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Hypersensitivity Type 1 2 3 4, Urticaria Anaphylaxis Immune Complexes I II III IV
http://www.stomponstep1.com/hypersensitivity-type-1-2-3-4-urticaria-anaphylaxis-immune-complexes-i-ii-iii-iv SKIP AHEAD: 0:26 – Definition of Hypersensitivity 1:12 – Mnemonic for remembering the 4 types 2:58 – Type I (Type 1) HS 6:48 – Anaphylactic Shock 7:45 – Type II (Type 2) HS 8:57 – Type III (Type 3) HS and Immune Complexes 10:29 – Type IV (Type 4) HS Hypersensitivity is when an otherwise healthy immune system has an undesirable exaggerated response to a foreign substance (or perceived foreign substance) that damages the body’s own cells. These are the same immune processes that are necessary to prevent infection, but they create problems when they are hyperactive or misguided. The way I remember the four different types of hypersensitivity is my ABCD mnemonic. I = Allergic Anaphylaxis and Atopy II = antiBody III = immune Complex IV = Delayed * Types I, II and III all can involve antibodies. Therefore, having antibody in the mnemonic for type II may be confusing. However, the “classic” role of antibody involving complement activation, NK cell activation and opsonization are part of Type II which is why I feel that is the simplest way to remember it. Type I Hypersensitivity is triggered by an innocuous foreign substance (like dust, pollen or animal dander) that would cause no problems in the majority of people. The antigen simultaneously binds more than one membrane bound IgE on a mast cell (or basophil). This process, called Crosslinking, triggers the release of mast cell granules full of histamine. Histamine then goes on to signal the various changes associated with allergies similar to how it functions during acute inflammation. This allergic reaction happens almost instantly and the symptoms can become evident within minutes. This is possible because the mast cells are Pre-Sensitized to the innocuous substance which means they have pre-formed membrane bound IgE that recognizes the particular innocuous antigen. To be pre-sensitized the immune system must have seen the antigen previously, because antibody (IgE) formation takes time. Histamine’s role in Type I Hypersensitivity is why Anti-Histamines (Histamine Antagonists) like Diphenhydramine or Loratidine can control some allergy symptoms. Type I Hypersensitivity is the process that leads to various different “allergies”. A more mild form would include Allergic Rhinitis (seasonal allergies) that cause things like coughing, sneezing, watery eyes and nasal congestion. Some individuals with these allergies also experience an atopic rash referred to as Urticaria (Hives) or Atopic Dermatitis (Eczema). This red rash is raised and pruritic (itchy). Through a similar mechanism Type I Hypersensitivity can lead to exacerbation of Allergic Asthma by environmental triggers. This type of hypersensitivity is also the mechanism behind more serious conditions like peanut or bee sting allergies that can lead to swelling of the lips/tongue/throat, shortness of breath, stridor, and anaphylactic shock. Anaphylatic shock is a life threatening condition in which systemic histamine directed inflammation causes hypotension via global vasodilation, an increase in vascular permeability and significant fluid movement into the tissue. It is treated with epinephrine, often in the form of an “Epi Pen” when outside of a medical setting. Epinephrine activates Alpha-1 Adrenergic Receptors to raise blood pressure via vasoconstriction and increased contractility of the heart. Type II Hypersensitivity is the process by which IgG or IgM binds to a cell to cause injury or death (Antibody Dependent Cytotoxicity). This process has the same mechanism of action as normal humoral immunity except it is targeted at the body’s own cells instead of pathogens. The variable region of the antibody binds to the host cell while the constant portion interacts with NK cells, complement and macrophages. Examples of this reaction can be seen in Rheumatic Fever (body’s own cell look similar to Strep Pyo), Goodpasture Syndrome (Anti-Glomerular Basement Membrane Antibodies) and Hemolytic Disease of Newborns/Erythroblastosis Fetalis (when a Rh- mother has a second Rh+ child and the maternal IgG targets fetal RBCs). The text for this video is too long for Youtube and exceeds the maximum allowed video description length. To read the rest of it go here http://www.stomponstep1.com/hypersensitivity-type-1-2-3-4-urticaria-anaphylaxis-immune-complexes-i-ii-iii-iv
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Pedigrees, Patterns of Genetic Inheritance, Autosomal Dominant Recessive X-Linked Mitocondrial
http://www.stomponstep1.com/pedigrees-patterns-of-genetic-inheritance/ Before you watch this video you should really watch the previous video in the section which covers Types of Inheritance (http://www.stomponstep1.com/genetic-inheritance-autosomal-dominant-x-linked-recessive-mitochondrial-disease/) Pedigrees are graphical representations of ancestry with respect to one or more disease(s). Males are represented with a square while females are represented with a circle. The shape is black/filled in if the individual is affected by the disease. The shape is empty/white if the individual is not affected by the disease (may be unaffected or carrier). Usually each generation (row) is labeled with a roman numeral while each individual is labeled with a number. Autosomal Dominant Autosomal recessive X linked recessive Mitochondrial Now that you are done with this video you should check out the next video in the Genetics section which covers Purine Salvage Pathway & Lesch-Nyhan Syndrome(http://www.stomponstep1.com/purine-salvage-pathway-lesch-nyhan-syndrome/)
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Odds Ratio & Relative Risk Calculation & Definition, Probability & Odds
ERRATA: At about the 3:00 mark the slide says "10,00" when it is really supposed to say "10,000." I added a pop up box to fix it. Thanks to Mehdi Hedjazi for pointing this typo out The terms odds and probability are used interchangeably in everyday life. However, in the setting of Biostats they are two different things. Generally speaking they both represent how likely something is, but they are calculated differently and used in different situations. Probability is essentially the same things as percentage. You are comparing the number of occurrences of a certain outcome to the number of total events measured. Probability ranges between zero and one. Odds is a ratio of the likelihood of an event happening compared to the likelihood of an event not happening. Odds can be zero or any positive number (not just values between 0 and 1). So the probability of rolling a 4 on one attempt with one six faced die is 1_6. The odds of rolling a 4 are 1_5. Here is another example. If 13 people of a 60 person sample have lung cancer the probability of a person in that group having lung cancer is 13_60 and the odds of a person in that group having lung cancer is 13_ 47. When we are talking about common events the difference between odds and probability is high. For example, flipping a coin one time gives you pretty different results. You have 1_1 odds of getting head and 1_2 probability of getting heads. However, as an event gets more and more rare the difference between odds and probability gets very small. Pretend there is a drawing with one winner and 10,000 people entered. The odds of winning are 1_9,999 (0.0001) and the probability of winning is 1_10,000 (0.0001). In this case, odds and probability are essentially identical. The difference between odds and probability is important because Relative Risk is calculated with probability and Odds Ratio is calculated with odds. Relative Risk (RR) is a ratio of probabilities or put another way it is one probability divided by another. Odds Ratio (OR) is a ratio or proportion of odds. I just remember that odds ratio is a ratio of odds and probability isn't a ratio of odds (AKA it is the other option). Relative Risk = Probability _ Probability Odds Ratio = Odds _ Odds Now that you have a general idea of what odds ratio and relative risk are you need to know when to use them. They don't always just ask you to calculate one or the other. Sometimes questions on Step 1 also require you to figure out which type of calculation is needed based on the situation. In clinical trials and cohort studies we use relative risk to compare the incidence of health outcomes between groups of differing exposure or treatment. For case-control trials we use odds ratio to compare the "incidence" of past exposures or treatments. Cohort Studies (and clinical trials) = Relative Risk Case-Control studies = Odds Ratio I remember this by thinking about a group of pirates (group = cohort) all saying "aRRrrr!". That reminds you that cohort studies use RR and the "other one" uses OR. Now that we understand the research setting for each term we can redefine RR & OR. I should note that I think memorizing these definitions is unnecessary because if you understand the simpler definitions you should be able to create these based on the scenario presented in the question. An RR or OR of 1 means there is no difference between the two groups being compared with respect to what you are measuring. In this case the treatment or risk factor being study has no effect on the rate of outcome development. Similarly, an OR or RR of 2 means whatever you are measuring is two times as likely to occur in the group being studied when compared with the control group. 0.5 means it is half as likely and so on. Later in the chapter we will cover how confidence intervals are applied to RR & OR. Now that you have finished this video you should check out the next video in the Biostats & Epidemiology section which covers Number Needed to Harm & Attributable Risk (http:__www.stomponstep1.com_number-needed-to-treat-absolute-risk-reduction-attributable-risk-number-needed-to-harm_).
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Psychosis: Schizophrenia, Schizoaffective Disorder, Delusional Disorder, Hallucinations
http://www.stomponstep1.com/psychosis-schizophrenia-schizoaffective-disorder-delusional-disorder-hallucinations/ SKIP AHEAD: 0:25 - Psychosis Symptoms (Hallucinations, Delusions, Catatonia & Disorganized Speech) 3:21 - Psychosis in mood disorders 3:54 - Schizophrenia 6:06 - Schizophreniform & Brief Psychotic Disorder 6:34 - Schizoaffective 7:29 - Delusional Disorder 8:08 - “Schizo Spectrum” Mnemonic Psychosis = disorganized thoughts and distorted perception of reality. Psychotic individuals will usually have a loss of function and a lack of insight (they don’t realize their perception of reality is distorted). • Hallucinations - hearing, seeing, feeling, tasting or smelling something that isn’t really there. This sensation has no external stimuli. Due to the lack of insight these individuals think that what they perceive is real. Schizophrenia is usually associated with auditory hallucinations where the individual hears voices. Tactile Hallucinations like the sensation of bugs crawling on their skin is usually related to street drugs. Olfactory (smell) hallucinations are more commonly seen in the aura before seizures. • Delusions - strongly held beliefs that are not based on fact. Due to the lack of insight trying to convince a psychotic person that their delusions are false is almost impossible no matter of how much evidence you present. Delusions of Persecution are the most common type and involve paranoia. These individuals think others are “out to get them” and are trying to follow them, spy on them, poison them, steal from them or otherwise harm them. Delusions of Grandeur are when an individual believes that have special powers, talents or intellect. They may think they are famous, have supernatural abilities or have religious prominence. Other common themes in delusion are guilt, thought control, thought broadcasting (belief that others can hear your thoughts) and ideas of reference (belief that people on TV/radio/print media are talking about you). • Disorganized Speech (Thought Disorder) is random, incoherent speech that may involve repeating phrases or words that sound similar. The patient likely is not aware that their speech makes no sense to others. This is sometimes referred to as “Word Salad.” • Catatonia –motor hyperactivity with repetitive purposeless motions or motor hypoactivity that leads to complete motor immobility & waxy flexibility (you can move the patient into an odd position and they will stay in that position for hours). It can include a complete disconnect from reality. This should not be confused with Cataplexy which is a type of narcolepsy where people have motor immobility while remaining completely aware of their surroundings. In the previous video in the Psychiatry section we covered mood disorders. There we briefly discussed Mania with psychosis and depression with psychosis. The key difference between schizophrenia and a mood disorder with psychosis is that the psychosis in mood disorders is “Mood Congruent.” This means that the psychosis is only present during mood “episodes” and that the psychosis is in line with their mood. So a manic individual may have delusions of grandeur and a depressed person might have delusions of guilt. Schizophrenia - a chronic progressive psychiatric condition characterized by psychosis and an abnormal interpretation of reality. They have a difficult time functioning in society due to progressive loss of function. Symptoms are categorized into 2 groups, Negative and Positive Symptoms. • Positive symptoms = behaviors or sensations that are not normally present. These symptoms are may be related to an excess of dopamine. Examples include hallucinations, delusions, catatonia & disorganized speech/behavior • Negative symptoms = The absence of normal behavior. Examples include a lack of initiative, diminished speech, disheveled appearance & flat affect. There used to be specific subtypes of Schizophrenia based on what types of psychosis were predominate, but the difference between those types was low yield and in the most recent version of the DSM those subtypes have been removed. The text for this video is too long and exceeds the maximum length set by youtube. To see the rest of it please click here http://www.stomponstep1.com/psychosis-schizophrenia-schizoaffective-disorder-delusional-disorder-hallucinations/ Picture Used: Derivative of “Flexibilitas cerea” available at http://en.wikipedia.org/wiki/Waxy_flexibility via Public Domain
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Hyperplasia, Hypertrophy, Metaplasia & Atrophy USMLE
http://www.stomponstep1.com/hypertrophy-hyperplasia-metaplasia-cellular-stress-adaption-cell-swelling-cell-injury-response/ Cellular Stress occurs when a cell is put in an inhospitable environment or required to do something it can't currently do. Overtime cells put under stress will either adapt to the new situation or die. Cells will also undergo changes if the amount of stress placed on them decreases or the type of stress changes. Hypertrophy is an increase in the size of individual cells. Examples would include muscles getting bigger due to weight training or the heart wall thickening due to hypertension (and an increased work needed by the heart). Hyperplasia is an increase in the number of cells in a tissue via mitosis. CNS and muscle (including heart tissue) cannot undergo hyperplasia as they are permanent tissues "stuck" in the G0 phase. These tissues can only undergo hypertrophy to meet increased demand. An example would be hyperplasia of the adrenal cortex in Cushing's Disease in order to be able to produce more cortisol. Metaplasia is when one cell type is replaced with a different cell type that is better equipped to handle new kind of stress placed on the tissue. This is a type of adaption is reversible. It can be physiologic or pathologic, but is not cancerous. However, prolonged Metaplasia can turn into Dysplasia which can become cancerous. An example would be Barrett's Esophogus. GERD leads to stomach acid in the esophagus and as a result stratified squamous esophageal cells are replaced by Goblet cells which can better handle stomach acid. Another example would be the replacement of pseudostratified columnar cells in the respiratory system with squamous epithelium as a result of cigarettes. Atrophy is a decrease in cell size or decrease in cell number (apoptosis) in response to a decreased level of stress placed on the cells Now that you have finished this video you should check out the next video in the Cell Injury, Cell Death & Cancer section which covers Apoptosis, Necrosis & Reversible Injury (http://www.stomponstep1.com/types-of-necrosis-and-apoptosis-definition-caspase-programmed-cell-death/)
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Sensitivity, Specificity, Screening Tests & Confirmatory Tests
http://www.stomponstep1.com/sensitivity-specificity-screening-tests/ Sensitivity (Sen) & Specificity (Spec) are used to evaluate the validity of laboratory tests (not results of the tests). Basically, you use sensitivity and specificity to determine whether or not to use a certain test or to determine what situations a certain test would work best in. It is important to note that Sen and Spec are fixed for a certain test as long as you don't change the cutoff point. Therefore, Sensitivity & Specificity are not affected by changing prevalence. Both are given as a percentage ranging from 0% to 100%. Sensitivity is the percentage of patients with the disease that receive a positive result or the percentage chance that the test will correctly identify a person who actually has the disease Sensitivity = TP _ (TP + FN) or Sensitivity = TP _ Diseased Specificity is the Percentage of patients without the disease that receive a negative result Specificity = TN _ (TN+FP) or Specificity = TN _ Not Diseased Imagine you have 2 very different guns. The first gun fires when you barely touch the trigger. A strong gust of wind could set it off. The first gun has high sensitivity and low specificity. It is sensitive to the smallest of signals to fire while not being very specific to an intentional pull of the trigger. You never miss a possible chance to shoot your gun (~ Low FN), but you often accidentally fire when you shouldn't (~ High FP). The second gun only fires if you pull the trigger really hard. This gun has high specificity and low sensitivity. It is very specific to firing only when you intentionally pull the trigger (~Low FP), but it isn't very sensitive to a weak pull of the trigger (~High FN). In the real world you never have a test that is 100% Sen and 100% Spec. We are usually faced with a decision to use a test with high Sen (and lower spec) or high Spec (and lower Sen). Usually a test with high sensitivity is used as the Initial Screening Test. Those that receive a positive result on the first test will be given a second test with high specificity that is used as the Confirmatory Test. In these situations you need both tests to be positive to get a definitive diagnosis. Getting a single positive reading is not enough for a diagnosis as the individual tests have either a high chance of FP or a high chance of FN. For example, HIV is diagnosed using 2 tests. First an ELISA screening test is used and then a confirmatory Western Blot is used if the first test is positive. There are also specific situations where having a high specificity or sensitivity is really important. Consider that you are trying to screen donations to a blood bank for blood borne pathogens. In this situation you want a super high sensitivity, because the drawbacks of a false negative (spreading disease to a recipient) are way higher than the drawbacks of a false positive (throwing away 1 blood donation). Now consider you are testing a patient for the presence of a disease. This particular disease is treatable, but the treatment has very serious side effects. In this case you want a test that has high specificity, because there are major drawbacks to a false positive. Now that you have finished this video you should check out the next video in the Biostats & Epidemiology section which covers the calculation of Predictive Value Positive & Negative (http://www.stomponstep1.com/negative-positive-predictive-value-equation-calculation/). That video has some mnemonics and concepts that also apply to this video.
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Malingering, Somatoform Disorder, Munchausen, Factitious Disorder Hypochondriac
http://www.stomponstep1.com/malingering-somatoform-disorder-munchausen-factitious-disorder-hypochondriac/ SKIP AHEAD: 1:50 – Malingering Disorder 2:49 - Factitious Disorder (AKA Munchausen) & Factitious by Proxy 3:36 – Somatization (AKA Somatoform Disorder) & Hypochondriasis This is a group of illnesses where the patient reports symptoms that have no medical explanation. The patient may be deliberately misleading the physician or unaware that their complaints have no identifiable cause. Each of these is a diagnosis of exclusion, and providers should not jump to the conclusion that a patient is “faking it” unless there is sufficient evidence to suggest that, because you could potentially miss what is really causing the patients symptoms. Never tell the patient nothing is wrong with them and never accuse them of lying. Even Hypochondriacs and drug seekers really do get sick so even a previous history should not automatically lead to a diagnosis. However, physicians must also avoid prescribing unnecessary treatments and diagnostics tests in these patients. Possible “treatments” include scheduling periodic office visits to discuss the patients concerns, refer the patient for therapy or trying to manage current stressors that could be contributing to the problem. Malingering = psychiatrically healthy patient is intentionally fabricating or exaggerating symptoms for personal gain such as obtaining narcotics, legal compensation, disability payments, a lesser criminal sentence, or trying to get out of school/work/military duty. After getting what they want (sometimes called an external or secondary gain) the symptoms disappear. The symptoms may also be absent when the doctor isn’t in the room. They are generally unwilling to undergo potentially harmful/painful treatments or tests. May become irritable when providers question symptoms. Factitious Disorder = psychiatrically unwell patient is consciously fabricating or exaggerating symptoms to get attention or sympathy from medical providers, friends, or family. This is sometimes referred to as internal or primary gain. These patients are often willing to undergo potentially harmful/painful treatment or tests. Munchausen Syndrome is a now outdated term for a severe chronic form of factitious disorder. Factitious Disorder by Proxy is when a person “fakes” symptoms in a person they care for (child or elderly) in order to get attention or sympathy. Somatization Disorder (A type of Somatoform Disorder) = psychiatrically unwell patient unconsciously fabricates symptoms. Their symptoms have no physical cause, but they are not aware of that. They perceive their symptoms as being real. They will have multiple vague complaints across various different organ systems. Conversion Disorder is an extreme type of somatization that results in the patient suddenly losing voluntary motor and/or sensory functions during a time of stress. For example sudden paralysis, blindness or paresthesia. It looks like a stroke, but isn’t. It is usually triggered by stress and most patients spontaneously recover. Oddly many of these patients are not very concerned about their symptoms. * In the recently released DSM V, the name Somatoform Disorders was changed to “Somatic Symptom & Related Disorder.” Also the diagnosis of Hypochondriasis was removed. Patients who previously met the criteria for Hypochondriasis would now be classified as either Somatic Symptom Disorder or Illness Anxiety Disorder. However, it takes years for the USMLE Step 1 exam to get updated so you will likely see the old nomenclature from DSM IV.
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Cohort, Case-Control, Meta-Analysis, Cross-sectional Study Designs & Definition
http://www.stomponstep1.com/cohort-case-control-meta-analysis-cross-sectional-study-designs/ Based on the types of bias that are inherent in some study designs we can rank different study designs based on their validity. The types of research studies at the top of the list have the highest validity while those at the bottom have lower validity. In most cases if 2 studies on the same topic come to different conclusions, you assume the trial of the more valid type is correct. However, this is not always the case. Any study design can have bias. A very well designed and executed cohort study can yield more valid results than a clinical trial with clear deficiencies. • Meta-analysis of multiple Randomized Trials (Highest Validity) • Randomized Trial • Prospective Cohort Studies • Case Control Studies or Retrospective Cohort • Case Series (Lowest Validity) Meta-analysis is the process of taking results from multiple different studies and combining them to reach a single conclusion. Doing this is sort of like having one huge study with a very large sample size and therefore meta-analysis has higher power than individual studies. Clinical trials are the gold standard of research for therapeutic and preventative interventions. The researchers have a high level of control over most factors. This allows for randomization and blinding which aren't possible in many other study types. Participant's groups are assigned by the researcher in clinical trials while in observational studies "natural conditions" (personal preference, genetics, social determinants, environment, lifestyle ...) assign the group. As we will see later, the incidence in different groups is compared using Relative Risk (RR). Cohort Studies are studies where you first determine whether or not a person has had an exposure and then you monitor the occurrence of health outcomes overtime. It is the observational study design with the highest validity. Cohort is just a fancy name for a group, and this should help you remember this study design. You start with a group of people (some of whom happen to have an exposure and some who don't). Then you follow this group for a certain amount of time and monitor how often certain diseases or health outcomes arise. It is easier to conceptually understand cohort studies that are prospective. However, there are retrospective cohort studies also. In this scenario you identify a group of people in the past. You then first identify whether or not these people had the particular exposure at that point in time and determine whether or not they ended up getting the health outcomes later on. As we will see later, the incidence in different groups in a cohort study is compared using Relative Risk (RR). Case-Control Studies are retrospective and observational. You first identify people who have the health outcome of interest. Then you carefully select a group of controls that are very similar to your diseased population except they don't have that particular disease. Then you try to determine whether or not the participants from each group had a particular exposure in the past. I remember this by thinking that in a case control study you start off knowing whether a person is diseased (a case) or not diseased (a control). There isn't a huge difference between retrospective cohort and case-control. You are basically doing the same steps but in a slightly different order. However, the two study designs are used in different settings. As we will see later, the incidence in different groups in a case-control study is compared using Odds Ratio (OR). A Case-Series is a small collection of individual cases. It is an observational study with a very small sample size and no control group. Basically you are just reviewing the medical records for a few people with a particular exposure or disease. A study like this is good for very rare exposures or diseases. Obviously the small sample size and lack of a control group limits the validity of any conclusions that are made, but in certain situations this is the best evidence that is available. Cross Sectional Studies are different from the others we have discussed. While the other studies measure the incidence of a particular health outcome over time, a cross-sectional study measures Prevalence. In this observational study the prevalence of the exposure and the health outcome are measured at the same time. You are basically trying to figure out how many people in the population have the disease and how many people have the exposure at one point in time. It is hard to determine an association between the exposure and disease just from this information, but you can still learn things from these studies. If the exposure and disease are both common in a particular population it may be worth investing more resources to do a different type of study to determine whether or not there is a causal relationship.
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Purine Salvage Pathway, Lesch-Nyhan Syndrome, SCID Gout treatment Allopurinol Uric Acid Renal Stone
Nucleic acids are constantly being recycled in the body. This salvages free purine bases which can be reused to make new nucleic acids. DNA or RNA breakdown releases free Guanosine Monophosphate (GMP) & Adenosine Monophosphate (AMP). The sugar and phosphate groups are removed to give us Adenosine & Guanine. Adenosine is then converted to an intermediate, Inosine. When needed Inosine & Guanine are recycled by Hypoxanthine Guanine Phosphoribosyl Transferase so they can be used in the formation of new DNA & RNA. Sometimes you have more nucleic acids than you need. So Hypoxanthine & Guanine can also be degraded. This process involves converting Hypoxanthine and Guanine into Xanthine. Xanthine is then acted on to form Uric Acid which can be excreted in the urine. In small amounts this process does not cause problems. However, if an excess amount of purines are being degraded the amount of uric acid will build up in the body as the kidney's ability to excrete it is no longer sufficient. This uric acid builds up and can form crystals in the joints (Gout) and kidney (Uric Acid Renal Stones). Allopurinol is a gout drug which inhibits the formation of uric acid from xanthine. Each of these items will be discussed more in chapters on the appropriate organ system. A deficiency of Adenosine Deaminase leads to a buildup of adenosine which is toxic to B & T cells. This is one mechanism of developing Severe Combined Immunodeficiency (SCID), a deficiency of B & T cells. This will be covered in more detail in the Immunology section. Lesch-Nyhan Syndrome is an X-linked recessive deficiency of Hypoxanthine Guanine Phosphoribosyl Transferase (HGPT). This deficiency prevents proper purine salvage. As purines cannot be recycled back into new nucleic acids, all of the purines from degraded DNA are converted to uric acid. This excess in uric acid exceeds the body's ability to excrete uric acid. The buildup of uric acid can be detected in the blood and causes urate crystal formation resulting in gout and renal stones. Lesch-Nyhan is also characterized by poor muscle control (spasticity), mild mental retardation and Lip/Finger Biting (self-mutilation). Now that you are done with this video you should check out the next video in the Genetics section which covers Neurofibromatosis, Tuberous Sclerosis & Von Hippel Lindau (http://www.stomponstep1.com/neurofibromatosis-tuberous-sclerosis-von-hippel-lindau/)
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Null Hypothesis, p-Value, Statistical Significance, Type 1 Error and Type 2 Error
SKIP AHEAD: 0:39 – Null Hypothesis Definition 1:42 – Alternative Hypothesis Definition 3:12 – Type 1 Error (Type I Error) 4:16 – Type 2 Error (Type II Error) 4:43 – Power and beta 6:33 – p-Value 8:39 – Alpha and statistical significance 14:15 – Statistical hypothesis testing (t-test, ANOVA & Chi Squared) For the text of this video click here http://www.stomponstep1.com/p-value-null-hypothesis-type-1-error-statistical-significance/ For my video on Confidence Intervals click here http://www.stomponstep1.com/confidence-interval-interpretation-95-confidence-interval-90-99/
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Tay Sachs Disease, Gaucher Disease, Neiman-Pick Lysosomal Storage Disease Disorders
ERRATA: There is hepatosplenomegaly in Gaucher and Neiman-Pick, but there is NOT in Tay-Sachs. I also misspelled Hexosaminidase A in the powerpoint slide. Sphigolipids are an important part of the cell membrane. However, when these lipids are improperly metabolized due to genetic disorders they build up in the lysosome causing problems. The collection of these diseases are called Sphigolipidosis, or Lysosomal Storage Diseases. If untreated these diseases can be lethal, but individuals often live long lives with proper enzyme replacement.We already covered I-Cell Disease, one example of a Lysosomal Storage Disease, in a previous section. Tay-Sachs, Gaucher & Neiman-Pick are all Autosomal Recessive deficiencies of enzymes which are involved in the degradation of sphigolipids. When an enzyme in this pathway is deficient, the substrate for the enzyme builds up and causes problems. All 3 of these diseases are more common among Ashkenazi (Eastern European) Jews. It can be tough to differentiate between different sphigolipidosis based solely on clinical presentation, because there is overlap in symptoms between the diseases. Thankfully the test writers usually aren't that evil. Most questions on this topic will be very straight forward. You are probably going to see something like "It is this disease. Which enzyme is deficient?" or "This substrate is building up. What disease is it?", but you might see a question that includes a clinical scenario so here are the basics. Now that you are finished with this video you should check out the last video in the Biochem section here (http://www.stomponstep1.com/where-is-the-rest-of-the-biochemistry-section/) Pictures Used: This work is a derivative of "Outline Man Runner Cartoon Sprint Running" available at http://pixabay.com/en/outline-man-runner-cartoon-sprint-34669/ under Creative Commons 1.0 Public Domain Dedication This work is a derivative of "Football Helmet" by Simanek available at http://openclipart.org/detail/86827/football-helmet-by-simanek under Public Domain Dedication
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Anxiety Disorders: OCD, PTSD, Panic Attack, Agoraphobia, Phobias, GAD Generalized
http://www.stomponstep1.com/anxiety-disorders-ocd-ptsd-panic-attack-agoraphobia-phobias-gad-generalized/ SKIP AHEAD: 0:25 – Anxiety Definition & Symptoms 1:13 – Anxiety Differential Diagnosis 2:12 – Generalized Anxiety (GAD) 3:05 – Panic Attacks, Panic Disorder & Agoraphobia 5:01 – Specific Phobia & Social Anxiety Disorder (Social Phobia) 7:55 – Obsessive-Compulsive Disorder (OCD) 9:29 – Posttraumatic Stress Disorder (PTSD) Anxiety is uncontrolled fear, nervousness and/or worry about trivial or non-existent things. It is an unpleasant fear of future events that are unlikely to occur. Some patients have insight and realize that their uneasiness is illogical, but that does not alleviate symptoms. A certain level of anxiety is considered normal in many situations, but frequent anxiety or anxiety that inhibits function is pathologic. During anxiety sympathetic nervous system activation can result in physical symptoms such as Palpitations, Tachycardia, Shortness of breath, Muscle tension, Restlessness, Lack of focus, Sweating or chills and Changes in sleeping pattern. In order to make a diagnosis of anxiety, one must rule out other potential causes of these symptoms. The differential diagnosis for anxiety includes other psychiatric disorders, cardiac abnormalities (such as myocardial infarction or valvular disease), endocrine disorders (like hyperthyroidism) and respiratory disease (such as asthma or Pulmonary Embolism). Substances such as street drugs and prescribed medications must also be ruled out as a potential cause of the symptoms. We are going to hold off on discussing most of the different treatment options for anxiety until a later video that will cover all of pharmacology for the psychiatry section. That video will cover things like SSRIs, anxiolytics and cognitive behavioral therapy which can be used to treat anxiety disorders. However, during this video I will mention a couple treatment options that are used for specific anxiety disorders. We will start our discussion with Generalized Anxiety Disorder or GAD. You can see here in the top right corner I give GAD a high yield rating of 2. For those of you who aren’t familiar with the High Yield Rating it is a scale from 0 to 10 that gives you an estimate for how important each topic is for the USMLE Step 1 Medical Board Exam. GAD is a prolonged period of near constant anxiety. Their anxiety is not linked to a specific item, person, or situation (AKA it isn’t a phobia). They usually worry about a wide variety of things including school/work performance, finances, health, friends and/or family members. Their anxiety is “generalized” across many situations. Their anxiety frequently presents with “physical” symptoms and may be severe enough to impair function. A Panic Attack is sudden onset period of extremely intense anxiety accompanied by numerous signs and symptoms of anxiety. The attack is often associated with a sense of impending doom. These “episodes” usually last 10 to 30 minutes and are disabling. The patient returns to their normal level of function soon after the panic attack. They may be brought on by an inciting event or be completely unprovoked. I’d like to stop here for a moment to clarify the difference between generalized anxiety disorder and a panic attack. GAD can be thought of as a constant moderate level of anxiety while panic attacks are short periods of severe anxiety. Panic Disorder is recurrent panic attacks that are unprovoked and have no identifiable trigger. The onset of these anxiety episodes is unpredictable. Patients may be relatively asymptomatic between attacks, but often have anxiety about having more attacks. Their fear is related to the panic attacks themselves rather than a particular external stimuli. This differentiates Panic Disorder from Panic Attacks that are caused by things like phobias. The text for this video is too long and exceeds the maximum allowed by youtube. For the rest of it please click here http://www.stomponstep1.com/anxiety-disorders-ocd-ptsd-panic-attack-agoraphobia-phobias-gad-generalized/
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Mean, Median & Mode Robustness, Standard Deviation, Skewed Right Positive Skew Skewed left
http://www.stomponstep1.com/standard-deviation-mean-median-mode-robustness/ SKIP AHEAD: 0:53 - Mean 1:46 – Median 2:30 – Mode 2:57 – Robustness 4:16 – Skewed Histograms 5:28 – Standard Deviation ERRATA: The Mean of 1+3+3+5+7+10+100 is 18.43, NOT 22 like I mentioned in the video. (1+3+3+5+7+10+100) / 7 = 18.43. The text below has been corrected and a note has been added to the appropriate point in the video 3 Measures of Central Tendency • Mean (average) = The sum of all of the values divided by the number of values. Least Robust • Median ("middle" value) = The value that is in the middle when all of the values are arranged in ascending order. If there is an even number of values there is no single middle value. Therefore, you take the average of the two middle value. Robustness is in between mean and mode • Mode (most common value) = The value that appears the highest number of times. Most Robust If you are given the list of values 1, 3, 3, 5, 7, 10. What is the mean, median, and mode? Mean = (1+3+3+5+7+10) _ 6 = 4.83 Median = average of the 2 middle values since there is an even number of values. (3+5)_ 2 = 4 Mode = most frequent value = 3 If you take the list of values from the previous question but now add an additional value of 100 how does the mean, median, and mode change? Mean = (1+3+3+5+7+10+100) / 7 = 18.43 Median = middle value = 5 Mode = most frequent value = 3 The above question illustrates how Robust, or resistant to change by an extreme value, the three measures of central tendency are. You can see that by adding one extreme value (an outlier) the mean has changed a lot and mode hasn't changed at all. This is because mean is the least robust of the three values and mode is the most robust. Median is less robust than mode, but more robust than mean. On Step 1 you may also be asked to compare mean, median, and mode in certain situations based on a histogram or set of values. For example, the answer looks like "mean is greater than mode" rather than a precise numerical answer. In most of these cases the data is skewed significantly in one direction and is not normally distributed. Normal Distribution, Normally Distributed, Skewed Right, Skewed Left, Positive Skew, Negative Skew, Negatively Skewed, Positively Skewed Standard deviation (greek symbol σ) measures how much the values in a data set differs from the mean. In other words, standard deviation measures dispersion or variability in a set of values. A data set with mostly similar values has a small standard deviation, while a data set with very different values has a large standard deviation. Standard deviation changes with changes in sample size (number of values or participants). With small sample sizes random chance has a bigger impact and therefore standard deviation for a small sample size is generally larger. Studies with more values generally have smaller standard deviations as chance plays less of a role.
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Epigenetics, Prader-Willi Sydrome, Angelman Syndrome, Methylation, Imprinting, Heterochromatin
http://www.stomponstep1.com/epigenetics-prader-willi-sydrome-angelman-syndrome/ While genetics is the study of DNA sequence, Epigenetics is the study of heritable changes that do not affect the DNA sequence. Genetics determines what is transcribed, while epigenetics determines how much is transcribed. Remember that negatively charged DNA is wrapped around positively charged histone proteins like beads on a string in the nucleus. Epigenetics primarily changes how tightly the DNA is condensed. DNA that is wrapped very tightly around the histones is not actively transcribed. It is clumped up so tight that the enzymes needed for transcription don't have enough room to work. Alternatively, DNA that is loosely associated with histones is more easily accessible. • Euchromatin -- loosely packed chromatin that is easily accessible by transcription enzymes and actively transcribed. Think People from the EU (European Union) tend to be relaxed and less uptight • Heterochromatin -- tightly packed chromatin that is not actively transcribed (silent) The most common type of epigenetic changes are DNA methylation, histone acetylation, and histone methylation. These changes affect the hydrophobic and/or electrical properties that control the attraction between histones and DNA. • Histone Acetylation removes the histones positive charged decreasing its level of attraction to DNA causing uncoiling and more active transcription • Histone or DNA Methylation -- makes histone/DNA more hydrophobic which causes it to clump up in the hydrophilic environment. Causes heterochromatin and less active transcription Acetylation  Active Methylation  genes are Missing Imprinting is when one allele is naturally inactivated by epigenetic changes and only 1 allele is expressed. This type of inheritance is only present in a small number of human genes. For some of these genes the allele from the mother is expressed while the allele from the father is silenced. Other genes are the opposite. When only one allele is being expressed, a single mutation can change the phenotype of a homozygous individual. • Prader-Willi Syndrome -- involves inheriting a mutated allele from the father while the allele inherited from the mother is naturally silenced. Causes mental retardation and Hyperphagia (excessive eating). • Angelman Syndrome -- involves inheriting a mutated allele from the mother while the allele inherited from the father is naturally silenced. Excessive laughter, happy demeanor, seizures, and mental retardation. Angelman Syndrome mnemonic Angels are Mother-like and Happy Angelman's = Maternal Mutation with Excessive Laughter Now that you have finished this video you should check out the next video in the Genetics section which covers different types of inheritance like Autosomal Dominant, Autosomal Recessive & X-linked recessive (http://www.stomponstep1.com/genetic-inheritance-autosomal-dominant-x-linked-recessive-mitochondrial-disease/) Picture Used: "Schutzengel" by Bernhard Plockhorst available at http://en.wikipedia.org/wiki/File:Bernhard_Plockhorst_-_Schutzengel.jpg under Public Domain • "The basic unit of chromatin organization is the nucleosome" available at http://commons.wikimedia.org/wiki/File:The_basic_unit_of_chromatin_organization_is_the_nucleosome,_which_comprises_147_bp_of_DNA_wrapped_ar.jpg by Creative Common 3.0 Attribution Share Alike
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2x2 Table False Positive False Negative True Positive True Negative for screening Tests
http:__www.stomponstep1.com_2x2-table-false-positive-false-negative-true-positive-true-negative_ Laboratory test results are usually a numerical value, but these values are often converted into a binary system. For example, urine hCG Pregnancy Test test may give you values ranging from 0 to 30 mlU_mL, but the numerical continuum of values can be condensed in two main categories (positive and negative). We do this by setting a Cut-off Point. All measurements above this cut-off value are categorized as "positive" and all values below are "negative." If you change that cut-off point the positive vs. negative classifications (as well as TP, FP, TN, & FN) change. In everyday life, positive things are good and negative things are bad. But remember in most laboratory tests, a positive result means the patient has a disease. A True result is a lab result that matches the truth or our best estimate of the truth based on the results of the best available test (called the Gold Standard Test). So a true result would be a positive HIV test in a person we know to clinically have HIV. A False measurement is obviously when the result does not match the truth. "Good" tests have mostly true measurements and few false measurements. • True Positive (TP) = A diseased person who is correctly identified as having a disease by the test • False Positive (FP) = A healthy person that is incorrectly identified as having the disease by the test • True Negative (TN) = A healthy person who is correctly identified as healthy by the test • False Negative (FN) = A diseased person who is incorrectly identified healthy by the test Here is another way to think about these definitions: • All with Disease = TP + FN • All without Disease = TN + FP • All that Tested Positive = TP + FP • All that Tested Negative = TN + FN Two-by-Two Tables Questions involving TP, FP, TN, and FN will usually have a two-by-two table. Sometimes they will give you the actual table and other times they will give you all of the data for the table in sentence form and you have to make the table for yourself. You may have learned to refer to the boxes in a two-by-two table as A, B, C & D. I am going to strongly recommend you not do this. First off, those letter labels have no meaning. It is therefore more likely for you to get confused and make a dumb mistake. Additionally, the top left box in a two-by-two table may not always represent true positive. Sometimes, test writers will mix up the order of the columns and_or rows. I suggest using TP, TN, FP, and FN instead. Sometimes they will give you an extra row and column that has totals. Don't let that throw you off. It is still a two-by-two table even though there are 3 columns and 3 rows. They just try to save you a step of calculation by giving you the row and column totals. Now that you have finished this video on 2 by 2 tables you should check out the next video in the Biostatistics & Epidemiology section which covers Sensitivity, Specificity & Confirmatory Tests (http://www.stomponstep1.com/sensitivity-specificity-screening-tests/)
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Personality Disorder Types: Borderline, Narcissistic, Antisocial Histrionic Schizoid Schizotypal
http://www.stomponstep1.com/personality-disorder-types-borderline-narcissistic-antisocial-histrionic-schizoid-schizo/ SKIP AHEAD: 0:28 – Personality Disorder Definition 1:15 – Cluster A, B & C 2:16 – Schizoid 3:22 – Schizotypal 3:55 – Paranoid 5:03 – Borderline 5:49 – Histrionic 6:20 – Antisocial & Conduct Disorder 7:29 – Narcissism 8:07 – Avoidant 9:00 – Dependent 9:41 – Obsessive Compulsive For a text version of this video please visit http://www.stomponstep1.com/personality-disorder-types-borderline-narcissistic-antisocial-histrionic-schizoid-schizo/ Pictures Used (In order of Appearance): “Octopus Purple Happy Smiling” available at http://pixabay.com/en/octopus-purple-happy-smiling-312102/ via public domain “Michael C. Hall 2011” by Keith McDuffee available at http://commons.wikimedia.org/wiki/File:Michael_C._Hall_2011.jpg under Creative Commons Attribution 2.0 Generic License “ChristopherLloydOct10” by Alex Archambault available at http://commons.wikimedia.org/wiki/File:ChristopherLloydOct10.jpg under Creative Commons Attribution 2.0 Generic License “Michael Richards 1992” by Alan Light available at http://commons.wikimedia.org/wiki/File:Michael_Richards_1992.jpg under Creative Commons Attribution 2.0 Generic License Derivative of “Jim Parsons, Johnny Galecki (The Big Bang Theory)” by MelodyJSandoval available at http://commons.wikimedia.org/wiki/File:Jim_Parsons,_Johnny_Galecki_(The_Big_Bang_Theory)_3781561561.jpg under Creative Commons Attribution 2.0 Generic License “Bundesarchiv Bild 183-S33882, Adolf Hitler (cropped2)” by German Federal Archives available at http://commons.wikimedia.org/wiki/File:Bundesarchiv_Bild_183-S33882,_Adolf_Hitler_(cropped2).jpg under Creative Commons Attribution-Share Alike 3.0 Germany License Derivative of “Richard M. Nixon – NARA” by U.S. National Archives and Records Administration available at http://commons.wikimedia.org/wiki/File:Richard_M._Nixon_-_NARA_-_558482.jpg via Public Domain “Stalin01” by Ullierlich available at http://commons.wikimedia.org/wiki/File:Stalin01.jpg via Public Domain Derivative of “Iraq, Saddam Hussein” by Cognition available at http://commons.wikimedia.org/wiki/File:Iraq,_Saddam_Hussein_(222).jpg via Public Domain Derivative of “Hulk odiar Sarrooooo Hulk hate Tartaaaaar” by Eneas De Troya available at http://commons.wikimedia.org/wiki/File:Hulk_odiar_Sarrooooo_Hulk_hate_Tartaaaaar_(2540708438).jpg under Creative Commons Attribution 2.0 Generic License Derivative of “Paris Hilton 3 Crop” by Glenn Francis available at http://commons.wikimedia.org/wiki/File:Paris_Hilton_3_Crop.jpg under Creative Commons Attribution-Share Alike 3.0 Unported Derivative of “The Joker Man Dress Up Face Paint” by Ben_Kerckx available at http://pixabay.com/en/the-joker-man-dress-up-face-paint-391713/ via Public Domain “You're a Drunk One, Mister Grinch” by Tom Hilton available at https://www.flickr.com/photos/tomhilton/6499274983/ under Creative Commons 2.0 Generic License Derivative of “Hugh Laurie 2009” by Kristin Dos Santos available at http://commons.wikimedia.org/wiki/File:Hugh_Laurie_2009.jpg under Creative Commons Attribution-Share Alike 2.0 Generic License Derivative of “Stephen Colbert 2” by David Shankbone available at http://commons.wikimedia.org/wiki/File:Stephen_Colbert_2_by_David_Shankbone.jpg under Creative Commons Attribution-Share Alike 3.0 Unported Derivative of “Bryan Cranston 2012” by Gage Skidmore available at http://commons.wikimedia.org/wiki/File:Bryan_Cranston_2012.jpg under Creative Commons Attribution-Share Alike 2.0 Generic License Derivative of “Michael Jackson 1984” by the White House Photo Office available at http://commons.wikimedia.org/wiki/File:Michael_Jackson_1984.jpg via Public Domain Derivative of “Tony Hale at the 2010 Streamy Awards (cropped)” by The Bui Brothers available at http://commons.wikimedia.org/wiki/File:Tony_Hale_at_the_2010_Streamy_Awards_(cropped).jpg under Creative Commons Attribution 2.0 Generic License “Steve Jobs Headshot 2010-CROP2” by MetalGearLiquid available at under http://commons.wikimedia.org/wiki/File:Steve_Jobs_Headshot_2010-CROP2.jpg Creative Commons Attribution-Share Alike 3.0 Unported License “Lips Mouth Smile Teeth Happy Laugh Red White” available at http://pixabay.com/en/lips-mouth-smile-teeth-happy-156991/ via Public Domain
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Chediak-Higashi Syndrome, I-Cell Disease, Kartageners Microtubules Inclusion Cell Disease
http://www.stomponstep1.com/chediak-higashi-i-cell-disease-kartageners-disease/ The cytoskeleton is a network of scaffolding that gives cells their shape. The cytoskeleton is made up of intermediate filaments, microtubules, actin, and myosin. Microtubules are cylinders of tubulin that can dynamically assemble and disassemble to change length. Microtubules are very important for multiple types of cellular movement (Mitosis, Axonal Trafficking, Cilia/Flagella...). Motor proteins Dynein and Kinesin travel along microtubules like trains on a track causing these movements. Microtubule functioning is inhibited by drugs like Colchicine (gout), Vincristine (cancer), Paclitaxel (cancer) and Mebendazole (parasites). Kartagener's Syndrome (Primary Ciliary Dyskinesia) is a genetic defect in Dynein motor proteins that prevents proper functioning of the Cilia. Cilia normally beat in a rhythmic wave forcing foreign material out of the body. Immotile cilia in the sinuses, ear, and respiratory tract result in Recurrent Infections (sinusitis, otitis media, pneumonia & bronchitis). Abnormal cilia also lead to Infertility in men (immotile sperm) and women (vaginal mucus builds up and is too thick). Chediak Higashi is a genetic defect in phagocyte microtubules which fuse the phagosome and lysosome. The defect prevents phagocytes from destroying what they engulf and Giant Granules of undigested material builds up. This causes Recurrent Infection (impaired phagocyte function), Albinism (impaired melanin trafficking) & peripheral neuropathy (impaired axonal transport). I-Cell Disease (Inclusion-Cell Disease) is a genetic defect which limits the ability to phosphorylate mannose in the golgi and leads to abnormal cellular trafficking. Mannose-6-Phosphate usually signals newly made enzymes to be delivered to the lysosome. Without this signal these enzymes meant for the lysosome follow the "default" trafficking pathway and are secreted outside of the cell (into the extracellular matrix) damaging other cells. Patients present with lysosomal enzyme deficiencies and the presence of Lysosomal Enzymes Where They Shouldn't Be (Blood, Urine...). This leads to a wide variety of symptoms such as Abnormal Facial Features, joint problems, and short stature. Additionally, lysosomes cannot function properly in degrading cellular debris which causes accumulation of cellular debris in the lysosome and the formations of inclusions bodies. Now that you are done with this video you should check out the next video in the Biochem section which coversMarfan Syndrome, Osteogensis Imperfecta & Ehlers Danlos (http://www.stomponstep1.com/marfan-syndrome-osteogenesis-imperfecta-ehlers-danlos/) Pictures Used (In order of Apearance) • This work is a derivative of "Microtubules and Alkaloids" by Simon Caulton available at http://commons.wikimedia.org/wiki/File:Microtubules_and_alkaloids.png under Attribution-Share Alike Creative Commons 3.0 • This work is a derivative of "Spindle Aparatus" by Lordjuppiter available at http://en.wikipedia.org/wiki/File:Spindle_apparatus.svg under Attribution-Share Alike Creative Commons 3.0 • This work is a derivative of "Kartagner" by Filip Em available at http://en.wikipedia.org/wiki/File:Kartagener.svg under Attribution-Share Alike Creative Commons 2.5 • This work is a derivative of "Alpha-Mannosidosis Electron Micrograph" by Dag Malm and Øivind Nilssen available at http://en.wikipedia.org/wiki/File:Alpha-mannosidosis_electron_micrograph.JPEG under Attribution Creative Commons Generic 2.0
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Antipsychotics, Mood Stabilzers Anxiolytics
SKIP AHEAD: 1:01 – Antipsychotic Mechanism 1:58 – Antipsychotics and their Indications 3:30 – Neuroleptic Malignant Syndrome (Typical Antipsychotic Side Effect) 4:18 – Extrapyramidal Symptoms (Typical Antipsychotic Side Effect) 6:19 – Atypical Antipsychotics and their side effects 8:57 – Mood Stabilizers 12:58 – Anxiolytics and Benzodiazepines We will start with a quick review of some material from my previous video on psychosis. Symptoms of schizophrenia can be broken down into 2 categories, Positive and Negative Symptoms. Positive symptoms include behaviors or sensations that are not normally present. Examples include hallucinations, delusions, and catatonia. These symptoms are thought to be related to an excess of dopamine. I remember this by remembering that “doPamine has a P in it”. So P for Positive and P for Dopamine. Negative symptoms are the absence of normal behavior. Examples include a lack of initiative, diminished speech, disheveled appearance & flat affect. These symptoms are thought to be related to an excess of serotonin. As we will see antipsychotics affect dopamine and serotonin to varying levels. The indications for this class of drugs includes psychosis (mainly schizophrenia), Mania (mainly bipolar disorder), aggression and Tourette's disease. Typical Antipsychotics primarily block dopamine receptors in a non-specific manor. Therefore, these drugs work best for positive symptoms, and have little effect on negative symptoms. The non-specific mechanism of the drug also means there are lots of side effects. Some of these medications come in a slow release injectable form so they can be used in non-compliant and aggressive patients. There are a lot of high yield side effects so we will break them down one by one Neuroleptic Malignant Syndrome (or NMS) is a rare but potentially fatal adverse reaction of typical antipsychotics. It involves fever, altered mental status, rigidity and autonomic instability (such as tachycardia, hypertension, diaphoresis etc.). You may also see elevated myoglobin in blood or urine and elevated Creatine Kinase (CK). One of the ways I think about it is that it looks kinda sorta like Serotinin Syndrome that you can see with antidepressatns. If you see this you have to emergently stop the medication, provide supportive care and consider adding Dantrolene Extrapyramidal Symptoms (or EPS) are due to blockage of Nigrostriatal dopamine. It can present with a number of different symptoms. Akasthisia is a general sensation of restlessness Acute Dystonia is involuntary continuous muscle contractions often of the neck. Another common presentation of acute dystonia is Oculogyris Crisis when your eyes get locked looking upward and you have to lean over to see Dyskinesia (AKA Pseudoparkinsonism) presents like Parkinson’s Disease with symptoms like a pill rolling tremor, cogwheel rigidity & bradykinesia (or slow movement) Tardine Dyskinesia (or TD) is uncontrollable facial tics, grimacing & tongue movements As scary as these symptoms may look, they are generally not medical emergencies. In most cases you will continue to use the drug with perhaps a reduction in the dose or the addition of an anticholinergic mediation like Benzatropine or Diphenhydramine. Tardive Dyskinesia is the exception and requires cessation of the medication as it can be permanent. Usually you would switch a patient with TD to a 2nd gen antipsychotic. Hyperprolactinemia is a side effect due to Blockage of Tuberoinfundibular dopamine. It presents just like any other disease that increases prolactin. So you can have galactorrhea, gynecomastia, decreased libido and menstrual irregularities. The text for this video is too long and exceeds Youtube max allowed length. To read the rest please go to http://www.stomponstep1.com/antipsychotics-mood-stabilizers-anxiolytics-benzodiazepines-tardive-dyskinesia-extrapyramidal-symptoms/
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Alcohol Metabolism, Methanol Poisoning, Fatty Change Alcoholic Hypoglycemia Fomepazole
http://www.stomponstep1.com/alcohol-metabolism-methanol-poisoning-fatty-change/ Ethanol is relatively harmless when consumed in small amounts, but problems can arise when alcohol is consumed in excess. When alcohol is consumed in large quantities Acetaldehyde, an intermediate of alcohol metabolism, builds up faster than it can be metabolized. This excess Acetaldehyde contributes to hangover symptoms. When alcohol is consumed in excess the NADH generated from alcohol metabolism can also cause many health effects. This buildup of NADH can be exacerbated when large quantities of alcohol are consumed without food being consumed. NADH is an electron transporter. Its presence signals liver cells that there is ample energy present. The presence of this signal leads to increased breakdown of glucose (Glycolysis), decreased creation of glucose (Gluconeogenesis), and decreased fat breakdown (Fat Oxidation). NADH is also used to convert Pyruvate to Lactate, which means high levels of NADH leads to increased Anaerobic Glycolysis and Lactic Acidosis. Alcoholism can also cause Traumatic Injuries Due to Falls or Esophageal Tears due to frequent vomiting. Alcoholism is also associated with many health outcomes which I will cover in other sections. Wernicke-Korsakoff, thiamine deficiency, is common among alcoholics, because alcoholics sometimes get a majority of their calories from alcohol. Excessive alcohol intake is also associated with Pancreatitis. Chronic steatosis can lead to liver inflammation ("non-viral" Hepatitis) and eventually Liver Cirrhosis. Unlike viral hepatitis, inflammation due to alcohol usually presents with an AST Elevated More than ALT. I remember this by thinking Alcohol --) Steatosis --) Higher AST. Excessive alcohol consumption by pregnant woman can also lead to Fetal Alcohol Syndrome and mental retardation. Alcohol Withdrawal must be watched carefully in any hospitalized patients with a history of alcoholism as it can be life threatening. It usually occurs a couple days after abrupt cessation of alcohol (usually in the hospital where alcohol is not accessible). Mild withdrawal may present as Agitation or aggression a couple days after being brought into the hospital. Severe withdrawal can include Tremors, Seizures, confusion, and psychosis. This collection of symptoms is referred to as Delirium Tremens (DTs). Treatment for DTs is Benzos. The best type of treatment for alcoholism is a 12 step program like Alcoholics Anonymous (AA). In some patients, Disulfiram is also used. This drug Inhibits Acetaldehyde Dehydrogenase and makes patients very sick if they drink any alcohol as Acetaldehyde builds up much faster. You are essentially giving them a really bad hangover on purpose to dissuade them from drinking. However, this it is not always effective as there is relatively low compliance for this drug. Patients considering drinking can think ahead and easily not take their medication to avoid the consequences. Disulfiram intentionally causes these hangover like symptoms after alcohol consumption, but other drugs (such as Metronidazole) inadvertently have this same effect. Drugs with this type of side effect are often described as having a Disulfiram-Like effect. Methanol is in antifreeze, paint thinner and improperly prepared moonshine (illegally produced spirits). It can accidentally be consumed by children or adults mistaking the liquid for ethanol. Methanol itself does not cause problems, but after being metabolized by Alcohol Dehydrogenase Formaldehyde is formed. Formaldehyde can cause blindness and death so treatment focuses on preventing aldehyde formation. Fomepizole Inhibits Alcohol Dehydrogenase decreasing the amount of methanol that is metabolized into Formaldehyde. Alcohol can also be given as it utilizes the same enzyme and will compete for alcohol dehydrogenase. Now that you are finished with this video you should check out the next video in the Biochemistry section which covers Chediak-Higashi, I-Cell Disease & Kartagner's Disease (http://www.stomponstep1.com/chediak-higashi-i-cell-disease-kartageners-disease/) Pictures Used (In order of Appearance) • This work is a derivative of "Bottle Beer Bottle Alcohol Drinking" available at http://pixabay.com/en/bottle-beer-bottle-alcohol-drinking-157844/ under Creative Commons 1.0 Public Domain Dedication • This work is a derivative of "Liver steatosis fatty change" available at http://en.wikipedia.org/wiki/File:Liver_steatosis_fatty_change.jpg under Public Domain
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Mood Disorders: Major Depressive Disorder & Bipolar Type 1, Cyclothymia, Hypomania MDD
http://www.stomponstep1.com/mood-disorders-major-depressive-disorder-bipolar-type-1-cyclothymia-hypomania-mdd/ SKIP AHEAD: 0:31 – Mood Disorder (Affective Disorder) Definition 1:09 – Euthymia and the Mood Continuum 3:36 – Depression, Major Depressive Disorder and Suicide 7:51 – Dysthymia 8:08 – Adjustment Disorder 8:57 – Bereavement and Grief 10:02 – Postpartum Depression, Postpartum Blues & Postpartum Psychosis 10:50 – Mania and Bipolar Disorder 12:20 – Type 1 vs. Type 2 Bipolar and Cyclothymia Mood Disorders which are also known as Affective Disorders, are a collection of psychiatric conditions that involve a pervasive distortion of one’s emotional state or affect. This should not be confused with normal fluctuations in mood. Everyone has periodic, mild changes in their affect as a result of their circumstances. Mood disorders have more extreme changes in mood that are often unrelated to an individual’s circumstances. However, mood disorders are characterized by periods of normal or near-normal affect and function in between more severe mood “episodes.” Euthymia can be thought of as a neutral or “normal” mood. This is when a person isn’t particularly happy or sad. Psychiatrically healthy individuals spend most of the time in a euthymic state, but a “normal” patient will have times when they feel happy or sad. In certain circumstances a healthy individual may even have transient feelings of elation or mild depression. For example, if a person has a really stressful work situation or they win the lottery it would be normal for them to have a big change in their mood. However, these emotions do not lead to a loss of function and do not persist. Changes in affect become pathologic when extreme emotions are felt, these feelings persist and a loss of function is involved. Mood can be thought of as a continuum ranging from extremely happy (mania with psychosis) to extremely sad (depression with psychosis and/or suicidal ideation). Mood disorders can primarily be differentiated based on where they lie on this continuum. And I think being able to look at that continuum in a picture helps simplify things a lot. So here is what we are going to be working towards during this video. I’m sure this is a bit intimidating, but don’t worry we are going to break it down piece by piece to make it really simple. If you want a high resolution version of this picture for your notes or because the video looks a bit fuzzy on your screen you can click on this orange box here to be taken to my website where that is available. As you can see in the middle of our mood continuum is euthymia or neutral mood. Then as you move in either direction you get more extreme moods. On the right we have happy affect and to the left we have sad affect. Healthy individuals will spend most of their time in a state of Euthymia, but they will have occasional fluctuations from being sad to happy so this is our range of normal mood. Way out to the right we have extremely happy mood which is mania with psychosis and way out to the left with have depression with suicidal ideation or psychosis. The extremes of the continuum have a loss of function where the individuals ability to function at home and at work or school are inhibited. As we move forward we will plot each mood disorder on this same picture. Depression can involve a loss of interest in previously pleasurable activities (AKA Anhedonia), low self-esteem, hopelessness and fatigue. Depressed individuals may sleep way more or way less than normal, have decreased libido, eat way more or way less than norma or have a decreased ability to concentrate. Moderate to severe cases can cause a Loss of Function. In severe cases depression can lead to suicidal ideation or psychosis. Psychosis is going to involve things like delusions and hallucinations but we are going to save that topic for the next video in the series Usually when somebody says a person has depression what they really mean is that person has Major Depressive Disorder (MDD) and they don’t want to waste all of those extra syllables. So Major Depressive Disorder gets shortened to Depression. But you need to recognize that depression is as emotion and MDD is a medical diagnosis with specific criteria. The text for this video exceeds the maximum length allowed by Youtube. Please click here for the rest http://www.stomponstep1.com/mood-disorders-major-depressive-disorder-bipolar-type-1-cyclothymia-hypomania-mdd/ ERRATA: I misspelled "Dysthymia" on the video so I tried to correct it by adding a pop up box on the video. Thanks to user "Gilbert Flowerface" for pointing out the error
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Transplant Rejection, Hyperacute Acute Chronic Graft versus Host
http://www.stomponstep1.com/transplant-rejection-hyperacute-acute-chronic-graft-versus-host/ SKIP AHEAD: 0:29 – Definition and Introduction to Organ Transplantation 1:50 – Intro to Transplant Rejection 5:00 – The high yield table 6:38 – Hyperacute Rejection 8:22 – Acute Rejection 9:03 – Chronic Rejection 10:34 – Graft vs. Host Disease Organ Transplantation is the replacement of dysfunctional tissue with healthy tissue from “somewhere” else. An individual can receive an organ donation from an animal (such as a pig heart valve) or “donate” tissue to themselves by moving healthy tissue from one part of their body to another (such as skin grafting). However, almost all Step 1 questions are about transplantation from one human to another individual who is not a twin. This type of transplant is known as an Allograft. The donor may be living or recently deceased. A wide variety of tissues can be transplanted, but our discussion will focus primarily on functional organs that require vascular connections like the heart, kidney and liver (not structural tissue like tendons). Blood transfusion is a type of transplant that will be covered in more depth in the Hematology section. When the organ donor is not the recipient themselves or a genetically identical twin, the immune response to the new organ becomes extremely important to prognosis. The grafted tissue expresses antigens that are not present in the host and these antigens are recognized as foreign. The immune system reacts as if the donated tissue is an infectious microbe and attacks the graft. The immune system needs to be kept in check to allow the organ to be moved successfully into the recipient. Transplant Rejection is when there is not immunologic tolerance to the new organ and the host’s immune system damages the transplanted tissue. The damage is often most evident in the vessels of the donated tissue where antigens lining the endothelium come into contact with the immune cells circulating in the hosts blood. Following organ transplantation, patients need to be monitored closely for the onset of symptoms related to dysfunction of the transplanted tissue and they will undergo periodic laboratory evaluation in hopes of identifying rejection as quickly as possible. When rejection is suspected a biopsy is usually done to confirm the diagnosis and rule out another disease process. Hyperacute Transplant Rejection occurs almost immediately and is often evident while you are still in surgery. It is caused by accidental ABO Blood type mismatching of the donor and recipient which almost never happens anymore. This means the host has preformed antibodies against the donated tissue. For example, a recipient with Type B blood would have pre-made antibodies targeted at the carbohydrates on the blood of a Type A donor. The presence of preformed antibodies is why the reaction takes places so quickly. This is an example of Type II Hypersensitivity and results in thrombosis and occlusion of the graft vessel. The transplanted organ must be removed immediately. Acute Transplant Rejection is the most common type of rejection and usually has an onset between weeks and months of the transplant. It is a T-Cell mediated response against foreign Major Histocompatibility Complex in the donated organ. Therefore, it is an example of Type IV hypersensitivity. This process results in leukocyte infiltration of the graft vessel. The risk of Acute Rejection can be diminished (but not eliminated) with prophylactic immunosuppression. If identified early Acute Rejection may be able to be treated with immunosuppressants and corticosteroids. Chronic Transplant Rejection occurs months to years after the transplant. The exact mechanism is not very well understood but it probably involves a combination of Type III and Type IV hypersensitivity directed against the foreign MHC molecules which look like self-MHC presenting a foreign antigen. It results in intimal thickening and fibrosis of graft vessels as well as organ atrophy. Chronic rejection is a slow progressive decline in organ dysfunction while acute rejection is a more rapid decline in function. Chronic Transplant Rejection can be thought of as accelerated aging. There is no treatment available and these patients need to receive a new organ transplant. When Chronic Rejection is suspected a full work up is done to rule out “late onset” Acute Rejection which can be treated. The text for this video is too long for Youtube and exceeds the maximum allowed video description length. To read the rest of it please click here http://www.stomponstep1.com/transplant-rejection-hyperacute-acute-chronic-graft-versus-host/
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Incidence & Prevalence Definition. Case-Fatality Rate Formula & Calculation
http://www.stomponstep1.com/incidence-prevalence-definition-case-fatality-rate/ In normal everyday conversations incidence and prevalence are used interchangeably. That is because broadly speaking incidence and prevalence both measure the frequency of a disease or outcome. In most situations Incidence & prevalence are also directly proportional. However, there are a few clear differences between the two measures that the test writers love to write questions about. • Prevalence = number of Total Existing cases divided by the total population • Incidence = number of New cases within a certain time period divided by the total number of susceptible individuals in the population To illustrate the differences, below is how you would calculate the incidence and prevalence of chicken pox in my home town of Boca Raton. In most cases, incidence and prevalence are directly proportional. When one goes up the other one goes up and vice versa. This intuitively makes sense. If you have more new cases of diabetes within a given year then you are likely to have a higher total number of people with diabetes at any particular point during that year. However, Prevalence and Incidence are not always directly proportional and test makers like to focus on these situations. Most of these situations include a change in the duration of the disease. Duration of a disease is the time from when a patient is diagnosed until they are cured or die. When duration is held constant, prevalence and incidence are directly proportional. The relationship between prevalence, incidence and duration of disease can illustrated with a simple formula. Prevalence = Incidence * Duration This relationship makes sense if you think about extreme examples. Consider a situation where there are 100 new cases of a disease per year but the disease only lasts one day. Annual incidence will be higher than prevalence as at any particular moment there is likely only going to be at most 1 person with the disease. Now consider a disease that has 100 new cases a year and the disease lasts for 40 years. The point prevalence is going to be higher than annual incidence, as at any given point you have the 100 or so newly diagnosed patients from this year plus people that have been diagnosed over the last 40 years that do not contribute to incidence. Another way to think about the relationship between incidence and prevalence is the "Sink Metaphor." The water coming into the sink from the faucet represents incidence and the newly diagnosed patients. The level of water building up in the sink is prevalence (the total number of patients at that moment). The drain of the sink represents patients either being cured or dying. If patients are cured quickly or are dying quickly then the level of the sink won't be very high because the drain is really big. If there are very few patients dying or being cured that is like the drain getting clogged up and the sink backing up. Case-Fatality Rate is a proportion of the people with a particular disease that die as a result of that disease. As the name implies, it compares the number of cases to the number of fatalities related to that disease. So if 20 people have a particular cancer and that cancer is fatal in 5 of them the case fatality rate is 5_20. Now that you have finished this video you should check out the next video in the Biostats & Epidemiology section that covers the Definition of Bias and Validity (http://www.stomponstep1.com/bias-validity-definition-in-research-study-design/). Picture Used: "Sink" by Last-Dino available at http://openclipart.org/detail/183124/sink-by-last-dino-183124as part of Public Domain
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Free Radicals, Glutathione, Superoxide NADPH Oxidase N Acetylcysteine CGD MPO CCl4
http://www.stomponstep1.com/free-radicals-glutathione-superoxide-nadph-oxidase-n-acetylcysteine/ Free Radicals are very reactive molecules which have unpaired (single) outer electrons. These molecules damage cell membranes via peroxidation and DNA via oxidation. Free radicals can be generated by things like ionizing radiation (X-rays & UV light), drugs (acetaminophen), poisons (carbon tetrachloride CCl4), or certain metals (Iron). However, free radicals are also naturally generated in the body by enzymes. For example, neutrophils use free radicals during acute inflammation to destroy things like bacteria. So free radicals are not always a “bad” thing. Normal oxidative phosphorylation in the mitochondria can also generate free radicals. Usually 4 electrons are added to oxygen to get water. However, if that process is somehow interrupted you can end up with free radicals. Reperfusion following ischemia generates free radicals as well. The ischemia generates inflammation which then meets the oxygen in the blood (which can be converted to superoxide) and inflammatory cells (which can create free radicals). This presents clinically as an MI patient who gets worse after treatment. The body has enzymes for neutralizing free radicals. There are also vitamins that can neutralize free radicals. These vitamins are called Antioxidants. Vitamins A, C, & E are the main antioxidants (Think Ace like the playing card). • NAPDH Oxidase converts oxygen to Super Oxide (O2- ) mainly in neutrophils • Myeloperoxidase (MPO) converts peroxide (H2O2) into Hydrochloric Acid (HOCl) mainly in neutrophils • Fenton Reaction generates Hydroxide (OH-) from peroxide (H2O2) using iron • Superoxide Dismutase (SOD) converts Super Oxide (O2- ) to peroxide (H2O2) • Glutathione convert Hydroxide (OH-) to water • Catalase converts Peroxide (H2O2) to water We will see in the immunology section that that a defect in NADPH Oxidase causes Chronic Granulomatous disease. This is an immunodeficiency due to the neutrophils inability to generate free radicals needed to destroy foreign material. Specifically this makes individuals susceptible to reoccurring infections by catalase positive organisms. Most microorganisms are catalase negative (they don’t have catalase) which means they have a small amount of naturally produced peroxide which can be converted to HOCl by the neutrophils. This HOCl can then be used in place of superoxide to destroy phagocytized material. Catalase positive organisms make their own catalase enzyme which degrades the peroxide and prevents this procedure. Another similar immunodeficiency if MPO deficiency which prevents neutrophils from creating HOCl. Glutathione is one of the enzymes that can remove free radicals. Glutathione must be in its reduced form to convert peroxide to water. NADPH, which is created by the pentose phosphate shunt, reduces Glutathione. Glucose-6-Phosphate Dehydrogenase Deficiency (which will be covered primarily in the hematology section) is a deficiency of a key enzyme in the pentose phosphate shunt that limits the creation of NADPH. This means less glutathione & more free radicals which end up damaging blood cells. Excessive amounts of Acetomenophen (like that seen in suicide attempts) can be metabolized by the liver into intermediates which bind to and remove glutathione. This reduction in glutathione means free radicals build up and damage the liver cells. The treatment is N-acetylcysteine which is a precursor to glutathione.
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Substance Abuse, Intoxication & Withdrawal, Uppers Downers & Hallucinogens MDMA LSD PCP
SKIP AHEAD: 0:32 – Substance Abuse vs. Substance Dependence 2:51 – Miosis vs. Mydriasis 3:21 – Uppers/Stimulants (Cocaine, Meth & MDMA/Ecstacy) 5:57 – Downers/Depressants Intoxication & Overdose (Alcohol, Opioids, Heroin) 10:58 - Downer Withdrawal 12:18 – Hallucinogen (PCP, LSD & Mushrooms) 14:15 – Marijuana/Cannabis Alcohol Link - http://www.stomponstep1.com/alcohol-metabolism-methanol-poisoning-fatty-change/ Psychosis Link - http://www.stomponstep1.com/psychosis-schizophrenia-schizoaffective-disorder-delusional-disorder-hallucinations/ Donate Link - http://www.stomponstep1.com/donate/ Substance dependence is an adaption to a pattern of substance use. It is primarily characterized by withdrawal (or symptoms that occur when use of the drug is discontinued), tolerance (or needing more to obtain the same desired effect), and spending a significant portion of their time engaged in drug related activities. Substance abuse is an overindulgence in an addictive substance as a result of a lack of control. It can be thought of as a more extreme version of substance dependence in which individuals have significant negative life effects with work relationships or school), poor health, or legal problems as a result of their substance use. In the general public this pattern of substance abuse would more generally be referred to as an addiction. There is very specific DSM criteria for each of these terms, but that isn’t important for the exam. For simplicity sake we will break the drugs down into 3 different categories. The 3 categories are Uppers, Downers and Hallucinogens. There are slight differences between drugs within individual categories, but for the most part you can get questions right by just knowing the general characteristics of the entire group. For example, you won’t see both cocaine and MDMA listed as answers on the same question. Also remember to not confuse intoxication and withdrawal. Most questions are on drug intoxication, but they may specifically ask you about withdrawal which usually has symptoms that are just the opposite of intoxication. So make sure you read the question carefully. For example, the question stem may fit stimulant withdrawal and depressant intoxication, but the last sentence of the question specifically asks about withdrawal. Keep in mind the most important things for Step 1 questions are the changes to the vitals and pupils. These should be the buzzwords you are looking for. You will almost always be given this information in these types of questions and if you just have that info you can usually narrow it down to at least 2 options. Also make sure you don’t get mydriasis vs. miosis confused. Mydriasis is the bigger word and has the bigger pupils. Miosis is the smaller word and has the smaller pupils. And obviously the best way to confirm a diagnosis of drug use is a urine drug screen and mental health services are important in the treatment of addiction. However, that is too easy so you won’t see either of those as an answer on the exam so I’m not going to spend much time on that. That brings us to Uppers or stimulants…. Now I’ll try my hardest to not make 20 references to Breaking Bad during this section, but I can’t make any promises. Most of the questions related to this category will be about cocaine, which is usually smoked in the form of crack cocaine or snorted. However, other street drugs such as Methamphetamines (Meth) & MDMA (Ecstasy & Molly) are also in this group. Prescription drugs used for ADHD, narcolepsy and weight loss are also stimulants, but are less likely to show up in this type of Step 1 question. The text for this video is too long and exceeds Youtubes Max. For the rest please go to http://www.stomponstep1.com/substance-abuse-intoxication-withdrawal-uppers-downers-hallucinogens-mdma-lsd-pcp/ Pictures Used:  Derivative of “Occhi222” by Ladysiria17 available at https://commons.wikimedia.org/wiki/File:Occhi222.jpg via Public Domain  Derivative of “Anizokoria” by Radomil available at https://commons.wikimedia.org/wiki/File:Anizokoria.JPG via Creative Commons 3.0 Attribution-Share Alike  “Crystal Meth” by Radspunk available at https://commons.wikimedia.org/wiki/File:Crystal_Meth.jpg via Creative Commons 4.0 Attribution-Share Alike  “Man sniffing” available at https://commons.wikimedia.org/wiki/File:Man_sniffing.jpg  “Alcohol desgracia” by RayNata available at https://commons.wikimedia.org/wiki/File:Alcohol_desgracia.jpg via Creative Commons Attribution – Share Alike  Derivative of “Amanita muscaria crop” by Onderwijsgek available at https://commons.wikimedia.org/wiki/File:2006-10-25_Amanita_muscaria_crop.jpg via Creative Commons 3.0 Attribution-Share Alike  Derivative of “kaleidoscope explosion colors” available at https://pixabay.com/en/kaleidoscope-explosion-colors-577317/ via Public Domain
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Oncogenes & Tumor Suppressor Genes Bax P53 MYC Bcl-2 BRCA Trastuzumab Rb
http://www.stomponstep1.com/oncogenes-tumor-suppressor-genes-bax-p53-myc-bcl-2-brca/ Along the cell cycle, there are numerous checkpoints in which the cell “doubles check” whether or not it should proceed to the next phase. At these checkpoints the cell decides whether or not it should move to the next step in the cell cycle. Abnormalities in these checkpoints are the keys to cancer formation, as dysregulation of these control mechanisms leads to unregulated cell division. The most important of these cell checkpoints is the point where the cell determines whether or not it should move from the G1 to S phase. Cells that pass through this checkpoint generally end up going through the full cycle of division. Rb and p53 are the most important control mechanisms at this check point. Tumor Suppressor genes are involved in preventing one of the steps in the pathway that causes cancer. Most often these genes are involved in regulating the cell cycle and causing apoptosis in abnormal cells. When tumor suppressors are functioning properly they prevent abnormal cells from passing through checkpoints (stop cell division to give the cell time to repair itself). Malfunctioning tumor suppressors are some of the most important contributing factors to cancer formation, because it allows unregulated cell division. Since Tumor Suppressors contribute to cancer through a loss of function mutation both alleles generally need to be mutated to cause cancer. Even 1 functioning allele is usually enough to regulate the cell cycle. This is an example of the “two hit hypothesis.” p53 is the most important tumor suppressor and is found to be mutated in about half of all cancers. p53 is activated by cellular damage or mutation to the DNA. p53 is a transcription factor which works by altering the transcription of downstream genes. When active, p53 stops the cell cycle (primarily at the G1-to-S Phase checkpoint) to give the cell time to repair itself. If repair is not possible, p53 causes apoptosis of the cell. We have already learned that cytochrome C leakage from the mitochondria into the cytosol activates caspases and leads to apoptosis. The interaction between Bcl-2 (oncogenic/anti-apoptotic) and Bax (anti-oncogenic/ apoptotic) is a key regulator of cyt C release. Bax is a protein embedded in the mitochondrial membrane with a pore that can open or close as a result of conformational shape changes. When this Bax pore is open, cyt C can flow out of the mitochondria into the cytosol and cause apoptosis. One of the actions of Bcl-2 is to close the Bax pore. Apoptosis is initiated by p53 by increasing the activity/expression of Bax and decreasing the activity/expression Bcl-2. Rb protein is another important tumor suppressor which controls the G1-to-S Phase checkpoint that is dysfunctional in many cancers. Rb stands for retinoblastoma which is the first cancer this protein was associated with. Rb stops the cell cycle by inhibiting the action of the E2F transcription factor. E2F activates genes which transition a cell from the G1 phase to the S phase. Therefore, the inhibition of EF2 by active RB protein prevents the cells transition into the S phase. When RB is phosphorylated it is inactivated which allows the cell to progress through the checkpoint in an unregulated manner. In HPV E6 protein is created and “flags” p53 for degradation using ubiquitin. HPV also creates protein E7 which inhibits the action of Rb. These functions inactivate these tumor suppressors and cause cancers primarily in the cervix. BRCA1 & BRCA-2 are tumor suppressor genes that fix double strand DNA breaks and perform mismatch repair. Germline (inherited) mutations and inactivation of either of these tumor suppressors can lead to familial types of breast and ovarian cancers. Pictures Used: Derivative of “Connecticut ComiCONN Superhero Mascot“ by ComiCONNMitch available at http://commons.wikimedia.org/wiki/File:Connecticut_ComiCONN_Superhero_Mascot..jpg via Creative Commons Attribution Share Alike Derivative of “Door Line Art” by gammillian available at http://openclipart.org/detail/75991/door-line-art-by-gammillian via Public Domain “Villain” by J.J. available at http://en.wiktionary.org/wiki/File:Villainc.svg via Creative Commons Attribution-Share Alike “Smiling Man 7” by TikiGiki available at http://openclipart.org/detail/174072/smiling-man-7-by-tikigiki-174072 Via Public Domain
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Folate & B12 Deficiency, Megaloblastic Anemia Hypersegmented Macrocytic Methylmalonic
http://www.stomponstep1.com/folate-b12-deficiency-megaloblastic-anemia-hypersegmented/ Vitamin B9 (Folate/Folic Acid) is very important for 1 carbon chemical reactions (AKA methylation) during the creation of DNA. These functions are particularly important in tissues that undergo frequent cellular division (like hematopoietic cells) and during periods of rapid cellular division (such as infancy and pregnancy). Folate is found naturally in leafy vegetables and Folium is the Latin word for leaf. Today many grains are also fortified with Folate. With so many items having Folate added a deficiency from decreased intake of Folate is not very common. Usually a deficiency is caused by an increased demand for folate through pregnancy or hemolytic anemias such as Sickle Cell Disease. Folate deficiencies in pregnant women are linked with the occurrence of Neural Tube Defects in the fetus. A deficiency can also be caused by drugs that inhibit the pathways that Folate is involved in such as Trimethoprim (antibiotic) and Methotrexate (Chemotherapy). A Folate deficiency primarily causes anemia (decreased red blood cells). Anemias can present with a wide range of symptoms including weakness, fatigue, pale skin and shortness of breath. Folate Deficiency causes a specific type of Anemia called Macrocytic/Megaloblstic Anemia where the size (Mean Corpuscular Volume) of the red blood cells increased. This is because as the creation of DNA is inhibited the cell cycle in the hematopoietic cells is stalled. Cellular division is stopped but the cell continues to grow resulting in a smaller number of cells which are larger than normal cells. Patients with this type of anemia also often present with Hypersegmented Neutrophils on a blood smear, which is a neutrophil with 5 or more "segments" in the nucleus. You are also going to see an elevation of Homocysteine levels in Folate Deficiency. This is because B12 needs to receive a methyl group from Folate so it can pass it on to Homocysteine to create Methionine. Less Folate means B12 doesn't have a methyl group to pass on and Homocysteine builds up. Unlike B12 deficiencies, Folate deficiency does not result in a buildup of Methylmalonic Acid or neurological symptoms. Vitamin B12 (Cobalamin) is a vitamin, like Folate, that is important for 1 carbon chemical reactions. B12 is found in many animal products and Vegans are at the highest risk of deficiency. B12 taken in through the diet is bound to proteins. Stomach acid and digestive enzymes must first separate B12 from the proteins. If there is a deficiency of stomach acid due to disease or medication (like proton pump inhibitors or antacids) it can cause decreased absorption and B12 deficiency. Once it is no longer protein bound, B12 binds Intrinsic Factor which is released by the Parietal Cells in the stomach. Intrinsic Factor then chaperones the B12 to the terminal ileum where it is absorbed. Pernicious Anemia is the autoimmune destruction of parietal cells which leads to less Intrinsic Factor production. Less intrinsic factor means less B12 absorption and B12 deficiency. Damage to the terminal ileum, such as in Crohn's Disease, can also inhibit B12 absorption. Folate and B12 work closely together handing off methyl groups to each other. It is sort of like a game of hot potato. Folate doesn't "want" the methyl group so it passes it on to B12. B12 doesn't "want" it either so it passes it off to methionine. In effect, B12 helps recycle methyltetrahydrofolate back into tetrohydrofolate which can be used to create DNA. This means that a deficiency of B12 can cause a deficiency of Folate as less Folate is being recycled into its "active" form. Therefore, B12 deficiency present very similarly to Folate deficiency. You get Macrocytic/Megaloblastic Anemia with Hypersegmented Neutrophils and increased Homocysteine levels. If you mistakenly diagnose Folate Deficiency when it is really B12 Deficiency the patient will get better with Folate supplementation, but permanent neurological damage will be done overtime. Odd chain fatty acids are broken down to eventually give Methylmalonyl CoA. B12 is a cofactor in the process that converts methylmalonyl CoA into Succinyl CoA which can then be used in the TCA cycle to generate energy. If there is not enough B12 this reaction is slowed and Methylmalonic Acid builds up. This Methylmalonic Acid build up is toxic to neurons and leads to demyelination in the posterior and lateral columns of the spinal cord. This is called Subacute Combined Degeneration and presents with peripheral numbness/tingling, spasticity, and loss of vibration and proprioception.
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Fat Soluble Vitamins and Water Soluble Vitamins Steatorrhea, Deficiency Toxicity List Lipid
http://www.stomponstep1.com/fat-soluble-vitamins-and-water-soluble-vitamins-steatorrhea/ Fat Soluble Vitamins are hydrophobic (fat loving) nutrients that are necessary in small amounts to sustain a healthy life. Excess fat soluble vitamins can be stored in the liver and fat (adipose tissue). Therefore, these vitamins do not need to be eaten every single day as stores of the vitamins can sustain a person for some time. This is why a deficiency may take months to develop as the stores of the vitamin can take a long time to be depleted. This ability to store vitamins in tissue can also lead to vitamin toxicity. This toxicity is a vitamin overdose caused by taking a vitamin in excess. Since fat soluble vitamins can be stored in the body they can accumulate to the point of causing illness. Fat soluble vitamins are usually absorbed as part of chylomicrons (fat lobules) in the small intestine after being digested by pancreatic enzymes. Therefore, if fat absorption is inhibited the digestion of fat soluble vitamins will also be limited. This malabsorption can result in a deficiency of fat soluble vitamins as they are being excreted in the feces rather than being absorbed. This condition of excess fat excretion in feces is called Steatorrhea. It results in bulky, foul-smelling bowel movements with an oily appearance that float. Common causes of Steatorrhea on the USMLE Step 1: • Cystic Fibrosis (Thick mucus = decreased ability to secrete pancreatic enzymes) • Pancreatitis or Pancreatic Cancer (decreased ability to secrete pancreatic enzymes) • Celiac Disease & Crohn's Disease (damages portions of small intestine responsible for fat absorption) • Liver disease, biliary cirrhosis and sometimes gallstones (= less bile for fat absorption) Water Soluble Vitamins are hydrophilic (water loving) nutrients that are necessary in small amounts to sustain a healthy life. Unlike fat soluble vitamins they are generally not stored in body tissues. If you take in excess water soluble vitamins, your kidneys excretes most of the excess in urine. This is why some people say the US has the most expensive urine in the world. We spend so much on expensive vitamin supplements and much of it just ends up in the toilet. B12 and Folate are exceptions as they are water soluble vitamins that are stored in the liver. Excreting excess in the urine and not storing much in the body means that water soluble vitamins need to be consumed daily and that deficiencies can become apparent quickly. Also toxicity of water soluble vitamins is much less common than toxicity for fat soluble vitamins, because excess water soluble vitamins don't easily build up in the body. Patients with renal damage may reach toxicity of water soluble vitamins at much lower doses as their excretion of excess water soluble vitamins in impaired * Usually on Step 1 they will give you the vitamin letter/number and the name in parenthesis. They wouldn't usually give you one without the other, so perfectly memorizing both is not necessary. I would just learn the letter/number as that is easier. Here is a mnemonic to help remember which vitamins are fat soluble & which are water soluble. Now that you are done with this video you should check out the next video in the Vitamins section which covers Fat Soluble Vitamin Deficiencies (http://www.stomponstep1.com/fat-soluble-vitamins-hemorrhagic-disease-of-the-newborn/) Picture Used: Derivative of "At the beach - male abdominal obesity" by Tibor Végh available at http://commons.wikimedia.org/wiki/File:At_the_beach_-_male_abdominal_obesity.JPG by Creative Commons 3.0 Attribution
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Bias & Validity Definition in Research Study Design
http://www.stomponstep1.com/bias-validity-definition-in-research-study-design/ Validity is how well the test or study answers the question it was supposed to answer. With regard to laboratory test results you would use sensitivity and specificity to measure validity. However, the term validity is more commonly used when referring to research. It is basically how valid the conclusions of the study are based on the study's design and results. There is internal validity which measures how well your results represent what is going on in the sample being studied and external validity which measures how well your results can be applied to other situations (or the overall population). Bias is a non-random (directional) deviation from the truth. High bias in a study means low validity and vice versa. With regards to research studies bias is problems with the study design or execution that cause you to consistency get distorted results. These results are non-random as you are consistently having the results skewed in the same direction. In most cases this means you are showing a stronger association between the factor being studied and the health outcome. Bias is different than the random error you might see with a low sample size. Bias means there is something fundamentally wrong with the study that is causing you to get incorrect results that are consistently different than the truth. You can't correct bias by having a larger sample size. The Ideal Research Study has the following characteristics: • The study population is similar to the overall population of interest • The two or more groups in the study should be as close to identical as possible at the start of the study except for the one variable you are trying to isolate • The different groups should remain close to identical throughout the study. This involves keeping as many patients as possible enrolled in the study until the end and treating the different groups the same except for the variable you are trying to isolate • All patients are compliant with any treatments or lifestyle changes assigned to them Now that you have finished this video you should check out the next video in the Biostats & Epi sections which covers Confounding, Randomization, Selection Bias & Sampling Bias (http://www.stomponstep1.com/confounding-placebo-stratification-randomization-blinding/).
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PKU, Phenylketonuria, Galactosemia, Hereditary Fructose Intolerance & Sorbitol Diabetic Cataracts
http://www.stomponstep1.com/pku-phenylketonuria-galactosemia-hereditary-fructose/ Phenylketonuria (PKU) is a genetic deficiency of either Phenylalanine Hydroxylase or its cofactor, Tetrahydrobiopterin (THB). This inhibits the conversion of Phenylalanine to Tyrosine. The lack of Tyrosine causes multiple health outcomes and the excess Phenylalanine is excreted in the urine as it builds up in the body. Untreated PKU is characterized by Mental Retardation and Seizures. A mild form of Albinism results from less tyrosine being available for melanin synthesis. The build-up of metabolites with aromatic properties leads to a Musty/Mousy Body Odor. Tyrosine is a non-essential amino acid as most people can create tyrosine by breaking down phenyalanine. However, tyrosine becomes essential in PKU. PKU is treated by supplementing tyrosine and restricting phenyalanine intake in the diet. Items that contain Aspartame (like diet soda) need to be avoided as well as aspartame is broken down into phenylalanine. In tissues, some glucose is converted to an alcohol called Sorbitol. Small amounts of sorbitol allow glucose to be sequestered in the tissue and do not cause a problem. Sorbitol Dehydrogenase converts sorbitol to harmless fructose to prevent sorbitol build up. However, some tissues (primarily in the eye) do not have enough Sorbitol Dehydrogenase to handle excessive amounts of sorbitol. Therefore, patients with chronic hyperglycemia (Diabetic Patients) have a buildup of sorbitol which can cause Cataracts and other damage to the visual pathway. Essential Fructosuria is an asymptomatic deficiency of Fructokinase. Hereditary Fructose Intolerance is a deficiency of Aldolase B that causes hypoglycemia, hepatomegaly, jaundice & vomiting. These patients should avoid fructose & sucrose (which contains fructose) Galactokinase Deficiency causes cataracts. Galactosemia is a deficiency of Galacto-1-P Uridyl Transferase that leads to cataracts, hepatomegaly, jaundice & retardation. Patients with both disorders should avoid lactose as it contains galactose. All four disorders above are Autosomal Recessive inheritance. Whichever sugar builds up, either the sugar by itself or the phosphorylated sugar, can be detected in excess in the urine and blood. Galactose disorders are more serious than fructose disorders because excess fructose is just excreted in urine while excess Galactose can be converted to Galactitol (alcohol) which can accumulate in tissues. Fructose disorders don't appear until the baby stops breastfeeding and is exposed to formula or other dietary sources with fructose. Lactose is a disaccharide of 1 Glucose and 1 Galactose. Therefore must be avoided in Galactose Disorders. Sucrose is a disaccharide of 1 Glucose and 1 Fructose. Therefore, Sucrose (table sugar) must be avoided in Fructose Intolerance. Now that you have finished this video you should check out the next video in the Biochemistry sections which covers Alcohol Metabolism, Alcoholism & Methanol Poisoning (http://www.stomponstep1.com/alcohol-metabolism-methanol-poisoning-fatty-change/) Pictures Used (in order of appearance): This work is a derivative of "Food Cartoon Coke Can Beverage Soda Cola" available at http://pixabay.com/en/food-cartoon-coke-can-beverage-33598/under Creative Commons 1.0 Public Domain Dedication "Simple Cartoon Mouse" available at http://openclipart.org/detail/17558/simple-cartoon-mouse-by-lemmlingunder Creative Commons 1.0 Public Domain Dedication This Work is a derivative of "Cataracts in Ghana" by Mate 1st Class (AW) Shane M Available at ttp://sn.wikipedia.org/wiki/File:Cataracts_in_Ghana.jpg under Public Domain
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Genetic Inheritance, Autosomal Dominant, X-linked Recessive, Mitochondrial Disease Polygenic mtDNA
http://www.stomponstep1.com/genetic-inheritance-autosomal-dominant-x-linked-recessive-mitochondrial-disease/ Autosomal Dominant Inheritance is when one allele, on any chromosome other than X or Y, is expressed over another allele of the same gene. This allele determines the phenotype (observable characteristics) and is referred to as dominant. The allele that is does not affect the phenotype is referred to as recessive. The dominant allele is often given the capital letter for a character while the recessive allele is given the lower case. Therefore, a heterozygous individual who is a carrier for the recessive gene would be represented as Aa. Usually on a pedigree nearly every generation has an affected individual. Autosomal Recessive Inheritance is basically the opposite of autosomal dominant. Recessive alleles only change the phenotype when there is no dominant allele present. Heterozygous individuals do not show the phenotype of the recessive allele, but can pass this allele on to their offspring. These heterozygous individuals are called carriers. Usually on a pedigree few individuals are affected. X Linked Recessive Inheritance is a type of recessive inheritance for genes on the X chromosome. Males express the phenotype when they inherit 1 effected allele, while females need to inherit 2 effected alleles. This is because the gene lies on the X chromosome, and males only receive a single X while females receive 2. Males cannot pass the effected X allele onto sons, because a son must receive a Y from the father to be male. Males are affected far more often than females. Women are very rarely affected by these disorders, and are primarily heterozygous carriers when they have the gene. Mitochondria have DNA (mtDNA) that is circular and separate from the chromosomes in the nucleus. Mitochondrial Inheritance is only through the mothers and the fathers mitochondrial DNA is not passed onto children. Heterosplasmy is when a single individual has more than 1 type of mitochondrial DNA in their body due to mutations. The most common disease with this type of inheritance is Mitochondrial Myopathy which presents with "Ragged Red" muscle fibers on biopsy Polygenic or Multifactorial Inheritance is when the phenotype is not dictated by a single gene locus. These types of diseases are determined by an interaction between many contributing genetic and environmental factors. Variable Expressivity = same genetic defect presents differently in different patients. Neurofibromatosis is an example Mosaicism = when populations of cells within a single individual have different genotypes due to post-fertilization changes. Often in reference to chromosomal abnormalities caused by improper mitosis. Germline Mosacism is when only gametes (sperm and eggs) are affected by the genetic defect. Therefore, the individual would not show signs of the disease, but they could pass it on to their offspring Pleiotrophy = a single genetic defect has multiple effects (same gene is expressed in many different tissues) Incomplete Penetrance = not everyone with genetic defect gets the disease. Low penetrance means many people with the genotype do not show the phenotype Pictures Used (In order of appearance) • "Autosomal Dominant" by Domaina available at ttp://en.wikipedia.org/wiki/File:Autosomal_dominant_-_en.svg via Creative Commons 3.0 Attribution Share Alike • "XlinkedRecessive" by US National Library of Medicine available at http://en.wikipedia.org/wiki/File:XlinkRecessive.jpg via Public Domain • "Mitochondrial" By US National Library of Medicine available at http://en.wikipedia.org/wiki/File:Mitochondrial.jpg by Public Domain
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Water Soluble Vitamin Deficiency, Scurvy Pellagra Wernicke-Korsakoff Syndrome Beriberi
http://www.stomponstep1.com/water-soluble-vitamin-deficiency-scurvy-pellagra-wernicke-korsakoff/ Thiamine (Vitamin B1) deficiencies are primarily seen in alcoholic patients. This scenario is so common on Step 1 that anytime you see alcoholism in a vitamin question, your first thought should be thiamine deficiency. Thiamine is found in a lot of different foods, so you usually only see deficiencies in people who are malnourished or getting a majority of their calories from alcohol. Deficiencies of Thiamine primarily affect 3 different areas; the CNS (Wernicke-Korsakoff Syndrome), PNS (Dry Beri-Beri), and the cardiac system (Wet Beri-Beri). Damage done to the cardiac system and the PNS can be reversed with treatment, but damage done to the CNS is permanent. Thiamine is an important cofactor in multiple processes that generate ATP from glucose sugar. Therefore, deficiencies are worsened by sugar intake (in the absence of thiamine administration) because the little bit of Thiamine left in the system is used up to metabolize the sugar. Wernicke-Korsakoff Syndrome is the collection of CNS damage that results from Thiamine deficiency. It includes amnesia (memory loss), confusion, ataxia (unsteady gait), and visual disturbances due to uncoordinated eye movement. The confusion and memory loss can lead to confabulation in which the patient has bizarre explanations for things like how they got injured. Wernicke-Korsakof syndrome characteristically affects the Mammillary Bodies and the surrounding structures (3rd/4th ventricle & aqueduct). Infarcts or hemorrhages in these areas can be seen on radiologic imaging. Dry BeriBeri is damage to the peripheral nervous system (PNS) that results from Thiamine deficiency. It causes muscle wasting, weakness, and diminished peripheral sensation. Wet BeriBeri is the cardiac effects of Thiamine deficiency. It leads to arrhythmias and/or heart failure by affecting the electrical system of the heart. Edema, dyspnea, increased cardiac output, and cardiac dilation can result. Niacin (Vitamin B3) is part of NAD+ and NADP+ which carry electrons in redox reactions. Vitamin B3 is made from tryptophan using a vitamin B6 cofactor. Therefore, Niacin deficiency can be the result of Vitamin B6 deficiency or tryptophan deficiency (Hartnup Disease or Carcinoid Syndrome). Niacin deficiency is called Pellagra. Pellagra is characterized by the "4 Ds" Diarrhea, Dementia, Dermatitis, and Death. Niacin is one way to treat high cholesterol. Niacin toxicity can result if a patient receives too high of a dose. This causes the side effect of Facial Flushing (red face with the sensation of warmth). Pyridoxine (Vitamin B6) is an essential coenzyme in many metabolic reactions. Deficiencies can cause peripheral neuropathy (numbness & tingling), seizures, anemia & irritability. Deficiencies of Vitamin B6 can also lead to deficiencies of Vitamin B3, because B6 is a cofactor in the pathway that converts Tryptophan to Vitamin B3. The most common cause of Vitamin B3 deficiency is Isoniazid (TB drug) Treatment. Therefore, some patients receiving Isoniazid are given B6 vitamins prophylactically. Vitamin C (Ascorbic Acid) is involved in the hydroxylation of certain amino acids in collagen that are important for crosslinking individual pro-collagen chains into a triple helix. Without this hydroxylation the collagen is very weak. Therefore, deficiencies of Vitamin C cause poor wound healing, gum abnormalities (pain, bleeding & loose/missing teeth) & bruising (purpura, ecchymosis, perifollicular hemorrhages). Scurvy results from not eating enough fruit and other fresh foods.
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B & T Cell Activation & Development, Cytokines, MHC 1 CD40 TNF B7 IL 2 LTB4 CD4 CD8
http://www.stomponstep1.com/b-t-cell-activation-development-cytokines-mhc-1-cd40-tnf-b7-il-2-ltb4-cd4-cd8/ SKIP AHEAD: 1:04 – Intro to the Adaptive Immune Response & Types of Lymphocytes 3:44 – T & B Cell Function & Activation 7:32 – B & T Cell Development (Hematopoietic Stem Cells, Secondary & Primary Lymphoid Organs) 9:36 – Negative Selection through Central & Peripheral Tolerance 11:18 – Major Histocompatibility Complex (MHC 1 & 2) 13:44 – T Cell Activation: Helper CD4 & Cytotoxic CD8 16:06 – B Cell Activation: T Cell Dependent & Independent 17:54 – Cytokines: Interleukin 1 (IL-1), IL-2, IL-8, Tumor Necrosis Factor (TNF), Interferon There are 2 main types of T-Cell, each of which is part of Cell-Mediated Immunity. CD8 T-cells, named for its CD8 surface marker, are the “Cytotoxic” T-Cell. These lymphocytes release perforin and granzyme to cause lysis of infected cells, similar to how NK cells function. These CD8 cells cause apoptosis of cells that are infected by intracellular pathogens (primarily viruses and intracellular bacteria like chlamydia). Cytotoxic T-Cells also play a role in triggering apoptosis of cancerous cells. CD4 T-Cells, named for their CD4 surface marker, are referred to as the “Helper” T-cells. They do not fight pathogens directly, but help various other cells to do so by releasing cytokines signals. There are 2 subtypes of CD4 Helper T-Cells, Th1 and Th2. Th1 Helper T-Cells primarily activate cytotoxic CD8 T-cells and Macrophages. Th2 helper T-cells primarily activate B-Cells. Both T-Cells & B-Cells begin life in the bone marrow and arise from multipotent hematopoietic stem cells. Immature B-Cells remain in the bone marrow to complete maturation (Think B for Bone Marrow), while the immature T-Cells leave the bone marrow and travel to the thymus to complete maturation (Think T for Thymus). The bone marrow and thymus are referred to as Primary Lymphoid Organs. These Primary Lymphoid Organs are where B-Cells and T-Cells differentiate and mature. Absence of a primary lymphoid organ, such as the absence of the thymus in DiGeorge Syndrome, prevents the normal development of white blood cells and can lead to immunodeficiency. Once mature, B-Cells and T-Cells move to Secondary Lymphoid Organs such as the lymph node and spleen. This is where these cells come into contact with foreign pathogens. If the pathogen the cell can interact with is present the cell will be activated. After activation the cells proliferate making clones of themselves that are all capable of recognizing and fighting against the same antigen. However, not all T & B Cells will be activated. A large majority of these cells will not encounter the type of foreign material they recognize. If the foreign material the B or T Cell can fight against isn’t present in the body there is no need to be activated. The foreign material or pathogen that the T & B Cells recognize is determined by their unique surface receptors. An Antigen is the specific structural sequence the receptor can bind to. For example, a protein fragment of a pathogen you want to mount an immune response against. All of the receptors on a given T or B Cell are the same and recognize the same antigen. When the receptor binds to the appropriate antigen it signals the cell to become activated and proliferate. You need a nearly infinite variability in these receptors so that you can fight almost any pathogen encountered. Therefore, while the leukocytes are in the primary lymphoid organs a wide variety of receptor variability is randomly generated through VDJ Recombination. This change in the portion of the genome that encodes for the cell’s receptors allows the different leukocytes to interact with a huge variety of antigens. The problem with randomly generating surface receptors is that some of these leukocytes will now be able to bind the body’s own cells. If these self-reactive lymphocytes where activated they would cause autoimmune damage where the immune system targets the body’s tissue instead of foreign material. The body has a 2 step process for preventing this called Negative Selection. In the primary lymphoid organs self-reactive leukocytes are removed by Central Tolerance (AKA Clonal Deletion). Developing T & B lymphocytes that interact too strongly with self-antigens undergo apoptosis or programmed cell death. In the secondary lymphoid organs there is a similar process called Peripheral Tolerance or Clonal Anergy. Here self-reactive T or B Cells that bind to soluble self-antigens undergo anergy. Anergy is when a cell is prevented from becoming active. These anergic cells are not killed, but they are prevented from proliferating. The text for this video is too long and exceeds the maximum allowed length by youtube. To see the full text please go here http://www.stomponstep1.com/b-t-cell-activation-development-cytokines-mhc-1-cd40-tnf-b7-il-2-ltb4-cd4-cd8/
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Metastasis, Cancer Nomenclature, Tumor Nomenclature Lymphatic Spread Metalloproteinase
http://www.stomponstep1.com/metastasis-cancer-nomenclature-tumor-nomenclature/ Mesenchymal (connective tissue, blood or lymphatic tissue) cancers have a specific naming system. There is a prefix for different types of tissue that make up the tumor and a suffix to signify whether it is benign or malignant. However, Cancers of blood cells (Leukemia) and lymph nodes (Lymphoma), both of which are always malignant, do not follow this pattern. Prefix + OMA = Benign Mesenchymal Cancer Prefix + SARCOMA = Malignant Mesenchymal Cancer Mesenchymal Cancer Prefix • Lipo- = Fat • Osteo- = Bone • Fib- = Fibrous Tissue • Chondro- = Cartilage • Hemangio- = Blood vessel • Leiomyo- = smooth muscle • Rhabdomyo- = striated muscle Cancers that originate from epithelium (glands and surface/cavity lining) have a naming system that is more complicated. Benign epithelial cancers that contain glandular tissue (such as prostate, adrenal glands and certain types of colon cancer) are called Adenomas. Adenomas often grow into the lumen of whatever organ they are in forming a Polyp. Cystadenomas are hollow cysts-like cancers that are usually filled with fluid. Benign cancers of stratified squamous epithelium that form “cauliflower” finger like projections are called Papillomas. Malignant epithelial cancers are called Carcinomas. Metastasis is the spread of a cancer from the original tumor location to “distant” sites in the body. This is generally thought of as being separate from cancer invasion, which is the direct extension of a cancer across an organ or to neighboring organs. Invasion is a tumor growing in size and taking up more space, while metastasis involves migration to a completely new site. Metastasis is the most important prognostic factor for a cancer and is represented by the cancer’s Stage (More important than the cancer’s level of differentiation or grade). Metastasis is usually via the lymphatic system or the blood vessels. In this way, the cancer cells use the lymph or blood as a highway to get to other sites in the body. Carcinomas tend to spread via the lymph while sarcomas more commonly spread via blood, but there are numerous exceptions to this general rule. Carcinoma = Lymphatic Spread Sarcoma = Hematologic (Blood) Spread To be able to spread cancer cells need certain abilities which are gained via additional mutations. These mutations allow the cancer cells to break away from the primary tumor, “eat” through the basement membrane (Type IV Collengenase), “eat” through the extracellular matrix (Metalloproteinases), enter the lymphatics/blood, survive travel in the fluid, exit lymphatics/blood, and survive in the new site. The original mass is called the primary tumor while all subsequent masses are secondary tumors. Cancers can spread almost anywhere once they are in the lymph or blood, but the location of secondary tumor sites is not random. The circulatory anatomy and how accommodating certain tissues are to cancers mean that secondary tumors arise in certain areas most often. Due to these tendencies the most likely location of metastasis can often be predicted. Secondary Tumor: Most likely Primary Tumor: • Liver GI cancers like colon cancer • Brain (gray-white junction) Lung & Breast • Bone (spine) Prostate (blastic), Lung (lytic) & Breast (Both) • Lung Breast Liver Metastasis is most common among cancers that arise in the GI tract (Like colon cancer), which makes sense as the liver receives blood from the GI tract through portal venous system. The Brain Metastasis usually present at the Gray-White matter junction. This is because the width of the vessels changes quickly at this junction and metastatic “emboli” are more likely to lodge here. Metastatic brain cancer generally presents as multiple lesions while a primary brain cancer is usually a single lesion. Lung and Breast are the most common primary site for brain metastasis. Lung Metastasis is most often from breast cancer. Primary bone cancers are rare, but Metastasis to Bone is relatively common. Metastasis to the spine (resulting in low back pain) from the prostate is a common presentation in step 1 questions. Different primary tumors have unique secondary bone cancer characteristics. Lytic lesions are where increased osteoclast activity eats away at the bone and releases calcium (seen as hypercalcemia). Blastic Lesions are where increased osteoblastic activity results in more bone being laid down than normal. 1o Lung Cancer --) osteoLytic 2o Bone Cancer 1o Prostate Cancer --) osteoblastic 2o Bone Cancer 1o Breast Cancer --) Both lytic and blastic 2o Bone Cancer Now that you have finished this video you should check out the next video in the Cell Injury, Cell Death & Cancer sections which covers Cell Cycle (http://www.stomponstep1.com/cell-cycle-interphase-labile-cell-stable-permanent-tissue/)
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Marfan Syndrome, Osteogenesis Imperfecta & Ehlers Danlos, Blue Sclera Hypermobile Joints Stretchy
http://www.stomponstep1.com/marfan-syndrome-osteogenesis-imperfecta-ehlers-danlos/ Collagen is the key component of connective tissue. Triple helix of individual procollagen chains (composed mainly of Proline and Glycine) are created in the fibroblast. Outside of the fibroblast collagen undergoes extensive posttranslational modification such as crosslinking via Hydroxyl-Lysine. Vitamin C is an essential cofactor for the hydroxylation of lysine and deficiencies (Called scurvy) lead to weak collagen. Type I collagen = bones & scar. Abnormal in Osteogenesis Imperfecta Type II Collagen = Cartilage. Type III Collagen = Skin, vessels & granulation tissue. Type IV Collagen = Basement membrane. Abnormal in Alport Syndrome Fibrillin/Elastin = Ligaments & Lungs. Abnormal in Marfan Syndrome & Emphysema Just think that type 1 is the strongest and it gets progressively weaker with each higher number. Bone (1) supports the whole body, cartilage (2) supports small parts of the body, skin (3) is a relatively weak covering, and basement membrane (4) only supports a layer of individual cells. Osteogenesis Imperfecta is a genetic disease that causes a defect in type 1 collagen. It results in many fractures, Blue Sclera, and hearing loss. Ehlers-Danlos is a disease caused by abnormal collagen synthesis. Different types of Ehlers-Danlos effect different types of collagen. The most common presentation includes "stretchy" skin, easy bruising, aneurysms (due to weak vessels) & hypermobile joints. Marfan Syndrome is a disease caused by abnormal Fibrillin (component of elastin) formation. Classically presents as a Tall patient with hypermobile joints. Mitral valve abnormalities and Aortic Dissection are also frequently seen. Now that you are done with this video you should check out the next video in the Biochemistry section which covers Tay Sachs Disease, Gaucher & Neiman Pick (http://www.stomponstep1.com/tay-sachs-disease-gaucher-disease-neiman-pick/) Pictures Used: • This work is a derivative of "Characteristically blue sclerae of patient with osteogenesis imperfecta" by Herbert L. Fred, MD and Hendrik A. van Dijk available at http://commons.wikimedia.org/wiki/File:Characteristically_blue_sclerae_of_patient_with_osteogenesis_imperfecta.jpg under Attribution-Share Alike Creative Commons 3.0 • This work is a derivative of "Ehlers Danlos Syndrome" by Piotr Dołżonek available at http://en.wikipedia.org/wiki/File:Ehlers-Danlos_syndrome4.jpg under Attribution-Share Alike Creative Commons 3.0 • This work is a derivative of "Ehlers Danlos Thumb" by Piotr Dołżonek available at http://en.wikipedia.org/wiki/File:Ehlers-Danlos_thumb.jpg under Attribution-Share Alike Creative Commons 3.0
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Immunodeficiency: DiGeorge Syndrome SCID IgA Deficiency Nitroblue Tetrazolium MPO
http://www.stomponstep1.com/immunodeficiency-digeorge-syndrome-scid-nitroblue-tetrazolium-iga-deficiency-mpo/ SKIP AHEAD: 1:12 – Immunodeficiency Keywords 2:08 – Microbe susceptibilities created by specific deficiencies 5:12 – X-Linked (Bruton’s) Agammaglobinemia 6:43 – Selective IgA Deficiency 7:44 – DiGeorge Syndrome 9:19 – Severe Combines Immunodeficiency (SCID) 10:41 – Chronic Granulomatous Disease (CGD) 13:38 – Myeloperoxidase (MPO) Deficiency “Recurrent” is often the key word when it comes to identifying an immunodeficiency in a question stem. Anybody can get an isolated infection, but if a patient is having frequent infections that is a sign that their immune system is not functioning properly. Immunodeficient people also tend to get infections in various different locations and have infections that persist despite proper treatment. Failure to thrive (an infant that is very small for their age) is also common in immunodeficiency as these disorders are inherited and often appear during infancy. Sometimes question stems will hint at a family history of recurrent infections which points towards the genetic nature of most immunodeficiencies. X-linked (Bruton’s) Agammaglobinemia is a rare mutation in Bruton Tyrosine Kinase which is important for the signal transduction that results in B-Cell maturation. Because maturation is inhibited only immature B-Cell Precursors are present. There is a resulting lack of germinal centers in the lymph node, because that is where B-Cells normally differentiate & proliferate. Very low levels of circulating B-Cells are present as well as almost no antibody of any class. The lack of antibody manifests primarily as a susceptibility to encapsulated bacteria that results in pneumonia, otitis media and cellulitis in early childhood. The defect is not apparent until about 6 months of age as infants are protected for the first 6 months by their mother’s antibodies. It is an X-linked disorder and therefore is much more common in boys. (Selective) IgA Deficiency is a common immune deficiency that results in low levels of IgA and normal levels of all other isotypes. It is inherited, but the cause is not well understood. This disorder is usually asymptomatic and many people don’t even realize they have it. IgA deficiency is often not diagnosed until a patient receives a blood transfusion and has an anaphylactic reaction to IgA in the donated blood. A small percentage of IgA deficient individuals have recurrent mucosal infections (ears, GI, respiratory…) such as Giardia infections. DiGeorge Syndrome is an abnormal development of the 3rd and 4th pharyngeal pouches that causes an absence of the thymus and parathyroid glands. Absence of the thymus means T-Cells cannot mature and absence of the parathyroid glands cause low levels of parathyroid hormone. This congenital hypoparathyroidism leads to low calcium levels and twitching/spasms. The low levels of T-Cells leads to susceptibility for viral and candida infections. The keywords here are absent thymic shadow on chest x-ray. DiGeorge Syndrome is also associated with Truncus Arteriosus and facial abnormalities such as a cleft palate and low set ears. Severe Combined Immunodeficiency (SCID) is a T-Cell deficiency COMBINED with a B-Cell deficiency. This can either be a defect in the IL-2 receptor or dysfunction the Adenosine Deaminase enzyme (adenosine builds up and is toxic to B & T Cells). There is an absent thymic shadow on the chest x-ray similar to DiGeorge, low levels of T-Cells and low levels of immunoglobulin of all isotypes. The text for this video exceeds the maximum allowed description length by youtube, so please visit http://www.stomponstep1.com/immunodeficiency-digeorge-syndrome-scid-nitroblue-tetrazolium-iga-deficiency-mpo/ to see the rest
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Types of Necrosis and Apoptosis Definition, Caspase Programmed Cell death Bleb Fas Ligand Fat
http://www.stomponstep1.com/types-of-necrosis-and-apoptosis-definition-caspase-programmed-cell-death/ Reversible Cellular Injury is harm done to a cell that can be undone once the stress on the cell is removed. Severe or prolonger reversible cellular injury will eventually lead to irreversible cell injury. Irreversible Cellular Injury is cell death via apoptosis or necrosis that is permanent (There are no zombie cells). Each type of cellular damage is characterized by specific cellular changes. Hallmark of Reversible Cell Injury =  ATP & Cellular Swelling Hallmark of Irreversible Cell Injury = Membrane Damage Reversible cellular injury is most often described in the setting of ischemia. There is a decrease in ATP because the cell is not receiving enough blood (oxygen and glucose). This decrease in ATP triggers the cascade that leads to cellular swelling. Apoptosis can be triggered by signals from within the cell (Intrinsic) or outside the cell (Extrinsic). In Intrinsic Apoptosis the cell "decides" to die because it is a normal part of physiology/development, the cell is no longer needed or the cell is too damaged to ever return to normal. Intrinsic Apoptosis signals can include decreased growth factors (genetically programmed), p53 triggers, or the release of triggers like cytochrome C as a result of cellular damage. In Extrinsic Apoptosis the cell is "told" to die by anther cell or the environment. Triggers for extrinsic apoptosis can include signals like Fas ligand on CD8 cytotoxic T cells. No matter what the original signals for apoptosis is eventually Caspace enzymes are activated. These active caspace enzymes then activate enzymes which degrade the cell. Unlike necrosis, apoptosis can sometimes be "good" (physiologic). Problems with apoptosis arise when there is either too much or not enough. There are various different types of necrosis that arise in different situations. • Coagulative = Occurs in most tissues, but is most often seen in heart & kidney ischemia. Think of coagulative as the default type of necrosis that occurs if one of the specific scenarios described below is not present. Histologically cells keep their overall shape (semi-solid) but lose their nuclei resulting in a light pink area without any dark nuclei. On gross specimens it usually appears as a pale area on the organ • Liquefactive = Present in the brain (stroke) & within abscesses (pus). Involves complete enzymatic degradation of the tissue into a liquid • Caseous = Occurs when TB (Ghon Complex) is present or within granulomas. Appearance is a mix of coagulative & liquefactive (Caseus is the Latin term for cheese) • Fibrinoid = Seen within the vessel wall in malignant hypertension & vasculitis. Protein from the blood leaks into the damaged vessel wall making it look pink • Fat Necrosis = Occurs in pancreatic diseases (peripancreatic fat) or trauma to the breast. Calcium from the blood and from lysed cells mixes with the fat in the tissue to create a white soap like substance (Saponification) • Gangrenous = Due to ischemia and/or infection (C. Perfringens). Common in the distal toes. More common in diabetics & smokers (Buerger's Vasculitis). May require amputation Now that you have finished this video you should check out the next video in the Cell Injury, Cell Death & Cancer sections which covers Free Radical Damage (http://www.stomponstep1.com/free-radicals-glutathione-superoxide-nadph-oxidase-n-acetylcysteine/)
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Types of Vaccination, Toxoid Sabin MMR DPT Conjugated Killed Attenuated vaccine salk rabies
Live vaccine, active immunization, killed vaccine, salk, attenuated vaccine, passive immunization, inactivated vaccine, Mmr, oral Polio vaccine, Rabies vaccination, Mumps, mumps, pertussis vaccination, tetanus shot, Toxoid, tetanus immunization, pertussis vaccine, immunologic memory, flu shot, tdap vaccine, chicken pox vaccine, inoculation, whooping cough, varicella zoster, meningitis vaccine, flu vaccine, pneumococcal vaccine, meningococcal vaccine, dtap vaccine dtp dpt shot, measles vaccination, influenza vaccine, rubella vaccination, sabin, conjugated vaccine, botulism Passive Immunization involves delivering preformed antibodies to an individual at risk of infection. You are taking the humoral immunity from one individual or animal and transferring it to another individual. It has an instant effect as the immunoglobulins are preformed and the body doesn’t need to “waste” any time figuring out how to make antibodies of its own that are targeted at the pathogen. However, passive immunity has a short duration of action because it only works for the lifespan of the transferred antibodies. This happens naturally in infants. IgA is transferred from mother to infant through breast milk. IgG is also transferred from the mother to the fetus through the placenta. Through these mechanisms an infant that does not yet have a mature immune system can be protected. Purified antibodies made by horses are also treatment options for tetanus, botulism and rabies. Following an infection with one of these organisms traditional (active) immunization is not an option, because it takes too long and the patient could die before it kicks in. Usually when you are discussing vaccination, you are referring to Active Immunization. This involves helping the host make their own antibodies against a pathogen. It takes longer to start working than passive immunity, but its affects are more potent and can last for many years. The rest of this section will discuss active immunity. Through the activation of adaptive immunity our bodies have immunologic memory which allows us to react faster and with higher potency the second time we see a particular pathogen. This works really well for relatively benign pathogens. For example, you get a cold once and then your immune system will be better at fighting the causative pathogen the next time it is exposed to it. However, this trial by fire method doesn’t work well for infections that have significant morbidity or mortality. We need a prophylactic way to prime the immune system. Vaccinations/immunizations are the way we gain immunologic memory without having an active infection. This involves exposing the patient to an antigen on the pathogen of interest in a way that is not dangerous. This “dress rehearsal” lets the immune system “practice” fighting the pathogen in a situation where the patient isn’t actually infected. After being exposed to the epitope present in the vaccine the patient will react much faster and with greater potency if they ever see the actual pathogen. Live/Attenuated Vaccination involves giving the patient a small amount of the living pathogen you are trying to immunize for. Attenuation is the process of altering a pathogen to diminish its virulence (for example growing the pathogen outside of a human host for many generations so that it adapts to a non-human environment). These attenuated pathogens can grow inside of the patient, but they grow very slowly and have lost their ability to cause disease. These attenuated pathogens look similar enough to the infectious pathogen that the immune response against the vaccine will also work against the real pathogen. The immunologic memory induced can last for decades meaning less booster shots are needed. The immune response is strong because the live pathogen induces humoral, mucosal and cell-mediated immunity. In rare cases the attenuated pathogen can mutate back into the virulent pathogen and cause the very disease you are trying to immunize against. Examples include MMR (Measles, Mumps & Rubella), Sabin (Oral Polio Vaccine), and the Varicella Zoster Vaccine. Killed/Inactivated Vaccination involves giving the patient a pathogen that has been “killed” with heat or formaldehyde. These dead pathogens still have surface antigens that are recognized by the immune system creating a relatively weak, short term humoral immunity. Booster shots are needed more frequently with this type of immunization. Because there is no live pathogen, this type of vaccination cannot cause infection. Examples include the Salk (Injected Polio Vaccine), Rabies Vaccine and Pertussis Vaccine. The Influenza Vaccine either contains full inactivated virus particles or fragments of inactivated virus particles. A Toxoid is a bacterial exotoxin that has been inactivated with heat or formaldehyde.
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Negative & Positive Predictive Value Equation & Calculation
http://www.stomponstep1.com/negative-positive-predictive-value-equation-calculation/ PPV & NPV are used to interpret test results once you have them. For example, if your patient just received a positive HIV test result you would use the PPV to evaluate what that test result means to your patient (what the percentage is that this person actually has HIV). It is important to remember that the PPV & NPV change as prevalence changes. This makes sense, because if the prevalence of a disease increases you are going to automatically get more TPs and less TNs just based on the fact that more people have the disease. Both measurements are given as a percentage ranging from 0% to 100%. Positive Predictive Value (PPV) is the percentage chance that a positive test result is a true positive or the percentage chance that a patient with a positive result actually has the disease. It is used when determining how to proceed after a patient gets a positive result. PPV increases with increases in prevalence. PPV decreases with decreases in prevalence. Negative Predictive Value (NPV) is the Percentage chance that a negative test result is a true negative or the percentage chance that a patient with a negative result is actually disease free. It is used when determining how to proceed after a patient gets a negative result. NPV decreases with an increase in prevalence. NPV increases with a decrease in prevalence. This is how I remember the formulas for Sen, Spec, PPV & NPV. First I think that the top value (numerator) is always a positive value and the bottom "left" value always matches the top value. The value of the bottom "right" is always false. Then I think that the term with positive in the name (PPV) has "all positives" & the term with negative in the name (NPV) has "all negatives." Next I think of Sen looking sort of like PPV & Spec looking sort of like NPV. You just swap out the value on the bottom "right" value. To remember which set of values are affected by prevalence I think that increasing Prevalence increases the formula with the most Ps in it. That lets you know PPV is directly proportional with prevalence and it is intuitive that NPV is the opposite because those two are an obvious pair. So in my head I'm seeing something like this. Occasionally, you will get these types of questions in graphical form. These questions with a picture are much less common than questions that test the definition of a term or ask you to make a calculation based on a two-by-two table. However, I am going to spend some time on this question format as I believe it helps to solidify the overall concept. These questions will have a graph that looks something like the above picture. That can be a little confusing to start with so let's break it down piece by piece. Now that you are done with this video you should check out the next video in the Biostatistics & Epidemiology section which covers the definitions & calculations of Prevalence & Incidence (http://www.stomponstep1.com/incidence-prevalence-definition-case-fatality-rate/)
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Neurofibromatosis, Tuberous Sclerosis & Von Hippel Lindau, Acoustic Neuroma Lisch Nodule NF1 NF2
ERRATA: Less than half of all VHL is caused by a deletion of the VHL gene. There are a number of different mutations to the gene that cause the disorder. Neurocutaneous Syndromes are a group of rare genetic disorders that affect multiple organ systems including the CNS, skin, visual pathway & auditory system. Many benign tumors develop. All of the ones we will cover are autosomal dominant. Neurofibromatosis: • Neurofibromas are tumors of peripheral nerves. They are benign but can cause problems by compressing nearby structures. They usually present just beneath the skin as many rubbery skin colored growths • Café-au-lait spots are small light brown macules on the skin. Similar to a birthmark but if there are many it is suggestive of neurofibromatosis • Bilateral vestibular schwannomas (bilateral acoustic neuroma) benign tumor of the vestibulocochlear nerve (Cranial nerve 8) that can compress nearby structures and lead to hearing loss • Pigmented Iris Hamartomas (Lisch Nodule) which presents as many small areas of pigmentation on the iris (colored part of the eye) • Other CNS tumors Tuberous Sclerosis: • Facial Angiofibromas (adenoma sebaceum) • Brain/Cortical Hamartomas called Tubers for which the disease gets its names • Subependymal Nodules in the ventricle • Renal Angiomyolipomas are tumors made up of vessels, fat and smooth muscle • Cardiac Rhabdomyomas • Ash Leaf Spots are hypopigmented areas of the skin • Seizures • Mental Retardation Von Hippel-Lindau Disease: deletion of the VHL gene • Cerebellar and/or Retinal Hemangioblastomas (tumors of capillaries) • Renal Cell Carcinoma • Cystic lesions of various structures throughout the body Now that you are done with this video you should check out the next video in the Genetics sections which coversTrinucleotide Repeat Expansion, Trisomy 21 & Translocations(http://www.stomponstep1.com/trinucleotide-repeat-expansion-trisomy-21-translocations/) Pictures Used (In Order of Appearance) • "Neurofibromatosis" by Almazi available at http://en.wikipedia.org/wiki/File:Neurofibromatosis.jpg by Public Domain • "NF-1-Tache cafe-au-lait" by Accrochoc available at http://en.wikipedia.org/wiki/File:NF-1-Tache_cafe-au-lait.jpg by Creative Commons 3.0 Attribution-Share Alike • "Lisch Nodule" by National Eye Institute available at http://en.wikipedia.org/wiki/File:Lisch_nodules.gif • By Public Domain • Derivative of "Patient with facial angiofibromas caused by tuberous sclerosis" by Herbert L. Fred, MD and Hendrik A. van Dijk Available at http://en.wikipedia.org/wiki/File:Patient_with_facial_angiofibromas_caused_by_tuberous_sclerosis.jpg by Creative Commons 3.0 Attribution-Share Alike
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Cell Cycle, Interphase, Labile Cell Stable Permanent Tissue Paclitaxel G1 G0 G2 phase
http://www.stomponstep1.com/cell-cycle-interphase-labile-cell-stable-permanent-tissue/ The cell cycle is the process of cell replication where two daughter cells are created from one parent cell. The cell cycle is made up of interphase & mitosis. Mitosis is the phase of actual cell splitting (duplication), while Interphase is made up of the G0, G1, S, and G2 phases which prepare the cell for mitosis. The S phase involves “Synthesizing” new DNA and doubling the amount of DNA present so there is enough for both daughter cells. G stands for “Gap” as these are the gaps in time between mitosis and the S Phase. Cells in G0 are no longer in the cell cycle. Cells in G0 are “resting” & no longer actively going through the phases of the cell cycle. Some tissue can easily transition between G0 & G1 with the right signals while other cell types are “stuck” in G0. Anti-metabolites chemotherapy drugs like 5-flourouracil & sulfa drugs (antibiotic) inhibit DNA synthesis and stall the S phase of the cell cycle. Chemotherapy Paclitaxel inhibits microtubule action involved in Mitosis. Therefore, cells being treated with this medication are stuck in M phase. Permanent tissues are “stuck” in the G0 phase and cannot undergo further mitosis. Permanent tissues include muscle (cardiac & skeletal) and the CNS. These tissues can only undergo hypertrophy (not hyperplasia) to deal with increased stress and form fibrous nonfunctioning scars during the healing process. Stable tissues are those that primarily reside in the G0 phase, but given the right signals can reenter the cell cycle. For example, lymphocytes are most often in a resting period, but during infection they are triggered to divide. Liver cells are another example of a stable tissue that can undergo replication following injury to the organ to facilitate healing. Labile Tissues are cells which are constantly replicating with no time in the G0 phase. These cells act as the stem cells for tissues such as the bone marrow and skin. Picture Used: Derivative of “Major events in mitosis” by NIH available at http://commons.wikimedia.org/wiki/File:Major_events_in_mitosis.svg by Public Domain Now that you have finished this video you should check out the next video in the Cell Injury, Cell Death & Cancer sections which covers Oncogenes & Tumor Suppressors (http://www.stomponstep1.com/oncogenes-tumor-suppressor-genes-bax-p53-myc-bcl-2-brca/)
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Amyloidosis, Apple Green Birefringence, Cardiac amyloidosis, Transthyretin congo red stain
http://www.stomponstep1.com/amyloidosis-cardiac-amyloidosis-transthyretin-congo-red-stain/ Amyloidosis is a collection of diseases that result from misfolded proteins becoming insoluble and aggregating in the extracellular matrix. These misfolded proteins generally form beta pleated sheets. Biopsy specimens of tissue with amyloidosis fluoresce with apple-green birefringence when stained with Congo Red and placed under polarize light. AL Amyloidosis is a systemic form of amyloidosis of light chain immunoglobulins. Primary amyloidosis. Plasma cell disorders like Multiple Myeloma create an excess of the light chain portion of antibodies which then aggregate. AA Amyloidosis is a systemic form of amyloidosis of Acute phase reactant called Serum Amyloid A (SAA). Secondary amyloidosis. Some other type of chronic inflammatory disease causes an increase in the number of acute phase reactants. Hereditary or Familial Amyloidosis is a form of amyloidosis made up of Mutated transthyretin (TTR) that localized to the heart and brain. A genetic mutation creates a protein related to albumin that is predisposed to forming amyloid. It is the only type of amyloidosis that is hereditary Senile Cardiac Amyloidosis is made up of Normal transthyretin (TTR) and localized to the heart. Asymptomatic accumulation of TTR associated with aging. Pancreatic Amyloidosis in diabetes mellitus is made up of Amylin and localized to Pancreas. Increased insulin creation leads to an increase in Amylin byproduct which builds up in the islets of the pancreas Alzheimer’s Amyloidosis is made up of Beta Amyloid Protein. For unknown reasons Amyloid precursor protein (APP) is cleaved to create a fragment know as Beta Amyloid Protein that aggregates in the brain Now that you have finished this video you should check out the next video in the Cell Injury, Cell Death & Cancer sections which covers Dysplasia & the Difference Between Benign & Malignant (http://www.stomponstep1.com/dysplasia-difference-between-benign-and-malignant/)
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USMLE Biochemistry High Yield List, Biochem High Yield Rating
http://www.stomponstep1.com/usmle-biochemistry-high-yield-rating-biochem-for-step-1/ Biochem Material Listed By High Yield Rating: 8 – Kartagners Syndrome 7 – Tay-Sachs) 5 – I Cell Disease 4 – Osteogenesis Imperfecta 3 – Methanol Poisoning 3 – PKU 3 – Cytoskeleton Basics 3 – Marfan Synrome 3 – Collagen and Elastin Basics 2 – Alcohol Metabolism 2 – Fructose Disorder 2 – Galactose Disorder 2 – Chediak Higashi 2 – Ehlers Danlos 2 – Gaucher 2 – Von Gierkes 2 – McCardles 1 – Nieman-Pick 1 – Sorbitol 1 – OTC Deficiency 1 – Hurler 1 – Fabry 1 – Maple Syrup Urine Disease “No Yield” (HYR of 0): • The Biochemical Structures of Almost Anything • Ammonia Transport • Specifics about Lipid Transport • Hartnup Disease • Cori Disease • Pompe Disease • Cystinuria • Protein structure • Specific functions of most organelles • Specifics about cilia structure • Types of intermediate filaments & associated immunohistochemical stains • Cellular trafficking signals other than Mannose-6-Phosphate • Peroxisome & Proteasome • Smooth vs. rough endoplasmic reticulum • Cytoskeleton assembly and disassembly • Henderson Hasselbalch Eqn • Chemical Bonds • Thermodynamics • Michaelis-Menton Eqn • Specifics about most Laboratory Techniques
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Confidence Interval Interpretation. 95% Confidence Interval 90% 99%
CORRECTION: Although my mistake is beyond the scope of the Step 1 exam, the interpretation of Confidence Interval that I used in the video is incorrect & a bit oversimplified. I stated that for an individual study there is a 95% chance that the true value lies within the 95% CI. However, confidence interval is a type of frequentist inference and the interpretation I gave in the video is really better suited for interpreting statistics of Bayesian Inference (Again please don’t feel like you need to know these terms for the exam). What I should have said is something like “if 100 similarly designed studies use a 95% confidence interval then 95 of these intervals will contain the true value and 5 will not. For more info on this misconception click here https://en.wikipedia.org/wiki/Bayesian_inference A Confidence Interval (CI) is the range of values the true value in the population is expected to fall within based on the study results. The results we receive in any study do not perfectly mirror the overall population and the confidence interval lets us get a better idea of what the results in the overall population might be. The confidence interval is based on a certain level of confidence. Don't get this confused with the value of the sample population. If the measured BMI in 100 people in your study population and the mean is 25 than you are very confident that the actual mean BMI in that group is 25. Confidence interval only comes into play when you try to extrapolate your study results to other situations (like to the population overall). If you have a 95% confidence interval (which is most common) that means there is a 95% chance that the true value lies somewhere in the confidence interval. You can also alter the width of the confidence interval by selecting a different percentage of confidence. 90% & 99% are also commonly used. A 99% confidence interval is wider (has more values) than a 95% confidence interval & 90% confidence interval is the most narrow. The width of the CI changes with changes in sample size. The width of the confidence interval is larger with small sample sizes. You don't have enough data to get a clear picture of what is going on so your range of possible values is wider. Imagine your study on a group of 10 individuals shows an average shoe size of 9. If based on the results you are 95% sure that the actual average shoe size for the entire population is somewhere in between 6 and 12, then the 95% CI is 6-12. Based just on your results you don't really know what the average in the population is, because your study population is a very small sliver of the overall population. Now if you repeat the study with 10,000 individuals and you get an average shoe size of 9 the confidence interval is going to be smaller (something like 8.8 to 9.3). Here you have a much larger sample size and therefore your results give you a much clearer idea of what is going on with the entire population. Therefore, your 95% CI shrinks. The width of the confidence interval decreases with an increasing sample size (n). This is sort of like the standard deviation decreasing with an increased sample size. Confidence intervals are often applied to RR & OR. For example, the odds ratio might be 1.2, but you aren't sure how much of an impact chance had on determining that value. Therefore, instead of just reporting the value of 1.2 you also report a range of values where the true value in the population is likely to lie. So we would report something like the odds ratio is 1.2 and we are 95% confident that the true value within the overall population is somewhere between .9 and 1.5. You can use the confidence interval to determine statistical significance similar to how you use the p-Value. If the 95% confidence interval crosses the line of no difference that is the same things as saying there is a p-value of greater than 5%. This is intuitive because if the confidence interval includes the value of no difference then there is a reasonable chance that there is no difference between the groups. If the confidence interval does not cross the line of no difference than the observed difference is statistically significant, because you know it is highly unlikely that the two groups are the same. For both relative risk (RR) and odds ratio (OR), the "line of no difference" is 1. So an RR or OR of 1 means there is no difference between the two groups being compared with respect to what you are measuring. This is because RR and OR are ratios and a value divided by itself is 1. If the 95% confidence interval of the RR or OR includes the value 1, that means it is possible the true value is 1 and there is no difference between groups. If that is the case, we say the null hypothesis cannot be rejected or that there is no statistically significant difference shown. This is the same thing as saying the p-value is greater than .05.
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Antidepressants: SSRI, SNRI & Tricyclic Antidepressatns. Citalopram Prozac Amitriptyline
SKIP AHEAD: 2:20 – Mechanism of Antidepressants 3:16 – General Principles of Antidepressant Use: Suicide, Mania & Serotonin Syndrome 7:51 – Tricyclic Antidepressants 9:10 – TCA Side Effects 10:40 – SSRIs 11:47 – SSRI Side Effects 13:01 - SNRIs 13:33 – Atypicals: Bupropion, Mirtazapine & Trazadone Antidepressant mechanism - One hypothesis for the pathophysiology of depression is that it is due to low levels of monoamine neurotransmitters (mainly serotonin, norepinephrine and dopamine). That is why antidepressants aim to increase the levels of these neurotransmitters in the synaptic cleft. They do this by slowing the reuptake of the neurotransmitters so that they stay in the cleft longer and interact with post synaptic receptors more often. The first drugs in this group were non-specific and increased all of the monoamines, which lead to lots of side effects and safety issues related to toxicity. Newer antidepressants are more selective and mostly only effect 1 or 2 monoamines. General principles: Unfortunately, antidepressants take at least a month to start working. Good patient education about the delayed onset of effect and close monitoring of the patient during this initial period is extremely important. Patients can become hopeless if they expect the drug to start working right away. This may be one reason why antidepressants are associated with suicide, especially in patients 25 years old and younger. Another proposed mechanism is that a depressed person may have the energy to carry out their suicide once the medications start to work. There is now a black box warning for suicide on antidepressants. Some psychiatrists argue that they don’t actually see this association with suicide in clinical practice, and that the thing that really increases the risk for suicide is not treating a depressed person with the proper medications. However, it is still standard practice to have a close follow up with patients you are starting on antidepressants. Usually this will involve a follow up visit about 2 weeks after the medication is started. At this visit the drug will not have started working yet so you can’t evaluate efficacy, but you can monitor for side effects like suicidality. Another serious side effect you have to be on the lookout for soon after initiating treatment is mania. If a bipolar individual is incorrectly diagnosed as having depression, an antidepressant may induce a manic episode. Another very serious side effect that has to be considered for antidepressants is Serotonin Syndrome. This usually occurs when you combined multiple antidepressants at the same time or combine an antidepressant with another medication that increases serotonin such as dextromethorphan or an opioid. It presents with tremor, diaphoresis, tachycardia, flushing and hypertension. If not corrected it can progress to delirium, AMS and death. Treatment includes medication cessation and the use of Cyproheptadine (a serotonin antagonist). In order to prevent this from happening you should have about a month “Wash Out” period when you are switching between antidepressants. So you taper the 1st medication down and then stop it, give the patient at least a month with no antidepressant and then start adding the new medication slowly. Most side effects begin immediately after starting the medication, but diminish over the course of a month. This is another reason why patient compliance is poor with these meds. It makes them sick and the drug doesn’t work during the first few weeks. However, if they can stick with it the medications will likely start working and the side effects will diminish over time. A principle that applies to all of the antidepressants is “start low and go slow.” This means that you start with a lower dose and slowly increase it in order to decrease side effects and increase patient compliance. The dose you start the patient on may not even be at a therapeutic level, but every month or so you can increase the dose a bit. The text for this video is too long and exceeds the max allowed character length for Youtube. You can read the rest here http://www.stomponstep1.com/antidepressants-ssri-snri-tricyclic-antidepressants-citalopram-prozac-amitriptyline/ Pictures Used: • “SynapseSchematic” by Thomas Splettstoesser available at https://commons.wikimedia.org/wiki/File:SynapseSchematic_unlabeled.svg via Creative Commons 4.0 Attribution-Share Alike • “Zoloft Bottles” by Ragesoss available at https://commons.wikimedia.org/wiki/File:Zoloft_bottles.jpg via Public Domain
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Eating Disorders: Anorexia Nervosa, Bulimia & Binge Eating Disorder
http://www.stomponstep1.com/eating-disorders-anorexia-nervosa-bulimia-binge-eating-disorder/ SKIP AHEAD: 0:22 – Intro to Eating Disorders 1:38 – Bulimia Nervosa & Binge Eating Disorder 2:49 – Anorexia Nervosa Eating Disorders are a collection of psychiatric conditions that involve abnormal eating habits associated with physical and/or psychological problems. There are many causes of abnormal eating habits, but if the situation is better explained by another medical problem it is not classified as an eating disorder. For example, a depressed patient who loses their appetite has an abnormal level of food intake, but does not have an eating disorder. Our discussion will focus on Anorexia Nervosa and Bulimia Nervosa which have many similarities. In both cases patients are preoccupied with food, their physical appearance and how much they weigh. They may have low self-esteem due to their distorted self-image. These disorders are significantly more common in young females. The treatment for both disorders primarily focuses on SSRI antidepressants and various types of therapy. There is a significant amount of overlap between the presentation of Bulimia and Anorexia Nervosa. The key distinguishing factor is the patient’s body mass index (BMI), which is very low in Anorexia Nervosa and normal to mildly elevated in Bulimia Nervosa. Despite popular belief, you cannot use the presence of purging activities alone to distinguish the 2 disorders. Patients with AN can use things like laxatives and intentional vomiting just like Bulimia. Bulimia Nervosa = Periods of overeating (AKA binging) followed by compensatory activities (AKA purging) such as intentional vomiting, excessive exercising or inappropriate laxatives use. Patients feel as if they lose control during periods of binge eating. BMI is within normal ranges or slightly high (greater than 20). Those that vomit may have alkalosis (due to loss of stomach acid), enlarged parotid glands, losses of enamel on teeth, or esophageal pathology. Those that use laxatives frequently may have acidosis due to the loss of bicarb. Although this warning is debated by some, current guidelines suggest not using Bupropion, an antidepressant, in Bulimic patients as they may have an increased risk for seizures as a side effect. Binge Eating Disorder was recently added the DSM so it is unlikely to show up on Step 1. It has similar binging behavior to Bulimia, but there is no purging and the patients don’t necessarily have body image issues. Anorexia Nervosa = eating very little and/or purging as a result of a distorted body image. These patients may feel like they are overweight even if they are very thin. They have low BMIs, less than17, and significant weight loss. Severe cases require hospitalization to correct starvation and the metabolic consequences. When a female’s body fat percentage gets very low the pulsatile release of GnRH from the hypothalamus stops and causes Amenorrhea. It’s like the endocrine system is saying “I can’t have a baby right now. I’m not even getting enough food for just me right now.” Chronic Anorexia Nervosa can lead to osteoporosis due to the low levels of estrogen. Can look similar to hypothyroidism with fatigue and changes to skin/hair, but the key difference is hypothyroidism has weight gain. * The term anorexia is used often in Step 1 to describe weight loss and a lack of appetite, but that is different than anorexia nervosa which is sometimes abbreviated as anorexia. Anorexia can be used to explain a symptom of any disease/illness or a side effect of a treatment. It is not psychological in origin. In fact patients with Anorexia Nervosa do not have Anorexia, because they usually still have an appetite and feel hungry. The presence of an appetite can be used to differentiate Anorexia Nervosa from things like depression.
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Fungal Infections and Antifungal Treatments Ringworm Candida Aspergillus Histoplasmosis
SKIP AHEAD: 0:32 – Intro to Fungi 2:17 – Systemic vs. Opportunistic Mycoses 4:52 – Coccidioidomycosis 5:41 – Histoplasmosis 6:23 – Blastomycosis 6:54 – Geographic Map of Systemic Fungi 7:26 – Cryptococcus 8:17 - Aspergillus 9:30 – PCP and Pneumocystis 10:06 - Zygomycosis (Mucormycosis & Rhizopus) 11:06 – Tineae (Athletes Foot, Ring worm, Tinea Versicolor …) 12:50 – Candida 14:07 – Sporothrix 14:29 – Azoles (Diflucan, Flucanazole, ketoconazole…) 15:20 – Amphotericin B & Nystatin 15:58 - Capsofungin & Micanofungin For the text and pictures in this video please go to my website http://www.stomponstep1.com/fungal-infections-antifungal-treatments-ringworm-candida-aspergillus-histoplasmosis/ Pictures Used: “Coccidioidomycosis_Spherule” by CDC available at https://commons.wikimedia.org/wiki/File:Coccidioidomycosis_Spherule.jpg via Public Domain ” Histoplasmosis Capsulatum” by CDC available at https://en.wikipedia.org/wiki/Histoplasmosis#/media/File:Histoplasmosis_capsulatum.jpg via Public Domain “Blastomyces dermatitidis” by CDC available at https://en.wikipedia.org/wiki/Blastomycosis#/media/File:Blastomyces_dermatitidis_GMS.jpeg via Public Domain Derivative of “Blastomycosis cropped” by Joel Mills available at https://commons.wikimedia.org/wiki/File:Blastomycosis_cropped.JPG via Creative Commons 3.0 Attribution-Share Alike Derivative of “Cryptococcus neoformans using a light India ink staining” by CDC available at https://commons.wikimedia.org/wiki/File:Cryptococcus_neoformans_using_a_light_India_ink_staining_preparation_PHIL_3771_lores.jpg via Public Domain Derivative of “Cryptoccocus Gram Film” by Graham Beards available at https://commons.wikimedia.org/wiki/File:Cryptococcus_Gram_film.jpg via Creative Commons 3.0 Attribution Share Alike Derivative of “Aspergilloma complicating tuberculosis 2” by Yale Rosen available at https://commons.wikimedia.org/wiki/File:Aspergilloma_complicating_tuberculosis_2.jpg via Creative Commons 2.0 Attribution-Share Alike “Aspergillosis, angioinvasive, intravascular” by Yale Rosen available at https://www.flickr.com/photos/pulmonary_pathology/5390967599 via Creative Commons 2.0 Attribution-Share Alike Derivative of “Zygomycosis/mucormycosis” by Yale Rosen available at https://www.flickr.com/photos/pulmonary_pathology/5390897069 via Creative Commons 2.0 Atribution Share Alike Derivative of “Zygomycosis, Mucormycosis 1” by Yale Rosen available at https://commons.wikimedia.org/wiki/File:Zygomycosis,_mucormycosis_1.jpg via Creative Commons 2.0 Attribution-Share Alike Derivative of “Zygomycosis” by Nephron available at https://commons.wikimedia.org/wiki/File:Zygomycosis.jpg via Creative Commons 3.0 Attribution-Share Alike “Ringworm on the arm, or tinea corporis due to Trichophyton mentagrophytes” by CDC available at https://commons.wikimedia.org/wiki/File:Ringworm_on_the_arm,_or_tinea_corporis_due_to_Trichophyton_mentagrophytes_PHIL_2938_lores.jpg via Public Domain “Teigne - Tinea capitis” by Grook Da Oger available at https://commons.wikimedia.org/wiki/File:Teigne_-_Tinea_capitis.jpg via Creative Commons 4.0 International Attribution Share Alike License “Onychomycosis due to Trychophyton rubrum, right and left great toe” by CDC available at https://commons.wikimedia.org/wiki/File:Onychomycosis_due_to_Trychophyton_rubrum,_right_and_left_great_toe_PHIL_579_lores.jpg via Public Domain “Tinea versicolor1” by Sarahrosenau available at https://commons.wikimedia.org/wiki/File:Tinea_versicolor1.jpg via Creative Commons 2.0 Attribution-Share Alike “Candida albicans” by Y Tambe available at https://commons.wikimedia.org/wiki/File:Candida_albicans.jpg via Creative Commons 3.0 Unported Attribution-Share Alike License “Human tongue infected with oral candidiasis” by James Heilman available at https://commons.wikimedia.org/wiki/File:Human_tongue_infected_with_oral_candidiasis.jpg via Creative Commons 3.0 Unported Attribution-Share Alike
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Viral Hepatitis: Hepatitis A, Hepatitis B, Hepatitis C, HBsAg HBeAg Vaccine HCV HBV HBsAb
SKIP AHEAD: 0:29 – Introduction to Hepatitis 2:09 – Viral Hepatitis Transmission 3:28 – Symptoms & acute vs. chronic 5:35 - Laboratory Tests and Councilman Bodies 7:03 – Hep B Serology (HBsAg & Anti-HBs) 14:39 – Treatment of Viral Hepatitis 15:27 - Vaccines For the text and pictures from this video please go here http://www.stomponstep1.com/viral-hepatitis-hepatitis-a-hepatitis-b-hepatitis-c-hbsag-hbeag-vaccine-hcv-hbv-hbsab/ Picture Used: “Ballooning degeneration high mag cropped” by Nephron available at https://commons.wikimedia.org/wiki/File:Ballooning_degeneration_high_mag_cropped.jpg via Creative Commons 3.0 Unported Attribution Share Alike
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Ethics & Legal for USMLE Step 1
http://www.stomponstep1.com/ethical-principles-confidentiality-capacity-medical-ethics-beneficence-bioethics-law/ Ethical Principles • Autonomy = respect patient's decisions about their own health • Non-maleficence = do no harm. Can still take calculated risk if potential benefits outweigh the potential risks • Beneficence = promote patients best interests • Justice = distribute medical benefits fairly and do not discriminate against any particular group Capacity/Competence Capacity is a person's mental ability to make informed decisions about their own health. A capacitated individual has to be able to understand the medical information given to them, retain that information, use the information given to them to make an informed decision and communicate that decision to their providers. The decision they make must be in line with their previous beliefs and not be the result of psychiatric symptoms (hallucinations of delusions). Certain psychiatric disorders, neurologic diseases, lack of consciousness, developmental disorders, age, severe pain, drugs or alcohol can all temporarily or permanently prevent someone from being capacitated. A couple clinical indicators or concern by a family member is not enough to deem a patient incompetent. A thorough examination of the patient must be performed before a patient is deemed incompetent. Patients are assumed to be competent until there is substantial proof showing otherwise. An individual who lacks capacity cannot give informed consent. Capacity is similar to the legal term Competence. When a lack of capacity is involved, the requirement for informed consent is not removed. In these situations the responsibility of informed consent is transferred to a family member, friend or social worker. The physician should not be making these decisions for patient. Deciding which person will speak for the incapacitated patient follows a set of criteria. The first option is the patient speaking for themselves through an advanced directive or will. In this case the patient decides ahead of time what types of treatment they will want in certain scenarios. However, there are an infinite number of different scenarios that cannot all be outlined by the patient so a person is also needed to speak for the patient. The first person chosen to fill this role should be an individual identified by the patient (before they became incapacitated) through medical power of attorney. This person (called a proxy or surrogate) is identified by the patient ahead of time. If no such person has been identified by the patient a family member such as a spouse receives the responsibility. Whoever ends up being selected to speak for the patient should not be choosing what they want for the patient. They should be trying to relay what they think the patient would want if they could speak for themselves. Minors and Capacity Minors (patients under the age of 18) are considered to not have the capacity to make medical decisions. This means that the patient's parents give consent for medical treatment instead of the patient and that certain rules of confidentiality don't apply to the parents. Emancipation is the process in which a minor obtains the right to make their own medical decisions. For medical purposes a minor is emancipated if they file to become officially emancipated, live on their own, are married, have children of their own or are pregnant. In these cases a minor is treated as if they were an adult. There are exceptions to the rule where minors have the right to confidentiality and do not need consent from a parent. The way I remember these exceptions is the phrase "sex, drugs and rock n' roll." Sex stands for contraception, treatment of STDs, treatment of pregnancy or just the fact that they are having sex which might be found during the history. Drugs stand for knowledge of alcohol or drug related activities as well as medical situations that may arise as a result of these substances. Rock N' Roll stands for emergency situation in which a parent may not be able to be contacted in time to provide care. Abortion is a situation where informed consent and confidentiality for minors is handled a bit differently. Some states require parent's permission for an abortion (informed consent must be obtained from the parent) and other states only require parental notification (confidentiality is broken and parents are notified but they do not need to consent).
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DNA Replication, Transcription, Translation, DNA Polymerase III, Topoisomerase, RNA Polymerase
http://www.stomponstep1.com/dna-replication-transcription-translation/ DNA Replication is the process of making 2 identical copies of DNA from one original DNA copy. This process is semi-conservative, meaning that each new copy ends up with one of the original strands of DNA. Essentially the DNA "unzips" and each of the original strands acts as a template for the new strands. DNA is synthesized in a 5'--)3' direction during the S phase of the cell cycle • DNA Polymerase is the enzyme responsible for DNA replication. It synthesizes new DNA strands in a 5'--)3' direction, but also has 3'--)5' exonuclease proof reading capabilities that removes improper base pairs. In Prokaryotes DNA Pol I mainly handles proofreading & replacement of RNA primer, while DNA Pol III synthesizes most of the DNA. • Topoisomerase is the enzyme that creates single strand breaks in the DNA's (Break phosphodiester bond) and allows free rotation to relieve supercoils created by replication/transcription process. Bacterial topoisomerase is the target of the antibiotic Fluoroquinolone (Cipro). An auto-antibody targeted at topoisomerase is common in Scleroderma. Transcription is when template DNA strand is converted to complementary coding RNA to begin gene expression. The RNA is very similar to DNA, except that it has Uracil (U) in place of Thymine (T) and it is single stranded. RNA is synthesized in a 5' --) 3' direction as the RNA Polymerase moves along the DNA in a 3'--) 5' Direction. • RNA Polymerase is the enzyme responsible for the conversion of DNA to RNA (transcription). In Eukaryotes RNA Pol I makes Ribosomal RNA (rRNA), II makes Messenger RNA (mRNA) & III makes tRNA. Post-Transcriptional Modification (RNA Processing) is the process of converting immature RNA to mature RNA that is ready to be translated. A 5' Cap of a modified guanine is added to the end of the RNA to help the ribosome recognize the RNA. A Poly A Tail is added to the 3' end. It is a AAUAAA sequence that is added without following a complementary DNA sequence and helps prevent degradation of the RNA. The splicesome also removes introns and joins exons. This splicing can be carried out multiple different ways creating different proteins from a single gene. Translation is the process by which a RNA sequence is converted into a set of amino acids (AKA a protein). Each amino acid is coded for by a 3 nucleotide sequence called a codon. The tRNA, which carries the amino acid, has a complimentary anti-codon which recognizes the codon. The mRNA is read in a 5'--)3' direction. Translation begins at the start codon (AUG) and ends at a stop codon. Now that you are done with this video you should check out the next video in the Genetics section which covers Epigenetics, Histone Modification, Prader-Willi & Angelman Syndrome. Picture Used: "Peptide Syn" by Boumphreyfr Available at http://en.wikipedia.org/wiki/File:Peptide_syn.png under Creative Commons 3.0 Share-Alike
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Vaginitis: Candida, BV, Trichomoniasis  - Wet Mount Whiff Test Vaginal pH Trich Albicans gardnerella
SKIP AHEAD: 1:18 – Wet Prep (Wet Mount) 2:54 – Vaginal pH 3:48 – Bacterial Vaginosis (BV) 6:01 – Vaginal Candida 8:01 – Trichomoniasis (Trich) For the text and pictures from this video please visit http://www.stomponstep1.com/vaginitis-candida-bv-trichomoniasis-wet-mount-whiff-test-vaginal-ph-trich-albicans-gardnerella/ Pictures Used: “ff clue cell” by isis325 available at https://www.flickr.com/photos/92708411@N07/8579634600 via Creative Commons Attribution 2.0 Generic License Derivative of “Clue cells – Pap test — very high mag” by Nephron available athttps://commons.wikimedia.org/wiki/File:Clue_cells_-_Pap_test_–_very_high_mag.jpg via Creative Commons Attribution-Share Alike 3.0 Unported license “Clue cells – CDC PHIL 3720” by CDC available at via https://commons.wikimedia.org/wiki/File:Clue_cells_-_CDC_PHIL_3720.jpg Public Domain “Candida albicans” by Y Tambe available at https://commons.wikimedia.org/wiki/File:Candida_albicans.jpgvia Creative Commons 3.0 Unported Attribution-Share Alike License Derivative of “Trichomas vaginalis oil best2” by schmidty4112 available athttps://www.flickr.com/photos/77092855@N02/6912948713 via Creative Commons 2.0 Generic Attribution License “Trichomonas vaginalis phase contrast microscopy” by Dr Graham Beards available athttps://commons.wikimedia.org/wiki/File:Trichomonas_vaginalis_phase_contrast_microscopy.jpg via Creative Commons 3.0 Unported Attribution Share Alike License “Lips Mouth Smile Teeth Happy Laugh Red White” available at http://pixabay.com/en/lips-mouth-smile-teeth-happy-156991/ via Public Domain
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