Assistant Professor, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine
The synthesis o lipoxins starts in one type o cell and ends in a second type o cell in a process termed transcellular synthesis women's health issues examples order serophene no prescription. The s ame enzymes als o catalyze the s ynthes is of leukotrienes of the 5 s eries from eicos apentaenoic acid menstrual upset stomach buy discount serophene 100 mg line. Le uko trie ne s Macrophages menopause kidney pain trusted serophene 25mg, mast cells women's health center alexandria la serophene 50mg amex, and leukocytes such as neutrophils, eosinophils, and monocytes synthesize leukotrienes rom arachidonic acid. In mast cells and macrophages, leukotriene synthesis is stimulated by antigens that combine with immunoglobulin E on the cell sur ace. Liberation o arachidonic acid rom a phospholipid in the endoplasmic reticulum membrane is the rst and rate-limiting step o leukotriene synthesis. Leukotriene A4 (L A4) is inactive; however, it gives rise to the active L B4 and L C4. L C4, L D4, and L E4 all contain a cysteine residue and are called cysteinyl leukotrienes. Once they meet a higher concentration o L B4, neutrophils activate secretion o their granules. Similarly, G s become active when epinephrine or norepinephrine activate 2-adrenergic receptors. Asthma is due to an in ammation o the bronchi and bronchioles that leads to contraction o smooth muscle in these airways, as well as recruitment o leukocytes. In the long term, asthma also leads to hypertrophy o smooth muscle and the glands that produce mucus. Short-acting 2-adrenergic receptor agonists, such as albuterol and levalbuterol, and long-acting 2-adrenergic receptor agonists, such as salmeterol and ormoterol, are used to dilate the bronchi in patients with asthma via activation o G s. Lipoxins inhibit activation o neutrophils and eosinophils, and they stimulate macrophages to phagocytose dead white blood cells. In both cases, synthesis is split into two so that it starts in one type o cell and ends in another type o cell; this is called transcellular synthesis. The requirement or two dif erent locations or lipoxin synthesis helps delay the action o lipoxins. Aspirin relieves pain not only by inhibiting prostaglandin synthesis (see Section 2. Current Western diets are rich in plant oils, which in turn provide plenty o -6 atty acids. Linoleic acid (C18:2) is converted to arachidonic acid (C20:4) and incorporated into membrane phospholipids. Leukotrienes made rom arachidonic acid induce bronchoconstriction and stimulate in ammation, thereby attracting white blood cells and increasing the permeability o blood vessels to plasma and leukocytes. Asthma is caused by prostaglandin- and leukotrienemediated in ammation o the bronchi and bronchioles. The ollowing agents are used in the treatment o asthma: the 5-lipoxygenase inhibitor zileuton, the CysL R1 antagonists montelukast and za rlukast, 2-adrenergic receptor agonists, and glucocorticoids. Eicosanoids and their drugs in cardiovascular diseases: ocus on atherosclerosis and stroke. Relative cardiovascular and gastrointestinal sa ety o non-selective non-steroidal anti-in ammatory drugs versus cyclo-oxygenase-2 inhibitors: implications or clinical practice. The resolution code o acute in ammation: novel pro-resolving lipid mediators in resolution. Cysteinyl leukotriene receptor-1 antagonists as modulators o innate immune cell unction. The antiplatelet ef ect o aspirin is ascribed to inhibition o the synthesis o which one o the ollowing Which one o the ollowing drugs is most suitable to inhibit the synthesis o leukotrienes and lipoxins, but not the synthesis o prostaglandins or thromboxanes Compare and contrast the signaling pathways of adrenergic receptors with those of activated glucagon receptors and glucagon-like peptide-1 receptors. Explain how the causes of Noonan syndrome and neuro bromatosis type 1 relate to a signaling pathway. The term autocrine signaling re ers to secretion o a substance into the extracellular space by a cell whereby the secreting cell is also the one that responds to the secreted product. The term paracrine signaling re ers to secretion o a substance into the extracellular space by a cell whereby a nearby cell responds to the secreted product. In paracrine signaling, the signal is typically short lived, such as in eicosanoid signaling (see Chapter 32). For almost every pathway that leads to an increase in output, there is at least one reaction that leads to a decrease in output. Activation occurs more quickly than inactivation and thus generates a timelimited signal. Protein kinases typically add a phosphate group, and protein phosphatases remove a phosphate group. Most kinases react a phosphate with the hydroxyl group o a serine or threonine side chain. A smaller group o kinases react a phosphate with the hydroxyl group o a tyrosine side chain. Signaling pathways o en generate a concentration wave o a signaling molecule because there are mechanisms or both starting and ending a signal. Phosphorylation/dephosphorylation and associated changes in protein con ormation are a common occurrence in intracellular signaling pathways. Many signaling pathways involve the conversion o an extracellular signal into an intracellular signal, ampli cation o the intracellular signal, and both stimulatory and inhibitory interactions with other pathways. Endocrine signaling typically involves the secretion o a hormone into the bloodstream and the recognition o that hormone in a distant tissue. Accordingly, endocrine secretion re ers to secretion o a substance into the blood, whereas exocrine secretion re ers to secretion o a substance into the lumen o the gastrointestinal tract, the airways, the urinary tract, the environment, and so orth.
Fecal impaction causing obstruction and sigmoid colon volvulus may develop in elderly patients menstruation hygiene generic serophene 25 mg on-line. A large foreign body inserted rectally (perversion pregnancy 6 weeks 3 days buy serophene no prescription, psychosis) may also obstruct the lumen womens health upenn buy 25 mg serophene with amex. The most common symptoms of high-grade colonic obstruction are abdominal pain 1st menstrual cycle after miscarriage 25 mg serophene free shipping, distention, vomiting, and constipation. These symptoms may be superimposed on vague symptoms related to the developing obstruction, such as flatulence, diarrhea, and variable degrees of abdominal distention. Strictures of the colon may result from cicatricial fibrosis (granulomatous ileocolitis or colitis, nonspecific ulcerative colitis, diverticulitis, venereal lymphopathy) or may occur as postoperative complications (anastomotic stricture, posthemorrhoidectomy). Extraluminal compression, usually caused by primary or metastatic pelvic tumors and rarely by pelvic inflammatory exudates or abscess formation, may obstruct the lower bowel at the level of the rectosigmoid or rectum. Reflux ileus may be encountered in patients with various lesions of the central nervous system. Intestinal atony may follow surgical anesthesia or the trauma of intraabdominal surgical manipulation, extensive rib fractures, or blunt abdominal trauma. Other clinical conditions in which ileus has reportedly occurred as a so-called reflex phenomenon include renal or biliary colic, pneumonia, torsion infarction of an ovarian cyst, coronary thrombosis, and retroperitoneal hemorrhage (fracture of spine or pelvis, dissecting aortic aneurysm, urinary extravasation, rupture of kidney). Paralytic or adynamic ileus occurs most often with purulent peritonitis caused by perforated appendicitis, perforation of a hollow viscus, pelvic inflammatory disease, leakage or dehiscence of an intestinal suture line, or wound evisceration. Ileus may follow the intraperitoneal extravasation of gastric or duodenal contents (perforated peptic ulcer), pancreatic juice (acute hemorrhagic pancreatitis), bile (perforated gallbladder, bile leakage from liver or bile ducts), and blood (postoperative hemorrhage; rupture of liver, spleen, or graafian follicle; ectopic gestation; chocolate cyst of ovary). In Sabiston A, editor: Textbook of surgery, vol 2, Philadelphia, 1986, Saunders, pp 1253-1298. Intestinal Ileus Nonmechanical impairment of intestinal motor function has been descriptively termed reflex, adynamic, or paralytic ileus. As a complication of various causative clinical conditions, the Mesenteric Vascular Occlusion Guillermo Higa and Raul J. Rosenthal 79 The mesenteric circulation receives approximately 25% of cardiac output under resting conditions. Mesenteric circulation is functionally complex, and its location within the peritoneal cavity makes objective assessment difficult. Mesenteric ischemic disorders result from chronic or acute insufficiency of blood flow to all or part of the intestine. Varied etiologies and degrees of ischemia produce different clinical manifestations and pathophysiologic changes requiring prompt diagnosis and aggressive management. Ischemic intestinal injury may be acute or chronic, extensive or segmental, recurrent or transient, and completely reversible. Reduced blood flow may reflect poor systemic perfusion or may result from local changes in the splanchnic vasculature. Narrowing of the major mesenteric vessels, focal atheromatous emboli, vasculitis, and mesenteric vasoconstriction can all lead to inadequate circulation at a cellular level. However, regardless of the cause, the end results include a spectrum of injury ranging from reversible functional alterations to transmural hemorrhagic necrosis throughout the bowel. Factors influencing ischemic injury of the bowel include the state of the general circulation, the extent of collateral blood flow, the response of the mesenteric vasculature to autonomic stimuli, circulating vasoactive substances, local humoral factors, and the products of cellular metabolism before and after reperfusion of the ischemic segment of bowel. Thrombosis of mesenteric artery Mesenteric Ischemia and Infarction Acute intestinal ischemia may be classified as occlusive or nonocclusive. Occlusion may result from an arterial thrombus or an embolus of the celiac or superior mesenteric arteries or from venous occlusion in the same distribution. Arterial embolus most often occurs in patients with chronic or recurrent atrial fibrillation, artificial heart valves, or valvular heart disease; arterial thrombosis is usually associated with extensive atherosclerosis or low cardiac output. Superior mesenteric artery embolus tends to lodge at points of normal anatomic narrowing, usually just distal to the origin of a major branch. An embolus may completely occlude the artery, but usually, partial obstruction of the vessel lumen occurs. Vomiting, anorexia, diarrhea, and constipation also occur frequently but are of little diagnostic help. Examination of the abdomen may reveal tenderness and distention; bowel sounds are often normal, even in patients with severe infarction. Some patients have surprisingly normal findings on abdominal examination despite the severe pain. Mild gastrointestinal bleeding is often detected by examining the stool for occult blood; gross hemorrhage is unusual except in ischemic colitis. A typical laboratory finding is pro- Thrombosis of mesenteric vein Figure 79-1 Mesenteric Vascular Occlusion. Later in the disease course, gangrene of the bowel occurs, with diffuse peritonitis, sepsis, and shock. Abdominal plain films in patients with mesenteric ischemia may reveal air-fluid levels and distention. Barium study of the small intestine reveals nonspecific dilatation, poor motility, and evidence of thick mucosal folds (thumbprinting). Patients thought to have acute arterial embolus should undergo immediate celiac and mesenteric angiography to localize the embolus, followed by embolectomy. Unfortunately, infarction and transmural necrosis are frequently found at surgery, necessitating resection. Arterial or venous thrombosis is not generally amenable to surgical removal of the thrombus; therefore, resection of the affected bowel is required. Similarly, patients with nonocclusive ischemia are not candidates for corrective vascular surgery because major vessels are patent.
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The process is relatively simple compared with the digestive and absorptive process that proteins and fats require breast cancer ribbon tattoo buy 25mg serophene with visa. Starches are the main energy-producing nutrients of all plant foods and consist primarily of amylose and amylopectin breast cancer gene buy serophene with american express. Dietary carbohydrate also includes lactose from milk; fructose menstruation hunger order serophene 50mg with mastercard, glucose menopause supplements purchase 25 mg serophene overnight delivery, and sucrose from vegetables and fruits; and sugars as additives in all drinks. Nonstarch polysaccharides are poorly digested by human enzymes and make up the major component of dietary fiber. Other unavailable carbohydrates that are poorly digested by human enzymes are pectins, gums, lignins, and alginates. These are readily metabolized by the enteric flora, and their products can be absorbed through the small and large intestinal mucosa (see Section V). Starch and sugar digestion occurs with the release of salivary and pancreatic amylases that cleave the -1,4 link of simple disaccharides and a long-chain starch. The degree of activity of salivary amylase depends on the duration of chewing and the proximity of the enzymes in the chyme, as well as the churning of the stomach. However, the major enzyme breakdown of starch occurs through pancreatic amylase activity in the duodenum, and hydrolysis mainly occurs intraluminally in the proximal small intestine. Monosaccharides and disaccharides are presented to the brush border of the enterocytes, where membrane hydrolysis occurs. Lactase, maltase, sucrase-isomaltase, isomaltase, and trehalase-enzymes in the brush border-are most active in the duodenum and jejunum. These enzymes cleave the disaccharides into glucose, galactose, and fructose, which are transported across the mucosa. Transport mechanisms are controversial, but it is agreed that an active sodium-glucose co-transporter exists and that much of the process is sodium dependent. The problems of disaccharidase deficiencies result in significant diarrhea and symptomatic syndromes. Less common are sucrose- and fructose-absorptive deficiencies, and less common and less well known are the trehalose deficiencies that result from absorption after mushroom ingestion. During fat digestion and absorption, fats are passed into the stomach, where gastric lipase may be active and prefers action at one-ester bonds. Approximately 95% of ingested fat is absorbed, undergoing complicated mechanisms to pass into the lymphatics and bloodstream. Intraluminally, the fat is broken down into emulsion droplets, which requires droplets to be coated with a phospholipid. Colipase, lipase, phospholipids, and bile salts are all involved in a complex mechanism of forming micelles, and a lipid phase transformed into an aqueous phase permits transport across the brush border. During this process, triglycerides are broken down into diglycerides and monoglycerides, in addition to the monoglycerides and diglycerides present in foods and absorbed. Bile salts are capable of forming micelles because they are ideal emulsifying agents. An unstirred water layer at the surface of the brush border readily permits short-chain or medium-chain fatty acid absorption but limits long-chain fatty acid absorption. Cholesterol, as well as monoglycerides, diglycerides, and triglycerides, is readily absorbed through these mechanisms. Once within the enterocytes, triglycerides resynthesize, lipoproteins form, and then chylomicrons form. The material is passed into the lymphatic and portal vein systems to the circulation. The process of fat digestion and absorption is complex; Figure 96-1 helps clarify the intraluminal process. It is also now clear that the small intestine has a great ability to adapt to changes through both hypertrophy and development of new transport systems. Dahlquist A, Semenza G: Disaccharidases of small intestine mucosa, J Pediatr Gastroeneterol Nutr 4:857-868, 1985. Some have been verified, others have not; regardless, their functions are important. Epithelial cells secrete a substance into the circulation that acts at a distance. The substance secreted by the epithelial cell affects processes in the cell itself. Neurons secrete chemical transmitters with peptides into synapses or onto other cell types that signal neurotransmission. Figure 97-1 demonstrates the diffuse and integrating effects of the peptide hormone substances gastrin, cholecystokinin, and serotonin. Gastrin secretion into the circulation and production by G cells are stimulated by food, and gastrin acts directly on parietal cells to stimulate acid production. Proteins and high-protein foods have a greater influence than other nutrients on the production of gastrin and on the pH of the stomach. High acid production inhibits gastrin release, and a high gastric pH is a good stimulus for its secretion. Hypergastrinemia occurs in several pathologic states, including Zollinger-Ellison syndrome (see Chapters 41 and 57). When gastric acid and chyme pass into the duodenum, secretin secretion is stimulated. Glucagon is produced by pancreatic alpha cells and in the ileum and colon by L cells. Somatostatin is found in interneurons and has an inhibitory effect by causing muscle relaxation.
Hence pregnancy zicam buy discount serophene 25mg, their peptide backbones follow s lightly different directions womens health 10k order serophene 25 mg online, creating a curvature in the -s heet (this is common) women's health kilojoule counter purchase serophene american express. The ins et on the lower right s hows all atoms of the three s elected -s trands in a s pace- lled cartoon (H-atoms are not s hown women's health ethical issues serophene 100mg with amex, and the view of oleic acid is almos t completely obs tructed). Every other s ide chain of the three -s trands points in the direction of the viewer. Crys tal s tructure and thermodynamic analys is of human brain fatty acid-binding protein. Hence, an increase in the number o interacting strands increases the number o hydrogen bonds per strand, which tends to avor -sheets o unlimited size (see also below). I the strands o a single polypeptide run in antiparallel ashion, just two extra amino acids su ce to accomplish a turn (called a -hairpin; see. However, i such strands run in parallel ashion, a much larger intervening sequence must cover the distance rom the end o one -strand to the beginning o the next -strand. The -sheet consists o antiparallel strands, and it coils into a cylindrical structure. This protein increases the ef ective solubility o atty acids in the cytosol, and it also protects the cell rom the detergent ef ects o the atty acids (see Chapter 27). The side chains point at a right angle to the plane o the ribbon, and they alternate between the two sides o the ribbon. Fibrous proteins (proteins that have a length >10 times their width) sometimes have antiparallel but usually not parallel -sheet structures. Several -strands can orm a single, curved, almost cylindrical -sheet that is called a -barrel. Alternatively, two or more -sheets plus connecting loops can orm the sides o a polygonal body; this arrangement o -sheets is called a -helix. Y another type o strucet ture is called a -propeller; each blade is made up o a -sheet, whereby the -strands closest to the center o the propeller are the shortest and those arthest away rom the center the longest. Mo tifs and Do mains A moti is a protein sequence pattern that is preserved through evolution and conveys a predictable property to a variety o proteins. For instance, Gly*Gly**Gly (* = any single amino acid residue) is a moti that helps a protein bind to a nucleotide. Obviously, these moti s are embedded in (and structurally dependent on) neighboring amino acid residues. A domain consists o a contiguous stretch o amino acid residues that can unction independently o other portions o the polypeptide chain and that is also physically distinct rom them. Another example is glucokinase, which contains two domains that move toward each other when glucose binds. Sometimes, domains are connected by hinges, which are short and exible segments that allow movement o one domain relative to another; such movements are o en a prerequisite or enzyme catalysis. Primary, Se c o ndary, The rtiary, and Quate rnary Pro the in Struc ture The term primary structure re ers to the sequence o amino acids in a protein. The term secondary structure re ers to elements repeatedly seen in the three-dimensional structure o proteins. The term supersecondary structure is sometimes used and re ers to the structure o just a ew (o en three) -helices and -sheets. The term tertiary structure re ers to a description o the relative location o all atoms o a protein in space. Some o these atoms are part o -helices, -sheets, -turns, other loops, moti s, or domains. The term quaternary structure is used or the description o the composition and three-dimensional structure o a protein complex. As detailed in Chapter 16, hemoglobin consists o a heterotetramer o globin subunits. The con ormation o any one globin subunit af ects the con ormation o all other globin subunits. Lo o ps The term loop re ers to the portion o a polypeptide chain that connects elements o secondary structure. Loops or coils vary tremendously in size and may either move around airly reely or else have a xed structure that is neither helical nor sheetlike. In globular proteins, approximately one-third o all amino acid residues are a part o loops. A short -turn typically consists o our amino acid residues and can accomplish a ~180-degree change o direction o the peptide backbone. In a -sheet with antiparallel Structure of Proteins and Protein Aggregates in Degenerative Dis eas es 91 5. Compared with structured, globular proteins, intrinsically disordered proteins or disordered regions o proteins contain ewer hydrophobic amino acids and more polar amino acids. There ore the hydrophobic ef ect, which contributes much to the stability o a structured protein, has signi cantly less ef ect on the structure o intrinsically disordered regions. Furthermore, intrinsically disordered proteins contain more glycine and more proline amino acids than well-structured proteins. The lack o structure in intrinsically disordered regions o proteins may acilitate posttranslational modi cation by enzymes and may help binding to other molecules. Phosphorylation, sul ation, or acetylation may af ect the charge distribution signi cantly and thus alter dramatically the behavior and con ormation o intrinsically disordered proteins. Intrinsically disordered regions generally bind to other molecules with high speci city. They o en also show a relatively low binding a nity, and they unbind relatively rapidly. Many intrinsically disordered regions have enough exibility to bind to several dif erent molecules.
