By Y. Kelvin. Remington College. 2019.
In 1840 Mayer was the physician on the schooner Java order discount flexeril online, which sailed for the East Indies discount flexeril 15 mg free shipping. While aboard ship best order for flexeril, he was reading a treatise by the French scientist Laurent Lavoisier in which Lavoisier suggested that the heat produced by animals is due to the slow combustion of food in their bodies. Lavoisier further noted that less food is burned by the body in a hot environment than in a cold one. He noticed that the venous blood, which is normally dark red, was nearly as red as arterial blood. Because in the tropics less fuel is burned in the body, the oxygen content of the venal blood is high, giving it the brighter color. Mayer then went beyond Lavoisier’s theory and suggested that in the body there is an exact balance of energy (which he called force). The energy released by the food is balanced by the lost body heat and the work done by the body. Mayer wrote in an article published in 1842, “Once in existence, force [energy] cannot be annihilated— it can only change its form. Conservation of energy is implicit in all our calculations of energy balance in living systems. The body of an animal contains internal thermal energy Et, which is the product of the mass and speciﬁc heat, and chemical energy Ec stored in the tissue of the body. In terms of energy, the activities of an animal consist of simply eating, working, and rejecting excess heat by means of various cooling mechanisms (radiation, convection, etc. Without going into detailed calculations, the ﬁrst law allows us to draw some conclusions about the energetics of the animal. For example, if the internal temperature and the weight of the animal are to remain constant (i. An imbalance between intake and output energy implies a change in the sum Ec + Et. The First Law of Thermodynamics is implicit in all the numerical calculations presented in Chapter 11. For example, when an object falls from a table to the ground, its potential energy is ﬁrst converted into kinetic energy; then, as the object comes to rest on the ground, the kinetic energy is converted into heat. The First Law of Thermodynamics does not forbid the reverse process, whereby the heat from the ﬂoor would enter the object and be converted into kinetic energy, causing the object to jump back on the table. The irreversibility of these types of events is intimately connected with the probabilistic behavior of systems comprised of a large ensemble of subunits. Suppose that we now shake the tray so that each coin has an equal chance of landing on the tray with either head or tail up. Of these, only one yields the original ordered arrangement of three heads (H,H,H). Because the probabilities of obtaining any one of the coin arrangements in Table 10. As the number of coins in the experiment is increased, the probability of returning to the ordered arrangement of all heads decreases. With 10 coins on the tray, the probability of obtaining all heads after shaking the tray is 0. We could shake the tray for many years without seeing the ordered arrangement again. In summary, the following is to be noted from this illus- tration: The number of possible coin arrangements is large, and only one of them is the ordered arrangement; therefore, although any one of the coin arrangements—including the ordered one—is equally likely, the probability of returning to an ordered arrangement is small. As the number of coins in the ensemble increases, the probability of returning to an ordered arrangement decreases. In other words, if we disturb an ordered arrangement, it is likely to become disordered. This type of behavior is characteristic of all events that involve a collective behavior of many components. The Second Law of Thermodynamics is a statement about the type of prob- abilistic behavior illustrated by our coin experiment. One statement of the second law is: The direction of spontaneous change in a system is from an arrangement of lesser probability to an arrangement of greater probability; that is, from order to disorder. This statement may seem to be so obvious as to be trivial, but, once the universal applicability of the second law is recognized, its implications are seen to be enormous. We can deduce from the second law the limitations on information transmission, the meaning of time sequence, and even the fate of the universe. One important implication of the second law is the limitation on the con- version of heat and internal energy to work. This restriction can be understood by examining the diﬀerence between heat and other forms of energy. Yet when we examined the details of this energy transfer, we saw that it could be attributed to transfer of a speciﬁc type of energy such as kinetic, vibrational, electromagnetic, or any combination of these (see Chapter 9). It is, in fact, possible to develop a theory of thermodynamics without using the con- cept of heat explicitly, but we would then have to deal with each type of energy transfer separately, and this would be diﬃcult and cumbersome. In many cases, energy is being transferred to or from a body by diﬀerent methods, and keeping track of each of these is often not possible and usually not necessary. The main feature that distinguishes heat from other forms of energy is the random nature of its manifestations. Similarly, when heat is transferred by radiation, the propagating waves travel in random directions. The radiation is emitted over a wide wavelength (color) range, and the phases of the wave along the wave front are random. Chemical energy, for example, is present by virtue of speciﬁc arrangements of atoms in a molecule. Potential energy is due to the well-deﬁned position, or conﬁguration, of an object. While one form of energy can be converted to another, heat energy, because of its random nature, cannot be completely converted to other forms of energy. First, let us examine how heat is converted to work in a heat engine (for example, the steam engine). Heat ﬂows into the gas; this increases the kinetic energy of the gas molecules and, therefore, raises the internal energy of the gas. The molecules moving in the direction of the piston collide with the piston and exert a force on it. The heat added to the gas causes the molecules in the cylinder to move in random directions, but only the molecules that move in the direction of the piston can exert a force on it. Therefore, the kinetic energy of only the molecules that move toward the piston can be converted into work. For the added heat to be completely converted into work, all the gas molecules would have to move in the direction of the piston motion. The odds against the complete conversion of 1 cal of heat into work can be expressed in terms of a group of monkeys who are hitting typewriter keys at random and who by chance type out the complete works of Shakespeare without error. Although some of the random thermal motion can be ordered again, the ordering of all the motion is very improbable. Because the probability of completely converting heat to work is vanishingly small, the Second Law of Thermodynamics states categorically that it is impossible.
However order flexeril 15 mg with mastercard, through the work of Bohr and others order 15 mg flexeril with mastercard, it was eventually realized that classical Newtonian mechanics failed at the atomic level of reality—atoms did not behave like billiard balls buy flexeril 15 mg overnight delivery. An alternative approach was needed for the quantitative evaluation of molecular phe- nomena. In the first three decades of the 20th century, there occurred many significant advances in theoretical physics and physical philosophy. Planck showed that energy is emitted in the form of discrete particles or quanta; Einstein expanded upon this theory with the proposal that an atom emits radiant energy only in quanta, and that this energy is related to the mass and to the velocity of the light; Schrödinger incorporated these evolving ideas of the new quantum theory into an equation that described the wave behavior of a particle (wave mechanics); Heisenberg formulated a complete, self- consistent theory of quantum physics, known as matrix mechanics; and Dirac showed that Schrödinger’s wave mechanics and Heisenberg’s matrix mechanics were special cases of a larger operator theory. The capacity for a robust, mathematical description of molecular-level phenomena seemed to be at hand. Since the Schrödinger equation (which lies at the mathematical heart of quantum mechanics) permitted quantitative agreement with experiment at the atomic level, the physicists of the 1930s predicted an end to the experimental sciences, including biology, suggesting that they would merely become a branch of applied physics and mathematics. Although in princi- ple the Schrödinger equation afforded a complete description of Nature, in practice it could not be solved for the large molecules of medical and pharmacological interest. Early hopes that quantum mechanics would solve the problems of drug design were dashed in despair. Over the past thirty years, however, three advances have changed the practical use- fulness of molecular quantum mechanics: 1. The advent of semi-empirical molecular orbital calculations and density functional theory, which employ mathematical assumptions to simplify the application of quantum mechanics to drug molecules of intermediate to large size. The development of molecular mechanics, which incorporates quantum mechanical data into a simplified mathematical framework derived from the classical equations of motion to permit reasonable calculations on biomolecules of large size. The construction of “supercomputers” capable of performing the massive calcula- tions necessary for considering very large biomolecules. Accordingly, quantum pharmacology has become an attainable goal and calculational computer modeling permits large molecules to be studied meaningfully. Starting with the X-ray structure of the macromolecule, a space- filling molecular model is created, including hydrate envelopes around it. By separately generating the three-dimensional model of a hypothetical drug, a modeler can manipu- late the two by modern fast computers and can directly examine the fit of the ligand in the active site; the investigator can change the substituents, conformation, and rotamers of the drug on the screen, and can repeat the docking. This enormous progress in computer hardware and software, elucidation of macro- molecular structure and ligand–receptor interactions, crystallography, and molecular modeling is hopefully bringing us to the threshold of a breakthrough in drug design. We are now able to design lead compounds de novo on the basis of the structure of the recep- tor macromolecule. However, computerized drug design is still only an instrument that reduces empiricism in an experimental science; the inherent approximations of innu- merable conformers and molecular parameters of drug and receptor, and the method- ological inaccuracies and difficulties of comparison, will never allow the elimination of insight and trial. Screening for antitumor activity has been carried on for more than 30 years by the U. National Cancer Institute, with tens of thousands of compounds being tested on tumors in vivo and in vitro. More recently, a computerized prescreening method has been applied to this process, saving time and expense, and hence the screening is not as random as it used to be. A successful random search for antibacterial action was conducted by several pharmaceutical companies in the 1950s. They tested soil samples from all over the world, which resulted in the dis- covery of many novel structures and some spectacularly useful groups of antibiotics, notably the tetracyclines (3. In fact, microbial sources have supplied an enormous number of new drug prototypes, sometimes of staggering complexity. Some would argue that drug discovery through screening provides the “irrational” counterpart to rational drug design. As mentioned, screening of compounds has a long and rather illustrious history and has produced many useful anticancer and antibiotic drugs. The discovery of the anticonvulsant drug phenytoin provides an early example of drug discovery through screening. By the latter half of the nineteenth century numerous hydantoin analogs had been synthesized, but only one, 5-ethyl-5-phenylhydantoin (nirvanol), demonstrated any clinical utility. Wernecke introduced nirvanol in 1916 as a “less toxic hypnotic”; however, enthusiasm rapidly waned when its chronic toxicity became recognized. Not surprisingly, a second hydantoin, 5,5-diphenylhydantoin (phenytoin), which had long remained on the labora- tory shelf, appeared doomed to obscurity; phenytoin had been first synthesized by Biltz in 1908, through a condensation of urea with benzil which exploited a pinacolone rearrangement. Putnam initiated a screening programme to search for new anti- convulsants, using protection against electroshock-induced convulsions as a selection criterion. A makeshift apparatus to execute these experiments was assembled using a commutator salvaged from a World War I German aircraft. Having studied the structure of phenobarbital, Putnam randomly requested a diverse selection of heterocyclic phenyl-containing compounds from a variety of chemical manufacturers. The Parke-Davis Company provided nineteen heterocyclic phenyl-substituted compounds that had been deemed “worthless hypnotics. Putnam screened hundreds of compounds but only phenytoin combined high activity with low toxicity. In 1936, Putnam’s colleague, Houston Merritt, initiated a clinical evaluation of phenytoin, which soon led to its widespread marketing as an anticonvulsant drug. The pioneering screening techniques that heralded the discovery of phenytoin pro- foundly influenced subsequent antiepileptic drug discovery. Hundreds of hydantoin analogs were synthesized and screened for biological activity; hundreds of other penta- atomic heterocyclic compounds (e. Many of these new compounds found their way into the market place, with varying degrees of therapeutic success. Modern drug discovery by screening is more of a systematic tech- nological tour de force than a hit-or-miss gamble. Although rational drug design is elegant, it is also slow and thus time-inefficient. It takes a long time to identify the proteins that are involved in a disease, then crystallize them and design drugs to bind to them. Worse, some proteins, especially membrane- bound proteins, seem to defy crystallization, while some diseases do not even have identifiable proteins involved in their pathogenesis and etiology. The crystal structures of key protein receptors do not have to be known; indeed, the proteins do not even have to be identified. If the bioassay is fast and efficient, and if the library of compounds being screened is diverse and comprehensive, then in principle it should be possible to identify a lead compound years before the practitioner of rational drug design. However, the key to success lies in the “goodness of the library of compounds” (i. If the library contains a million compounds that are all analogs of each other, then it may be large but it is probably not sufficiently diverse. The library should have the full range of functional groups (cations, anions, hydrogen bond donors, hydrogen bond acceptors, lipophilic, aromatic, etc. Combinatorial chemistry is both the philosophical and the practical method with which to create structurally diverse compound libraries. Combinatorial chemistry is defined as that branch of synthetic organic chemistry that enables the concomitant syn- thesis of large numbers of chemical variants in such a manner as to permit their evalu- ation, isolation, and identification. Combinatorial chemistry affords techniques for the systematic creation of large but structurally diverse libraries. From a technical perspec- tive, there are several avenues of approach to library creation: 1.
It is easy to understand why this is thought: by the time you have acute pain attacks order flexeril 15 mg mastercard, some stones are in the gallbladder order flexeril 15mg, are big enough and sufficiently calcified to see on X-ray discount 15mg flexeril with mastercard, and have caused in- flammation there. When the gallbladder is removed the acute attacks are gone, but the bursitis and other pains and digestive problems remain. People who have had their gall- bladder surgically removed still get plenty of green, bile-coated stones, and anyone who cares to dissect their stones can see that the concentric circles and crystals of cholesterol match textbook pictures of “gallstones” exactly. Lugol’s Iodine Solution It is too dangerous to buy a commercially prepared solution. The recipe to make 1 liter (quart) is: 44 gm (1½ ounces) iodine, granular 88 gm (3 ounces) potassium iodide, granular Dissolve the potassium iodide in about a pint of the water. Most of the organisms listed below are dead on commer- cially available and prepared slides (see Sources for biological supply companies). Some testing was done with a more accurate frequency generator at a lower power level so some bandwidths are reported much more narrowly. If the same person retests the same specimens with the same equipment within a few days, the results will be absolutely identical (within 1 Hz) 90% of the time. Some specimens have more than one range listed; this may be characteristic of the organism or may be due to having an undocumented organism on the same microscope slide. Blank locations represent organisms for whom there are prepared slides available, but whose bandwidth has not been determined. Tapeworms can have very large bandwidths (range of fre- quencies), and it varies by the length of the specimen! If you accidentally kill middle segments instead of working your way up from the bottom, you may conceivably promote dispersion! Finding out the frequencies of these illnesses helps you identify them (use the Pathogen Frequency Chart) and also lets you know if you are chronically getting them back. This is because I never could find them present in the white blood cells, and I finally gave up searching for them. Most of them were obtained as Atomic Absorption Standard Solutions and are, therefore, very pure. They were stored in ½ ounce amber glass bottles with bakelite caps and permanently sealed with plastic film since testing did not require them to be opened (they get close enough to the frequency field). The exact concentration and the solubility characteristics are not important in this qualitative test. The main sources of these substances in our environment are given beside each item. These are chemicals, very pure, obtained from chemical supply companies, unless other- wise stated. Only the vitamin sources listed were found to be pollution-free, and only the herb sources listed were found to be potent, although there may be other good sources that have not been tested. The author has no financial interest in, influence on, or other connection with any company listed, except for having family members in the Self Health Resource Center. Note to readers outside the United States of America: Sources listed are typically companies within the United States because they are the ones I am most familiar with. You may be tempted to try a more convenient manufacturer in your own country and hope for the best. This chapter will be updated as I be- come aware of acceptable sources outside the United States. Bando American makes other belts, some of which might be the right size for your dryer. Call for a dealer near you, make sure it says "Made In America", right on the belt. Black cherry concentrate Health food store Black Walnut Hull Tincture Self Health Resource Center, New Action Products Borax, pure Grocery store Boric acid, pure Now Foods, health food store, pharmacy Cascara sagrada Natures Way, health food store Chemicals for testing. Citric acid Now Foods or health food store Cloves San Francisco Herb & Natural Food Co. Hydrogen peroxide 35% New Horizons Trust (food grade) Iodine, pure Spectrum Chemical Co. Lysine Bronson Pharmaceuticals Magnesium oxide Bronson Pharmaceuticals Marshmallow root (herb) San Francisco Herb & Natural Food Co. Niacin 100 mg or 250 mg time release, Bronson Pharmaceuticals Ornithine Now Foods, Jomar Labs Ortho-phospho-tyrosine Aldrich Chemical Co. Rascal Kroeger Herb Products, New Action Products (as Raz-Caps) Salt (sodium chloride), Spectrum Chemical Co. Vitamin E capsules Bronson Pharmaceuticals Vitamin E Oil Now Foods Washing soda (sodium Grocery store carbonate) Water filter pitchers Pure Water Products Wormwood capsules Self Health Resource Center, Kroeger Herb Products, New Action Products Zinc Bronson Pharmaceuticals Zinc oxide Spectrum Chemical Co. The living things are both large and small: from worms we can see, to microscopic bacteria, viruses and fungi. The non living things are pollutants in our air, food, dental metal and body products. The good news is that our body can reclaim its sovereignty by throwing the rascals out. With the new electronic insights and technology, our parasitic invaders can be vanquished with the closing of a switch. The tragedies of surgery, organ replacements, radiation, chemotherapies, doses of drugs, even death can be avoided. Killing your invaders is an easy matter: you simply purchase or build the device that can do that and take the proper herbs. Cleaning up dentalware is under your control, too—a financial expense not beyond your reach, hopefully. Trading your body products for unpolluted varieties is a job but not insurmountable. Use your new wisdom and sharp eye to choose a new dwelling as free of pollutants as you can. They allow invaders into the most jealously guarded recess of your being: your genes. You simply need your own genes back on the job, directed by your own body, working for you. Leads To New Discoveries… In every case of the “mysterious” disease diabetes, you find the not-so-mysterious parasite Eurytrema, and the fairly common pollutant wood alcohol. And New Cures… You don’t need dangerous, expensive prescription drugs to get rid of the causes of your illness. Once you know what you are fighting you can pick herbal, electronic, or avoidance methods. And New Hope… Follow the advice in this book preventively, and never worry about your health again! Hulda Regehr Clark began her studies in biology at the University of Saskatchewan, Canada, where she was awarded the Bachelor of Arts, Magna Cum Laude, and the Master of Arts, with High Honors. After two years of study at McGill University, she attended the University of Minnesota, studying biophysics and cell physiology. In 1979 she left government funded research and began private consulting on a full time basis. Six years later she discovered an electronic technique for scanning the human body.
As volume is increased initially purchase genuine flexeril on line, there is no increase in pressure until a certain point generic 15 mg flexeril with mastercard, designated "Vo' cheap flexeril 15mg on line. There is a term which is frequently used in discussions of the end-diastolic ventricular properties: "compliance". Undoubtedly you will hear this word used in the clinical setting, usually in a casual manner: "The patient’s heart is noncompliant. At this instant of the cardiac cycle, the muscles are in their maximally activated state during the cycle and it is easy to imagine the heart as a much stiffer chamber. As for end diastole, we can construct a pressure- volume relationship at end systole if we imagine the heart frozen in this state of maximal activation. There is no reason to expect that this relationship should be linear, it is simply an experimental observation. In the above discussion we have described the pressure- volume relationships at two instances in the cardiac cycle: Ventricular Physiology - Robert Turcott, M. The idea of considering the pressure-volume relation with the heart frozen in a given state can be generalized to any point during the cardiac cycle. That is, there exists a pressure-volume relationship at each instant of the cycle. For the most parts of the cycle these relations can be considered to be linear and all intersect at a common point, namely Vo. A rough approximation of the instantaneous elastance throughout a cardiac cycle is shown in Fig. With this function it is possible to relate the instantaneous pressure (P) and volume (V) throughout the cardiac cycle: P(V,t) = E(t) [V(t) - Vo]  where Vo and E(t) are as defined above and V(t) is the time varying volume. This relationship breaks down near end- diastole and early systole when there are significant nonlinearities in the pressure-volume relations at higher volumes. The implication of this equation is that if one knows the E(t) function and if one knows the time course of volume changes during the cycle, one can predict the time course of pressure changes throughout the cycle. The term was originally coined in studies of isolated strips of cardiac muscle where a weight was hung from the muscle to prestretch it to the specified load before (pre-) contraction. Enddiastolic wall stress is the measure which most closely corresponds to the definition of preload developed for the muscle. By 'intrinsic strength" we mean those features of the cardiac contraction process that are intrinsic to the ventricle and are independent of conditions imposed by either the preload or afterload (i. We see that in the top panel that the actual amount of pressure generated by the ventricle and the stroke volume are different in the three cases, but we stated that these loops were obtained by modifying the arterial system an not changing anything about the ventricle. Thus, the changes in pressure generation in that figure do not represent changes in "contractility". Basically, we consider ventricular contractility to be altered when any one or combination of the following events occurs: 1. You will recall that calcium interacts with troponin to trigger a sequence of events which allows actin and myosin to interact and generate force. The more calcium available for this process, the greater the number of actin-myosin interactions. Here we are linking "contractility" to cellular mechanisms which underlie excitation-contraction coupling and thus, changes in ventricular contractility would be the global expression of changes in contractility of the cells that make up the heart. Stated another way, ventricular contractility reflects "myocardial contractility" (the contractility of individual cardiac cells). Through the third mechanism, changes in the number of muscle cells, as opposed to the functioning of any given muscle cell, cause changes in the performance of the ventricle as an organ. However, in acknowledging this as a mechanism through which ventricular contractility can be modified we recognize that ventricular contractility and myocardial contractility are not always linked to each other. Humoral and pharmacological agents can modify ventricular contractility by the first two mechanisms. Epinephrine increases the amount of calcium released to the myofilaments and is also believed to modify myofilament affinity for calcium, both creating an increase in contractility. In contrast, propranolol, an agent which blocks the actions of epinephrine, blocks the effects of circulating epinephrine and norepinephrine and reduces contractility. Nifedipine is a drug that blocks entry of calcium into the cell and therefore reduces contractility. One example of how ventricular contractility can be modified by the third mechanism mentioned above is the reduction in ventricular contractility following a myocardial infarction where there is loss of myocardial tissue, but the unaffected regions of the ventricle function normally. The major draw back to the use of Ees in the clinical setting is that it is not that easy, at present, to measure ventricular volume. First, methods for measuring ventricular volume (both invasive and noninvasive) are currently being perfected and should be available in the next several years (indeed, some are already being validated in clinical research protocols). The main disadvantage of this index is that it is a function of the properties of the arterial system. There is a term used in discussions of arterial properties in regard to its influence of ventricular performance: "afterload". There are numerous measures of afterload, and there has been much debate over which is "the best". Time has proven that there is no one best measure of afterload ; different measures provide different information which may be useful in answering different questions. This provides a measure of the pressure that the ventricle must overcome to eject blood. Thus, many people use the mean value when considering this as the measure of afterload. Second, as will become clear below, aortic pressure is determined by properties of both the arterial system and of the ventricle. Thus, it does not provide a measure which relays information exclusively about the arterial system. The stress (force per unit area) in the wall of the ventricle can be estimated from ventricular pressure and knowledge of the structure of the ventricle. This definition of afterload most closely matches afterload as it was originally defined for a strip of cardiac muscle lifting a weight. As with aortic pressure, wall stress varies with ventricular properties as well as ventricular preload. Unlike aortic pressure by itself, this measure is independent of the functioning of the ventricle. According to its mathematical definition, it can only be used to relate mean flows and pressures through the arterial system. This is an analysis of the relationship between pulsatile flow and pressure waves in the arterial system. It is based on the theories of Fourier analysis in which flow and pressure waves are decomposed into their harmonic components. It is more difficult to understand, most difficult to measure, but the most comprehensive description of the properties of the arterial system as they pertain to understanding the influence of afterload on ventricular performance.
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