By T. Frithjof. Greenwich University. 2018.
The dietary advice that we eat a variety of food helps to protect us against the ingestion of a toxic level of any one xenobiotic compound cheap 60 mg cialis extra dosage erectile dysfunction drug companies. It is also suggested that we reduce consumption of salt-cured discount cialis extra dosage 100 mg overnight delivery erectile dysfunction treatment abu dhabi, smoked, and charred foods, which contain chemicals that can contribute to the development of cancer. Other guidelines encourage the ingestion of fruits and vegetables that contain protective chemicals called antioxidants. Otto Shape sought help in reducing his weight of 187 lb (BMI of 27) to his previous level of 154 lb (BMI of 22, in the middle of the healthy range). Otto Shape was 5 feet 10 inches tall, and he calculated that his maximum healthy weight was 173 lbs. He planned on becoming a family physician, and he knew that he would be better able to counsel patients in healthy Physicians have an average lifes- behaviors involving diet and exercise if he practiced them himself. With this infor- pan that is longer than the general mation and assurances from the physician that he was otherwise in good health, population, and generally practice Otto embarked on a weight loss program. One of his strategies involved recording healthier behaviors, especially with regard all the food he ate and the portions. To analyze his diet for calories, saturated fat, to fat consumption, exercise, alcohol con- and nutrients, he used the Interactive Healthy Eating Index, available online from sumption, and smoking. Physicians who the USDA Food and Nutrition Information Center. Ivan Applebod weighed 264 lb and was 70 inches tall their patients. He is cur- rently almost 100 lb overweight, and his BMI of 37. Applebod’s physician cautioned him that exogenous obesity (caused by overeating) represents a risk factor for atherosclerotic vascular disease, particularly when the distribution of fat is primarily “central” or in the abdominal region (apple CHAPTER 1 / METABOLIC FUELS AND DIETARY COMPONENTS 19 shape, in contrast to the pear shape, which results from adipose tissue deposited in the The prevalence of obesity in the buttocks and hips). In addition, obesity may lead to other cardiovascular risk factors U. In such as hypertension (high blood pressure), hyperlipidemia (high blood lipid levels), 1962, 12. That number elevation in both systolic and diastolic blood pressure. Applebod was referred to the hospital’s weight reduction center, where a 1998 (BMI 25. Therefore, more team of physicians, dieticians, and psychologists could assist him in reaching his than 50% of the population is currently over- ideal weight range. Increased weight increases cardiovascu- Ann O’Rexia. Because of her history and physical examination, Ann lar risk factors, including hypertension, dia- O’Rexia was diagnosed as having early anorexia nervosa, a behavioral dis- betes, and alterations in blood lipid levels. It order that involves both emotional and nutritional disturbances. Miss also increases the risk for respiratory prob- O’Rexia was referred to a psychiatrist with special interest in anorexia nervosa, and lems, gallbladder disease, and certain types of cancer. Percy Veere weighed 125 lb and was 71 inches tall (with- out shoes) with a medium frame. For his height, a BMI in the healthy weight range corresponds to weights between 132 and 178 lb. Veere’s malnourished state was reflected in his admission laboratory profile. The results of hematologic studies were consistent with an iron deficiency anemia complicated by low levels of folic acid and vitamin B12, two vitamins that can affect the development of normal red blood cells. His low serum albumin level was caused by insufficient protein intake and a shortage of essential amino acids, which result in a reduced ability to synthesize body proteins. The psychiatrist requested a con- sultation with a hospital dietician to evaluate the extent of Mr. Veere’s marasmus (malnutrition caused by a deficiency of both protein and total calories) as well as his vitamin and mineral deficiencies. Dietary Reference Intakes (DRIs) are quantitative estimates of nutrient intakes that can be used in evaluating and planning diets for healthy people. They are prepared by the Standing Com- mittee on the Scientific Evaluation of Dietary Reference Intakes (DRI) of the Food and Nutrition Board, Institute of Medicine, and the National Academy of Science, with active input of Health Canada.
Estrogens contribute to ous system can result in poor stomach emptying generic cialis extra dosage 200 mg erectile dysfunction viagra free trials. This may explain the weakness and poor onset of menstruation buy discount cialis extra dosage 40mg on-line erectile dysfunction surgery cost, and the development and func- 12 tissue repair seen in people who have been diabetic for tioning of the reproductive organs. It may also explain the reduced resistance The other hormone produced by the ovaries, called to infection noted in diabetic patients. All the sex hor- Careful management of diabetes can reduce the sever- mones are discussed in more detail in Chapter 23. Patients must follow their prescribed diet consistently, take medication as ordered, Checkpoint 12-13 In addition to controlling reproduction, sex eat at regular times, and follow a regular program of exer- hormones confer certain features associated with male and fe- male gender. Patients on insulin must test their blood sugar regu- larly. These tests have traditionally been done on blood obtained by a finger prick, but new devices are available The Thymus Gland that can read the blood glucose level through the skin and even warn of a significant change. A test for long-term glu- The thymus gland is a mass of lymphoid tissue that lies cose control measures average blood glucose during the in the upper part of the chest superior to the heart. This previous 2-3 months based on glucose bound to hemoglo- gland is important in the development of immunity. Its bin (glycosylated hemoglobin or HbA ) in red blood cells. An alternate method for administration of insulin up residence in lymph nodes throughout the body. The insulin is placed in a device that then injects The Pineal Gland it into the subcutaneous tissues of the abdomen. People taking insulin injections are subject to episodes of low The pineal (PIN-e-al) gland is a small, flattened, cone- blood sugar and should carry notification of their disease. The pineal produces the hormone melatonin (mel-ah- stage. Researchers are also studying the possibility of TO-nin) during dark periods. Little hormone is produced transplanting islet cells to take over for failed cells in peo- during daylight hours. This pattern of hormone secretion ple with diabetes. The Sex Glands ◗ Other Hormone-Producing Tissues The sex glands, the female ovaries and the male testes, Originally, the word hormone applied to the secretions of not only produce the sex cells but also are important en- the endocrine glands only. The term now includes vari- 256 CHAPTER TWELVE Box 12-2 Clinical Perspectives Seasonal Affective Disorder: Seeing the LightSeasonal Affective Disorder: Seeing the Light e all sense that long dark days make us blue and sap our As light strikes the retina of the eye, it sends impulses that de- Wmotivation. Are these learned responses or is there a crease the amount of melatonin produced by the pineal gland in physical basis for them? Because melatonin depresses mood, the final effect of of light in the environment does have a physical effect on be- light is to elevate mood. Evidence that light alters mood comes from people found to improve the mood of most people with SAD. Exposure who are intensely affected by the dark days of winter—people for 15 minutes after rising in the morning may be enough, but who suffer from seasonal affective disorder, aptly abbreviated some people require longer sessions both morning and evening. When days shorten, these people feel sleepy, depressed, Other aids include aerobic exercise, stress management tech- and anxious. Research suggests that SAD has a genetic basis and may be as- sociated with decreased levels of serotonin. Prostaglandins are active in promoting inflammation; Many body tissues produce substances that regulate the certain antiinflammatory drugs, such as aspirin, act local environment. Some of these other hormone-produc- by blocking the production of prostaglandins. Some ing organs are the following: prostaglandins have been used to induce labor or abortion and have been recommended as possible contraceptive ◗ The stomach secretes a hormone that stimulates its own agents.
One would think neural activity can only be affected after remarkable effort discount 100 mg cialis extra dosage impotence 21 year old. FIGURE 13 Statue of a parkinsonian woman by Paul Richer (From Ref cheap 100 mg cialis extra dosage amex erectile dysfunction exercise video. Richer worked with Charcot, and as an artist and sculptor produced several works that depicted the habitus, joint deformities, and postural abnormalities of patients with Parkinson’s disease. FIGURE 14 Evolution of parkinsonian disability (from Ref. The ﬁgures drawn by Charcot’s student, Paul Richer, capture the deforming posture and progression of untreated Parkinson’s disease over a decade. Charcot’s teaching method involved side-by-side comparisons of patients with various neurological disorders. In one of his presentations on Parkinson’s disease, he showed two subjects, one with the typical or archetypal form of the disorder with hunched posture and ﬂexion and another case with atypical parkinsonism, showing an extended posture. The latter habitus is more characteristic of the entity progressive supranuclear palsy, although this disorder was not speciﬁcally recognized or labeled by Charcot outside of the term ‘‘parkinsonism without tremor’’ (4). Charcot adapted the sphygmo- graph, an instrument originally used for recording arterial pulsation, to record tremors and movements of the wrist. His resultant tremor recordings (lower right), conducted at rest (A–B) and during activity (B–C), differentiated multiple sclerosis (top recording) from the pure rest tremor (lower recording) or mixed tremor (middle recording) of Parkinson’s disease. Pencil sketch of a man with Parkinson’s disease drawn by Jean-Martin Charcot during a trip to Morocco in 1889 (from Ref. Referring to the highly stereotyped clinical presentation of Parkinson’s disease patients, Charcot told his students (3,4): ‘‘I have seen such patients everywhere, in Rome, Amsterdam, Spain, always the same picture. Charcot’s advice was empiric and preceded the recognition of the well-known dopaminergic/cholinergic balance that is implicit to normal striatal neurochemical activity. FIGURE 19 Micrographia and tremorous handwriting (from Ref. Charcot recognized that one characteristic feature of Parkinson’s disease was the handwriting impairment that included tremorous and tiny script. Charcot collected handwriting samples in his patient charts and used them as part of his diagnositic criteria, thereby separating the large and sloppy script of patients with action tremor from the micrographia of Parkinson’s disease. OTHER NINETEENTH-CENTURY CONTRIBUTIONS FIGURE 20 William Gower’s work. William Gower’s A Manual of Diseases of the Nervous System shows sketches of patients with Parkinson’s disease (left) and diagrams of joint deformities (right) (from Ref. More known for written descriptions than visual images, William Gowers offered one of the most memorable similes regarding parkinsonian tremor: ‘‘the movement of the ﬁngers at the metacarpal-phalangeal joints is similar to that by which Orientals beat their small drums. Osler published his celebrated Principles and Practice of Medicine in 1892, one year before Charcot’s death. As an internist always resistant to the concept of medical specialization, Osler was inﬂuential in propogating information to generalists on many neurological conditions, including Parkinson’s disease. Osler was less forthcoming than Charcot in appreciating the distinction between bradykinesia and weakness, and he sided with Parkinson in maintaining that mental function was unaltered. Osler was particularly interested in pathological studies and alluded to the concept of Parkinson’s disease as a state of accelerated aging (22). Brissaud was a close associate of Charcot and contributed several important clinical observations on Parkinson’s disease in the late nineteenth century. Most importantly, however, he brought neuropathological attention to the substantia nigra as the potential cite of disease origin. In discussing a case of a tuberculoma that destroyed the substantia nigra and in association with contralateral hemiparkinsonism, he considered the currently vague knowledge of the nucleus and its putative involvement in volitional and reﬂex motor control. Extending his thoughts, he hypothesized that ‘‘a lesion of the locus niger could reasonably be the anatomic basis of Parkinson’s disease’’ (23). Horowski R, Horowski L, Vogel S, Poewe W, Kielhorn F-W. An essay on Wilhelm von Humboldt and the shaking palsy. London: Whittingham and Rowland for Sherwood, Neeley and Jones, 1817.
The thyroid protein thyroglobulin to form a tyrosine quinoid and then a 3 -monoiodotyrosine gland enlarges (forms a goiter) in an attempt to produce more thyroid hormone purchase 40 mg cialis extra dosage amex impotent rage. It has been suggested that a second iodide is added to the ring by sim- United States buy cialis extra dosage 40mg overnight delivery erectile dysfunction treatment without side effects, table salt (NaCl) enriched with ilar mechanisms to form a 3,5-diiodotyrosine (DIT) residue. Because iodide is added iodide (iodized salt) is used to prevent to these organic compounds, iodination is also referred to as the “organification of hypothyroidism caused by iodine deficiency. T3 and T4 are stored in the thyroid follicle as amino acid residues in thyroglobulin. Under most circumstances, the T4/T3 ratio in The thyroid gland is unique in that it has the capacity to store large thyroglobulin is approximately 13:1. This storage accounts for the low transport proteins in the blood. Of these transport proteins, thyroid-binding globulin overall turnover rate of T3 and T4 in the body. This free fraction of hormone has biologic activity because it is the only form that is capable of diffusing across target cell membranes to interact with intracellular receptors. The transport proteins, therefore, serve as a large reservoir of hormone that can release additional free hormone as the metabolic need arises. The thyroid hormones are degraded in liver, kidney, muscle, and other tissues by deiodination, which produces compounds with no biologic activity. SECRETION OF THYROID HORMONE The release of T3 and T4 from thyroglobulin is controlled by thyroid-stimulating hormone (TSH) from the anterior pituitary. TSH stimulates the endocytosis of thy- roglobulin to form endocytic vesicles within the thyroid acinar cells (see Fig. Lysosomes fuse with these vesicles, and lysosomal proteases hydrolyze thyroglobulin, releasing free T4 and T3 into the blood in a 10:1 ratio. In various tis- sues, T4 is deiodinated, forming T3, which is the active form of the hormone. TSH is synthesized in the thyrotropic cells of the anterior pituitary. Its secretion Hypothalamus is primarily regulated by a balance between the stimulatory action of hypothalamic thyroid-releasing hormone (TRH) and the inhibitory (negative feedback) influence TRH of thyroid hormone (primarily T3) at levels above a critical threshold in the blood – bathing the pituitary thyrotrophs. TSH secretion occurs in a circadian pattern, a surge beginning late in the afternoon and peaking before the onset of sleep. In addition, + TSH is secreted in a pulsatile fashion with intervals of 2 to 6 hours between peaks. TSH stimulates all phases of thyroid hormone synthesis by the thyroid gland, Pituitary including iodide trapping from the plasma, organification of iodide, coupling of monoiodotyrosine and diiodotyrosine, endocytosis of thyroglobulin, and proteoly- sis of thyroglobulin to release triiodothyronine (T3) and tetraiodothyronine (T4) (see TSH Fig. In addition, the vascularity of the thyroid gland increases as TSH stim- – ulates hypertrophy and hyperplasia of the thyroid acinar cells. The predominant mechanism of action of TSH is mediated by binding of TSH to its specific receptor on the plasma membrane of the thyroid acinar cell, leading to an increase in the concentration of cytosolic cAMP. Recent evidence indicates, T3 however, that TSH also increases the cellular levels of inositol trisphosphate and T3 2 T4 + diacylglycerol, causing a rise in cytosolic Ca within the thyroid cell. The large protein thyroglobulin, which contains T3 and T4 in peptide linkage, is stored extracellularly in the colloid that fills the central space of each thyroid folli- cle. Each of the biochemical reactions that leads to the release and eventual secre- Liver and other cells tion of T3 and T4, such as those that lead to their formation in thyroglobulins, is Thyroid TSH-dependent. Rising levels of serum TSH stimulate the endocytosis of stored Fig. Feedback regulation of thyroid thyroglobulin into the thyroid acinar cell. Lysosomal enzymes then cleave T3 and T4 hormone levels. T3 and T4 are secreted into the bloodstream in response to ris- stimulates the release of TSH from the anterior ing levels of TSH. T4 is converted to T3 gland rises, the feedback loop is closed.
The vitamin K–dependent car- boxylase cialis extra dosage 60 mg without prescription biking causes erectile dysfunction, which adds the extra carboxyl group generic cialis extra dosage 40mg fast delivery erectile dysfunction treatment in bangladesh, uses a reduced form of vitamin K (KH2) as the electron donor and converts vitamin K to an epox- ide. Vitamin K epoxide is reduced, in two steps, back to its active form by the enzymes vitamin K epoxide reductase and vitamin K reductase. Complex assembly has two physiologically important consequences. First, it enhances the rate of thrombin formation by as much as several hundred thousand- fold, enabling the clot to form rapidly enough to preserve hemostasis. Secondly, such explosive thrombin formation is localized to the site of vascular injury at which the negatively charged phospholipids are exposed. From our knowledge of the location of such phospholipids in cellular and subcellular organelle membranes, these surface-binding sites are only exposed at an injury site in which cell rupture exposes the internal membrane surface (recall that certain phospholipids only face the cytoplasm; if these lipids are now exposed to the environment, substantial cell damage must have occurred). VITAMIN K REQUIREMENT FOR BLOOD COAGULATION The formation of the -carboxyglutamate residues on blood coagulation factors takes place in the hepatocyte before release of the protein. Within the hepatocyte, vitamin K (which is present in the quinone form) is reduced to form vitamin KH2 by a microsomal quinone reductase (see Fig. Vitamin KH2 is a cofactor for carboxylases that add a carboxyl group to the appropriate glutamate residues in the proenzyme to form the carboxylated proenzyme (e. In the same 836 SECTION EIGHT / TISSUE METABOLISM Warfarin (Coumadin®) is a slow- Activated protein C-protein S and long-acting blood anticoagu- complex destroys Protein S lant with a structure resembling that factors Va and VIIIa of vitamin K. The structural similarity allows 2+ Ca PL the compound to compete with vitamin K and prevent -carboxylation of glutamate residues Activated protein C in Factors II, VII, IX, X, and proteins C and S. The noncarboxylated blood clotting protein Thrombin Protein C precursors increase in both the blood and plasma, but they are unable to promote blood br coagulation because they cannot bind cal- cium and thus cannot bind to their phospho- Thrombomodulin lipid membrane sites of activation. Thrombin, bound to thrombomodulin on the endothelial cell surface, activates protein C. Activated protein C, in complex with protein S, binds to the platelet membrane, and the activated complex destroys Factors Va and VIIIa, CH thereby inhibiting the coagulation cascade. OH CH2 C reaction, vitamin K is converted to vitamin K epoxide. To recover active vitamin CH3 KH2, vitamin K is first reduced to the quinone form by vitamin K epoxide reduc- tase, and then to the active hydroquinone form. Regulation through Feedback Amplification and thus is occasionally encountered in emergency departments in cases of acciden- and Inhibition tal poisoning. It is effective as a rat poison Once the formation of the clot (thrombus) begins, clot formation is accelerated in because it takes many hours to develop an almost explosive manner by a number of processes collectively termed feedback pathologic symptoms, which allows one poi- amplification. THE ROLE OF THROMBIN IN REGULATION tionality of protein C or protein S Thrombin has both a prothrombotic regulatory role (feedback amplification) and an increases the risk for venous throm- boembolism. Homozygous individuals for antithrombotic regulatory role (feedback inhibition). The prothrombotic action is these mutations do not survive the neonatal initiated when thrombin stimulates its own formation by activating Factors V, VIII, period unless given replacement therapy. Thrombin also promotes clot formation by activating platelet aggregation, stimulating the In European populations, a point release of Factor VIII from vWF, and cleaving Factor XIII to Factor XIIIa. Thrombomodulin abolishes the clot- ment of an arg with a gln in the preferred ting function of thrombin and allows thrombin to activate protein C, which has anti- site for cleavage by activated protein C, ren- coagulant effects. Heterozygous individuals have a sixfold to eightfold increased risk of deep vein throm- 2. PROTEINS S AND C boses, and homozygous individuals have a Protein C and its cofactor protein S serve to suppress the activity of the coagu- 30- to 140-fold increased risk. After activation, protein C forms a complex with protein S. Pro- Leiden mutation does not appear to be asso- tein S anchors the activated protein C complex (APC) to the clot through ciated with increased risk for arterial throm- bosis, such as myocardial infarction, except Ca / -carboxyglutamate binding to platelet phospholipids. The APC also stimulates Leiden mutation arose after the separation endothelial cells to increase secretion of the prostaglandin PGI2, which reduces of the European, Asian, and African popula- platelet aggregation. The frequency of this variant indicates that it conferred some selective advantage at 3. In the developed world, inherited APC resistance is the most prevalent risk fac- Many proteases of the blood coagulation enzyme system are serine proteases. Because uncontrolled proteolytic activity would be destructive, modulating CHAPTER 45 / BLOOD PLASMA PROTEINS, COAGULATION AND FIBRINOLYSIS 837 mechanisms control and limit intravascular proteolysis. The serpins (serine pro- tease inhibitors) are a group of naturally occurring inhibitory proteins present in the plasma at high concentration (approximately 10% of the plasma proteins are ser- pins).