20 Matching Annotations
  1. Jul 2020
    1. du jour

      French, literally "of the day"

    2. 40 different V segments, about 25 different D segments, 6 different J segments, and so on.

      40x20x6x10 = just less than 50,000...not anywhere close to the 100million we need.

    3. Edward Jenner

      He saw a large enough population of patients to notice that milk maids had a different but similar disease and that they almost never got the disease.

    1. The bapineuzumab trials seem to have been more of an unqualified failure. This antibody drug targets the amyloid-[besa] plaques, in hopes of awakening the immune system to clear them from the brain. But two trials in approximately 2,400 patients failed to show any benefit compared with a placebo,

      Removing A-beta by activating immune cells has no impact compared to placebo.

    2. The drug is meant to recognize and block amyloid-[besa] before it forms plaques. In patients with mild and moderate forms of disease, however, solanezumab failed to meet its main goals of slowing the decline in memory and other cognitive measures, or in the ability to perform tasks such as eating and maintaining personal care.

      Blocking A-beta formation does not appear to slow memory decline.

    1. Whereas viral, bacterial, and autoimmune diseases of the CNS can resemble their extraneural counterparts morphologically, the concept of “neuroinflammation” has gradually expanded to also describe diseases that display none of Celsus’ cardinal signs, that do not attract conventional inflammatory cells, and that most neuropathologists would classify as degenerative rather than inflammatory.

      Neuronal Inflammation does not resemble conventional inflammation.

  2. Mar 2020
    1. In the absence of insulin, the entry of glucose into skeletal, cardiac, and smooth muscle and other tissues is decreased (Figure 24–8). Glucose uptake by the liver is also reduced, but the effect is indirect. Intestinal absorption of glucose is unaffected, as is its reabsorption from the urine by the cells of the proximal tubules of the kidneys. Glucose uptake by most of the brain and the red blood cells is also normal.

      Q: Is this because it's not an issue with taking in glucose, it's an issue with letting go of all the glucose you have saved up?

      It's like the difference between generational wealth and binge/purge wealth. On a metabolic level. Oof.

    2. Disordered plasma glucose homeostasis in insulin deficiency. The heavy arrows indicate reactions that are accentuated. The rectangles across arrows indicate reactions that are blocked.

      At first I was like, why is this causing an issue with the brain, doesn't the brain like having glucose and having ketones on top? That sounds great! But the issue is when there is no longer food, you did not store anything. It's the classic story of the grasshopper and the ant. Without glut4, your body does not store glucose as glycogen in the muscles, it doesn't store it as fat in the adipocytes (i mean it doesn't do it well, these still occur to some extent). So, in the lean times between meals, your body/brain starves. :(

    3. Diabetes is characterized by polyuria (passage of large volumes of urine), polydipsia (excessive drinking), weight loss in spite of polyphagia (increased appetite), hyperglycemia, glycosuria, ketosis, acidosis, and coma. Widespread biochemical abnormalities are present, but the fundamental defects to which most of the abnormalities can be traced are (1) reduced entry of glucose into various “peripheral” tissues and (2) increased liberation of glucose into the circulation from the liver. Therefore, there is an extracellular glucose excess and, in many cells, an intracellular glucose deficiency—a situation that has been called “starvation in the midst of plenty.” Also, the entry of amino acids into muscle is decreased and lipolysis is increased.

      It's like throwing away your own money, and the handouts people give you!

      Normally, the cell punches holes specific to glucose in the plasma membrane, but without insulin, it's like trying to feed a tsunami of glucose through the a couple small windows of glut receptors.

    4. When insulin binds to its receptors, they aggregate in patches and are taken up into the cell by receptor-mediated endocytosis (see Chapter 2). Eventually, the insulin–receptor complexes enter lysosomes, where the receptors are broken down or recycled. The half-life of the insulin receptor is about 7 h.

      !!! No way! The receptor is a 1-and-done binder? It's immediately takenup and recycled. That's got to be energetically exhausting for the cell.

    5. Insulin receptors are found on many different cells in the body, including cells in which insulin does not increase glucose uptake.

      Your body uses it as a flag that energy is abundant. Cells take note of this, and their response may be independent to glucose regulation.

    6. Failure to grow is a symptom of diabetes in children, and insulin stimulates the growth of immature hypophysectomized rats to almost the same degree as growth hormone.

      IF you don't have a hypothalamus to release growth factor, but you do have insulin administered, you're good!

    7. Insulin causes K+ to enter cells, with a resultant lowering of the extracellular K+ concentration. Infusions of insulin and glucose significantly lower the plasma K+ level in normal individuals and are very effective for the temporary relief of hyperkalemia in patients with renal failure.

      Huh. You can give insulin to someone with hyperkalemia. Unlike other electrolyte imbalances, you are more likely to see paralysis or fatal arrhythmia than seizures.

      ALSO insulin + protamine is a double wammy. On the one hand, insulin will trigger your cells to take up K+, lowering blood K+. On the other, protamine inhibits heparin, and chronically elevated heparin can cause hypoaldosteronism which prevents K+ excretion. So the protamine will help lower K+ too!

    8. In the tissues in which insulin increases the number of GLUTs in cell membranes, the rate of phosphorylation of the glucose, once it has entered the cells, is regulated by other hormones. Growth hormone and cortisol both inhibit phosphorylation in certain tissues. Transport is normally so rapid that it is not a rate-limiting step in glucose metabolism. However, it is rate-limiting in B cells.

      Q: Why would you want to inhibit phosphorylating glucose, trapping it in the cell, when you are stressed out (cortisol)? Why would you want to inhibit it during growth and repair (growth hormone)?

      Are they trying to divert glucose to other tissues, selectively inhibiting glucose from being trapped in non-essential tissues?

    9. The insulin then crosses the basal lamina of the B cell and a neighboring capillary and the fenestrated endothelium of the capillary to reach the bloodstream. The fenestrations are discussed in detail in Chapter 31.

      I'm still fuzzy on the different tissues that have fenestrated capillaries. Follow up and read Ch. 31

    10. Porcine insulin differs from human insulin by only one amino acid residue and has low antigenicity.

      Did you know that porcine insulin (derived from pigs) is super similar to human insulin!? That's so wild. Here is an article discussing diabetes in Islam: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1279173/

      "Pork and non-halal meat are absolute taboos in Islam. Thus pork insulins, pork-based synthetic insulins, and beef (non-halal) insulins are unacceptable to devoted Muslims. Non-porcine synthetic (human) insulin should be given in preference. If a forbidden insulin is the only choice, a religious leader or doctor should be encouraged to mediate and reduce the patient's guilt feeling and spiritual pain. These advisers would use the doctrine of ‘the sanctity of life’, permissible in Islam. It means that life must be saved at all cost"

    11. blood from the islets, like that from the gastrointestinal tract (but unlike that from any other endocrine organs) drains into the hepatic portal vein

      Endocrine hormones produced by pancreas go directly to liver before entering IVC and reaching rest of body tissues

    1.  Increased ketone uptake

      Q: Why would you take up ketones. Is this just the opposite of when you send out ketones during a glucagon state?

    2.  Increased K+ uptake

      Q: Why though. What do you need K for?

  3. Feb 2020
    1. Note that decreased outward recoil of the chest wall increases its compliance

      The increased compliance is in the outward direction.