DD+LOs+Unit+3

toc =**Preamble**= (from James Rose, the author of these notes) Monday, December 15, 2008

What follows is the original preamble (same as the notes from M2M). A few points on D+D: it’s a lot like M2M, with the unfortunate exception of actually being useful clinical information so you can’t tune it out. The block directors are well-meaning but it’s a sort of a hodgepodge course with a little of everything. Rest assured that by the time you hit ID you will likely remember about 3% of what you’re about to learn with regards to infection. That said, having a basic vocabulary to talk about common pathogens makes you look a little less like an idiot at your preceptor’s. And for the 3 or 4 people who really, desperately want to be dermatologists, the derm section will enable you to suck up to the derm staff with terrifying efficiency. So go to it, try and retain as much important info as you can, don’t kill yourself worrying about remembering pharmacokinetics, and enjoy. Trust me, first year is the time to really enjoy your classes. –jcr

=**Cell Growth and Neoplasia**=


 * [Note that rate of cancer in a given tissue is related to how quickly the cells of that tissue turns over.]
 * **[Cancers of connective tissues, like fibroblasts, adipose cells, cartilage, or bone: called** sarcomas** . These cells are slow to proliferate and rarely turn into cancer (less than 10,000 new sarcomas in 2006).] **
 * **[Cancers of hematopoietic cells, red or white, give rise to** leukemias** and **lymphomas** . About 10 times more common than sarcomas.]
 * Distinction between leukemia and lymphomas: if malignant cells are mainly in the circulation and marrow, it's called leukemia; if they're mainly in the lymphatic system, it's called lymphoma. Note that lymphomas can become leukemia depending on mobility.


 * **[Cancers derived from epithelial cells (most common cancers):** Carcinomas** .] **
 * **Define: atrophy, hypertrophy, hyperplasia and metaplasia, give examples of each, and discuss reversibility vs irreversibility of each type. Compare hypertrophy and hyperplasia.**
 * Atrophy** : Decrease in size of an organ or tissue - often 2o to disease or malnutrition - due to increased cell death. **
 * Hyperplasia** : Process in which there's an increase in the size of an organ or tissue __due to increase in the number of cells, not their size__.
 * Note this is due to increase in cell death (apoptosis) relative to cell division.
 * [Aplasia: no cell division in organ tissue; usually incompatible with life.]


 * Hypertrophy** : Process in which there's an increase in the size of an organ or tissue __due to increase in cell size, not number__.
 * **Metaplasia** : Substitution of one __type__ of adult tissue for __another__.
 * Ie: When a cell, usually a glandular cell (eg. columnar) turns to another kind of cell (usually to a squamous cell). A way to respond to injury (squamous cells are more resistant to damage); occasionally metaplasia triggers oncogenesis.
 * This seems to happen due to a change in the stem cells.
 * Note this happens more commonly at squamo-columnar junctions (where a bunch of squamous cells meet a bunch of columnar cell).

[Dysplasia = cells that 'just look abnormal.']
 * Although his notes don't seem to mention reversibility or not, I'm reasonably sure that the first three are reversible. The fourth (metaplasia) I'm not sure about, though he does mention that dysplasia (which presumably may include metaplastic features) is potentially reversible.
 * Cite the six features that characterize a neoplasm (he mentioned six features that characterize dysplasia and didn't mention neoplasm features; let's stick with those.)
 * Dysplasia:
 * Irregular nuclear membrane
 * Enlarged, darkened, or vesicular nuclei
 * Increased nucleus to cytoplasm ratio
 * Loss of normal cell orientation
 * Increased proliferation rate, with or without decreased apoptosis
 * Not invasive or metastatic, not disruptive of normal tissue (no tumor)
 * List the features of, and compare/contrast benign and malignant neoplasms.
 * Neoplasm: "New growth"-- can be either benign or malignant.
 * Benign neoplasms:
 * Multiple cell types, cells differentiated as in normal tissue.
 * Slow, regular growth.
 * No local invasion; new blood vessels don't cross basolateral membrane.
 * No distal invasion (metastasis).
 * Malignant neoplasms:
 * Single cell type, cells less well differentiated; abnormal architecture.
 * Erratic, variable-speed growth.
 * Locally invasive; new blood vessels and cells invade surrounding tissues.
 * Frequent distal invasion.
 * Define cancer and list the two key behavioral characteristics of cancers. Describe their pathogeneses. Define seed.
 * Cancer: A malignant growth of cells from any progenitor cells. Classified by:
 * Grade: how well differentiated it is. Note that the extent of de-differentiation indicates damage to stem cells.
 * Stage: how extensively it's metastasized.
 * Four stages are local //(in situ// ) //,// regional (proximal lymph nodes), contiguous (more distal lymph nodes), and distant (through blood).
 * You would probably want a high-grade instead of a high-stage cancer-- you can, in principle, get it removed and that's the end of it.
 * [Note that if I was going to answer this LO from the notes I'd say that two key behavioral features of cancerous cells is the capacity of their growth to actively invade other nearby cells and their ability to metastasize (see next lecture).]
 * Seed: the features of a cancer cell that allow it to grow in certain locations and not in others when metastasizing.
 * ["Anaplasia": such a high grade tumor that it's impossible to tell from what lineage they originally came.]

=**Neoplasia, Invasion, and Metastasis**=


 * Discuss the mechanisms of metastasis: lymphatogenous, hematogenous, cavitary
 * Essentially this asks: how do cancerous cells get from one place to another?
 * __Lymphatogenous__: through lymph system.
 * Tends to occur in __melanomas__ (cancers in melanocytes) and __carcinomas__.
 * __Hematogenous__: through bloodstream.
 * Tends to occur in __sarcomas__.
 * __Cavitary__: through body cavities-- pleura, peritoneum, pericardium.
 * Notice that it takes a lot of cancer cells in the bloodstream to produce a metastasis (probably a random or stochastic process which cells 'stick' to a new tissue).
 * Notice also that the cancer cells generally need some kind of proteases - their own or nearby cells' - to get though the basolateral membrane and begin to spread.
 * Define and discuss the clinical significance of dormancy in metastasis.
 * Dormancy: the secondary, metastatic site can lie dormant for a long, long time before breaking out into cancer activity.
 * Makes it hard to study and hard to find.
 * **List typical primary and resulting secondary cancer sites. Discuss four major theories to explain the bias of metastasis towards certain organs.**
 * **As noted in last lecture, there seems to be something inherent in particular cells that let them metastasize to particular places and not others.**
 * **__Breast cancers__ often go to** ovaries ** and **bone** . **
 * **__Kidney cancers__ go to** thyroid** . **
 * **__GI__ cancers go to** ovaries** . **
 * **__Thyroid__ cancers go to** bone** . **
 * **__Prostate__ cancers go to** bone** . **
 * Some ideas about why this happens:
 * (1) Cancer cells go to all organs equally, but only multiply in organs that have the right growth factors.
 * (2) Vascular endothelial cells in target organs express certain adhesion molecules (selectins) that select for particular types of cells.
 * (3) Organ-specific chemoattractant molecules are given off by certain organ cells that attract certain other kinds of cancer cells.
 * (4) Evidently, (4) is that (1) and (3) seem to be the leading contenders.
 * Discuss the role of metastasis in death by cancer.
 * Metastasis is the most common cause of death by cancer.
 * Direct effects: the more local metastasis in an organ, the less function you get out of that organ.
 * Note that direct effect of cancer in organs, according to Dr. Holt, is generally fairly rare as a cause of death (organ failure, both from direct and indirect causes, account for about 19% of total non-leukemic cancer deaths).
 * Holt points out in addition that direct-effect mortality is highly variable from person to person-- a small cancer in one person kills that person, while another person can have a tumor five times the size in the same place and survive.
 * When you get a 'cancer burden' big enough that you can't fight off infections any more, that tends to be it-- infection is the biggest cause of metastasis-related death, in part because of the immunosuppressive treatment.
 * Indirect effects: __Paraneoplastic effects__-- secondary, endocrinal/hormonal effects caused by tumor secretions or by antibodies against the tumor.
 * Can cause lesions, clotting, cachexia (wasting), joint and muscle pain, DIC, kidney damage, etc.
 * ["Scirrhus": dense collection of fibrous tissue produced by fibroblasts attracted by tumor.]

=**Epidemiologic and Environmental Aspects of Cancer**=


 * Understand how epidemiology implicates environmental factors causing most cases of cancer.
 * More than 80% of all malignant neoplasms are caused by environmental factors, not genetic. Persons who emigrate to different countries or regions change their cancer risk accordingly, a trend which continues through multiple subsequent generations.
 * **Know the three most common types of cancer (other than skin cancer) among men and women (incidence), and the three leading types responsible for cancer mortality for men and women (mortality) in the United States.**
 * Male common types: Prostate, lung, colon.
 * Female common types: Breast, lung, colon.
 * Male mortality: Lung, prostate, colon.
 * Female mortality: Lung, breast, colon.
 * Note that the death rate for men is almost always higher than the death rate for women-- women outlive men with comparable cancers by an average of 8 years. Seems to be partly due to disproportionate infection rates.
 * **Explain how environmental chemicals cause cancer and the importance of “activation” by microsomal enzymes.**
 * Four main groups of carcinogens: polycylic aromatic hydrocarbons (in smoke), aromatic amines (in dyes), nitrosamines (produced in stomach due to amine reaction with ingested food), and aflatoxins (produced by Aspergillus fungus, found in contaminated grain).
 * **The thing that all these share is that all of them** have to be metabolized by CYP450 enzymes to become carcinogenically active**.
 * (CYP450 enzymes are called the 'microsomal fraction' of liver enzymes.)


 * Once activated, these compounds (electrophilic) react preferentially with proteins, DNA, and RNA.**


 * Essentially the compounds need to be oxidized into epoxides before becoming active.
 * (Note that not all carcinogens need to be activated, but vast majority do.)


 * Understand the Ames test.
 * Ames test: determines ability of a given chemical to produce mutations.
 * Chemical is put in a dish with Salmonella bacteria that have a mutation in one of their genes that means that they need histadine to grow, along with a microsomal fraction of liver enzymes. The media in the dish has no histadine, so bacteria won't grow on their own without some kind of mutation to get their histadine synthesis gene working again.
 * If the chemical is mutagenic, colonies of bacteria that no longer need exogenous histadine to grow begin to arise around the chemical.
 * Understand the “principles of carcinogenesis” learned from animal testing of carcinogens.
 * The mutagenic effect of a chemical is generally dose-dependent.
 * A specific carcinogen usually causes one specific kind of neoplasm.
 * Carcinogenesis requires time (years) and cell proliferation (the faster the cells proliferate, the more likely to develop cancer faster).
 * Carcinogenesis occurs mainly in stem cells (fully differentiated cells never become malignant), and carcinogenic changes are transmitted to their daughter cells.
 * These stem cells don't differentiate normally and develop through two stages: **initiation** (carcinogenesis, irreversible) and **promotion** (through continual action of non-carcinogenic promoting agents; reversible).
 * Understand the two-step model of carcinogenesis, and the difference between carcinogen and tumor promoter.
 * This is what I just mentioned-- initiation is the chemical trigger that's caused by the carcinogen, promotion is the ongoing trigger that's caused by noncarcinogenic chemical factors. Even though a promoter may not be a carcinogen, it can be a promoter of tumorigenesis by promoting cell proliferation.
 * Know the evidence that tumor promotion plays a role in the development of human cancers.
 * Former smokers lose their high risk for cancer (cigarette smoke contains promoters and pro-inflammatory factors) after 14 years.
 * Notice, however, that his figures show the risk of cancer doubling in the year immediately after quitting smoking. Probably shouldn't read too much into that, but still.
 * Bile salts (promoters) promote cancer in benign colon polyps in rats.
 * Be able to propose an explanation of why cancer is much more common in the elderly compared young adults.
 * Acquisition of genetic damage over long periods of time.
 * Exposure to more carcinogens and more promoters over long periods of time.
 * Cancers are, generally, slow. Makes sense they'd mainly show up later.
 * Understand the difference between somatic and germline mutations that cause cancer, and so-called “epigenetic” factors that cause cancer.
 * Somatic: Can't be passed on to offspring. Germline: Can be.
 * Epigenetic factors: not directly coded for in DNA, but modifications added to proteins or DNA (eg. methylation). Loss of methyltransferases can activate normally repressed genes.

=**Anti-tumor agents**=


 * Understand differences and purposes of different kinds of chemotherapy- adjuvant, neoadjuvant and primary chemotherapy.
 * Primary chemotherapy: the drug treatment is the primary treatment; no surgery or radiation.
 * Is occasionally curative (generally when given to patients with particular kinds of tumors); more often it's given to patients who have advanced tumors and metastasis for which no other treatment exists. The idea is to give them some more time, but not to effectively cure them.
 * Neo-adjuvant chemotherapy: Chemotherapy given to patients before surgery or radiation.
 * The idea is to make the other treatment more effective-- ie., if you can reduce the size of the tumor with chemotherapy, you make the excision of the tumor easier and more complete (may kill micrometastases near the tumor that might otherwise remain).
 * Fairly easy to measure response, since can always measure the primary tumor to determine the response.
 * Adjuvant chemotherapy: Chemotherapy given to patients after surgery or radiation.
 * Point is to reduce recurrence of the disease, both locally and systemically, by going after remaining metastatic tumor cells.
 * Difficult to measure response, since the primary tumor has been removed.
 * Understand major differences between “targeted therapies” and conventional cytotoxics.
 * Conventional cytotoxics: have been used for decades, will be used for some more. Kill tumor cells by interfering with general functions of most or all cells.
 * Therapeutic window is very narrow. The concentrations necessary to cure are close to the concentrations necessary to kill or cause irreversible injury.
 * Frequently have large individual differences in pharmacokinetics. Some people see more benefits than others, some people have more side effects than others. Partly this is due to pharmacogenetics (how well do people's CYP systems or conjugation systems work?).
 * Mechanism: triggers apoptosis due to cellular damage.
 * Targeted therapy: The new thing. Identifies specific genetic damage responsible for tumor, use drug that targets cells that contain this particular defect.
 * Sometimes hard to dose due to difficulty gauging response.
 * Drugs chosen based not on the tumor site or histology, but on the underlying defects.
 * Obviously, the $64,000 question is how to determine how a particular person's tumor has come about.
 * Notice that cytotoxic agents **do** 'target' specific pathways in cells; it's just that they target those pathways in **all** cells. Targeted therapies try to aim at **damaged cells only**.
 * Understand basis for combining anti-tumor agents.
 * Generally, conventional chemotherapy agents are combined to be most effective.
 * Combining agents kills tumors more effectively, can treat cancers with some genetic variation, slows cancer drug resistance.
 * If you're going to combine drugs, try to avoid giving two drugs that have overlapping toxicities (toxicities at the same sites).
 * Also try to keep intervals where there is no treatment as short as possible while still allowing the patient to recovery (during periods of no treatment, the cancer can develop drug-resistant mutations). To get this done, can use growth factors to accelerate bone marrow recovery.
 * Along the same line, try not to remove drugs from the combination therapy (allows development of resistant cell line).
 * For targeted-therapy agents, a little different- not always combined, but when combined, usually target two different steps in the same pathway or use two different apoptotic mechanisms.
 * Understand mechanism of action, major toxicities and resistance mechanisms of prototypical drugs for each class of anti-tumor agent.
 * General notes on conventional cytotoxic agents:
 * Mainly interfere with fundamental aspects of cancer cell activity. Toxicity comes from the fact that they're fundamental aspects of every other cell in the body also.
 * Resistance:
 * Often comes out of the underlying biology of apoptosis. All apoptotic pathways ultimately feed into the same 'death mechanism' signaling pathway; when a cancer has a mutation that inhibits that pathway (which is somewhat likely, if it's developed into cancer to begin with), can be resistant to a wide variety of agents.
 * This is somewhat counteracted by the fact that cell-growth signals (which most cancers also have) sensitize the apoptotic pathways as well.
 * Can be from reduced uptake of the drug into tumor cells, or efflux of the drug out of the cells. Notice that this can affect multiple drugs, even if it's developed only by one drug.
 * Some mutations alter the cellular target of the drug. (note this generally only affects the one drug, not many.)
 * Can be from increased particular repair mechanisms of cellular damage-- prevent apoptosis. Generally against one drug, not many.
 * Sub-population of cells ("tumor stem cells") in a tumor can be resistant to multiple drugs and capable of regenerating the tumor.
 * Generally it's like treating bacteria: there's a strong selective pressure on the cells to adapt to become more resistant.
 * Specifics. It's probably more productive to go through and figure the resistance mechanisms and side effects out from their mechanisms of action than to just list them out. Also I'm lazy.
 * __Hot off the presses__: the ever-detail-oriented Jeff Dunn has gone through the trouble to type these up. I was just barely not-lazy enough to format them and stick them in:
 * Alkylating agents
 * Mechanism of action (MOA): Damages DNA by forming covalent chemical adducts and crosslinks preventing replication and activating apoptosis.
 * Resistance: Glutathione (GSH) inactivates, DNA repair removes alkyl groups or crosslinks via NER
 * Toxicities: Targets all rapidly dividing cells (bone marrow, GI, gonads, alopecia--hair loss), can also cause cancer possibly by mutating DNA
 * Topoisomerase interacting agents: etoposide, anthracyclins
 * MOA: topoisomerase is needed to break and re-ligate DNA during replication. These drugs prevent topoisomerase from re-ligating DNA => damage => apoptosis
 * Resistance: Drug efflux, topoisomerase mutations that resist drug (seen in vitro but not in patients)
 * Toxicity: Myelosuppression common, secondary malignancies, anthracyclins cause cardiotoxicity
 * Microtubule interacting agents: Vinblastine, vincristine, taxanes
 * MOA: Vinblastine/vincristine bind MT ends causing depolymerization.Taxanes stabilize MT preventing depolymerization which blocks mitosis.
 * Resistance: Drug efflux, tubulin mutations
 * Toxicity: Neurotoxicity (vincristine), myelosuppression (vinblastine, taxanes)
 * Hormonal agents: Tamoxifen, Anti-androgens
 * MOA: Work on steroid (nuclear) receptors.Tamoxifen blocks steroid binding to estrogen receptors, Anti-androgens bind to androgen receptors preventing their function as TF
 * Resistance: Receptors can be altered so they activate by phosphorylation instead of hormone binding, or they may be altered so the drug activates rather than inhibits the receptor
 * Toxicity: women:hot flashes, decreased bone density; men:gynecomastia
 * Antibodies:
 * MOA: Ab against particular cells or proteins- B cells, VEGF, etc). Can alter function of target or help the immune system kill the cell (ADCC). Can also be conjugated with toxins or radioisotopes to directly kill tumor cells
 * Resistance: none mentioned
 * Toxicity: very little--targeted therapy
 * Kinase inhibitors (imatinib and dasatinib, Gleevec)
 * MOA: either prevent the binding ability of tyrosine kinase receptors or prevent the phosphorylation activity by acting as an ATP analog
 * Resistance: mutations alter drug binding (can use a cocktail of imatinib/dasatinib to overcome)
 * Toxicity: very little (even though ATP is a fairly ubiquitous molecule)
 * [Platinum compounds: Cisplatin and analogues]
 * MOA: crosslinks DNA via intrastrand CpG sequences preventing replication and apoptosis
 * Resistance: reduced drug uptake and increased efflux, GSH inactivation, DNA repair and increased tolerance for DNA damage
 * Toxicities: nephrotoxicity, n/v, ototoxicity, some types cause myelosuppression, platelet toxicity, sensory neuropathy
 * [Antimetabolites:]
 * Methotrexate (MTX)]
 * MOA: Folate analog. Reversible, competitive inhibitor of dihydrofolate reductase (DHFR) required for purine synthesis.
 * Resistance: Increased expression of DHFR or expression of DHFR mutant with reduced binding affinity. Decreased capacity to make polyglutamated MTX which is necessary for MTX affinity for DHFR
 * Toxicities: Myelosuppression, GI, renal, hepatotoxicity, neurotoxicity, teratogenicity
 * 5-FU
 * MOA: Pyrimidine analog activated to dTTP form by thymidine kinase, inhibits thymidylate synthase (TS) from producing dTTP => inhibits DNA synthesis => apoptosis
 * Resistance: increased expression, alteration in TS target enzyme
 * Toxicity: Rapidly growing cells (bone marrow suppression, GI, alopecia)

=**Colon Cancer: Genetics**=


 * Review the anatomy and histology of the normal colon and understand where colon cancer arises, and how the cancer invades and metastasizes.
 * . Note that colon cancer often metastasizes to the liver due to the portal drainage.
 * Histologically speaking, slides of colonic mucosa show columnar cells, either mucosal goblet cells (producing mucus) or absorptive cells (reabsorbing water and electrolytes).
 * Normal colonic cells have nuclei that are pushed up against the basal side of the cell, with most of their cytoplasm towards the lumen.
 * In dysplasia, the nuclei begin to detach from the basal side and move towards the lumen.
 * They're regenerated by a handful of highly active stem cells per gland. It's a highly labile tissue, replaced quickly and constantly-- thus, recall, at risk for cancerigenesis.
 * Pretty much, colon cancer arises in glandular cells. This means **adenocarcinomas** -- cancer from gland cells in the epithelia. The cancer cells attempt to form glands (preserve some differentiation), some of which can still produce mucin.
 * Colon cancers often form "napkin rings" around the local circumference of the colon.
 * Colon cancers invade through the muscularis propria (layer beneath the submucosa)-- either into the lymphatic system or the venous system, generally.
 * Know the evidence that colon cancer usually arises in pre-existing polyps.
 * At-risk populations have a high prevalence of adenomatous polyps (benign glandular-epithelial tumors that protrude into the lumen).
 * Distribution of these polyps along the colon and rectum is similar to that of colorectal adenocarcinomas.
 * Polyps generally develop before carcinomas.
 * Large adenomatous polyps (particularly villous polyps) often have a small area of carcinoma inside.
 * Hereditary predisposition to polyps correlates to high cancer risk.
 * [Types of polyps:]
 * Hyperplastic polyp: completely normal-looking 'bumps' or growths. Not a cancer risk, at least at present state of knowledge.
 * Tubular (broccoli-on-a-stalk) adenomas: thin fibrovascular 'stalk' connecting underlying epithelia with tumor head. More common than villous (below). Some risk for malignancy.
 * Villous (cauliflower floret) adenomas: broad, no stalk. High risk for malignancy.
 * [The idea is that crypt (stem) cells start overproducing and the epithelia starts 'piling up' on the epithelial surface-- thus a polyp.]
 * [Note that the size of the polyp correlates with likelihood of malignancy.]
 * Take-home message: take out polyps before they develop into malignancy.
 * Understand the concept that colon cancer develops in steps and requires probably at least 6 mutations, resulting in loss of tumor suppressor genes and acquisition of oncogenes (mutated, activated proto-oncogenes).
 * The first mutation in colon is generally the loss of APC (see below), which results in increased cell proliferation and destabilized chromosomes.
 * Know some of the oncogenes and tumor suppressor genes that have been shown to be important to colon carcinogenesis.
 * Not entirely sure. Here's a partial list he mentions:
 * p53 seems to be important as a tumor suppressor. APC and Rb likewise.
 * DCC/MCC proteins (deleted and mutated respectively)
 * Ki-RAS (protein kinase, can be mutated to pro-tumor)
 * Understand the three pathways to colon cancer development discovered from studies of hereditary colon cancer that have been identified so far.
 * **FAP** (familial adenomatous polyposis)-- lots and lots of adenomas throughout colon and rectum in patients' 20's and 30's. Gene responsible isolated as __APC__.
 * APC protein: part of __Wnt__ signaling pathway.
 * **Beta-catenin** : transcription regulator-- carries various factors into the nucleus to activate their targets.
 * APC normally keeps beta-catenin at a very low level in the cell by binding it to be degraded.
 * Without APC (as in FAP), beta-catenin signaling pathway is constantly turned on.
 * MIN mouse = knockout for APC. Wind up getting lots of tumors and cancer in colon, like FAP patients.
 * **Hereditary non-polyposis** colon cancer: different pathway. HNPCC patients get a smaller number of cancers than FAP patients and get it later in life.
 * Defect in DNA mismatch repair pathway (excise a stretch of DNA around mismatch, repair).
 * Particularly, get problems repairing __microsatellites__ (small repetitive segments) in pro-apoptotic genes (such as TGF-beta). Mutations in these genes cause an increased risk of malignancy.

Also have a syndrome in which there's a loss of base-excision DNA repair pathway.
 * Understand the importance of the Wnt signaling pathway in colon carcinogenesis, and key players involved in the signaling pathway.
 * Wnt regulates cell growth and division, mainly by regulating the amount of beta-catenin in the cell. Normally, as noted above, beta-catenin is kept at very low levels in the cell by APC; loss of APC allows beta-catenin to take all its pro-proliferative transcription factors to the nucleus and have a ball.
 * Understand how loss of APC allows polyp formation and promotes the development of colon cancer.
 * We sort of went through this up above. Without APC, beta-catenin isn't degraded normally and can carry transcription factors into the nucleus to activate pro-replication genes. This would result in an abnormally proliferative stem cell in the colon, which would eventually push up into the lumen as some manner of polyp. If the proliferating cells in the polyp develop additional mutations, such as those that allow them to invade nearby cells, can develop cancer.
 * Understand what is meant by the idea of a “mutator” phenotype.
 * Neither the word "mutator" nor the word "phenotype" occurs anywhere else in his notes. I'll write him about it. Wiki sez it's the tendency of tumor cells to start acquiring mutations very quickly under stress conditions.


 * Problem with repairing microsatellite DNA injury: hereditary non-polpyosis colon cancer**

=**Prescription Writing**=


 * Describe the role of federal, state, and local governments in regulating the prescription writing process.
 * Generally, __feds decide what drugs can be prescribed__ (safety and efficacy evaluations); __states decide who can prescribe__ (licenses to physicians, though note __controlled-substance exception__ below).
 * Drugs that aren't tested for safety and efficacy: dietary supplements, pretty much. DSHEA act of 1994 sez can't mandate testing these.
 * Drugs that are tested: prescription drugs (habit-forming drugs, drugs not safe for use without expert supervision, drugs that are specifically limited under a new drug application) and over the counter drugs (self-diagnosable conditions, low toxicity and addiction, etc-- is it safe, non-addictive, and relatively idiot-proof?).
 * Controlled substances are generally controlled because they're addictive-- regulated by DEA, who give out licenses to prescribe controlled substances.
 * As stated, mostly states are the ones who decide who can prescribe stuff-- controlled substances are the exception.
 * Note OTC drugs are not dietary supplements-- the former are safety and efficacy tested, the latter are not.
 * Note that although drug companies can only market a drug for uses that it's been through clinical trials for, you as a doctor can prescribe drugs for off-label use. Note you have less legal protection if it screws up your patient.
 * Note that drug safety data doesn't usually make it onto prescribed drugs unless you specifically put it there.
 * Dietary supplements: can be pretty much anything. The ones that we tend to use are vitamins, minerals, and amino acids (glucosamines).
 * Burden of proof with herbal supplements is on the FDA to show that they're __dangerous__, unlike with drugs, where the burden's on the drug company to show that they're__not__.
 * Although dietary supplements can't make particular claims about certain diseases ("cures hyperlipidemia!"), they can make general claims about the same symptoms ("maintains healthy cholesterol levels!").
 * Note that the manufacturing of vitamins, minerals, and amino acids/derivatives isn't highly regulated-- though this is changing.
 * Distinguish the different categories of drug equivalency (chemical, pharmaceutical, biologic, and therapeutic) and the relevance to generic vs. brand name products.
 * Narrow-therapeutic-index drugs are generally the only ones (seizures disorders, anti-coagulants, thyroid hormones) where brand should be chosen over prescription.
 * Don't switch patients from one to the other once they're stabilized.
 * __Pharmaceutical equivalency__: Same active ingredient, same dosage formulation (capsule, tablet, etc).
 * Pharmaceutical alternative (not the same thing): same 'therapeutic moiety,' but can change the dose, formulation, salt used.
 * __Biological equivalence__: more or less the same bioavailability (area under the Cp/time curve) through the same pathway of administration (generally within 5%).
 * __Therapeutic equivalency__: make sure generic drug has same efficacy and safety as the brand drug. French sez generic equivalents no longer need to prove this equivalency in clinical trials-- it's assumed after biological equivalence is proven.
 * Generally, the thing that's different between brand and generic is the stuff that binds and releases the active drug.
 * Describe the legal components of a written prescription in Colorado.
 * (1) Date
 * (2) Identity of prescriber
 * (3) Patient information
 * (4) "Rx" (archaic)
 * (5) Drug and strength
 * (6) Directions to patient on usage
 * (7) Chart order for hospital settings
 * (8) Refill information. Note that __all prescriptions expires in 12 months__.
 * (9) Childproof container
 * (10) Signature, DEA number for controlled substances
 * Convert apothecary/avoirdupois/household measures to metric equivalents (and vice-versa).
 * Milligrams to grains: ~65 mg to 1 grain
 * Grams to ounces: ~30 g to 1 ounce
 * Kilograms to pounds: .454 kilos to a pound, 2.2 pounds to a kilo
 * mL to teaspoons: 5 mL = 1 teaspoon
 * mL to tablespoons: 15 mL = 1 tablespoon
 * mL to fluid ounces: ~30 mL = 1 fluid ounce
 * List the Latin and English abbreviations for common medical terms or phrases.
 * I'm just selecting some of the ones that seem common to me; the full list is in the notes.
 * bid: twice a day
 * qd: every day
 * qod: every other day
 * qid: four times a day
 * prn: when needed
 * po: by mouth
 * ad: right ear
 * as/al: left ear
 * au: both ears
 * od: right eye
 * os/ol: left eye
 * ou: both eyes
 * Explain the special requirements for prescribing controlled substances in Colorado.
 * Controlled substances are schedule-ranked from I to V based on abuse potential.
 * I: No medical use according to United States legislature. See "misguided and horribly expensive misadventures in jurisprudence," between "2000 elections" and "Abu Ghraib."
 * II: Medical use but high abuse potential.
 * III: Medical use but moderate abuse potential.
 * IV: Medical use, low abuse potential.
 * V: Medical use, little to no abuse potential.
 * Can't prescribe schedule I drugs.
 * II-IV require prescription (in CO, also V).
 * II have to be handwritten prescriptions (no phoning it in).
 * III-IV (in CO, also V) can be phoned in, but may only be refilled a maximum of 5 times in 6 months.
 * Give examples of suggestions for improved prescription writing.
 * Ask pharmacist if there's any uncertainty.
 * Write legibly.
 * Use metric system.
 * Don't put zeros after decimal points at the end of the dose (2.0).
 * Always use zeros before decimal points (0.5)
 * Don't use abbreviations.
 * Note French makes a point of saying that prescriptions that actually follow these points are usually forged.
 * Summarize the preclinical and clinical phases (1 - 4) of the new drug approval process of the FDA with respect to types of subjects, number of subjects, approximate time involved, limitations in pronouncing a new drug as "safe".
 * [Not actually responsible for this, according to Dr. French.]

Pharmaceutical equivalent vs pharmaceutical alternative defn

=**Clinical Dermatology, Terminology and Functions of the Skin**=


 * [Interesting: nerves can release neuropeptides at their skin of action on the skin that have specific messenging functions. Stimulate mast cells, release cytokines, etc.]
 * [Keratinocytes makes IL-1: can be stimulated to do this by capsaicin application, etc.]
 * [Langerhan cells: APCs in epidermis; essentially dendritic cells in skin.]
 * [Hair follicles:]
 * anagen = hair growth stage
 * telogen = resting stage
 * catagen = regression stage
 * [Sebaceous glands: secrete specialized lipids to promote barrier function of epidermis.]
 * [Dermal microvasculature: regulates body temperature, angiogenesis after skin injury, modulates cutaneous immunological events.]
 * [Macrophages in skin are sometimes called "histiocytes."]
 * [SC fat: actively, not just passively, involved in homeostasis. Exact mechanism unclear.]


 * Define each of the following terms:
 * Macule: flat area of color change less than 1 cm in diameter, can be seen but not felt. (over 1 cm = a patch.)
 * Papule: A solid or cystic elevation less than 1 cm in diameter.
 * Nodule: A solid or cystic elevation more than 1 cm in diameter.
 * Plaque: An elevated lesion more than 1 cm in diameter (generally fairly flat).
 * Scale: Thin, dried epidermal cells that flake on the skin surface.
 * Erythema: Redness of the skin.
 * Describe elements of the history pertinent to evaluation of skin that are important to elicit in a history and physical.
 * Not entirely sure, I may have missed this in lecture and it didn't make it into her slides. I would hazard to guess you should ask about UV exposure, anything they've recently put on their skin for the first time, family history, previous treatment, whether they've noticed any change in the shape or color of their moles, etc.
 * Be able to take a relevant and appropriate history from patients with skin disease
 * More or less what we just covered.
 * Describe a comprehensive skin exam
 * Patient needs to be in gown, under good illumination.
 * Be systematic in inspection.
 * When describing findings, describe the morphologic appearance of individual lesions, their distribution, their arrangements, and how many are present.
 * Describe the morphology of various types of skin lesions.
 * Macule/patch: flat.
 * Papule/plaque/cyst/nodule: raised, smooth.
 * Papule with scales/plaque with scales: raised, scaly.
 * Vesicle/bulla/pustule: fluid-filled
 * Erythema/erythroderma/telangiectasia: redness
 * Ecchymoses/petechiae/palpable purpura: purpura (bruises)
 * Understand appropriate infectious precautions when performing a skin examination.
 * Universal precautions (hand washing, gloves).
 * List in order, the layers of skin and their major functional components
 * Epidermis (keratinocytes, melanocytes, Langerhans cells), dermis (collagen, elastin, ground substance, nerves, vessels), subcutaneous fat (fat).
 * Display basic knowledge of skin anatomy and be able to draw a transverse section through skin & label structures
 * Epidermis on top (cells get less columnar and more squamous as they get towards the surface), dermis in the middle (with glands, hair follicles, vessels, nerves, mast cells, lymphocytes), fat on the bottom.
 * Understand functions of skin and which parts of the skin contribute to these:
 * Physical Barrier (keratinocytes in epidermis). Prevents:
 * Micro-organisms/chemicals getting in
 * Body fluids/protein getting out (eg burns)
 * Reduces penetration of UV irradiation (melanocytes in epidermis)
 * Thermoregulation (eccrine glands in dermis)
 * Prevents heat loss
 * Prevents overheating
 * Sensory organ (nerves in dermis)
 * (diabetic/sensory neuropathy and ulceration)
 * Immune surveillance (Langerhans cells in epidermis)
 * (micro-organisms, neoplastic transformation)
 * Vitamin D production (epidermis)
 * (ricketts)
 * Cosmesis- I generally like my girls with all their skin attached. Unless they're 9 year-old girls with severe epidermolysis bullosa who like to listen to Hannah Montana, in which case they're perfect the way they are.
 * Describe various diagnostic examinations and laboratory tests that aid in the diagnosis of skin conditions.
 * Again I'm not sure what she's referring to. Skin biopsies are useful for looking at histology. You want to make sure you hit all the relevant points in examining/describing: appearance, distribution, arrangement, and number of lesions.

=**Epidermal Structures and Diseases**=


 * [Hemidesmosome: epidermal-to-dermal junctions, anchor the epidermis down.]
 * [Desmosome: cell-to-cell adhesion junctions, provide some of the tensile strength in squamous epithelium. Contains interlinkage proteins called desmogleins.]
 * To appreciate the biological role and importance of the epidermis.
 * Oh, I do.
 * Fine, here's specifics.
 * Barrier
 * Homeostasis
 * UV protection
 * Vitamin D synthesis
 * Peripheral immune system/protection from infection
 * Social
 * To know three types of cells that normally inhabit the epidermis
 * Keratinocytes: derived from ectoderm; the main type of epidermal cell. Mature and differentiate as they progress upwards from the basal cell layer (where they are viable columnar cells) to the stratum corneum (at which point they are effectively dead, squamous ex-cells).
 * Melanocytes: derived from neural crest, secrete melanin into keratinocytes to absorb UV radiation. They reside in the basal cell layer-- each melanocyte transfers melanin to about 20 keratinocytes (superior to its nucleus to protect the DNA from UV damage). This lends skin its color. The same compound also helps determine eye color.
 * Langerhans cells (immune system cells): professional APCs (dendritic cells) in the epidermis. Engulf antigens, take to lymph nodes, you know the drill.
 * To understand the structure and function of the basement membrane zone, the cellular epidermis, and the stratum corneum.
 * Epidermis: about 0.05 mm thick in all; 4 components from surface going deeper:
 * **Stratum corneum** (literally "horny layer," you see why they stuck with Latin) (very surface, generally thin layer)
 * **Granular cell layer** (stratum granulosum) (thin layer towards surface)
 * **Spiny/squamous cell layer** (stratum spinosum) (thick layer comprising most of the normal epidermis)
 * **Basal cell layer** (stratum basale) (thin layer running along the rete ridges where the epidermis and dermis connect)
 * __Basement membrane zone__: Complex region **under** the basal cell layer where the epidermis is stuck to the dermis. Keratin proteins from basal keratinocytes are attached to the dermis through attachment sites called __hemidesmosomes__ (recall these from M2M?). Specific proteins in the hemidesmosomes that mediate this attachment are called __BP 180 proteins__ (important for a certain disease later).
 * __Stratum corneum__: End product of epidermal differentiation (effectively dead cells). Formed of a complex of keratins and filaggrins surrounded by secreted lipids (cholesterol, free fatty acids, ceramide). Its barrier function is primarily mediated by the lipids.
 * Note that "__cellular epidermis__" refers to the three layers that aren't the stratum corneum.
 * Mitosis generally occurs in cells in the basal cell layer. (Note that they evidently don't call these "stem cells.")
 * The new cells exit the basal cell layer and begin to differentiate as they move through the upper layers, eventually becoming stratum corneum.
 * Spiny/squamous cell layer: cells are still columnar (despite the name) but are starting to die from lack of nutrients. They are also pumping out cytokeratin to anchor themselves to adjacent cells through __desmosomes__.
 * Granular cell layer: abundant in basophilic granules, containing profilaggrin (converted to filaggrin, a structural protein, as the cell leaves the granular layer and moves upwards into the stratum corneum).
 * Note that a genetic deficiency in filaggrin is what causes most __eczema__.
 * To recognize how abnormal structure and function of the epidermis is reflected in disease.
 * __Bullous pemphigoid__:
 * Autoimmune, blistering disease (IgG vs. BP180 proteins in hemidesmosomes in the basement membrane zone).
 * Activates complement, get subepidermal blister.
 * __Pemphigus vulgaris__:
 * Autoimmune, blistering disease (IgG vs. desmoglein 3 proteins in intercellular desmosome junctions).
 * Results in intraepidermal blister due to loss of keratinocyte cohesion with each other.
 * More serious than BP- the patient can lose a large amount of epidermis.
 * __Epidermolysis bullosa simplex__:
 * [EBs in general: blistering diseases due to minor trauma to the skin. "Epidermolysis": lysis of the epidermis. "Bullosa": blistering.]
 * EB simplex is a genetically-mediated disease due to mutations within one of the keratin proteins (K5 or K14) of basal cell keratinocytes. Fragile skin, recurrent blister formation.
 * Blisters formed 'through' the basal cell layer (Wiki says they're formed 'in keratinocytes,' which is about as unhelpful).
 * Psoriasis:
 * "Complex genetic disease influenced by environmental factors." (ie. we have no real idea.)
 * Hyperproliferation and abnormal maturation of keratinocytes, causing thickening of the epidermis.
 * May be some kind of immunologic dysfunction.
 * My skin's on fire!
 * Warts:
 * Epidermal inoculation of latent HPV virus. When activated, the result is local thickening of the epidermis, abnormal maturation of keratinocytes, abnormal stratum corneum.
 * Note we don't actually know why the virus doesn't spread from the focal area of the wart.
 * Skin cancer:
 * Most commonly, basal cell and squamous cell carcinomas. See "Skin Tumors" and "Pigmented Lesions" for more detail.
 * Generally due to UV-induced mutations with a possible contribution from genetic factors.

=**Dermal Structures and Diseases**=


 * [Today's jolly fact: "xerosis" = dry skin.]
 * Identify the structural components of the dermis.
 * Dermis contains all the blood vessels, nerves, glandular structures, etc-- it keeps the epidermis alive, since the epidermis has none of these structures (except the very ends of free nerve endings). It is much thicker than the epidermis. It lies under the epidermis and above the subcutaneous tissue.
 * Contains hair follicles, sweat glands, vessels, nerves.
 * Divided into a papillary layer and a reticular layer.
 * The papillary layer interlocks with the epidermal base to provide shear strength and increase area available for diffusion.
 * The reticular layer contains everything else.
 * __Components__:
 * Collagen: provides most of the tensile strength in the skin. Note that the tensile strength doesn’t, mainly, come from the epidermis.
 * Collagen is secreted as procollagen by fibroblasts and assembled into collagen __extracellularly__-- requires vitamin C as cofactor (which is why vitamin C deficiency causes a skin disease called scurvy).
 * Scurvy: easy bruising, abnormal hair structure, bleeding gums, delayed wound healing. Easy bleeding due to lack of collagen sheath around blood vessel.
 * Collagen stains eosinophilic.
 * Ground substance: between collagen, allows for diffusion in dermis.
 * Elastic fibers: allow resiliency (elasticity).
 * Much thinner than collagen fibers.
 * Can't usually see these without special staining.
 * All of these are made by fibroblasts.
 * Distinguish between the types of collagen relevant to the skin.
 * Collagen I: 85% of adult dermis; also a major component of bone.
 * Collagen III: large part of the fetal dermis.
 * Evidently, this is why fetal skin doesn't scar like adult skin.
 * Collagen IV: found in basement membrane zone. Prominent around some vessels in the dermis.
 * Collagen VII: anchoring fibrils between dermis and epidermis.
 * Understand the function of elastic fibers in the skin
 * Allow resiliency (elasticity).
 * Be familiar with the ground substance components of the dermis.
 * Protein-sugar moieties (ie GAGs, like hyaluronic acid, that absorb a tremendous amount of water.)
 * Dr. High: "pie filling."
 * Identify disorders associated with defects in collagen and elastin
 * **Ehlers-Danlos Syndrome** : A defect disease of __collagen__, not elastin, despite its seemingly elastic manifestations. This would make a really obvious test question.
 * Hyperextensible skin and joints.
 * "Molluscoid psuedotumors" (soft, spongy tumors, made of fat and collagen) in easily damaged locations.
 * Often don't have a lingual frenula (membrane attachment of inferior surface of tongue to base of mouth).


 * Solar elastosis** : acquired disorder of elastic fibers.
 * The elastic fibers are damaged due to UV exposure. This turns the elastin fibers basophilic (blue-staining), a good indication that you're looking at the dermis of someone who's either older or has had a lot of UV exposure.

Psuedoxanthoma elastica ** (PXE): genetic elastin disease; elastin becomes calcified and brittle. **
 * Can lead to arterial rupture in the retina, can lead to blindness.
 * Skin also has a "plucked chicken" appearance ([]).


 * **Know the vascular supply and innervation of the skin as well as associated disorders.**
 * As mentioned, vascular supply and innervation are located in the dermis only, not the epidermis. Blood vessels go to the very top of the dermis, at the epidermal interface.
 * As should not be surprising by this point, dermal vasculature is significant for wound healing, homeostatic control, and modulation of inflammatory responses.
 * Dilated, torturous dermal capillaries are noted in diseases with increased epidermal turnover:
 * Psoriasis
 * Verruca (warts)
 * Note removal of scales in psoriasis causes pinpoint bleeding-- this still doesn't mean there are blood vessels in the epidermis, just that you've ripped open the capillaries right under the epidermis.
 * Can get vasculitis in the dermis from immune complex deposition in the dermal vasculature (standard type III immunopathology, here called "Gell and Coombs" reaction pattern). Tends to manifest, on this scale, as __palpable purpura__ (as per "Rheumatology Review and Vasculitis" from B+L notes) and nonblanching petechiae.
 * **Nerves: can end in a variety of ways in the dermis:**
 * Pacinian corpuscles** : sensitive to __pressure__ (__P__acinian = __P__ressure) **
 * Meissner's corpuscles** : sensitive to light touch (finger pads of hands) **
 * Free nerve endings** in dermis: itch, pain, temperature, etc. **
 * Types of neurons in the skin:
 * Type A: heavily myelinated, conduct quickly
 * Type C: unmyelinated, conduct slowly
 * Important because various anesthetics block different types of neurons. Local anesthetics block conduction of type A (pain) fibers.
 * Identify the major adnexal structures of the skin
 * Hair follicles:
 * "Terminal hair" (dark thick, coarse)
 * "Vellus hair" (fine, thin, apigmented)
 * Three regions of hair:
 * Top third = infundibulum;
 * Middle third = isthmus;
 * Bottom third = matrical area.
 * Sebaceous glands: next to hair follicles; lubricate the hair and prevent splitting.
 * Eccrine glands = sweat glands (watery, odorless). Used primarily for thermoregulation.
 * Numerous on forehead, palms/soles, axilla, cutaneous lips, etc.
 * This seems important (as emphasized twice by Dr. High): These are stimulated by acetylcholine, but are sympathetic glands. Note that acetylcholine usually stimulates the parasympathetic system.
 * Apocrine glands = secrete a different kind of sweat (give off body odor when acted upon by bacteria).
 * Called apocrine due to their method of secretion: membrane 'blebs' off in apical direction.
 * Apoeccrine glands = hybrid, produce both eccrine sweat (watery, odorless) and apocrine sweat (odiferous); located mainly in the axilla and can produce an enormous volume of sweat.
 * "Hyperhidrosis": excess production of sweat. Note can use botox (botulinum toxin) to prevent acetylcholine release to treat this condition.

=**Skin Tumors**=


 * Diagnose common benign skin tumors in infants and adults.
 * Basically that's all of the following aside from the carcinomas. Oh, and port wine stains aren't tumors, they're vascular malformations.
 * Know the cell type of origin for each of the skin growths included in this lecture.
 * __Vascular tissue__- cherry angiomas, hemangiomas, port wine stains
 * __Keratinocyte__- basal/squamous cell carcinomas, actinic keratosis, seborrheic keratosis
 * __Fibroblast__- dermatafibroma
 * __Sebaceous gland__- nevus sebaceous, sebaceous hyperplasia
 * Differentiate between skin tumors that are benign and those that are malignant or have malignant potential.
 * Again, benign: non-carcinomas or melanomas (see "Pigmented Lesions").
 * Describe clinical features of different types of sebaceous neoplasms including sebaceous hyperplasia and nevus sebaceus.
 * Sebaceous hyperplasia
 * Appear as yellow papules (globules) on skin, often with a central dell (sunken area).
 * Common, benign tumors of the sebaceous glands.
 * Increasing frequency after middle age; often found on face, trunk, and extremities, in that order.
 * Nevus sebaceus
 * Smooth yellow plaques on the scalp or face.
 * Directly open up onto the skin surface; their area is hairless (alopecia).
 * During puberty, plaques can become more raised and rough-surfaced.
 * Report of increased basal cell carcinoma on nevus sebaceous areas. Some controversy about this.
 * Describe clinical features of different types of vascular neoplasms including hemangiomas and cherry angiomas.
 * Infantile hemangioma ("strawberry hemangioma")
 * Rapidly growing tumors (discoloration and/or swelling) for the first year of life; slowly shrink by about 10% a year after that. Generally heal without scarring.
 * Benign endothelial cell neoplasm; more common in girls, but noninherited.
 * Generally no treatment needed unless location interferes with eating, breathing, vision, etc.
 * Stain with GLUT-1 (placental-associated vascular marker).
 * Cherry angioma
 * Bright red or purple small papules, maybe 1-4 mm in diameter. Can be numerous. Primarily found on the trunk.
 * Occur in middle age and tend to accumulate; not associated with underlying disease.
 * Recognize the fact that port wine stains are congenital vascular malformations.
 * Yep.
 * [Info on these:]
 * Similar to infantile hemangiomas, but instead of being a tumor, these are vascular malformations (I think they result from having too many or too-dilated capillaries in the dermis, based on what the laser treatment guy said). Also unlike infantile hemangiomas, these persist into adulthood.
 * No gender predilection.
 * Don't stain with GLUT-1.
 * Sometimes found with Sturge-Weber syndrome (development of glaucoma, seizures, developmental delay).
 * Treat with laser therapy.
 * Describe clinical features of different types of keratinocyte growths including seborrheic keratosis, actinic keratosis, basal cell carcinoma and squamous cell carcinoma.
 * Seborrheic keratosis
 * Superficial, oval, slightly raised papule with a "stuck-on" appearance.
 * Benign tumor of the hair follicles, usually presents later in life on trunk or scalp.
 * Generally harmless but can be a sign of internal malignancies if they're rapidly proliferating.
 * Evidently these are not UV-induced but arise due to inherited tendency.
 * Actinic keratosis
 * Most common __pre-malignant__ skin neoplasm. Grows slowly.
 * Appears as small, rough (hyperkeratotic) papules, pink-red or flesh-colored.
 * Due to UV exposure- often in sun-exposed areas of fair-skinned people.
 * Roughly 1 in 1,000 develops into squamous-cell carcinoma.
 * Basal cell carcinoma
 * Flat, firm, pale areas, or small, raised, pink/red translucent areas. May have depressed area in the middle (dells) or discolored areas. May bleed easily with minor trauma.
 * Most common cancer, as well as most common skin cancer, in the US: 800,000 new cases in US/year.
 * Locally invasive but rarely metastatic.
 * Squamous cell carcinoma
 * Growing lumps, often with a rough surface, or flat, slowly growing red patches. Can also show up as "craters" on skin.
 * Second most common cutaneous malignancy: 200,000 estimated new cases in US/year.
 * Can metastasize, but is rare.
 * Recognize the risk factors for non-melanoma skin cancer.
 * Note that non-melanoma skin cancers are rarely fatal.
 * Immunosuppression, particularly after organ transplantation
 * UV exposure
 * Fair skin
 * Genetic predisposition
 * Certain chemicals (arsenic, industrial tar/coal, etc)
 * Having already had a skin cancer
 * Phototherapy (UV light treatment, like that given to psoriasis patients)
 * Genetic skin diseases (basal cell nevus syndrome, xeroderma pigmentosum)
 * HPV infection
 * Smoking (at especial risk for squamous only, not basal)
 * Understand the components of non-melanoma skin cancer prevention.
 * Limiting UV exposure: wear more clothes and a hat, use sunblock, wear sunglasses, etc, etc.
 * This really isn't that different from melanoma skin cancer prevention.
 * [Not in her LOs but mentioned in her talk:]
 * Dermatofibroma
 * Benign tumors of the fibroblasts; most common on women's legs.
 * Brown, firm papules. Extend into the dermis.
 * Acrochordon:
 * "Skin tags": small papules, can be snipped off or left on. Larger variants are called "soft fibromas."
 * Generally found in areas of friction (neck, axilla, around or between women's breasts, etc. I didn't make up the breast thing, it's in her notes.).

Sebaceous hyperplasia: yellow globular papules, mainly face/trunk

Nevus sebaceous: hairless yellow plaques, scalp or face

Hemagioma: grow first year, shrink afterwards. GLUT-1.

Cherry angioma: red papules, mainly on trunk.

Seborrheic keratosis: "stuck-on" oval papules on trunk/scalp. Not UV-induced.

Actinic keratosis: hyperkeratotic papules, can be slightly reddish. Common pre-malignancy. UV-induced. Grow slowly.

Basal cell carcinoma: most common cancer/skin cancer. Flat firm pale areas, small raised pink/red translucent areas. Sometimes have dells. UV-induced.

Squamous cell carcinoma: second most common skin cancer. Growing lumps, sometimes hyperkeratotic, or slowly growing erythematous patches, or 'craters'.

=**Dermatology: Pharmacologic, Surgical, and Laser Treatments**=


 * [These are a little scattered.. like his lecture. Use only as directed by your physician.]
 * [Basics: oils and ointments are grease. In creams, lotions, pastes, etc, you add water and other stuff to make it smell better, spread better, etc. Gels have alcohols and acetone in them to help absorption.]
 * Compare the differences between different vehicles of topical therapy (ointment, cream, lotion).
 * Water-soluble/polar drugs (creams, lotions, pastes) don't penetrate the lipid barrier in the skin well.
 * __Ointments and oils__: More common in Colorado. Retain heat, hydrating, less likely to produce a contact allergy, deliver most medication. In wet climates they feel sticky and uncomfortable because they make you sweat; they feel better in sweatless, arid climates like this godforsaken desert state. Ointments should be applied twice a day; creams every 2 hours. Also, creams require preservatives (see below) that may cause contact allergy or irritation.
 * Ingredients: "solid grease": petrolatum or lanolin. Respectively a gasoline byproduct and rendered sheep hair. Yay.
 * __Petrolatum__: mildly vasoconstrictive; promotes re-epithelialization (fibroblasts have increased motility in wet conditions, thus better wound closure).
 * Note that due to allergy development to bacitracin/neomycin, this is what's often used to salve biopsy sites in derm clinics.
 * Mineral oil: effectively petrolatum with a slightly different preparation.
 * There are no allergies to petrolatum; there's occasionally an allergic reaction to lanolin (~1/3,000).
 * __Irritant__: affects everyone, it's an effect of slightly damaging the tissue.
 * __Allergies__ are specifically an effect of an immune reaction that only certain people mount (thus atopic).
 * Oils and ointments have no preservatives; creams and lotions do.
 * __Creams, lotions, pastes__: Ointments (grease) + water. The water's potential for bacterial infection requires preservatives, which increases risk of contact allergies.
 * Additives: emulsifying agents, preservatives, fragrances, water-binders, organic solvents (help absorption of water-based substances).
 * Common preservatives:
 * Formaldehyde and/or its releasing agents
 * PABAs, sorbic acid, hexachloraphenes
 * Preservatives are the most common allergen
 * Fragrances: low concentrations to avoid allergic reaction
 * Water-binding agents: mainly alcohols.
 * Organic solvents: polyethlyene glycols/propylene glycol (very irritating substances).
 * Also have 'stiffeners'-- bee's wax, glycerin, etc, for texture.
 * A quick search of the Web indicates that these agents (creams, lotions, pastes) vary mainly by viscosity (thus water content).
 * __Gels__: like lotions, but have alcohol and acetone in them to liquefy when they contact the skin. Can be very irritating due to xerosis.
 * Dosing:
 * Notice that patients usually use about 5 times more than they need but don't use it for long enough to make a lasting change.
 * Ointments: twice daily application for 2 weeks on the face, hands, or genital area: should be about 60 grams. Same dosage for each arm, back, or chest = 80 g; each leg = 120g; entire body = 840 g.
 * [Eczema: disease of the skin barrier due to mutations in filaggrin genes.]
 * Dry skin, presence of flexural dermatitis, onset before age 2.
 * Treat dry skin; the greasier the agent, the better. Use Vaseline (petrolatum).
 * Define and describe appropriate indications for keratolytics, antimicrobials, immunomodulators, and antipruritics. List at least 1 condition where each of these agents could be used.
 * Dr. Morelli after class: "Don't worry about that."
 * List factors that increase absorption of steroids from the skin.
 * Oil is absorbed well. Water isn't. Organic compounds help partially water-based compounds to be absorbed but can also leave the skin dehydrated.
 * Increased humidity results in increased water-binding in the skin and consequent enhanced penetration of water-soluble agents.
 * Heat and inflammation also increase percutaneous absorption.
 * List conditions where laser therapy or surgical excision is commonly used.
 * Laser therapy: port wine stains, some pigmented lesions, hair removal, skin peel. Essentially, if you don't want to section it to see if it's malignant, you can burn it off.
 * Surgical excision: benign or precancerous skin lesions (you want to section those).
 * Understand the advantages of topical therapy as well as the components of topical preparations
 * Topical therapy: targeted to affected area, avoid systemic effects.
 * Two major general components of optical preparations: the active ingredient and the delivery system, or vehicle.
 * Specific components: see above.
 * **Be familiar with common physical modalities used in skin treatments including cryotherapy, electrosurgery and lasers**
 * **Lasers: destruction by heating. You'd like this to be as specific as possible, obviously. Convert light to heat targeted to a particular absorbing molecule. The spread of the heat (which is depends on how long the laser is on) is significant also-- that's why you pulse the laser, to prevent heat from spreading out.**
 * Chromophore** : the molecule that's absorbing the laser heat (target). **
 * Thermal relaxation** : spread of heat from the chromophore. Generally you want to limit this except in skin resurfacing. **
 * Uses: chromophore is __hemoglobin__ in treating vascular lesions (birthmarks/port wine stains), __melanin__ for pigmented lesions and hair removal, and __water__ for destruction of dermis (peels).
 * Vascular lesions: Short-pulse (about 450 microseconds) can seal tiny (capillary-sized) blood vessels in the dermis and avoid scarring the dermis.
 * Pigmented lesions: Used on "age spots" or café-au-lait spots, or tattoos (tattoos are a little different since the different colors in the tattoos require different lasers). Tiny pulses (nanoseconds).
 * Hair removal: Epidermis generally cooled, to reduce epidermal melanin destruction (want to destroy melanin in hair but not melanin in keratinocytes).
 * Skin resurfacing: correctly severely photodamaged skin (destroy entire epidermis, allow skin to heal. Painful, prolonged healing time. Tuned to water; here you actually want heat spread, so it's possible to use continuous burn lasers as long as you keep moving them to different areas.
 * Electrosurgery: "burning things off," usually for low-grade skin cancers in areas that aren't cosmetically important or that are fairly small. Cauterizes blood vessels as it goes to stop bleeding.
 * Cryotherapy: done mostly for warts (take out HPV-infected skin cells). Usually use liquid N2 because it's so damn cold (to test, dump some liquid nitrogen in a -80 degree freezer and watch it instantly boil).
 * Use spray device to do this, generally (which strikes me as a bad idea but, as he said, beauty knows no pain). The area of freezing is generally as wide as it is deep. Results in a blood blister and crust. Can also use for actinic keratosis.
 * __Note that all three of these are tissue-destructive__-- don't want to do them on anything where you may need histology on it later (so cut a sample of it first).
 * Understand the concept of selective photothermolysis in laser surgery:
 * Photothermolysis: "photo," light, "thermo," heat, "lysis," cell destruction. Thus literally "light-heat cell destruction." Basically what was just described with laser therapy. Remember that you can't section something you just burned to a crisp.
 * [clinical vignette on port-wine-stain treatment:]
 * Use lasers to destroy superficial capillary abnormalities. Problem seems to be too many microvessels in skin that are full of blood; they start pink and tend to darken with age. By destroying these capillaries (you're targeting the hemoglobin in red cells but wind up sealing the vessels), you can erase at least most of the discoloration.
 * __Dermis thickens with age__; the sooner you zap a kid's port wine stain, the more of it you're going to get (only so deep a laser can go without putting a new hole in the kid).
 * Size of lesion, location on body, and age at treatment predicts outcome of therapy.

=**Pigmented Lesions**=


 * [Shout-out to Dr. Dunnick for correcting these for me. They should now be more or less complete.]**
 * Diagnose benign and malignant melanocytic tumors
 * Benign: nevi (moles). Diagnostic criteria follow.
 * Malignant: melanomas.
 * Differentiate between nevi and melanoma
 * Nevi: moles, or benign 'nests' of melanocytes. Can get irritated but are generally harmless-- though can progress to less pleasant things. Aren't lasered or frozen off (always want to preserve the tissue to send to pathology).
 * Melanoma: cancer of melanocytes (pigment-producing cells). Malignant, invasive, extremely dangerous due to a high tendency to metastasize.
 * Possible progression: melanocyte to nevus to dysplastic nevus to //in situ// melanoma to invasive melanoma. Note, however, that many melanomas likely arise //de novo//, from melanocytes not associated with nevi, and most nevi never progress to dysplasia.
 * Lifetime risk of melanoma is very high (although still behind lung, breast, prostate, and colon/rectal). About 8,000 deaths in 2007 from melanoma. The median age for melanoma is 53, but it can also occur in younger people. Melanoma is the second most common cancer in women age 20-29.
 * Describe clinical features of different types of nevi and melanoma
 * Nevi: Can show onset from infancy to adulthood. Distributed on any skin surface, including the mucous membranes, but tends to be more common on sun-exposed surfaces.
 * Types of nevi are generally classified by where the melanocyte nests are found in the dermis/epidermis:
 * Intradermal nevi: Nevocellular (nest) melanocytes are located in the dermis, and are raised but often appear flesh-colored (papules or nodules). Found mostly on the head and neck.
 * Junctional nevi: Nevocellular melanocytes are located in the dermal-epidermal junction and are generally flat and hyperpigmented (macules). Found anywhere, but particularly on the plantar/palmar surfaces.
 * Compound nevi: Nevocellular melanocytes are in both the dermis and dermal-epidermal junction, and are generally both raised and pigmented (brown papules/nodules). Found largely on the trunk and proximal extremities.
 * Nevi can be either acquired or congenital. Congenital (aka familial) tend to be a bigger risk for melanoma development.
 * There are blue nevi. They're rare. They're generally harmless.
 * Dysplastic nevi: acquired or congenital, melanocyte proliferation. Can present appearing round, oval, or irregular, with different colors inside it (color variegation), often with indistinct margins; "fried-egg" presentation. Big risk factor for melanoma, particularly the familial variant.
 * Size classification of congenital nevi:
 * Small nevus: less than 1.5 cm. Medium nevus: between 1.5 and 20 cm. Large nevus: greater than 20 cm.
 * Types of melanoma:
 * Superficial spreading (slowly spreading flat patch)
 * Nodular (rapidly enlarging lump)
 * Lentigo maligna (slowly spreading flat patch in sun-exposed area)
 * Acral lentiginous (plantar and palmar surfaces and nails)
 * Desmoplastic (neurotropic, nerve infiltration)
 * **Recognize the risk factors for melanoma**
 * Melanomas can arise within dysplastic nevi, particularly familial dysplastic nevi.
 * **Clinical signs of melanoma:**
 * A** symmetry **
 * B** order irregularity **
 * C** olor variegation **
 * D** iameter greater than 6 mm (not actually a good diagnostic tool) **
 * E** volution or change over time **
 * Look for nevi that are different from the other nevi on the body.
 * Risk factors for melanoma:
 * Fair skin
 * Excessive UV exposure
 * Immunosuppression
 * Malignant melanoma in a first degree relative
 * White people (damn)
 * Large congenital nevus
 * Sporadic (not familial) or familial dysplastic nevi
 * Know the difference in Breslow depth and Clark’s level used in staging of melanoma as important prognostic factors of melanoma
 * __Breslow depth__: absolute depth in millimeters of how far beneath the surface the bottom of the melanoma is.
 * __Clark levels__: what levels of the skin is it in? (higher = deeper)
 * level 1: into epidermis
 * level 2: into the papillary dermis
 * level 3: into mid-dermis
 * level 4: into deep dermis
 * level 5: into subcutaneous fat
 * Prognosis is better and correlated with thinner Breslow depth. __Clark's levels are not as strongly correlated with prognosis as Breslow’s depth__.
 * To look for metastasis (ie. to stage the cancer), look in 'sentinel node' (nearest lymph node to cancer).
 * Note that there aren't good treatment options for metastatic malignant melanomas.
 * Understand the components of melanoma prevention
 * Watch out for UV radiation, pretty much, and maybe know your family history. UVA/UVB sunblock, lots of clothing, broad-brimmed hat.
 * [Café-au-lait macules: can be sign of neurofibromatosis (if there's 6 or more greater than 1.5 cm in adults or greater than 0.5 cm in kids). See class notes for diagnostic criteria of type 1 neurofibromatosis. This is an example of skin as a marker of systemic disease.]

Nevi: Intradermal - raised, flesh-colored Junctional - flat, hyperpigmented Compound - raised, hyperpigmented Dysplastic - irregularly shaped or colored; "fried-egg"

Melanoma: Superficial spreading - patch Nodular - lump Lentigo maligna - patch in UV exposed area Acral lentiginous - plantar/palmar Desmoplastic - neural**

=**Skin Infections and Infestations**=


 * **There's a lot of information here; I strongly suggest looking at the slides (on the computer, as the printouts are fairly useless) as a good follow-up. Also note that there is a printed-out prose note section from him that didn't make it into my (and maybe your) handout packet. It's online and is considerably more involved than what's below.**


 * **Identify peptides involved in innate immunity of the skin.**
 * A** lpha-defensins (hNP1, hNP2) **
 * B** eta-defensins (hBD-1, -2, -3) **
 * C** athelicidin (hCAP-18) **
 * Psoriasin
 * RNase7
 * Essentially these are all antibiotic to some extent.
 * **For common cutaneous viral infections, recognize the clinical characteristics and identify the etiologic agent.**
 * a. __Human Papillomavirus__:
 * Etiologic: papovavirus (non-enveloped dsDNA virus).
 * Clinical:
 * Shows up as verrucas (warts). Different types show up most commonly on fingers, hands, elbows, and knees, or palmar and plantar surfaces.
 * Verrucas: hyperkeratotic papillomas with punctuate black dots that represent thrombosed capillaries.
 * **b. __Herpes Simplex Virus__:**
 * Etiologic: dsDNA virus, acquired through breaks in skin/mucosa through saliva, vaginal secretions, vesicular fluid, etc.
 * Clinical:
 * Primary lesion: grouped vesicles on an erythematous base.
 * Can show up on lips, gums, fingers, genitals, etc.
 * Note patients with eczema can get a whole lot of outbreaks if they get herpes.
 * Latent period (virus in nervous tissues) followed by recurrent re-emergence of infection.
 * Detect with Tzanck test.
 * c. __Varicella Zoster Virus__:
 * Etiologic: again, a herpesvirus (dsDNA).
 * Clinical:
 * Initially: fever, thin-walled vesicles on erythematous base
 * New 'crops' of these vesicles for 3-5 days ("dew drops on a rose petal"-- someone's a frustrated English major).
 * Like herpes simplex, lies latent; re-manifests as shingles (varicella zoster)-- hurts like crazy due to inflammation in spinal nerve affected.
 * **For common cutaneous bacterial infections, recognize the clinical characteristics and identify the etiologic agent.**
 * a. __Impetigo__:
 * Etiologic: caused by superficial infections with either beta-hemolytic streptococci (strep pyogenes, less common) or staph aureus (most common).
 * Clinical:
 * Divided into bullous and non-bullous. A bulla is a large, fluid-filled blister, thus bullous means blistering and non-bullous means non-blistering.
 * Non-Bullous Impetigo (most common):
 * Most commonly affects the face. Usually begins as a single lesion, frequently followed by other lesions adjacent to it.
 * "Honey-colored crust": characteristic lesion.
 * Bullous Impetigo:
 * Anywhere on the body; show up as flaccid, superficial blisters (no bleeding when they pop).
 * The organism cleaves the skin surface and lives right beneath the stratum corneum.
 * Detect with Gram stain: look at blister contents.
 * **b. __Cellulitis__:**
 * Etiologic: caused by deeper microorganism infections that get into/beneath the dermis due to microscopic or macroscopic breaks in skin (macroscopic: cuts, ulcers, surgeries, etc). More common in humid, warm areas and in the very young or very old.
 * **Clinical:**
 * **Two classes of cellulitis, classified according to where they show up. They're divided up this way because different lymphatic drainage patterns in different locations create different appearances.**
 * Erysipelas** : cellulitis that occurs mainly in the face, mostly streptococcal. **
 * **If the lesions occur mainly in the hands or extremities, it's just called** cellulitis** . **
 * Erysipelas: Several days post-infection: acute, red, hot, painful, __sharply demarcated__ plaque. Usually unilateral. Regional lymphadenopathy. Sometime systemic symptoms.
 * Cellulitis in extremities: Same thing, but tend to have lymphangitis (red streaks following lymph pathways) and the plaques are __not__ as sharply demarcated.
 * Detect with tissue culture; can also use Gram stain. Probably a good idea to do a blood test to make sure it hasn't gotten into the vasculature.
 * c. Syphilis:
 * Etiologic: //Treponema pallidum// spirochete, high motility, can't be cultured. Acquired through sex.
 * Clinical:
 * Primary syphilis: pops up 2-6 weeks after intercourse as a papule that breaks down to produce an oval, indurated (hardened) ulcer, frequently non-tender.
 * Secondary syphilis: Rash ("can look like just about anything"), lymphadenopathy, systemic malaise. Classic presentation on palms and soles. Note can produce "moth-eaten alopecia" (patchy hair loss).
 * Detect with serology.
 * For common cutaneous fungal infections, recognize the clinical characteristics and identify the etiologic agent.
 * a. Dermatophyte Infections:
 * Recall that dermatophytes eat keratin: hair, nails, skin. These are the sites they attack in infections.
 * Etiologic: Acquired through environment; attacks stratum corneum.
 * Clinical:
 * Tinea capitis: scaly plaques on head, 'eats hair;' can produce permanent hair loss. (Tinea = ringworm; a fungus, not a helminth.)
 * Tinea barbae: same thing, but shows up on face.
 * Tinea cruris: jock itch. Scaly plaques in grain. Notice that it does __not__ affect the scrotum.
 * Tinea pedis: athlete's foot. "Likes" various toes more than others; doesn't like the space between the big toe and second toe.
 * Two-feet-one-hand: tinea pedis diagnosis.
 * Note that it eats nails, so can see some unpleasant things.
 * Depending on where it's acquired, can prompt ferocious host immune response.
 * Detect with KOH prep (shows up as hyphal forms) and culture.
 * b. Candidiasis:
 * Affects mucous membrane and skin (eats blood sugar).
 * Etiologic: mainly //Candida albicans//.
 * Clinical:
 * Thrush/Oral candidiasis: white, creamy plaques in mouth
 * Can show up at immobilized, moist, unaerated sites (diaper rash)
 * Common cause of vaginitis ('yeast infections').
 * Shows up as "satellite lesions"
 * "Candida loves the scrotum" (as opposed to tinea).
 * Without an immune response, candidiasis can get really nasty. Mainly in AIDS patients.
 * Detect with KOH prep (shows up as psuedohyphae and singular forms).
 * c. Tinea (Pityriasis) Versicolor:
 * Etiologic: //Malassezia furfur// fungus. Eats follicular lipids.
 * Clinical:
 * Can show up as tan, slightly scaly macules.
 * Can be hypopigmented (inhibition of melanocytes).
 * Can have follicular papules on trunk, arms, face.
 * For common skin infestations, recognize the clinical characteristics and identify the etiologic agent.
 * a. Scabies:
 * Etiologic: //Sarcoptes scabiei// organism: "mites."
 * Clinical:
 * Intense pruritis; show up in symmetrical pattern.
 * Primary lesions: small erythematous papules, usually in soft areas of skin (bites of male mites)
 * "Burrows" (female mite's tunnels): thin lines on skin.*
 * In genital regions, produce larger nodules instead of small papules.
 * Detect with scrape biopsy.
 * b. Lice Infestation:
 * Etiologic: bloodsucking wingless insects (//Pediculus// / //Phthirus// )
 * Clinical: intense pruritis.
 * Head lice: white ovals (eggs) attached to hair shafts.
 * Body lice: eggs only found on trunk.
 * Public (crab) lice: eggs found in genital areas.
 * c. Cutaneous Larva Migrans:
 * Etiologic: found in GI tract of dogs and cats; acquired through their feces through fissured human skin. Note that they can't get into the GI tract (or reproduce) in humans.
 * Clinical:
 * Can't get through the basement membrane zone- just crawl around in the epidermis. Eventually die off by themselves. You can track the raised lesions indicating the progress of the worm.
 * Maybe I've been typing these too long, but this could be the next big gambling experience: two worms at the starting gate (say the ankle), see which gets to the knee first. Could name them like you name racing horses - Flatworm Or Bust, The Nematode Experience, The Great White Hope, etc. People will bet on any damn thing.
 * **Explain the clinical utility and indications for the following diagnostic procedures in dermatologic patients:**
 * a. Tzanck smear: take blister, break it open, smear the blister base on a slide, stain. Can be used to identify herpes simplex, varicella viruses.
 * b. Gram Stain: you know this one. Used for bacterial classification.
 * c. KOH Prep: you know this one too. Used for fungal classification.
 * **d. Wood’s light exam: Not in his notes. Wiki: A** Wood's lamp** is a diagnostic tool used in dermatology by which ultraviolet light is shone (at a wavelength of approximately 365 nanometers) onto the skin of the patient; Wood's light is useful in diagnosing conditions such as tuberous sclerosis and erythrasma, both in distinguishing them from other conditions and in locating the precise boundaries of the condition. It is also helpful in diagnosing fungal infections (Microsporum audouini), bacterial infections (Corynebacteriium minutissimum, Pseudomonas), and pigmentary disorders. **
 * e. Wet Prep for scabies: Not in his notes. Wiki: The suspicious area can be rubbed with ink from a fountain pen or alternately a topical tetracycline solution which will glow under a special light. The surface is then wiped off with an alcohol pad; if the person is infected with scabies, the characteristic zigzag or S pattern of the burrow across the skin will appear.

HSV: grouped vesicles on red base

VZV: initial fever, new crops of vesicles

Honey-colored crust: characteristic of non-bullous impetigo, mostly on face. Flaccid, superficial blisters: characteristic of bullous impetigo.

Erysipelas: on face, acute, warm, red, painful, sharply demarcated Peripheral cellulitis: lymphangitis, not sharply demarcated Both: regional lympadenopathy

Primary syph: papule producing a painless, hard ulcer. Secondary syph: some kind of rash, malaise, lymphaden. Classic rash on palms/soles; some patchy alopecia.

Dermatophyte: eats keratin: hair, nails, skin. "Tinea". Capitis, barbae (face), cruris (__doesn't affect scrotum__), pedis. Classic tinea pedis: two-feet-one-hand presentation. Eats nails.

Candida: eats blood sugars. Loves the scrotum. Satellite lesions.

=**Inflammatory Skin Disease**=


 * Recognize the clinical presentations and different patterns that may occur in all of the types of dermatitis discussed.
 * __Atopic dermatitis__:
 * Common, particularly in young people.
 * Pruritis plus three or more of:
 * Involvement of skin folds or face
 * History of asthma/hay faver
 * History of xerosis (dry skin)
 * Visible flexural eczema
 * Under 2 years of age
 * Note you often get eosinophilia.
 * Note the "atopic triad"-- allergies, asthma, atopic dermatitis.
 * I think the idea here is that it's some kind of allergic reaction on the skin. Really as simple as that? Dunno.
 * Histologically: get spongiosum (swelling of keratinocytes); chronically you get a deepening of the 'interlacing' (rete ridges) between the epidermis and dermis.
 * Note that due to the inflammation, you can get hypopigmented areas after the dermatitis has cleared up.
 * Presentation can vary:
 * Infancy: dry red scaly areas __around the cheeks__; may get hypopigmentation due to scratching.
 * Childhood: involvement of flexural areas.
 * Adult: involvement of flexural areas, eyelids, hands, anogenital area.
 * Contact dermatitis:
 * __Allergic contact dermatitis__:
 * Delayed hypersensitivity immune reaction-- Th1-mediated macrophage activation through IFN-gamma. Pruritic, erythematous papules and plaques. Note that first exposure to allergen doesn't usually provoke a response unless it's a week-long exposure or more.
 * Most common skin allergen: nickel.
 * Increasing allergies: bacitracin, neomycin.
 * She strongly hinted that the top-ten list of allergens in her notes is testable material. I find this retarded. But here it is.
 * #1: Nickel
 * Neomycin
 * Balsam of Peru (sure glad I memorized that one)
 * Fragrance
 * Thimerosal
 * Gold
 * Quarternium-15
 * Formaldehyde
 * Bacitracin
 * #10: Cobalt
 * If it presents as a rash all over, it's probably related to topical medications that they're smearing around. First-exposure reaction comes in about 8-10 days (need to build Th1 response), second-exposure happens a lot faster (Th1 already in place).
 * Note that certain viruses (like EBV) can kick up a systemic rash similar to drug allergies.
 * __Irritant contact dermatitis__:
 * Non-immunologically mediated reaction (can get reaction from first exposure); caused by the cytotoxic effect of agent, not Th1 and macrophages. Can be severe or mild (mild takes prolonged exposure to cause damage-- like friction). Also presents as pruritic, erythematous papules and plaques.
 * Eczematous dermatitis:
 * Often used interchangeably, though incorrectly, with atopic dermatitis. That's all she seems to want to say about it.
 * She only mentioned these other kinds of dermatitis at the last minute:
 * Seborrheic dermatitis:
 * Sharply demarcated, yellow/pink plaques with thin, 'greasy' scales. Occurs in areas that have a lot of sebaceous glands (scalp, face, ears, chest).
 * Stasis dermatitis:
 * Lower extremity edema leads to dermatitis in immobilized patients.
 * Compare and contrast the clinical presentations of atopic dermatitis and psoriasis.
 * __Atopic dermatitis__: erythematous plaques, commonly in specific regions like the cheeks or flexural areas. Th2 type response (IgE, eosinophils-- standard Type I immunopathology).
 * __Psoriasis__: classically ('plaque psoriasis'), erythematous plaques ('salmon pink') with silvery scale. Th1 type response (standard Type IV immunopathology).
 * List common clinical associations and clinical variants of atopic dermatitis and psoriasis.
 * Atopic dermatitis:
 * Associated with dry skin, a history of allergies, keratosis pilaris (papules around the hair follicles), eye problems (cataracts, conjunctivitis, retinal breaks, keratoconus), pityriasis alba (pigmentary changes), and increased skin infections.
 * Also family history.
 * Psoriasis:
 * Associated with:
 * Pinpoint bleeding from scale-peeling due to dilated superficial capillaries.
 * Reiter's syndrome (see/pee/climb a tree), associated with infections. Classically shows up as pustules on palms and soles of feet (that's another reason not to climb a tree), and possibly red plaques on the penis (that's another reason not to pee).
 * Seronegative psoriatic arthritis, largely in digits.
 * Droplike, scattered pink papules with overlying silvery scale ('__guttate psoriasis__'). Strong association with //Streptococcus// infection.
 * Note the rebound effect from too-sharply withdrawn steroid treatment: can lead to big flare after temporary abatement.
 * Also family history.
 * Know the pathogenesis and common causes of the different types of "dermatitis".
 * Atopic:
 * Caused primarily by type I allergic reaction (Th2-mediated).
 * Note that this can be exacerbated because the skin's barrier function is disrupted and it's easy for bacteria to colonize the skin. Staph, in particular, can act as a superantigen.
 * Contact:
 * Allergic: As mentioned, type IV reaction: Th1-mediated macrophage damage due to contact with a sensitized antigen.
 * Irritant: cytotoxic effect of agent.
 * Seborrheic:
 * Caused by a yeast (//Malassezia furfur// ), normally standard skin flora. Possibly due to floral imbalance (wow, I just had to kick my own ass a little for typing that).
 * Stasis:
 * Patients that stay put too much (hospitalized or me over break).
 * Urticaria: recurrent "whealing" on the skin; each individual wheal should resolve within 24 hours. Caused by type I reaction and mast cell degranulation in skin.

=**UV damage and repair**=

It would be nice to have a derm lecturer who sticks to their LOs. To dream the impossible dream. Best guess, and it's pretty disheveled, follows. Note with high doses of UVA, can still get burned (like those in tanning beds, which use exclusively UVA bulbs).
 * Discuss the role of ultraviolet radiation in the development of various pathologic skin diseases including skin cancers.
 * Effect of UV radiation on the skin:
 * Damage to DNA, RNA, lipids, proteins
 * Thymine dimers caused by UVB
 * Hydroxyguanosine: UVA
 * Pyrimidine-6-4 pyrimidone: UVB
 * These forms of damage can be excised or repaired if they're limited; they can also either induce apoptosis or progress to carcinoma. Note that p53 is the main regulator of DNA repair in the skin, so without p53 (Li-Fraumeni comes full circle), you're kind of screwed.
 * Pro-inflammatory effects (erythema, white cell infiltration of tissue)
 * Primary cytokines: IL-1, TNF-alpha (induce inflammation)
 * Secondary cytokines: IL-6 (fever, acute phase response), IL-8 (neutrophil chemotaxis), IL-10 (anti-inflammatory, negative feedback), GM-CSF (make more neutrophils and monocytes)
 * Lipid mediators: platelet activating factor, prostaglandins, leukotriene B4 (also neutrophil chemotaxis)
 * Growth factors: VEGF, a bunch of other stuff. The idea is that UV exposure can cause tumor growth.
 * Mast cell activation
 * Immunosuppression (doesn't help cancer development)
 * Note that UV radiation's interleukins skew the Th system ("immune deviation," recall from Immunopath I lecture) towards Th2 (which is also ineffective against tumors).
 * UV radiation reduces Langerhans cell population in the skin.
 * Induction of innate immune system
 * Induction of apoptosis
 * Vitamin D synthesis
 * Ie: without any UV exposure at all, you do get some problems with Vit D.
 * Notice: UV damage to stratum corneum is above the reach of most defensive mechanisms against cancers.
 * Note that certain medications, like soralins, accentuate the effect of ultraviolet light.
 * Describe vitamin D metabolism in the skin
 * UV (specifically UVB) induces synthesis of Vitamin D3 and D2 in the epidermis. These are then transported to the liver and kidney and activated.
 * Vitamin supplements contain both D2 and D3, mainly D2 (which is less active). There is some controversy over whether the benefits of UV exposure can be fully supplied with vitamin supplementation.
 * [Defenses vs UV: DNA repair (p53 is activated by UV radiation), melanin, antioxidant proteins in the epidermis, etc.]
 * [Xeroderma pigmentosum: loss of DNA repair enzymes, develop cancers therefrom.]
 * [Note that basal cells in epidermis are naturally resistant to induced cell death, which makes sense since they're constantly exposed to UV. However, this means that if they turn into nasty mutants, they have a natural leg up on most nascent cancer cells.]
 * [Stuff on melanocytes:]
 * Note that melanocytes don't have stem cells on most of the body (except in the scalp's hair follicles)-- so if they're destroyed, no replacements. This condition (hypo- or apigmentation) is called vitiligo.
 * Melanocytes: produce melanosomes (specialized lysosome) filled with melanin. They transport enzymes and cofactors necessary for melanin synthesis into the cell and prevent leakage of those enzymes and cofactors out (factors to produce melanin are very toxic).
 * Once melanosome is created (absorbs light across entire UV spectrum), it is transferred to nearby keratinocytes, which carry them as they progress towards the skin surface. Note you make melanin from tyrosine. Mutations from the tyrosine-to-melanin pathway results in albinisms.
 * Tyrosinases and related proteins generally control this process. Various kinds. Red hair results from a problem in melanin production-- red-haired people also tend to be at highest risk for melanoma.
 * The melanosomes tend to migrate superficial to the nuclei, presumably to protect the nuclear material from UV. Differences in melanosomal structure, distribution, and synthesis are the basis for racial pigmentation differences.
 * Note: enzyme called MART1 is a target on the melanocyte surface used in treating melanoma.
 * MITF: key melanocyte-inducing transcription factor: controls melanocytes survival, pigmentation, etc. Can be turned on by Wnt, alpha-MSH, stem cell factor (SCF). May also be activated by UV exposure (more melanin in reaction to more UV). Note that mutations in genes that control expression of the MITF gene can also result in unpleasantness.
 * Define SPF, what increasing or decreasing SPF means, and the rationale for the use of sunscreen agents.
 * SPF: sun-protective factor for UVB alone. Should have UVA also.
 * UVA: involved in photoaging and some melanoma along with UVB
 * Good sunscreens: UVA has a longer-lasting effect.
 * Parsol 1789 (avobenzone) = good ingredient (lasting UVA protection)
 * Neutrogena Helioplex = current gold standard
 * SPF15 is not sufficient especially for photosensitive, skiers, cancer risk patients, etc- want at least SPF 30. Avoid noontime exposure.
 * List dermatologic conditions caused by ultraviolet radiation
 * Basal/squamous cell carcinomas, melanomas
 * Idiopathic: solar urticaria (hives due to UV exposure) PMLE (polymorphous light eruption), actinic prurigo. No, I have no idea.
 * DNA repair defects: Xeroderma pigmentosum
 * Chemical: drug induced, porphyria
 * UV-exacerbated: Psoriasis (but note can use UV as therapy also), atopic dermatitis
 * Understand and discuss the risk factors for various types of skin cancers.
 * The obvious: cover up, wide-brim hat, sunscreen.
 * Mentioned in passing that UVA and UVB can both cause skin cancer.
 * Recognize clinical signs and symptoms of various skin cancers
 * Didn't get into it. See "Pigmented Lesions" and "Skin Tumors" for details on melanomas and basal/squamous cell carcinomas.
 * Understand the diagnostic role of biopsy
 * Didn't say a thing about it.
 * Know which types of ultraviolet radiation cause various conditions (i.e. sunburn, photoaging, corneal burns etc).
 * Noon, or so, is the time of day at which the sun is closest to your particular patch of earth, so it's also the easiest time to get a lot of UV exposure.
 * 3 types of UV radiation:
 * UVA, UVB, UVC: short-wavelength = C, middle-wavelength = B, long-wavelength = A (ie. C = highest energy, B = middle energy, A = low energy)
 * The longer the wavelength, the more deeply the radiation penetrates into the skin--
 * UVC only penetrates superficially; most damaging to tissue with small stratum corneum and doesn't have a lot of layers to it-- like the cornea.
 * UVB: partially into dermis (I think that's what he said)
 * UVA: completely or near-completely through dermis (again, I think)
 * __UVC radiation__ doesn't get to the surface of the earth, but __is highly damaging to the cornea__ (still found in some old types of industrial lamps) and burns the skin quickly.
 * __UVB radiation causes sunburn__.
 * Note UVB exposure varies with season: UVB radiation at sea level is generally much less intense during the winter and much stronger in the summer. Not so much in Colorado.
 * Note UVB also causes vitamin D synthesis.
 * __UVA radiation causes photoaging__.