes in body physiology that result from disease or injury FYI: pathology & pathophysiology come from Latin root word “pathos”—suffering.) C. Examples: 1. physiologic amenorrhea (menstrual flow ceases because of menopause, pregnancy, etc) versus pathophysiological amenorrhea (menstrual flow ceases because of cancer, for ex.) 2. physiologic albuminuria versus pathophysiological albuminuria II. Some basic physiologic concepts.  2 A. Homeostasis—maintenance of constant conditions in the body’s internal environment 1. Cells must have constant supply of nutrients, H2O, O2, and exist in narrow pH & temperature range 2. Maintaining homeostasis is essentially a balancing act-- the body is always trying to “right itself” when homeostasis is challenged by changes. 3. These challenges to the body’s balance are sometimes called stressors. B. Compensation and decompensation 1. The return to homeostasis after being challenged by a stressor is called compensation; similar words are adaptation, healing, etc. a. Compensation is achieved by the body’s use of control mechanisms, also called compensatory mechanisms. b. Control / compensatory mechanisms examples: 1) Example of compensatory response to “normal” daily-life stressors: when exposed to an elevated external temperature (Texas summer) or heavy exercise → body temperature rises → the hypothalamus senses the elevated core temperature and sends a signal to the skin to produce sweat → heat loss occurs through evaporation. Dilation of the superficial blood vessels also occurs → as “heated blood” circulates from the core to the periphery → heat loss occurs through radiation (heat removed from body into surrounding air). 2) Example of compensatory response to pathologic stressors: if you’ve lost a lot of blood (massive bleeding) or water (dehydration), the body uses certain compensatory techniques to keep remaining fluid volume circulating as effectively as possible (temporary measures until the cause of the problem gets fixed) : a) heart rate would increase to get blood around faster to temporarily make up for loss of volume. b) also, arteries in your periphery (arms and legs) would constrict, shunting whatever blood volume is left to the central areas, that is, to your most important organs— brain, heart, lungs, kidneys. Expect to find cool hands and feet. 2. If the body is unable to appropriately meet the challenge of stressors-- for example, if the control mechanisms are “exhausted”-- compensation can deteriorate either rapidly or slowly into decompensation— the failure to compensate, adapt, heal, etc. III. Pathophysiologic concepts & terminology A. Disease vs disorder vs syndrome 1. a disease is a harmful condition of the body (and/or mind); a disorder is a disturbance in the healthiness of the body; a syndrome is a collection of symptoms  3 2. for this class these terms will be basically interchangeable, as they all are a disturbance in body homeostasis; most of the time I will use the term disease (or abbreviate as “dz.”) B. Terms relating to elements leading up to a disease 1. risk factors a. factors that or contribute to and/or increase probability that a dz will occur …”setting the stage” b. ex-- heredity, age, ethnicity, lifestyle (smoking, eating habits, etc), environment 2. precipitating factor a. a condition or event that triggers a pathologic event or disorder …. the “kick-off” b. ex—“an asthma attack can be precipitated by exertion” C. Terms relating to causes of a disease 1. etiology-- the cause of a disease; includes all factors that contribute to development of dz; examples: a. etiology of AIDS: HIV (human immunodeficiency virus) b. etiology of rheumatic heart disease: autoimmune reaction c. TB (tuberculosis): mycobacterium 3. idiopathic—dz with unidentifiable cause 4. iatrogenic problem -- occurs as result of medical treatment ex—if kidney failure is due to improper use of antibiotics prescribed by a healthcare provider you could say “the etiology of the kidney failure was iatrogenic.” 5. nosocomial problems—result as consequence of being in hospital environment ex— urinary tract infection is called a nosocomial infection if it developed while patient was in the hospital. D. Terms relating to course of a disease 1. Clinical manifestations (ie, S&S)-- the demonstration of the presence of a sign and/or symptom of a disease a. signs-- manifestations that can be objectively identified by a trained observer b. symptoms -- subjective manifestations that can only be reported by the person experiencing them-- pain, nausea, fatigue (***note, most often on a patient chart, “signs and symptoms” appear as “S & S” or S/S; also, often in medical vernacular, “symptoms” is used as a shortcut instead of saying “signs and symptoms.”) c. local versus systemic S&S: 1) some S&S are local: redness, swelling, heat, rash, & lymphadenopathy in a particular area 2) others are systemic, such as fever, urticaria (hives), malaise (“I feel dragged out” or “awful all over”), systemic lymphadenopathy d. acuity and timing of S&S 1) acute S&S: a) fairly rapid appearance of S&S of dz (over a day to several days); usually last only a short time  4 ex: “The patient had an acute URI (upper respiratory infection) that resolved within a few days.” b) also can mean increase in severity ex: “The acuity of the patient’s URI increased and he had to be hospitalized.” 2) chronic S&S —develop more slowly; S&S are often insidious and last longer and/or wax and wane over months or years. a) remissions—periods when S&S disappear or diminish significantly (wane) b) exacerbations—periods when S&S become worse or more severe (wax); exacerbate—to provoke, to make worse. ex: “The patient had an exacerbation of his chronic asthma and had to go to the hospital.” e. terms relating to location of manifestations: 1) central a) usually refers to problem, situation, etc, that is occurring towards the center, or “core,” of the body b) often used when referring to essential organ systems like brain, heart, lungs, kidneys; ex— when someone loses a lot of blood, the body shunts most of the remaining blood away from non-essential areas such as gut, hands, feet, so that the essential organs are oxygenated—ie, most of the volume of blood ends up circulating centrally. c) the more central an area or problem is, the more proximal to the core it is; ex— “the arm was fractured proximal to the elbow.” this means a break between elbow & shoulder 2) peripheral, or periphery a) refers to problem, situation, etc, that is occurring towards the outer parts of the body, away from core Basic definition of i. ex—if we lose a lot of blood, the blood vessels of “shock:” the periphery often constricts so that not a lot of low BP plus S&S blood can circulate into those areas (mainly arms of not getting & legs) enough blood to different parts of ii. thus there is more blood going to central areas the body (ex— such as the heart, brain, lungs, and kidneys— confusion from blood has been shunted to those areas not getting blood iii. this is why sometimes a sign of shock is cool, pale to brain). extremities. b) the more peripheral an area or problem is, or further away from the core of the body, the more distal it is ex— “distal to the blood clot in the left coronary artery, the tissue lost oxygenation & died.”  5 2. Prognosis-- the predicted outcome of a dz based on certain factors: a. the usual course of that particular dz b. individual’s characteristics; ex: 1) age: patients at either end of age spectrum --infants & the elderly are at higher risk for a poor prognosis due to immature or “worn out” immune systems, respectively. 2) presence of comorbidities– two or more coexisting medical conditions; this increases chance of poor prognosis ex— “The patient’s comorbidities of heart disease and lung disease contributed to his poor prognosis in recovering from pneumonia.” D. _sequela (plural: sequelae): aftermath of a disease 1. a sequela is any abnormal condition that follows and is the result of disease, injury, or treatment; synonym = complications 2. occasionally the term is used as simply “outcome,” such as: “A positive sequela of getting pneumonia was that the patient stopped smoking;” but most of time “sequela” is used with a negative connotation. 3. severity of sequela varies; examples of sequelae with various degrees of seriousness: a. sequela of rheumatic fever can sometimes be a bad heart valve. b. possible sequela of chicken pox→ scarring c. possible sequela of stroke→ weakness on one side of the body ************************************************************** Here is a partial list of terms to look over to make sure you understand them (other terms may come up that you will need to look up as well). Many should be familiar from A&P. YOU WON’T BE SPECIFICALLY TESTED ON THESE, but they will help you parse out word meanings. a/an – prefix meaning not, without ab- prefix meaning from, away from, off ad- prefix meaning increase, adherence, to or toward aer- prefix meaning the air, or gas algia- suffix referring to pain or painful condition ascend- to move upward to a higher position asymmetrical –denoting a lack of symmetry between two or more parts that are alike bi- prefix meaning twice or double bilateral- relating to or having two sides blast- denotes an immature precursor cell brady- prefix meaning slow dorsal- pertaining to the back dys- prefix referring to “bad” or difficulty ectomy- suffix denoting removal of an anatomical part emia- suffix meaning “in the blood” hemo- prefix referring to blood hemorrhage- escape of blood from the intravascular space. To bleed. hyper- prefix meaning excessive, above normal hypo-prefix deficient, below normal ICU- IntensiveCare Unit “i” – suffix that often creates plural form; ex—one embolus, two emboli. iasis—suffix meaning state or condition. idio- prefix meaning private, distinctive, or peculiar to. inferior- situated below or directly downward itis – suffix meaning having to do with inflammation or infection IV- intravenous lipo – pertaining to fat lytic- suffix creates adjective form of lysis  6 lysis- suffix refers to destruction of a substances, usually a cell macro- prefix meaning large, long megaly- suffix meaning large micro- prefix denoting smallness necro-prefix meaning death ostomy- suffix meaning artificial opening (stoma) into the urinary or gastrointestinal tract or trachea ology- suffix meaning the study of a subject osis—suffix meaning condition otomy- suffix meaning a cutting operation plasty- suffix referring to molding, shaping or the result there of a surgical procedure. scopy- suffix referring to viewing or seeing superior- situated above or directly upward symmetrical- equality in two like parts tachy- prefix meaning rapid unilateral- confined to one side of the body only ventral – pertaining to the front side (as opposed to dorsal) VS—vital signs: o BP—blood pressure (measured as systolic over diastolic mm of Hg) o HR—heart rate (measured in beats per minute). o RR—respiratory rate (breaths per minute) o T or temp—temperature. o SO2 or pulse oximeter or pulse ox or O2 sat—oxygen saturation (measured as percentage—we will go into this more in a later lecture) ************************************ ALSO, VERY IMPORTANT!! FOR EACH SET OF READINGS, MAKE YOUR OWN VOCABULARY LIST FOR YOUR OWN STUDY BENEFIT. For this set of readings only, I made a list to give you an example. (In any set of readings, if there are words that I have not explained, and that you do not know, look them up in your book or a medical dictionary and/or ask me about them. You will be responsible for all vocabulary. NOTE: vocabulary of basic concepts will be used throughout the semester in other readings and on tests, so BE SURE to get familiar with them. physiologic pathologic See last couple of pages of “How-Manual” if remission homeostasis you would like to know how to do a exacerbation compensation “flashcard concept map.” The emphasis in central decompensation peripheral doing flashcards this new way is to realize etiology proximal that knowing a word and its definition (rote risk factors distal memorization) is not enough—you must prognosis etiology understand its CONTEXT. That’s what gives comorbidity precipitating factor sequela it true meaning & application potential. idiopathic acute / acuity iatrogenic chronic nosocomial ______________________________________________________________________________________________ Genetic Influence in Disease Objectives /outcomes DESCRIBE/DISCUSS/IDENTIFY: 1. Genetic alterations resulting in chromosomal aberrations and their relationship to disease processes such as trisomy 21 and Philadelphia-chromosome linked chronic myelocytic leukemia. 2. Genetic alterations resulting in protein synthesis defects and their relationship to disease processes such as sickle cell anemia and polycystic kidney disease. 3. Some therapeutic uses of recombinant DNA..~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ NOTE: Here between the wavy lines is a little A&P background (a very brief review about what you should already have learned in A&P [see the Prep & related textbook chapter if you need more A&P]… this first part won’t be on a test per se, but it is important foundation for patho info.) 1. Gene definition and function  7 a. Definition of a gene--a segment of a DNA molecule that is composed of an ordered sequence of nucleotide bases (adenine, guanine, cytosine, thymine) b. Main functions of genes: coding for synthesis of proteins that form our traits and functional characteristics. 1) Examples of these include “permanent” proteins such as eye pigment, hair color, and blood type in a developing fetus, as well as more subtle inherited traits like outgoing personality or susceptibility to certain diseases. 2) There are also “day-to-day” functional proteins such as hormones, antigens, antibodies, enzymes, etc. c. When there is a mutation of a gene, the protein it is responsible for often malfunctions. 1) You can have a pretty good idea of what type of disorder & S&S occur when you understand this pathologic process. 2) Ex—if the gene that codes for lactase becomes mutated, lactase cannot properly breakdown and process lactose. Lactose ingestion then causes diarrhea. This is called lactose intolerance. 2. Packaging of genes: chromosomes a. The DNA helix containing genes goes through many shapes during the cell life but at one point takes the shape that we are most familiar with– the rod-shaped body in the nucleus of cells called a chromosome. 1) To summarize: a sequence of nucleotide bases forms a gene; genes make up a DNA molecule, and that DNA molecule forms into a specialized shape called a chromosome 2) A chromosome can be thought of (very simplistically) as a string of multi- purpose beads, with the beads being genes. b. A person receives 23 chromosomes from each parent, so you end up with 23 pairs, or a total of 46. 1) 22 pairs are autosomal– ie, NOT sex chromosomes– and each pair is closely alike. 2) The other pair is the sex chromosomes– XX or XY. 3) For purposes of study they can be arranged in a karyotype (a picture) ex— chromosome #1 from mom is matched up with chromosome #1 from dad. c. Autosomal chromosome pairs (#1-22). 1) For these pairs, each has genes that closely match “partners” on the other chromosome. 2) Partner genes have the same location (“locus”) on each respective chromosome, code for the same trait, and are called “a pair of alleles.” 3) A pair of alleles are almost exactly alike except that one can be dominant & one can be recessive (or they can both be dominant or both be recessive). 4) We notate recessive genes with a lower-case letter & a dominant gene as an upper-case letter. a) The combinations are called genotypes & represent what was inherited from mom & dad. b) Examples of various combinations (randomly using the letter “g”), can be GG (homozygous dominant); gg (homozygous recessive); Gg (heterozygous).  8 d. There is one pair of sex chromosomes (#23) which work very differently. There is info on them & on sex-linked disorders later in these notes, but you won’t be tested on that info. e. If a geneticist is trying to figure out the percent chance of two people with certain genotypes having a child with certain genetic characteristics, a Punnett square is often used. (Note: You must understand HOW genetic diseases are inherited BUT you will not be asked to configure a Punnett square for the exam). Genotype: overall genetic composition. Refers to a specific set of alleles. Phenotype: a person’s observable characteristics (anatomic, physiologic, biochemical, behavioral) as determined by genes and environment. ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Outline for Reading & Studying Genetic Influence in Disease: A. Overview 1. definition of genetic disorders 2. categorizing genetic disorders 3. mitochondrial DNA disorders 4. multifactorial 5. chromosomal 6. single-gene B. Single-gene disorders 1. overview/ categories: autosomal recessive, autosomal dominant, sex-linked 2. autosomal recessive a. overview b. example of autosomal recessive disorder--sickle cell anemia 3. autosomal dominant a. overview b. example of autosomal dominant disorder—polycystic kidney disease 4. sex-linked—FYI C. Recombinant DNA– a form of genetic engineering A. Overview 1. broad definition of “genetic disorders” -- a disease caused by abnormalities in an individual’s genetic material 2. there are several ways of categorizing genetic disorders: a. inherited vs “spontaneous” 1) example of inherited disorders—sickle cell disease is caused by an inherited, altered (AKA, “mutated”) gene (see below) 2) example of spontaneous— free radicals form as a result of aging→ causes damage to the DNA→ protein synthesis is altered leading to gene mutations → an “oncogene” develops which causes rapid, wild proliferation of cell growth→ cancer may develop. b. other ways to categorize include using the following four groupings: disorders of mitochondrial DNA, multifactorial, chromosomal, single-gene. Some explanations3. mitochondrial DNA disorders of terms: a. majority of DNA is found in nucleus of cells but small bits of DNA are also “Environmental” is used here to found in mitochondria mean any b. disorders of this DNA are very uncommon & won’t be discussed futher. influence other than inherited. 4. multifactorial genetic disorders -- combination of environmental triggers and “Onco” prefix means “cancer- variations / mutations of genes, plus sometimes inherited tendencies; examples: related”  9 a. various cancers such as lung cancer: begins by smoke & toxins irritating bronchial tissue→ one or more genes in cells of that tissue begin to be deranged—oncogenes created → code for wild, uncontrolled growth of cells. b. many common diseases such as hypertension (HTN), coronary artery disease (CAD) & diabetes mellitus (DM) are now known to be caused or highly influenced by a mix of environmental and inherited components. c. teratogenic disorders: 1) a teratogen is any influence — eg, drugs, radiation, viruses-- that can cause congenital defects 2) congenital defects are abnormalities that are either detectable at birth and/or can be attributed to fetal development “glitches.” 3) so “teratogenic disorders” and “congenital defects” are virtually interchangeable terms 4) specific examples: a) fetal alcohol syndrome (FAS) occurs because toxicity of alcohol causes gene mutations during gestational development. b) “thalidomide babies” – born with abnormal arms and legs due to mothers taking the drug thalidomide for nausea during early pregnancy. 5. chromosomal disorders (AKA, chromosomal aberrations) a. definition-- a type of genetic disorder that results from alterations to the numbers or structure of a chromosome, which in turn alters the “local” genes FYI: chromosomal disorders occur in ~1% of (genes in the immediate area)--the genes’ functionality is disrupted and they live births (2% for women don’t code proteins correctly, giving rise to the phenotype (S&S) of the older than 35 years) & are leading known cause of disorder. mental retardation & miscarriage--about 50% of b. alteration to NUMBERS of chromosomes: all recovered first-semester 1) Down’s syndrome is a disorder of abnormal numbers of chromosomes spontaneous abortions (miscarriages) have major and is sometimes associated with pregnancies of women >35 years chromosome abnormalities that would have made old. them not viable. 2) it is a “glitch” that occurs in very early cellular division and chromosomal distribution of a fertilized egg: instead of ending up with “somy” is suffix that means the normal number--46 chromosomes-- the fetus ends up with 47 “having to do with chromosome 3) the extra chromosome occurs at site #21 -- the 21st chromosome set numbers.” Polysomy—more chromosomes has three chromosomes instead of two. than normal; so Down’s is a a) thus the other name for this type of Down’s is trisomy 21. disorder of polysomy. b) phenotype of trisomy 21 includes mental retardation and typical physical characteristics such as low-set ears, epicanthic fold to the eyes, short limbs, and a larger-than-normal tongue. c. alterations to STRUCTURE of chromosomes—Philadelphia chromosome 1) some types of chromosomal aberrations are caused by alterations in chromosomal structure, such as deletion, duplication, or rearrangement of gene sites (translocation) on the chromosome 2) an example of this is the Philadelphia chromosome, which results from translocation & will be discussed further in another set of readings. 6. single-gene disorders – discussed below…. FYI: there are more than 6,000 known single-gene disorders, which occur in about 1 out of every 200 births.  10 B. Single-gene disorders 1. overview a. single-gene disorders are usually due to an inherited mutated gene b. since genes code for proteins, when a gene mutates so that its protein product can no longer carry out its normal function, a disorder can result. c. single-gene disorders are inherited in recognizable patterns: autosomal recessive, autosomal dominant, and sex-linked. 2. autosomal recessive disorder a. overview 1) an autosomal recessive disorder occurs when a mutated (“diseased”), FYI: other examples: recessive (“weak”) gene partners up with an allele that is also phenylketonuria (PKU), recessive & diseased; those alleles are notated with two lower-case cystic fibrosis, Tay-Sachs disease, Wilson’s disease, letters. and many more. 2) the protein that they code for will then malfunction & an abnormality/ disease/ disorder will occur that relates to that “bad” protein b. example of autosomal recessive disorder--sickle cell anemia 1) genotype and patho development a) at a certain locus on a certain pair of chromosomes, a pair of KEY to drawings: alleles has the job of coding for the creation of normally shaped = mutated gene hemoglobin (Hgb) = normal gene b) but if during fertilization a person inherits a sickle-cell disease gene from mom – ie, a recessive, mutated Hgb-coding gene – and ALSO inherits a sickle-cell disease gene from dad: (1) this person would have a homozygous genotype of the d d recessive sickle cell genes: dd Remember: When assigning notations for autosomal recessive diseases, the “big” letter will be the dominant, normal, non-diseased allele, and the “little” letter will be the diseased allele. (2) those abnormal recessive alleles will code for abnormally- shaped Hgb (sickle-shaped), which will make the RBCs sickle-shaped (there are ~300 Hgb molecules per RBC, so enough sickled Hgbs in an RBC will deform the RBC too) The suffix “emia” means “in the blood.” Anemia literally means “no blood,” but in (3) because these RBCs do not have the usual round & actuality it is used to mean “there are less- smooth shape, they are more easily damaged as they go than-normal numbers of RBCs in the blood.” through the blood stream; ultimately this results in less- than-normal numbers of RBCs—this is the definition of anemia. 2) phenotype—a person who has an ss genotype will HAVE the disease sickle cell anemia—ie, their phenotype is having the S&S caused by the above genotype and patho development: a) SOB (shortness of breath), weakness & fatigue due to (WHEN YOU ARE STUDYING decreased O2 being carried to tissues of the body; this decreased MATERIAL IN THIS carrying capacity is because of: COURSE, BE SURE TO KNOW HOW TO LINK S&S (1) anemia: less numbers of RBCs to carry the Hgb which in TO THE PATHO OF THE turn carries the O2 DISEASE & VICE VERSA; this section is good example of being able to do that.)  11 (2) deformed Hgb simply cannot carry the usual numbers of O2 molecules If cells are not getting enough b) ischemic pain, especially in the joints; patho of this type of pain: oxygen and it is due to a circulatory malfunction, the (1) the deformed RBCs “clog” up the capillaries that usually problem is called ischemia. Pain carry O2-rich blood to the tissues in the tissue that is not getting enough oxygen is called ischemic (2) this results in distal tissues that are starved to O2 & “cry pain. out” in pain. 3) other combinations of alleles a) if during fertilization a person inherits a sickle-cell disease gene from one parent but a normal Hgb-coding gene from the other parent, the person’s genotype for Hgb would be: _Dd_ b) we call this a “heterozygous genotype for sickle cell anemia” & we know that because the NORMAL gene is dominant over the sickle-cell recessive gene, the person will NOT have the disease but they may pass on the gene to offspring. (1) this is called being a carrier; so Dd is a sickle cell carrier. (2) rarely, a carrier will have a milder phenotype of the disease—ie, mild S&S; this situation is called “having the trait.” (Someone with sickle cell trait has the genotype Dd but has mild S&S of sickle cell disease.) c) someone with the genotype DD doesn’t have to worry about either having the disease or passing it on—they are what is called “homozygous normal.” 3. autosomal dominant disorders a. overview 1) occurs when a person inherits a mutated, diseased gene that is dominant 2) ie, the gene that codes for a certain disease characteristic is dominant, and the gene that codes for the normal characteristic is recessive (exactly opposite of autosomal recessive) b. example of autosomal dominant disorder—polycystic kidney disease (PKD) FYI: other examples: Huntington’s disease 1) genotype & patho development neurofibromatosis, a) at a certain locus on a certain pair of chromosomes, a pair of Marfan’s syndrome alleles has the job of coding for the creation of normal kidney tissue When assigning notations b) if during fertilization a person inherits a kidney tissue gene for autosomal dominant diseases, the “big” letter will that has a mutation, that gene will “want” to code for abnormal be the dominant, diseased kidneys. allele, and the “little” letter c) in a dominant disease such as PKD, the mutated gene is the will be the normal, non- strong one, so even if it is paired with a normal allele, it will diseased allele. override the normal allele’s coding. d) in PKD, this results in the kidney tissue developing cysts, which can reduce various kidney functions and lead to kidney failure as a person goes through life.  12 2) genotype notation a) if we use the letter “P” to designate PKD, the genotype for see if you can draw & label all 3 possible allele pairing combinations for this someone that HAS the disease would look like this: PP or Pp. autosomal dominant disorder; I will start b) only a person with a genotype of pp you with just plain circles and you can fill in “P” or “p”…. Then think: will this (homozygous recessive) would NOT have the disease person HAVE the disease or not? or or 3) S&S a) hematuria (blood in urine), proteinuria, frequent kidney infections b) pain at costovertebral angles and abdomen c) kidney stones Sex-linked disorders will NOT be on the test. The following info is just FYI. 4. sex-linked disorders a. normal physiology of sex chromosomes: When assigning notations for X- 1) The two X’s in a woman work just like autosomal chromosomes – a linked recessive gene on one X has a partner allele at the same locus on the other X diseases, use XX for women & XY that usually code for the same trait. for men. Then 2) But in a male the genes on his X have no comparable partner allele on attach letters to the X’s. his Y. The “big” letter 3) We notate these as such: Xl Xl (homozygous female); XL Xl will be dominant, normal, non- (heterozygous female); Xl Y or XL Y for the male. diseased allele, b. types of sex-linked disorders: and the “little” letter will be the 1) possibilities include X-linked dominant, X-linked recessive, & Y-linked. diseased allele. 2) X-linked dominant and any kind of Y-linked diseases are rare—sex- linked diseases most commonly fall under X-linked recessive 3) therefore “X-linked” and “sex-linked” terminologies are often interchanged, and when someone says “sex-linked,” they often mean “X-linked recessive.” c. X-linked recessive diseases are caused by a recessive allele that is always located only on an X chromosome 1) in most cases, a female who has the diseased recessive gene on one of her X chromosomes is protected by a normal dominant gene on her other X chromosome, so a female will rarely have an X-linked disease—she will only be a carrier 2) but a male who gets an X chromosome with the diseased gene will not have a matching normal gene on another X chromosome, because FYI: Other examples include certain types of he only has a Y chromosome muscular dystrophy. 3) therefore, the phenotype of most X-linked disorders is usually expressed in male offspring. d. example of sex-linked disorder—hemophilia 1) there are several types of hemophilia, each caused by different gene mutations on the X chromosome.  13 2) normally the genes code for one of the coagulation factors that facilitates normal clotting when there is an injury; examples—Factor XIII & Factor IX. 3) if one of these genes mutates, it may code for a defective coagulation factor, resulting in altered ability to clot. 4) because the hemophilia gene is an X-linked gene, the genotype for someone that has the disease would look like this: Xh Y; genotypes of Xh XH, XH XH, or XH Y would not have the disease ***In each category of autosomal dominant and autosomal recessive be sure you are able to figure out the percent chance of two people with certain genotypes having children with varying genotypes & possible phenotypes – do this with Punnett squares. C. Recombinant DNA– a form of genetic engineering 1. many alterations in DNA came about as a natural part of evolution, but now we can deliberately alter DNA in the interests of medicine and science. 2. recombinant DNA is a “new” DNA that results from purposefully combining two or more different sources of DNA; ex-- altering (“engineering”) DNA codons in bacteria to make proteins the bacteria would not ordinarily produce 3.current applications of this process: a. human growth hormone for children lacking it. b. exogenous (“from outside the body”) insulin for diabetics. c. factor VIII for hemophiliacs. d. drugs like tPA & tenecteplase—given as “clot-buster” in patients having MI (an MI, a myocardial infarction is when a clot develops in a coronary artery & blocks blood flow to the distal tissue, which begins to die… thus if a drug can get rid of the clot, flow will be restored & tissue will be saved.) __________________________________________________________________________ Intracellular Functions and Disorders Objectives /outcomes DESCRIBE/DISCUSS/IDENTIFY: 1. The concepts of physiologic and pathophysiologic fluid shifts between the body’s fluid compartments as driven by alterations in osmolality, oncotic pressure, tonicity, hydrostatic pressure, and control mechanisms such as RAAS, natriuretic peptide system, & ADH. 2. The effect of alterations of key molecular substances such as hydrogen, sodium, potassium, chloride, calcium, phosphorus, magnesium, proteins, O2, CO2, HCO3 and glucose on fluid shifts and other body processes, including acid / base balance. 3. Normal cellular metabolism and its alternate states, including anaerobic metabolism and the processes of glycogenesis, glycogenolysis, and gluconeogenesis. 4. The relationship of all the above to certain disease processes and signs and symptoms (S&S), including: fluid overload and fluid deficit states, including SIADH & DI. basic states of acidosis and alkalosis. hyperpolarized and hypopolarized plasma membrane. alterations of glucose availability. alterations in usage of certain vitamins.  14 Outline for Intracellular Functions and Disorders I. Overview IMPORTANT NOTE: As you come across various numbers in your A. Alterations in cellular-level function reading, be aware that very few of them will need to be memorized. Exceptions include numbers that I feel will be very useful to know in your B. Etiology of these disruptions nursing practice. Those numbers I will indicate with wordage such as II. Hypoxia’s effect on cellular-level function “know now and forever.” That means they may come up again at any A. Overview of hypoxia time in the semester and you will STILL need to know them. Please feel free to ask me about this issue and any other. B. Sequelae of hypoxia III. Effect of nutritional alterations on cellular-level function. A. Overview B. A review of NORMAL glucose use and back-up systems C. Examples of disease processes related to cellular metabolism “back-up plans” D. Examples of other disorders that can contribute to disruption in metabolic pathway IV. Alterations in solute status A. A&P overview of select solutes This is A&P review info & won’t be tested as such. However, understanding it is CRUCIAL B. A&P overview of normal electrical function of cells to understanding the patho. C. A&P overview of body fluid compartments D. Cellular electrical problems secondary to alterations in electrolyte balance E. Acid / base sequelae of solute imbalance, ie, acid / base imbalance ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ Again, please review and understand the concept map I. Overview “THE METABOLIC PATHWAY & DISTURBANCES.” A. Alterations. in cellular-level function 1. Many normal daily changes in body homeostasis can affect the metabolic pathway (upon which we depend for energy in the form of ATP), and usually the body can adjust & maintain equilibrium—sort of an ongoing “fine-tuning.” 2. But there are also problems that more seriously disrupt homeostasis of cellular metabolism and the provision of ATP for body needs; it is more difficult for the body to adjust & return to equilibrium in these cases. 3. Many of the disorders & disease processes that we will study in this course either CAUSE or are CAUSED BY some sort of cellular-level disruption that eventually leads to decrease in ATP. B. Etiology of these disruptions include: 1. hypoxia —decrease in amount of oxygen to cell or ability to use oxygen appropriately (part II) 2. nutritional problems such as decreased glucose & vitamin availability for cell use (part III) 3. changes in balance of electrolytes & other solutes, including acid/base imbalance (part IV) 4 changes in fluid distribution (this will be discussed in RRD 2). FYI: All of above imbalances rarely “stand alone”—usually one abnormality triggers another; ex: a bacteria causes disturbance in permeability of lung cells’ plasma membrane→ there is pathological influx of water into cells→ causes swelling in organelles such as mitochondria→ interrupts electron transport chain functioning→ no ATPs to fuel energy needs of lung cells→ breathing is compromised→ hypoxia (diminished O2 to cells)→ reliance on glycolysis→ lactic acidosis→ further disturbance in function of lung cells & other cells of body (body’s cells “hate” acidosis!)→ etc.  15 II. Hypoxia (decrease in oxygen)—effect on cellular-level function A. Overview of hypoxia: has a spectrum of etiology and seriousness: from simply overworked muscles in extreme exercise (the muscles use up immediate available oxygen), to someone who is having difficulty breathing & therefore cannot get enough oxygen to the heart to circulate it to the tissues, to someone whose artery in the arm is cut, so the tissues distal to the trauma cannot get oxygen, and so on. B. Sequelae of hypoxia (see page 2 of concept map) 1. if there is hypoxia: a. cellular metabolism has to “recycle” through glycolysis rather than continue down the usual aerobic pathway Aerobic– O2 is present b. this is because glycolysis is the only step that can operate under (this is the ideal, normal, aerobic conditions, AND can also operate under anaerobic “normal” conditions situation). Anaerobic– low 2. positive side to anaerobic glycolysis: or absent O2. a. it can give 2 molecules of ATP per molecule of glucose to give energy to the cell. b. thus, it is a temporary stop-gap measure that keeps your body going until the cells can get more O2 so that aerobic metabolism can be re- acidosis—a state of established. greater-than-usual 3. negative side to anaerobic glycolysis: concentration of acidic substances in a. 2 molecule of ATP is not enough to keep going for a long time. the blood and cells. b. also, every time the metabolic process must “recycle” through glycolysis, multiple molecules of pyruvate (pyruvic acid) accumulate, resulting in acidosis. 4. summary: two main sequela result from hypoxia: Key physiologic principle: The byproducts of the body’s a. deficiency of ATP for cellular functions; ex—without ATP, the normal metabolic activities are Na / K pump of each cell cannot maintain normal electrical cell slightly more acidic than alkaline. To counteract that membrane status and propagation of electrical impulses will be acidic tendency, the body disrupted. “likes” to keep a very narrow and slightly alkaline pH range of b. altered acid/ base balance, especially acidosis; significance: acidosis the blood— from something like hypoxia or reliance on gluconeogenesis (more on 7.35 to 7.45 (Know this range “now & forever.”) this in next section) can dangerously tip body pH out of its narrow, desirable range fairly quickly 5. all the above can cause damage and death to tissues (more on “altered tissue” in another RRD). refer to concept map III. Effect of nutritional alterations on cellular-level function. Glycogen is a largeA. Overview molecule that is too 1. cells have certain nutritional needs to carry on normal metabolic function big to be used for energy as it is, but a. glucose is obtained from carbohydrates to begin the cellular metabolic when necessary it can be stimulated to break pathway that leads to energy provision in the form of ATPs down into small b. vitamins (and other substances) provide the “support staff” for the glucose molecules that can be used metabolic pathway. more effectively. 2. process of glucose access & usage depends on cellular metabolic needs at Think of it as “stored glucose.” any given moment.  16 B. A review of NORMAL glucose use and back-up systems: 1. if you have just eaten, glucose in the blood normally goes up, a state of temporary hyperglycemia; this triggers the pancreas to secrete insulin to circulate to cells and assist in getting glucose molecules from the blood into the cells to use as the main source of cellular energy. 2. if intake of food / glucose is greater than immediate cellular energy needs, insulin directs the excess glucose to be stored as glycogen_ in the liver. This is called _glycogenesis (genesis = “creation of”). The processes above are considered to be “regulatory:” insulin triggers regulatory, “building up” processes of 1) glucose entering cells, & 2) the creation of glycogen (glycogenesis). 3. later, if you don’t eat and / or the availability of glucose is less than cellular energy needs, a state of _hypoglycemia (low blood sugar)usually exists. a. certain hormones called the counterregulatory hormones are triggered by low blood glucose: AKA, stress hormones 1) epinephrine from the adrenal medulla because hypoglycemia is 2) cortisol from the adrenal cortex stressful for the body, so they come “to the rescue.”. 3) growth hormone (GH) from the pituitary 4) glucagon from the pancreas. b. roles of these hormones include: 1) “alarms”—sensations of hunger, shakiness, sweating, irritability BACK UP PLAN #1: —these are telling you to “EAT!” 2) if you don’t eat, the body takes the first step in its “back-up Glycogenolysis plan:” the counterregulatory hormones stimulate the conversion of glycogen to glucose. a) this process is called glycogenolysis (lysis = “breakdown”) & results in a higher blood sugar, correcting the hypoglycemia & making glucose available to the cells for energy use. b) many times a day if our body needs some glucose & we cannot immediately take it orally, glycogenolysis takes place as a “stop gap measure” till we can take in glucose. c. the next step in body’s normal “back-up plan” BACK UP PLAN 1) if glucose is either unavailable or cannot get into the cell to participate #2: in the metabolic pathway, and glycogenolysis has already exhausted a person’s store of glycogen, the body breaks down fats and protein. Gluconeogenesis 2) this is called gluconeogenesis--the use of any other substance besides carbohydrates for cellular energy; this means breaking down fats and proteins for energy. 3) one of the breakdown products of fats and proteins is ketones FYI: 3 main ketones: a) “good” characteristic of ketones: they can offer the body some a) acetoacetic acid energy—usually enough to be a “stop gap” till glucose is b) beta-hydroxybutyric acid available. c) acetone (another acid) b) two “bad” characteristics of ketones: (1) they are acids-- over time there is a danger of acidosis (2) they can’t be used by brain cells—brain cells MUST have glucose for energy.  17 ***If you’ve ever felt dizzy, dull-witted or cognitively challenged when hypoglycemic, it’s because your brain cells are ESPECIALLY reliant on glucose for energy. If brain cells are deprived of glucose, they can become electrically disturbed and a person can become unconscious, have a seizure, and / or even die. Clinical significance: Often when a patient presents with an altered level of consciousness, one of the first things we do is test the blood sugar. Summary: Glycogenolysis & gluconeogenesis are considered to be “breaking-down,” “counterregulatory” processes triggered by the counterregulatory hormones when hypoglycemia is present. C. Examples of disease processes related to cellular metabolism “back-up plans” 1. glycogen storage diseases -- abnormalities in glycogenesis or glycogenolysis a. ex-- McArdle’s disease—an autosomal recessive disease in which which normal ability to breakdown glycogen (glycogenolysis) is diminished. b. S&S that might occur in a person with this kind of disease-- muscle weakness & cramps during exercise because of no energy reserves. 2. Type I diabetes: gluconeogenesis taken to extreme: (gluconeogenesis is normal body back-up process, but if disease process alters it or causes sustained usage, then has potentially detrimental consequences) a. people with Type I diabetes mellitus do not make insulin→ without insulin, blood glucose levels increase → without insulin, glucose is not able to get into cells and body turns to sustained gluconeogenesis (BACK-UP PLAN #2) as its main energy pathway. b. this is ok for awhile, but eventually sustained gluconeogenesis causes ketone over-accumulation, resulting in hyperketonemia (high levels of ketones in the blood) c. hyperketonemia is manifested by: FYI: Of course, a diabetic 1) blood test showing high serum ketones. would also have high serum 2) AND usually the following as well: glucose (no insulin = no ability to move glucose from a) blood test showing LOW ( 7.45 heavy alkali guy outweighs light 2) alkalosis is a much less common abnormality than acidosis, acid gang, though both can be very serious. making the pH 3) types of alkalosis: metabolic and respiratory, depending on high cause b) metabolic alkalosis 1) etiology-- a metabolic problem that results in one or more of acid gang light, pH high the following: a) excess accumulation of HCO3 in the body b) not enough excretion of HCO3 in the urine. c) too much acid (H+ and others) being excreted in the alkali guy heavy urine or lost in other metabolic ways. d) not enough acid being made  26 2) any of the above can create a state of high pH and high HCO3 3) some causes of metabolic alkalosis: a) large amount of vomiting. b) over-ingestion of bicarbonate (HCO3). 4) compensation is via lungs, by decreasing rate & depth of respirations. c. respiratory alkalosis 1) state of high pH caused by hyperventilation—increased rate of breathing results in “blowing off” more CO2— less CO2 in the blood = LESS ACID GANG = higher pH. (more on this in pulmonary lecture). 2) example of a cause of respiratory alkalosis: _anxiety (when someone is anxious, they begin to hyperventilate)_. 3) compensation is via kidneys, by _decreasing amount of HCO3 made or increasing its excretion. 3. summary of acid /base imbalances: a. respiratory acidosis: the cause is some sort of respiratory problem in For test 1, which not enough CO2 is exhaled → CO2 is retained & causes concentrate mostly the pH to drop to < 7.35. on metabolic ABGs alterations as b. metabolic acidosis: the cause is some sort of metabolic problem reflected in pH & usually related to anaerobic metabolism and /or the kidneys not HCO3; there might be an answer choice being able to get rid of H+ or to make HCO3 (such as in renal for respiratory failure)—this causes the pH to drop to < 7.35. acidosis or alkalosis, but look at the c. respiratory alkalosis: the cause is some sort of respiratory problem in HCO3 and if it has which too much CO2 is exhaled and causes the pH to go up to > 7.45. changed out of the norm, you know the d. metabolic alkalosis: the cause is some sort of metabolic problem imbalance is usually related to too much HCO3 ingestion, sick kidneys not getting metabolic. In test 3 material, we will rid of HCO3, or vomiting too much acid—this cause the pH to go up to encompass all this > 7.45. info, adding PO2 & PCO2 then. e. re: compensating for an acid/base imbalance: the kidneys compensate for an imbalance caused by a respiratory problem; the lungs compensate for an imbalance caused by a metabolic problem (remember, “metabolic” includes kidneys).