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Carbohydrate Metabolism I, II, III

*know the rate-limiters *know two uses for NADPH (lipid biosynth + reduction of glutathione cross-links in RBC) *NADH is oxidized to generate ATP, NADPH is oxidized to reduce biomolecules such as glutathione I. Explain how glucose is metabolized and stored by various tissues in the body. a. Glucose Sources  Starch and glycogen [α amylase]tri/disaccharides[intestinal lumen enzymes]monosaccharides  Sucrose [intestinal disaccharidase]glucose + fructose  Lactose (milk)glucose + galactose  Taken up by intestinal cells that prefer to use glutamine instead of glucose b. Glucose absorption:  Na dependant co transport: Glucose and Galactose  Na independent co transport: Fructose c. GLUT (glucose transporters)  GLUT1 – RBC, brain  GLUT2 – Liver, intestine, kidney, pancreas  GLUT3 – brain, kidney, placenta  GLUT5 – muscle, spermatozoa (prefers fructose)  GLUT4 – muscle, adipose, heart (insulin-dependant plasma membrane expression) 1. Responds to insulin 2. Stored in vesicles until insulin signaling (blood glucose requires more cellular uptake) 3. Eg: Type I diabetes (insulin secretion deficiency) – GLUT4 not expressed on plasma membrane = hyperglycemia 4. Eg: muscles with defective GLUT4 transporters are weak d. Tissue Glucose Storage
Insulin Response Glucagon Response Glycolysi s AcetylCoA Pentose Phosphate Pathway and NADPH fate Lipid Biosynthesi s Glycogenesi s Other

Tissue

Liver

glycogenesi s glycolysis

glycogensis glycogenolysis gluconeogenesi s glycolysis

Yes

Krebs + OP, FA synthesi s

Yes

     

Glycolysis Glycogenesis Gycogenolysis Gluconeogenesis Lipid synth (PPP) Drug detox

Brain

No GLUT4

No GLUT4

Yes

Krebs + OP

Lipid Biosynthesi s Reduces Glutathione

No

 Glycolysis  Lipid synth (PPP)

RBC

No GLUT4

No GLUT4

Yes

Lactic acid (no

No

 Glycolysis  Lactic acid

mito)

= membranes Lipid Biosynthesi s Lipid Biosynthesi s Yes (not for body)

fermentation

Muscle and Heart Adipos e

glucose uptake by GLUT4 glucose uptake by GLUT4

Yes

Krebs + OP

 Glycolysis  Glycogenesis  Lipid synth (PPP)  Glycolysis  Glycogenesis  Lipid synth (PPP)

Yes

Krebs + OP, FA synthesi s

Yes

I.

Part b: Describe how metabolism of lactose and galactose in individuals can affect fructose intolerance and galactosemia, respectively. Disease Deficiency Stuff that collects Symptoms Fructose Intolerance Aldolase B: Fructose 1 Phosphate glyceraldehyde + DHA Fructose 1 Phosphate  ATPPFK1 glycolysis lactic acid (glycolysis product)  Hypoglycemia  Lactic acidosis

Galactosemia

Galactose-1-Phosphate uridyl transferase: Galactose 1-P UDPgalactose + Glucose 1-P

Galactose-1-P and Galactose

 Cataracts, mental retardation  Fail to thrive, vomiting and diarrhea after milk ingestion

Lactose Intolerance

Lactase : Lactose Glucose + Galactose

Lactose which feeds happy gut microbes

The runs

II.

Describe how high glucose (hyperglycemia) and low glucose (hypoglycemia) in the circulating blood cause release of hormones from pancreas, which affect key enzymes involved in glycolysis, gluconeogenesis and glycogen synthesis and its breakdown. Enzyme Insulin Glucagon Other Controls

Step:

cAMP level Glycolysis (Glucose glucose-6phosphate) Hexokinase

↓ (phosphatases are active) -

↑ (kinases are active) Inhibited by G6P

Glycolysis (Glucose glucose-6phosphate) Glycoysis (fructose-6-phosphate  fructose-1,6bisphosphate) Glycolysis (fructose-6-phosphate  fructose-2,6bisphosphate)

Glucokinase

↑ transcription= ACTIVE -

-

Liver only

PFK1

-

(+) by AMP & F2,6BP (-) by ↓pH, citrate, ATP Allows insulin to indirectly control PFK1

PFK2

dephosphorylate = ACTIVE (liver)

Phosphorylation=INACTIVE (liver)

Glycolysis (posphoenol pyruvatepyruvate) Glycogenolysis Glycogenglucose-1phosphate Glycogenesis (UDP glucoseglycogen) Gluconeogenesis (Glucose 6 phosphate glucose)

Pyruvate kinase Glycogen phosphorylase Glycogen Synthase Glucose-6phosphatase

Dephosphorylated: ACTIVE DephosphorylatedINACTIVE DephosphorylatedACTIVE (A-form)

Phosphorylation:INACTIVE

Phosphorylated-ACTIVE

Phosphorylated-INACTIVE

Transcription =ACTIVE

Liver and kidney only

Sucrose is converted to glucose and fructose. Lactose is converted to glucose and galactose. Galactose is a monosaccharide. Other sugars Fructose goes to fructose-1-phosphate by fructokinase. Aldolase B converts this further. And fructose metabolites are eventually broken down to pyruvate, which enters the glycolysis pathway. -A deficiency in aldolase B causes fructose intolerance. Lactose is converted to glucose and galactose by lactase. -Galactose has specific enzymes associated with it: Galactose is converted to galactose-1phosphate by galactokinase. -Galactose-1-phosphate and UDP glucose are converted to UDP galactose and glucose-1phosphate by uridyl transferase. Glucose-1-phosphate is converted to glucose-6-phospate and goes down the glycolytic pathway. -Lack of or deficiency of lactase leads to lactose intolerance. -A deficiency in galactose-1-uridyl transferase leads to galactosemia.

Glycogenesis Glycogen synthesis occurs in liver and skeletal muscle. 10% of the total weight of liver is composed of glycogen while 1-2% of muscle is composed of glycogen. Since a person has more muscle than liver, there is a greater absolute amount of glycogen in muscle. Glucose is converted to G-6-P by glucokinase (liver) and hexokinase (elsewhere). G-6-P is converted to G-1-P by mutase. G-1-P is converted to UDP-glucose by glucose-1phosphate uridyltransferase. Glucose can be stored in glycogen using two kinds of linkages. These are 1,4 and 1,6 linkages.

Glycogenolysis Overall: Glycogen is converted to G-1-P, which is converted to G-6-P and glucose. When blood glucose is low, the liver releases the hormone glucagon. This hormone releases the secondary messenger cAMP, which activates protein kinase A. -The second messenger can also be activated by the hormone, epinephrine. In the liver, this causes glucagon breakdown. Since muscle doesn’t contain glucagon receptors, glycogen breakdown occurs through activity of epinephrine. This enables to fight-or-flight response. When blood glucose is high, the liver releases the hormone insulin. This hormone activates phosphatase activity. Condition Fasting Carbohydrates Consumed Exercise Hormones Glucagon Insulin Epenephrine cAMP Levels High Low High Metabolic Process Glycogenolysis Glycogenesis Glycogenolysis

Clinical Correlations:

1) Patient has abnormally enlarged liver and hypoglycemia is observed far more often than expected. The patient is tested for deficiency in liver enzymes. What are your two differential diagnoses? Answer: Deficiency in glucose-6-phosphatase (von Geirke’s disease) or a deficiency in liverspecific glycogen phosphorylase would explain the symptoms.

2) Patient has a sugary meal but soon starts to feel sick. A blood test reveals the patient to have hypoglycemia, lactic acidosis, and increased hemolysis. Also, intracellular ATP is reduced. Explain the diagnosis and the symptoms. Diagnosis: The patient has fructose intolerance. Lack of aldolase B causes an accumulation of fructose-1-phosphate (substrate for aldolase B). Fructose-1-phosphate sequesters free phosphate, which prevents the formation of ATP. Low intracellular ATP is a positive regulator of phosphfructokinase-1, which stimulates glycolysis and explains symptoms. 3) Two infants at the same hospital show a poor response to milk. Both infants have diarrhea after but one also presents with an enlarged liver, vomiting, and a failure to thrive. What do these infants have and what are their prognoses? Diagnosis: The first infant has lactose intolerance. It is non-lethal and easy to correct with dietary changes. The second infant has galactosemia, which is far more serious. In the avsence of an enzyme, galactose is converted to galacitol which leads to cataract formation. Toxic effects are lessened when milk is minimized in the diet but the infant will still show long-term complications including mental retardation. 4) Patient has exercise-induced muscular pain as well as cramps and progressive hypoglycemia. Liver is normal. What enzyme deficiency would explain this? Diagnosis: A deficiency in muscle-specific glycogen phosphorylase would explain symptoms as well as why the liver is unaffected.
Gluconeogenesis: Creation of glucose from lactate occurs in Liver - also in Kidney under starving conditions - occurs 18-24 hours after eating, glycogen stores are depleted Precursors: - Lactate - Alanine: converted to Pyruvat - Glycerol

Note which Enzymes are different than Glycolysis Glycolyis Hexokinase/ Glucokinase Phosphofructokinase-1 Pyruvate Kinase Gluconeogenesis G-6-Phosphatase Fructose-1,6-Bisphosphatase PEP carboxykinase Pyruvate Carboxylase

5. Explain how a genetic deficiency of glucose-6-phospate dehydrogenase in RBCs leads to hemolytic anemia G-6-P Dehydrogenase converts:

This reaction generates NADPH as it reduces the NADP+ cofactor.

- NADPH is a cofactor in reducing GSSG  GSG - GSSG = oxidized glutathione - GSH = Glutathione (reduced) -GSH oxidizes to GSSG to break cross-linking of sulphidryl (-SH) groups - A reduction GSH will result in increased cross-linking, leading to rigid blood vessels which lyse easily in capillary beds and the pulp of the spleen. - Oxidant drugs dramatically exacerbate this problem 6. Describe how hyperglycemic conditions generate glucose-protein adducts (AGE) which are deleterious to cells AGE formation is due to prolonged high blood glucose levels exposed to hemoglobin molecules. AGE binds to RAGE (AGE receptor) resulting in the release of chemokines and cytokines. These cause monocytes to transmigrate across the arterial wall and uptake oxidized LDL. These monocytes become Foam Cells and cause inflammation and atherosclerosis (thickening of the wall) in the artery. 7. Explain how AGE molecules (HbA) are used as a metabolic index of diabetes control AGE (advanced glycation end products) are covalent linkages between glucose and proteins. The adducts form without enzymes through non-enzymatic glyocsylation. The amount of adducts formed is directly proportional to the glucose concentration and duration of exposure to macromolecules (specifically Hemoglobin). Higher concentrations of HbA1c indicate a long-term hyperglycemia in the blood. Because HbA1c concentrations are not immediately susceptible to changes in blood glucose levels, they provide a gauge of glucose levels that isn’t affected by prior food consumption (as opposed to insulin levels, or blood glucose levels). Example: After fasting, a diabetic could have a glucose lvl of 150 mg/dL but a HbA1c of 7.8%

Cell-cell/Cell-matrix interactions Multicellularity allows cells to specialize and carry out more tasks simultaneously To become multicellular: - Contact and communicate with other cells - Regulate passage of environmental substances into and out of organism - Recognize self/non-self Occluding/tight junctions: do not involve cytoskeletal elements Formed by claudin and occludin (transmembrane proteins) associations Form tight seal that that not allow most molecules to pass through Found usually on apicolateral surface of cells (epithelial usually) Anchoring junctions: do involve cytoskeletal elements Actin Microfilament associated Adherens junctions Cell-cell junction (mediated by cadherins) Focal adhesions Cell-matrix junction (mediated by integrins) Homophilic vs. heterophilic binding Cadherin family: Calcium-dependent adhesion molecules Low Ca++: cadherins are largely disorganized ~1mM Ca++: Dimers form extracellularly, nucleates other dimers – ‘molecular zipper’ Adherens Junctions: E-, N-, VE-cadherins (‘classical’) Linked to actin cytoskeleton via α/β catenin Desmosomes: Desmocollin, desmoglein Linked to IF via plakoglobin/desmoplakin

Intermediate Filament associated Desmosomes Hemidesmosomes

*Cadherins mediate cell-cell sorting where cells expressing the same cadherins (hemophilic binding) associate with each other and organize into structures Other adhesion molecules: Ig superfamily: Ca-independent family of proteins that are weaker than cadherins and can be both homophilic and heterophilic Selectins Ca-dependent group of adhesion molecules that bind oligosaccharide lectins (heterophilic) Low affinity binding. Responsible for leukocyte ‘rolling’

ECM Hydrated, polysaccharide gel substance with fibrous proteins embedded, important for physical stability and diffusion of important substances. Usually formed via fibroblasts. The basal lamina is a specialized form of ECM laid down by epithelial cells. ECM components Glycosaminoglycans (GAGs): Unbranched, repeating disaccharide units. Hydrophilic, highly negatively charged- responsible for resisting compressive forces Ex: hyaluronan Proteoglycans: Protein + GAG = proteoglycan Formed by a tetrasaccharide link Structral and cell-cell signaling roles Fibrous proteins: Collagen – long inflexible fibers providing strength Elastin - mesh-like fibers that provide flexibility Fibronectin – recognized by attachment proteins Laminin - recognized by attachment proteins Integrins Transmembrane receptors (heterodimeric) with affinity for RGD motif in fibronectin. Linked to actin/IF cytoskeleton via talin. Can communicate bi-directionally. ECM →cell: Leukocyte recruitment Cell → ECM: ECM remodeling for ‘pathfinders’ Communicating junctions: mediate chemical or electrical signals from one cell to another Gap junctions Mediated by membrane channels called connexons, which are formed by 6 connexin proteins Permeability affected by pH and Ca++ (open with high pH, low Ca++) Chemical synapses Fast type of paracrine signaling

Blood: Never Let Monkeys Eat Bananas
Element Function Identifying characteristic no nucleus or other organelles, biconcave shape, appear electron dense Abundan ce Lineage proerythroblasts -> erythroblasts -> reticulocytes (no nucleus) -> RBCs (left bone marrow, no more RNA) megakaryoblast >megakaryocyte (in bone marrow) --> 1000 platelet clumps (made of cytoplasm)

Erythrocyte

Thrombocyte (platelets)

Neutrophil

Eosinophil

Basophil

transport O2, transport a little CO2 trigger thrombi to limit blood loss at injury site; aggregate w/ platelets, alter blood flow, initiate coagulation cascade phagocytosis & destruction of bacteria destroy larger parasites / modulated allergic response release histamine & heparin (anticoagulation) mature into macrophages --> phagocytosis B cells --> plasma cells; T cells --> immune rxns produce platelets; located in bone marrow produce RBCs; located in bone marrow found in connective tissue; secrete targeted antibodies found in connective tissue; phagocytic; act as antigen-presenters

most abundant

discoid, small fragments (small specks interpsersed w RBCs) multilobed; clear or light pink granules

many

60-70%

myeloid cell myeloid cell

multi-lobed (2); pink/orange granules S-shaped nucleus, blue/black granules

1-3% myeloid cell <1% lymphoid cell: enter lymphoid organs --> macrophages (Myeloid lineage) myeloid cell: B cells --> plasma cells

Monocyte

irregular, kidney-shaped nucleus; no granules large, round, dark nucleus largest cell; has clusters of proplatelets look like RBCs but still have RNA (blue stain in cytoplasm) lots of rough ER that is dilated; clumps of heterochromatin; no storage vessicles many cytoplasmic processes, numerous lysosomes

4-10%

Lymphocyte

20-30%

Megakaryocyte

Reticulocytes

Plasma cells

Macrophages

Pharmacology: Drugs and Development
MSP NOTE These are the 3 things you need to know 1. Phase 1: is for dosage and safety 2. Phase 2: is for efficacy 3. Phase 3: benefit/risk ratio Major stages of drug development a. Drug Discovery i. FDA role: minimal 1. Guidelines and regulations 2. Review non-clinical findings ii. How would you like to make your drug? 1. Modify known molecules 2. Design a new molecule based on known biology and chemical of substrates and enzymes 3. Randomly screen natural or synthetic products 4. Recombinant technology 5. Use genetics to discover new drug targets 6. Modify antibodies 7. Get lucky (ex. Penicillin) b. Initial Drug Screening/ Non-clinical Research Phase i. Sponsor submits an IND (Investigative New Drug) investigational exemption to FDA showing a drug is reasonably safe for small-scale human clinical trials ii. FDA role: active iii. What is in the IND (Investigative New Drug) investigational exemption application 1. 30 Day waiting period for FDA to improve a. no answer from FDA: Proceed with trials 2. Ultimate Goal: ensure safety of compound for volunteers when drug goes to clinical trials iv. Information needed by FDA on the IND app 1. Drug composition and source 2. How drug is manufactured 3. Plans for the clinical study and protocol 4. Credentials and names of physicians 5. safety review of the non-clinical research data to determine whether clinical trials should be allowed 6. pharmacological profile of lead compound to assess therapeutic action, activity, and selectivity a. molecular activity b. cellular effect c. effect on systems 7. determine acute single dose toxicity a. on 2 species of animals

i. animals used to find out pharmacokinetics and pharmacodynamics ii. from weeks to years, esp. if drug is designed for longterm use b. two routes of administration (ex. Oral, intravenous, subcutaneous) 8. determine subacute (short-term) toxicity i. 2wks or 3 months long depending on whether the drug is intended for long term or short term usage

Phase

Blind/Not Blind; Study design
Non-blind (this is not true!)

Subjects

Length

Study goals

Potential roadblocks
FDA hold on study (sponsor does not disclose study risk, protocol does not meet objectives) - SAEs (serious adverse events)

Phase I

20-80 Health volunteer s (often paid)

6-12 mths

-PK (safety and minimum effective dose) -PD (metabolic and pharmacologic effect  adverse events) -dosing: greater phylogenetic difference from human= greater dilution of minimal effective animal dosage (ex. If primate’s minimal effective dosage is 10 g/L, then a human’s minimum dose will be 5 g/L

Phase II

-Single and Double Blind both present -Randomized control studies to observe effect on specific factors (age, sex, disease progression, etc.)

Several hundred patients with target disease

months to 1 yr

-PK (efficacy and safety) -PD: short term AEs and risks -PD: initial studies into long AEs

-FDA hold -Placebo effect -Presence of SAEs

Phase III

Double blind

-Several 100several

1-4 years

-PK: effectiveness -safety

-FDA hold -SAEs

1000 -Done across the country in multiple centers

-benefit>risk? -PD: less common and rare AEs -create a dosage regime for physicians to give to patients variable -long term safety -fine tune delivery and dosage -catch unexpected or rare AEs

-NDA (New Drug Application) does not get FDA approval to go on the market!! (2 months to 7 years to get approved) -major AE is discovered that is egregious health risk -FDA pulls the drug off the market

Phase IV (Postmarket ing Surveill ance)

-done after NDA approval -surveys of current users and physicians -clinical trials -annual reports from manufacturers

Patients currently taking the drug

4. List essential information to be developed in Phase I, II, III and IV (see above) Orphan Drugs -an orphan disease is a disease that afflicts less than 200,000 Americans -pharmaceutical companies are incentivized by the FDA to make drugs for such diseases, even though it would be a loss of profit for the companies -incentives include grants to pay for the drug development Accelerated Development -some diseases have a dire need for drugs (ex. When AIDS first appeared, there were no drugs to combat the disease, many cancers also fall into this catergory) -as such, the FDA is willing to accelerate the time of clinical trials to a shorter duration to get said drugs onto the market -Another part of accelerated development is that patients can be subjects during phase I, because many of these patients have already exhausted all treatment options.

Epidemiology 3: Introduction to Study Designs
1. State the “exposure-disease” hypothesis when given a description of a study.

Exposure (E) = the independent variable Disease (D) = the dependent variable; may also be called “outcome” Basic hypothesis: “If exposed, then disease.” 2. Recognize possible explanations for an observed association; e.g. recognize that any association observed in a hypothesis-testing study might be causal, or due to chance, confounding, or bias. Questions to ask when evaluating possibilities besides causality: - Chance: What is the p-value and/or alpha-value? What is the probability that the observed association could have occurred by pure chance when there is no actual relationship? Is it possible that we are rejecting the null when it is true (type I error)? - Confounding: Are there other variables that could be in play besides E and D? What other factors might be connected to E? What else might cause or contribute to D? - Bias (ex. selection bias, information bias): Are there any issues with the study design (ex. sampling technique, reliability of reported data, etc.) that might affect the results? 3. Describe the criteria used for judging whether an association is causal. 1. Temporal relationship – E precedes onset of D 2. Strength of association – Stronger associations are more likely to be causal; look for a high, statistically significant relative risk (RR) value 3. Dose-response relationship – Strength of the association shows a relationship with the level/dose of exposure 4. Consistency – Same association is observed in multiple different types of studies and in different populations 5. Biological plausibility – Reasonable explanation for how E  D; experimental evidence 6. Consideration of alternate explanations – Other possibilities (see objective #2) have been controlled for or otherwise ruled out 7. Cessation of exposure – rate of D decreases after E is eliminated/reduced; similar to doseresponse relationship 4. Understand the differences between descriptive and analytic studies. Descriptive studies describe patterns of disease occurrence relative to characteristics of person, place, time; can be used to identify correlations and formulate hypotheses, but do not have capacity to test them; do not examine a specific exposure-disease association

Analytic studies focus on and test hypotheses regarding exposure-disease associations *Note: Testing does not necessarily mean experimental or intervention studies (actively assigning E to subjects in order to observe results); observational studies are considered analytic too, in that they are also designed to find evidence of causality for a particular E-D association - Cross-sectional studies could be considered either descriptive or analytic 5. List the major types of descriptive studies, and describe the advantages and limitations of descriptive study designs.

Type of Descriptive Study

Pros

Cons

Case reports, case series – give information on a single patient or group of patients (usu. for unusual/rare conditions) PERSON

- Most basic type of descriptive study – easy, inexpensive - Early warning – brings attention to new/rare conditions - Can help generate hypotheses

- No comparison groups – cannot test hypotheses - Deals with single or small number of cases (which might be exceptions, not a representative sample), so limited generalizability

Ecological studies (correlational studies) – document disease occurrence in relation to specific population characteristics (measures of exposure for population as a whole, i.e. averages); E and D data on populations, not individuals (usu. based on geographic regions) PLACE

- Also relatively easy, inexpensive; data usually already available - Can work with data that is only available/possible to report as a population-based measure (ex. air pollution in a given city) - Can help identify potential risk factors for a disease, generate hypotheses applicable to individuals

- No way to control for confounding factors (if group data on these factors is not available) – cannot test hypotheses - Beware of ecological fallacies – cannot distinguish in group data whether individuals with disease were in fact the ones who were exposed, so unable to form an E  D conclusion

Studies of disease frequency – examine change in disease/death frequency with respect to personal characteristics (age, gender, race, etc.), location (geographic

- Can help identify potential exposures that are causing differing disease rates in specific populations, locations, or time periods; generate

- Again, cannot test hypotheses from these studies alone

area, city or rural, etc.), over time PERSON, PLACE, and TIME

hypotheses

6. For each of the major types of descriptive and analytic study designs: (a) Describe in general terms the basic process for conducting the study (b) Distinguish between designs from a brief description.

Analytic Studies
Cross-sectional: Take sample from specified population, then ascertain both E and D status at same time for each subject in sample.

Observational (Nonexperimental; the three C’s)

Cohort: First identify E or non-E status in subjects without D, then follow to observe onset of D. (Can be retrospective if info on E status is obtained from past records)

Case-control: First identify cases and non-cases of new/incident D, then ascertain E status (current or past).

Intervention (Experimental)

Intervention: Randomly assign E to subjects, then observe effect on D. Can be E1 vs. E2, or E vs. placebo/control.

For the types of descriptive studies, refer to first column of the table for objective #5.

Epidemiology 4: Analytic Study Design
1. For each of the major epidemiologic study designs be able to: a. Identify the type of study design from a brief description of the study b. Recognize the major advantages and disadvantages inherent in the design c. Recognize situations in which each would be the most appropriate study design d. Describe which measures of association are commonly used with each design
Study name Pros Cons When do you use it Measures associated with this study How is it different from the other studies? -lack of time variable -no %s (AR%, PAR%) -common E and O

CrossSectional

-2nd cheapest and quick -generates hypotheses -results can be generalized to the population

-temporality bias -prevalence bias -selection bias -hard to find subjects with rare exposures or disease

-when you don’t know time or don’t have it -when you are observing a common E and O in a defined population -when you just want incidence of O -when E is rare

-prevalence -odds ratio -relative risks

Cohort

-no temporality issues -no ethical issues -rare exposures can be followed -it’s okay if we get multiple outcomes -more robust to selection bias -less likely that results will bias our study -we can find incidence rates!

-expensive -not good for rare disease outcomes, but if your exposure is rare disease, that’s fine -validity (presence of information bias, confounding, and loss to follow-up can screw things up) -nonparticipation: many will be ineligible for a rare disease study, makes the study difficult to generalize

-Absolute Risk -Relative Risk -AR% -PAR%

You can’t get an odds ratio -You can control time! (prospective vs. retrospective)

CaseControl

-cheapest -rare diseases can be studied multiple exposures can be investigated simultaneously -efficient -OR can be used to estimate relative risk

-validity (information bias, selection bias, prevalence bias, confounding, and temporal relationship bias)

-Odds Ratio -AR% -PAR%

-you can’t get relative risk. At all.

Intervention

-this can “prove” causality -no temporal bias -no selection bias -multiple outcomes can be studied -incidence rates can be measured directly

-expensive -not always feasible -not always ethical -outcomes can be limited by time, money, etc. -validity placebo effect, information bias, loss to followup, noncompliance, confounding)

You assign exposure and monitor through time to see outcome

-incidence rate -relative risk -AR and AR% -PAR and PAR%

-you can measure incidence rates (not like case-control)

2. Describe the differences between cohort studies: “specific exposure” vs “general population” cohort studies, and “prospective” vs retrospective” cohort studies. a. Specific exposure vs general population i. Specific exposure: subjects are chosen to represent a specific exposure ii. General population: subjects are chosen to represent the population, which has a wide range of exposures iii. What’s the difference: one exposure versus several iv. Examples, which is which? 1. You are chosen for a study that is interested in seeing if there is a relation between taking the MCAT and the average stress level of all current graduate school students (exposure: MCAT, disease: stress level) over the course of 4 years 2. You are chosen for a study that is interested in seeing if exposure to cadavers, hospitals, and libraries leads to the development of any stress-related diseases b. Prospective vs retrospective

3.

4.

5. 6.

i. Prospective: subjects are chosen who are exposed, and the investigator follows the cohort into the future to see if exposure leads to disease ii. Retrospective: subjects are chosen who have already been exposed and show disease iii. What’s the difference: one hasn’t shown signs of disease yet and the other already has iv. Examples, which is which? 1. You choose subjects for a study on lung cancer based on their exposure to asbestos before retirement 2. You choose subjects for a study on lung cancer based on their current exposure to asbestos Explain the purpose, process, and effects of matching in a case-control study. a. Purpose: to prevent confounders (the reason why we do anything in statistics, really) b. Process: Pair control and exposed group based on matched control variables (ex. Age, race). But it’s tricky to match more than two controls c. Effect: By eliminating as many confounders as possible, you increase the chance that a relationship between exposure and disease are associated, and not due to chance (think back to t-tests) d. Examples i. A study of a new diabetes medication’s efficacy in lowering blood glucose levels compared to the current market’s top grossing diabetes medication is done via case-control study. The control group and case group are all of the same race, age, and sex ii. Your turn! Describe the process of conducting and advantages of a nested case-control study, and recognize examples from brief descriptions of studies. a. Nested case-control: when members of a cohort develop the disease of interest, you can select members from the cohort who have yet to get the disease to be their controls. So basically you create a control group in a cohort study b. How we do this: we separate diseased from non-diseased. We match up those with the disease to a control ‘partner’ in the non-diseased group. We then look to the previous information we’ve gathered on the cohort members to determine what the exposure was that brought about the disease c. Example: Nurse Health Study. If a group of nurses in this study cohort developed alcoholism do to exposure to over 200 trauma cases per year, we can attempt to prove this relation by making the non-alcoholic nurses the control and the alcoholic nurses our exposed group d. Your turn! Explain why an incidence rate ratio cannot be calculated directly in a case-control study a. The controls that we select for a study is only a small fraction of the population that is not exposed. Explain why the odds ratio is a good estimator of the RR in a case-control study. a. Odds ratio is a good estimator because of the nature of the case-control study, which is looking at disease, aka outcome, measurement, and not the exposure measurement. (because we supposedly already know what they were exposed to or exposed them to it) b. Example: (which is totally, not mine, it’s from http://www.childrensmercy.org/stats/journal/oddsratio.asp and super brilliant)

c. Consider a case-control study of prostate cancer risk and male pattern balding. The goal of this research was to examine whether men with certain hair patterns were at greater risk of prostate cancer. In that study, roughly equal numbers of prostate cancer patients and controls were selected. Among the cancer patients, 72 out of 129 had either vertex or frontal baldness compared to 82 out of 139 among the controls (see table below). Cancer cases Balding Hairy Total 72 55 129 Controls 82 57 139 Total 154 112 268

d. So you can estimate the probability of balding for cancer patients (72*57)/(82*55), but you can’t calculate the probably of cancer for bald patients. e. This is because we are looking for information on the outcome. There are plenty of bald people out there who don’t have cancer, but that would be a huge probability that is clearly not represented in the data we have here. f. So you would need additional information or a different type of research design to estimate the relative risk of prostate cancer for patients with different types of male pattern balding. g. You can always calculate and interpret the odds ratio in a case control study as long as the outcome event is rare 7. Recognize the purpose for randomization in intervention studies. a. Ex: A study on 1st graders’ height growth wants to see the association between drinking milk with increases in height. They plan to give the control group one extra cup of water at lunch everyday, and the exposure group one extra cup of milk at lunch everyday. b. The researchers notice that some of the children are definitely smaller than the others…and they worry that maybe the children aren’t getting enough nutrition at home c. So they decide to put all the smaller children in the milk-drinking group d. What could potentially happen to these smaller children that were not randomly assigned to the exposure group? What could potentially happen to the study’s results as a whole? i. The small kids grow a lot the study claims that kids have dramatic height growth when they drink milk everyone makes their kids drink milkmany kids and parents are disappointed when they don’t grow much ii. The small kids don’t grow much, they just get fat the study finds not enough information to associate milk and height, but they instead say there is an association between weight gain and milk everyone stops their kids from drinking milk many kids and parents are disappointed when they don’t grow much e. And that’s why you randomize your intervention studies. B&SM, N-1

N-1 Meeting Nutritional Needs
Learning Objectives 1. Compare nutrient-based and food-based approaches to evaluating or planning dietary intake a. Nutrient based Approach – Based on the nutrients within food i. DRIs – Dietary Reference Intakes 1. RDA – Recommended dietary allowance a. Not a minimum requirement designed to meet the needs of 97% of a healthy population b. Built in Safety cushion – specific to age, gender, life stage c. AI – Adequate intake: used instead when a range is necessary ie when we don’t have enough information to determine a discrete level of intake 2. UL – Tolerable upper limit. When to be concerned that too much of a nutrient becomes toxic (supplements) 3. EAR – Estimated average intake a. Not used as often as RDA. Designed to meet the needs of 50% of population 4. DV and %DV – food label not very detailed. Does not take age, gender, nor life stage b. Food based approach – takes into account food people eat i. Daily Food Plan, MyPlate, MyPyramid ii. Food intake patterns – Personalized plan iii. Food groups – Grains, meat and beans, dairy, vegetables, fruit, discretionary calories 2. Describe the features of the MyPlate, DASH diet and ADA Exchange Plan. a. MyPlate – Meal based plan as opposed to a plan for the day i. 9” plate; 0.5 fruits and vegetables, 0.25 grains, 0.25 protein. Dairy is a “side” b. DASH – Dietary approaches to stop hypertension i. Plan for individuals with hypertension or are pre-hypertension (OK for nonhypertensives) ii. Low sodium, fruits and vegetables emphasis, low/non-fat dairy iii. 1500g Na per day (very low) c. ADA Exchange system – American Diabetes Association i. foods organized into groups based on similar macronutrient and energy content (EXCHANGE one food for another) ii. Used for individuals with diabetes, not endorsed for those without (although many hospitals use it for patients) 3. Explain how energy needs are determined. a. Medical Nutrition Therapy(MNT) – diet modification due to illness or disease b. Look at dietary intake and anything that my interfere with nutrients being digested, absorbed, or used. Take into account food consistency, abnormal losses, increased requirements, impaired metabolism c. Food consistency, feeding approach (discussed in #7) d. Social/cultural concerns – RS loves his pizza! 4. Describe what factors affect protein requirements and how protein needs are estimated. a. Protein RDA is 0.8g/kg/day

b. Needs range depending on Protein catabolic rate(g/day) i. Hypermetabolic patients derive more energy from protein as physiologic stress increases c. Catabolic rate from 24hr Urinary urea nitrogen measurements i. Protein catabolic rate = (24-hr UUN + 4)*6.25 (DON’T MEMORIZE) ii. Add about 10g/day to calculated need 5. Describe seven methods for modifying a normal diet (as part of medical nutrition therapy). Table 2. Methods to modify “normal” diets Modification Example 1. Change in consistency of foods: Liquid diet, soft diet, low-fiber diet 2. Change in energy content: High-calorie diet, weight reduction diet 3. Change in type of foods consumed: Na-restricted diet, lactose-restricted diet, high-fiber diet 4. Omission of specific foods: Gluten-free diet, allergy diet 5. Change in energy distribution: (% kcal from CHO, fat and protein)Diabetic diet, renal diet, low-fat diet 6. Change in number and frequency of meals: Diabetic diet, post-gastrectomy diet 7. Change in route of delivery of nutrients: Enteral and parenteral nutrition 6. Distinguish between enteral and parenteral nutrition support. a. Oral – eat the food through your mouth b. Parenteral – nutrients provided into systemic circulation i. PPN –peripheral parenteral nutrition though IV 1. cannot supply all energy needs (3-4 days) ii. TPN – Total parenteral nutrition through subclavian vein (all nutrients provided) iii. GI track is non-functional c. Eneteral – provides nutrient solutions into the GI track through tube i. Bypass mouth, can be inserted almost anywhere in GI ii. 100 cm of functional small intestine needed 7. Discuss what happens during refeeding syndrome and under what conditions refeeding syndrome is likely to occur. a. Refeeding results in Shift from fat to CHO metabolism, insulin release, cellular uptake of electrolytes b. Occurs with rapid and excessive feeding of patients with severe underlying malnutrition, primarily hypometabolic patients c. Occurs in first 24 to 48 hrs – can result in death d. Hypermetabolic patients i. Meet but not exceed needs ii. Hyperglycemia, impaired immune function and wound healing, infection risk iii. Problem with TPN

8. Explain the risks associated with refeeding and why hypometabolic, starved patients are at increased risk. a. Risk of hypophosphatemia (critical – weakness, paralysis, resp failure, decreased card. output), hypokalemia, hypomagnesemia, hypocalcemia b. Hypometabolic patients at risk because of their adaptation to energy deprived state 9. Describe how refeeding risks can be avoided. a. Longer bowel rest – slower refeeding b. Check for hyperglycemia in hypermetabolic patients

Nut2: Macronutrients
1. List and describe characteristics of macronutrients Carbs Proteins Energy 4 kcal/g 4 kcal/g Function -source of energy (spares -tissue maintenance and protein) growth -necess. For fat metabolism -fluid balance -acid-base balance -hormones/enzymes -immune function -energy (sometimes) Intake -45-65% 10-35% Essential None Thr, trp, val, leu, lys, ile, nutrients met, phe, his Endogenous Gluconeogenesis Lean-body tissue, Glycogenolysis transamination Exogenous Plant Animal + Plant Storage Glycogen None Metabolic H2O, CO2, ATP H2O, CO2, ATP, N Fate Lipids 9 kcal/g -energy -comprise membranes -lubricants -signaling molecules -flavor/heat retention to food 20-35% Linoleic and linolenic acid Adipose tissue Animal + Plant Adipose H2O, CO2, ATP

2. How is dietary fiber part of maintaining health o Dietary fiber- cannot be digested, defined as CHO, diverse group of polysaccharides i. Insoluble fiber- not soluble in H2O, decreasing transit time in intestine ii. Soluble fiber- forms gel matrix in intestinal track when mixes with H 2O 1. Slows absorption of substances (i.e. glucose)and slows movement of contents through intestine 3. Describe glycemic index and glycemic load and explain differences

o GI- physiological/functional classification of CHO i. Determined by comparing the effect on blood sugar of equal amounts of carbohydrate (50g) in the test food and a reference food o GL- does not take into account amount of CHO in food per serving but rather the amount of food typical eaten i. Better predictor of impact of food on blood sugar (takes into account GI and amount of CHO in that food) 4. Describe what happens when someone is lactase deficient, state name of condition, and describe treatment options o Lactose intolerance- deficiency of lactase enzymeinability to break the α1,4-galactosidic bond between galactose and glucose i. Symptoms- bloating, cramping, diarrhea, after consuming lactose ii. Treatments- avoid lactose and using lactase enzyme supplements 5. Describe trans fatty acids and clinical relevance o Trans fatty acids- formed by partial hydrogenation of naturally occurring PUFA trans isomer MUFA i. Naturally occurring, but account for small amount of dietary trans fatty acid intake ii. Clinical relevance- associated with adverse health effects (incr. risk for cardiovascular disease, increased LDL (“bad chol.”) and decreased HDL (“good chol.”) Remember: MUFA > PUFA > SFA > TFA 6. Describe conditions under which ketone bodies are formed, what organ produces them, and what cells use them as fuel sources (incl. conditions) o Ketone bodies are formed by glycogenolysis during fasting lasting less than two days and production increases during fasting lasting more than two days o Formed by the liver o Used as a source of energy for cells (i.e. muscle) and can cross the bloodbrain barrier 7. Discuss nutrient fuel during fed vs. fasting states o Fed: origin of blood glucose is exogenous and all tissues use glucose as fuel i. Dietary fat deposited in adipose tissue ii. Amino acids from protein used for protein synth. Or degraded iii. Excess energy stored as glycogen, then trigylcerides o Fasting: i. Up to 48 hours: glucose is preferred fuel source (most going to brain) 1. Gluconeogenesis in liver to meet metabolic demand for glucose 2. Glycogenolysis in liver (maintaining blood glucose levels) and in muscle (providing source of glucose for muscle cells) a. Livery glycogen depleted in 12-24 hours b. Ketone bodies synthesized (increasing plasma levels of free fatty acids from adipose tissue)

3. Lipyolysis, but not major source of energy ii. After 48 hours: metabolic shift to spare body protein 1. Shift from gluconeogenesis to lipolysis 2. Increased reliance on fatty acids as fuel source 3. Increased production of ketone bodies by liver

SPP Case #2: Diabetes
Type 1 Pathophysiology - Due to partial or complete loss of insulin production by pancreatic beta cells - Islet cell antibodies involved in etiology: patients will present with antibodies to islet cell proteins, meaning autoimmune process has begun Type 2 - Due to gradual resistance to insulin - Asymptomatic at first - Slowly develop insulin resistance, leading to obesity and other metabolic changes - Diagnosed based on finding elevated levels of glucose in blood, or glucose in urine - Abnormal levels: >125 mg/dL fasting or >200 mg/dL any time Treatment Insulin supplements - Can be treated in earlier stages with oral medication and lifestyle management (diet, exercise) - Need to cut back on carbs more than any other nutrient Prevalence of all cases Age Weight Lifestyle Infection risk Symptomatic 5-10% Any age, but usually young Thin to average No associations found Increased Mostly symptomatic 90-95% Usually over 40 years old 80% obese Sedentary Increased Occasionally asymptomatic

Weakness or fatigue Polydypsia/ polyuria Polyphagia with weight loss Blurry vision

Often Often (3Ps) Often Often (increased ECF glucose causes swelling) Rarely Often

Occasionally Rarely Rarely Rarely

Peripheral neuropathy Ketonemia or ketonuria

Occasionally Never

Long-term complications    Result from hyperglycemia and metabolic changes Leading cause of polyneuropathy, end-stage renal disease, and blindness Eyes o Damage of arterioles or retina  microaneurysms, hemorrhages o Increased formation of cataracts o Gradual vision loss can lead to blindness Kidneys o Glomerular renal damage diagnosed by elevated protein and glucose in urine o Decreased renal function results in renal failure Vascular and Nervous systems o Increased atherosclerosis o Polyneuropathy (damaged nerves, especially in the periphery), angiopathy (damaged vessels, especially coronary arteries and feet)  Combined with an infection, may need to amputate feet or leg  GI tract can also develop autonomic dysfunction o Smoking greatly increases risk of atherosclerotic (cardiovascular) disease in diabetics  95% of all amputees are smokers because of decreased oxygen to tissues  Increases blood pressure, lipids, insulin resistance

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Embryology I Objectives
Describe the general timing of human development: Day 0 Week 1 Weeks 2-3 Weeks 3-8 Weeks 9-38 Fertilization* Preimplantation Early development and gastrulation The “embryonic” period** The “fetal” period **

*All times in this class are from fertilization, not last menstrual period **We’re not really going to differentiate between embryo and fetus for the purposes of this class.

Most important developmental milestones happen in “embryonic” period: Day 21: heart has formed, begins to beat. 22-24: increased neural tube development, begin to define head, fetus has a tail 28-36: limbs begin to develop, tail begins to recede, heart large compared to body 44-48: differentiates fingers, toes, facial features 52-56: finally developed all the parts, recognizable as a baby Describe how the fertilized egg develops to the implantation stage: Oogenesis: Woman’s eggs established during embryonic development, mature oocytes remain stable until puberty, when one is mobilized per month until menopause. (By end of reproductive period, the oocyte has been dormant for ~40 years, high risk of Down syndrome.) Fertilization: Egg is released from the ovary, fertilized in the fallopian tube. Once sperm and egg unite, embryo is called a zygote. Formation of blastocyst: Single cell zygote travels down fallopian tube, has many cell divisions without growing in overall size. At 32 cell stage, begins to hollow out with fluid inside sphere— called blastocyst. One section is a bit thicker— called the inner cell mass, which becomes the embryo proper. The rest of the blastocyst is called the trophectoderm, which will become the placenta. Central hollow cavity called the primary yolk sac. Implantation: On day 4, the blastocyst reaches the uterine cavity. Day 6, it adheres to the uterine wall. Penetrates endometrial (uterine) epithelium and underlying tissue by growth of the trophectoderm—called implantation. Size of blastocyst still the same at end of week 1, implantation and maternal nutrients allow subsequent growth.

Core I: MM, B-11 Bioenergetics and Oxidative Metabolism Objectives 1. Role of the ATP cycle in anabolic and catabolic pathways:  Catabolic reactions generate ATP by oxidation: carbs, fats, aa  Anabolic reactions utilize ATP in the synthesis of macromolecules, muscle contraction, active transport, nerve conduction and thermogenesis.  “High energy” bond in ATP = phosphoanhydride bond between gamma and beta carbons 2. Name the three general classes of substances that are oxidized in order to from ATP  Carbohydrates (Glycogenolysis  glucose  pyruvate)  Fats (Lipolysis  fatty acids  acetyl CoA)  Proteins (Proteinolysis  amino acids  pyruvate, acetyl CoA) 3. Write an equation relating Gibbs free energy (G) to enthalpy (H) and entropy (S). Describe how changes in G are related to exergonic and endergonic reactions and to equilibrium  G = H - TS  Exergonic reaction: G < 0  Endergonic reaction: G > 0  At equilibrium G = 0 4. Explain the importance of pyruvate dehydrogenase (PDH) in oxidative metabolism and describe its regulation. Name the five cofactors utilized by this enzyme.  Pyruvate: alpha-keto carboxylic acid, glucogenic, decarboxylated  acetyl CoA + CO2  Pyruvate dehydrogenase functions: Krebs cycle, FA synthesis, FA oxidation, ketone body synthesis and oxidation, cholesterol synthesis, aa, FA metabolism  PDH in oxidative metabolism: pyruvate is transported across inner mitochondrial membrane into the matrix where it is oxidized by PDH to acetyl CoA  PDH structure: 3 catalytic subunits (E1, E2, E3), 2 regulator subunits, one binding protein. Three subunits pass the substrate along to complete the whole reaction.  Regulation: (+) Mg2+, Ca2+, (-) PD products, NADH, Acetyl CoA  Indirect Feedback Regulation: lipoyl-lysine binds pyruvate dehydrogenase kinase 3 (PDK3), stimulates kinase, phosphorylates PDH E1, inactivates enzyme  PDH cofactors: i. Coenzyme A ii. NAD (nicotinamide adenine dinucleotide) iii. FAD (flavin adenine dinucleotide) iv. TPP (thiamine pyrophosphate) *vitamin B deficiency = Beriberi v. Lip (Lipoic acid) 5. Name the most important function of the Krebs cycle and list three other functions.  Production of ATP  Acetyl CoA is oxidized to 2 molecules of CO2, CoA released  ? 6. Identify three energy-rich products produced by the Krebs cycle and discuss their role in bioenergetics.  NADH (electron carrier, 2e-, 1H+) enters ETC, needed for ATP production  FADH2 (e- carrier) enters ETC, needed for ATP production

 GTP )= ATP (cellular energy) 7. Recognize the names of the enzymes and intermediates in the Krebs cycle.  Citrate  Isocitrate  Ketoglutarate  Succinyl-CoA  Succinate  Fumarate  Malate  Oxaloacetate 8. Briefly describe how the Krebs cycle intermediates are generated.  Regulation based on availability of substrates, availability of O2, need for energy (ATP), and allosteric enzyme regulation  Krebs cycle: delta G << 0, highly exergonic  ? 9. Name the intracellular location of the Krebs cycle and oxidative metabolism.  Kreb Cycle: mitochondrial matrix  Oxidative metabolism: inner mitochondrial membrane

Thoracoabdominal Wall and Breast
Describe the bones and muscles of the thoracic body wall. Bony thorax composed of: Sternum (manubrium, body, xiphoid process), Xiphoid process can calcify. Ribs: (usually) 12 pairs; articulate posteriorly with vertebrae; anteriorly #1-7 articulate directly with sternum via costal cartilages (true ribs), #8-10 cartilages articulate with cartilage of rib immediately superior to it, (form costal arch; 8-10 have cartilage to attach to the rib. The design is great in order to allow expansion of the bony rib cage that is necessary for breathing); #11 & 12 are “floating” ribs which end in the abdominal wall musculature. Thoracic inlet: superior opening of thoracic (chest) cavity, bounded by vertebral body, 1st rib, manubrium of sternum; passage of important structures: trachea, esophagus, large vascular channels=important structure goes through. Thoracic outlet: inferior boundary of thoracic cavity; 12th thoracic vertebral body posteriorly, cartilages of 12th-

Note these landmarks: trapezius, clavicle; pectoralis major (ant fold of axilla; latissimus forms posterior fold); External abdominal oblique, internal abdominal oblique, tranversversus abdominis muscle and rectus abdominus

List the layers of the thoracic body wall from the skin to the pleural cavity. EpidermisDermisSuperficial fasciadeep fascia(muscle depending on region, but if over pectoralis major then…pectoralis majorpectoralis minor)external intercostal musclesinternal intercostal musclestransverse thoracis musclesendothoracic fasciaparietal pleura Diagram a typical intercostal space showing the muscles and neurovascular bundle.

External intercostal: most external; “hands in pocket” orientation; continuous posteriorly but membranous anteriorly; Internal intercostals: next layer; fibers are at right angles to those of ext intercostals; membranous posteriorly; seen well just lateral to sternum Innermost intercostals are included for completeness; they are inconstant and not necessary for you to know. Neurovascular bundle runs under the ribs. Discuss the dermatomes of the body, including specific levels

Each area represents cutaneous innervation from 1 spinal cord level, is continuous around the thorax or abdomen with the back, and is derived from the dorsal and ventral rami of the given spinal cord level. T4 spinal nerve innervates the body wall at the level of the nipple

T10 spinal nerve innervates the body wall at the level of the umbilicus Realize also that there is considerable overlap of the dermatomes.

Describe the muscles of the anterolateral abdominal wall, and compare them to the muscles of the thoracic body wall, including fascicle orientation and segmental innervation. Anterolateral abdominal wall muscle External abdominal oblique Internal abdominal oblique Orientation Thoracic body wall muscle External intercostal muscle Internal intercostal muscles Orientation

“hands in pocket” Fibers perpendicular to external

“hands in pocket” Lies lateral to the sternum, perpendicaular to external Inconstant, know tranvsverse thoracis muscle as representative position of the vein, artery and nerve

Transversus abdominis muscle

Fibers are oriented transversely

Transverse thoracis muscles

Rectus Abdominis

Vertical muscle

Muscles of the anterolateral abdominal wall: • Protect and support contents of abdominal cavity • Compress abdominal cavity and contents • Flexion and rotation of torso; maintaining posture The intercostal nerves are the ventral rami of the spinal nerves T1-T11; T12 is called the subcostal nerve. These nerves segmentally innervate the thoracic wall, with somatomotor fibers going to the intercostal muscles and somatosensory to the overlying skin and the fascia. The anterolateral abdominal wall is innervated by extensions of intercostal nerves from T7-T11, the subcostal nerve T12, and two branches from L1. These nerves begin as ventral rami and course laterally and anteriorly between the internal abdominal oblique and transversus abdominus.

Describe the functions and boundaries of the breast:

Boundaries: Rectus Abdominis Vertical muscle

 comprised principally of fat, connective tissue, and mammary glands (modified apocrine sweat gland specialized for milk production)  lies anterior chest wall between the 2nd and 6th ribs from the sternum almost to the midaxillary line o mostly overlies the pectoralis major muscle (2/3) but extends inferolateral over the serratus anterior (1/3) o axillary tail: extension of the female breast toward and into the axilla Nipple: no hair, fat, or sweat glands; termination of the lactiferous ducts; in males is over 4th intercostal space (variable in women) (T4 Innervation)

Structure:

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Suspensory (Cooper’s) ligaments: help support weight of the breast and partition breast’s fat and glandular tissue into lobules; well-developed skin ligaments o attaches to underside of the dermis and to a connective tissue layer on the deep surface of the breast overlying but separable from the deep fascia of chest muscles. o dimpling occurs through attachment to dermis when breast cancer causes the suspensory ligaments to contract (shorten). o Mammograms: contrast between radiolucent lobules of fat and more radiodense connective tissue network can be seen and differentiated from tumors and calcifications that appear as abnormal radiodensities. Mammary gland: 15 to 20 lobules of glandular tissue embedded in and interspersed throughout the fatty superficial fascia of breast. o Breast size increases during lactation as the glandular tissue hypertrophies. In aged female atrophied mammary gland cannot be differentiated from fat and connective tissue. Lactiferous ducts: begin in each mammary lobule, converge beneath the areola, and end on the nipple. Lymphatic drainage o Axillary nodes: located in the fatty connective tissue of the axilla (receive lymph from lateral 75% of the breast)

o Parasternal nodes: receive lymph from the medial 25% of the breast nearest the sternum o contralateral breast may receive lymph that drains across the midline of the chest (normal but minor) - may be more likely if the axillary and/or parasternal pathways nodes are blocked by cancer o Cervical (supraclavicular) nodes: located in the supraclavicular fossa; may receive lymph from the breast if the axillary and/or parasternal pathways are blocked (very metastatic cancer)