Lorenzo Biassoni, MSc, FRCP, FEBNM

• Honorary Senior Lecturer, Institute of Child Health,
• University College London
• Consultant in Nuclear Medicine,
• Department of Radiology, Great Ormond Street Hospital for
• Children, London, United Kingdom

Hydrogen bonds are represented in diagrams by dashed or dotted lines antibiotic resistance oxford cheap 50 mg nitrofurantoin, and covalent bonds by solid lines antibiotic viral infection purchase genuine nitrofurantoin online. For example infection mercer generic 50mg nitrofurantoin free shipping, some molecules interact with a "lock-and-key" arrangement that can only occur if both molecules have precisely the correct shape antibiotic associated colitis order 50 mg nitrofurantoin amex, which in turn depends in part upon the number and location of hydrogen bonds antibiotics for sinus ear infection purchase nitrofurantoin no prescription. Although we draw diagrammatic structures of molecules on flat sheets of paper 2013 discount nitrofurantoin 100 mg on-line, molecules are three-dimensional. Within certain limits, the shape of a molecule can be changed without breaking the covalent bonds linking its atoms together. As we will see in subsequent chapters, the three-dimensional, flexible shape of molecules is one of the major factors governing molecular interactions. The ionization of each of these groups can be reversed, as indicated by the double arrows; the ionized carboxyl group can combine with a hydrogen ion to form a nonionized carboxyl group, and the ionized amino group can lose a hydrogen ion and become a nonionized amino group. Free Radicals As described earlier, the electrons that revolve around the nucleus of an atom occupy energy shells, each of which can be occupied by one or more orbitals containing up to two electrons each. An atom is most stable when each orbital in the outer shell is occupied by its full complement of electrons. An atom containing a single (unpaired) electron in an orbital of its outer shell is known as a free radical, as are molecules containing such atoms. Free radicals are unstable molecules that can react with other atoms, through the process known as oxidation. When a free radical oxidizes another atom, the free radical gains an electron and the other atom usually becomes a new free radical. Ionic Molecules the process of ion formation, known as ionization, can occur not only in single atoms, as stated earlier, but also in atoms that are covalently linked in molecules. Note that a free radical configuration can occur in either an ionized (charged) or a nonionized molecule. We begin with a review of some of the properties of water that make it so suitable for life. Water is the most abundant solvent in the body, accounting for 60% of total body weight. A majority of the chemical reactions that occur in the body involve molecules that are dissolved in water, either in the intracellular or extracellular fluid. The covalent bonds linking the two hydrogen atoms to the oxygen atom in a water molecule are polar. Therefore, as noted earlier, the oxygen in water has a partial negative charge, and each hydrogen has a partial positive charge. At temperatures between 08C and 1008C, water exists as a liquid; in this state, the weak hydrogen bonds between water molecules are continuously forming and breaking, and occasionally some water molecules escape the liquid phase and become a gas. If the temperature is increased, the hydrogen bonds break more readily and molecules of water escape into the gaseous state. However, if the temperature is reduced, hydrogen bonds break less frequently, so larger and larger clusters of water molecules form until at 08C, water freezes into a solid crystalline matrix - ice. Body temperature in humans is normally close to 378C, and therefore water exists in liquid form in the body. Nonetheless, even at this temperature, some water leaves the body as a gas (water vapor) each time we exhale during breathing. This water loss in the form of water vapor has considerable importance for total-body-water homeostasis and must be replaced with water obtained from food or drink. Many large molecules in the body are broken down into smaller molecular units by hydrolysis, usually with the assistance of a class of molecules called enzymes. These reactions are usually reversible, a process known as condensation or dehydration. Free radicals are formed by the actions of certain enzymes in some cells, such as types of white blood cells that destroy pathogens. The free radicals are highly reactive, removing electrons from the outer shells of atoms within molecules present in the pathogen cell wall or membrane, for example. In addition, however, free radicals can be produced in the body following exposure to radiation or toxin ingestion. For example, oxidation due to long-term buildup of free radicals has been proposed as one cause of several different human diseases, notably eye, cardiovascular, and neural diseases associated with aging. Thus, it is important that free radicals be inactivated by molecules that can donate electrons to free radicals without becoming dangerous free radicals themselves. Dehydration reactions are responsible for, among other things, building proteins and other large molecules required by the body. Other properties of water that are of importance in physiology include the colligative properties - those that depend on the number of dissolved substances, or solutes, in water. For example, water moves between fluid compartments by the process of osmosis, which you will learn about in detail in Chapter 4. In osmosis, water moves from regions of low solute concentrations to regions of high solute concentrations, regardless of the specific type of solute. Osmosis is the mechanism by which water is absorbed from the intestinal tract (Chapter 15) and from the kidney tubules into the blood (Chapter 14). Having presented this brief survey of some of the physiologically relevant properties of water, we turn now to a discussion of how molecules dissolve in water. Keep in mind as you read on that most of the chemical reactions in the body take place between molecules that are in watery solution. Therefore, the relative solubilities of different molecules influence their abilities to participate in chemical reactions. Molecular Solubility Molecules having a number of polar bonds and/or ionized groups will dissolve in water. In contrast, molecules composed predominantly of carbon and hydrogen are poorly or almost completely insoluble in water because their electrically neutral covalent bonds are not attracted to water molecules. The strong attraction between polar molecules "squeezes" the nonpolar molecules out of the water phase. Such a separation is rarely if ever 100% complete, however, so very small amounts of nonpolar solutes remain dissolved in the water phase. A special class of molecules has a polar or ionized region at one site and a nonpolar region at another site. Such molecules are called amphipathic, derived from Greek terms meaning "love both. This arrangement provides the maximal interaction between water molecules and the polar ends of the amphipathic molecules. Nonpolar molecules can dissolve in the central nonpolar regions of these clusters and thus exist in aqueous solutions in far greater amounts than would otherwise be possible based on their decreased solubility in water. As we will see, the orientation of amphipathic molecules plays an important role in plasma membrane structure (Chapter 3) and in both the absorption of nonpolar molecules from the intestines and their transport in the blood (Chapter 15). For example, the extracellular signaling molecules described in Chapter 1, including neurotransmitters and hormones, cannot alter cellular activity unless they are present in appropriate concentrations in the extracellular fluid. The concentration of a solute in a solution can then be expressed as the number of grams of the substance present in one liter of solution (g/L). A comparison of the concentrations of two different substances on the basis of the number of grams per liter of solution does not directly indicate how many molecules of each substance are present. For example, if the molecules of compound X are heavier than those of compound Y, 10 g of compound X will contain fewer molecules than 10 g of compound Y. Concentrations in units of grams per liter are most often used when the chemical structure of the solute is unknown. When the chemical structure of a molecule is known, concentrations are expressed based upon Nonpolar region Polar region + Amphipathic molecule + ­ + Water molecule (polar) + + + ­ ­ + + + ­ ­ + + + + + + + + + ­ + + ­ + + ­ + + + + ­ ­ + + + + + + + + ­ + + ­ + + Concentration Solute concentration is defined as the amount of the solute present in a unit volume of solution. Their polar regions form hydrogen bonds with water molecules at the surface of the cluster, whereas the nonpolar regions cluster together and exclude water. The molecular weight of a molecule is equal to the sum of the atomic masses of all the atoms in the molecule. For example, glucose (C6H12O6) has a molecular weight of 180 because [(6 3 12) 1 (12 3 1) 1 (6 3 16)] 5 180. One mole (mol) of a compound is the amount of the compound in grams equal to its molecular weight. A solution containing 180 g glucose (1 mol) in 1 L of solution is a 1 molar solution of glucose (1 mol/L). If 90 g of glucose were dissolved in 1 L of water, the solution would have a concentration of 0. Thus, a 1 mol/L solution of glucose contains the same number of solute molecules per liter as a 1 mol/L solution of any other substance. The concentrations of solutes dissolved in the body fluids are much less than 1 mol/L. By convention, the liter (L) term is sometimes dropped when referring to concentrations. Thus, a 1 mmol/L solution is often written as 1 mM (the capital "M" stands for "molar" and is defined as mol/L). An example of the importance of solute concentrations is related to a key homeostatic variable, that of the pH of the body fluids, as described next. Maintenance of a narrow range of pH (that is, hydrogen ion concentration) in the body fluids is absolutely critical to most physiological processes, in part because enzymes and other proteins depend on pH for their normal shape and activity. When hydrochloric acid is dissolved in water, 100% of its atoms separate to form hydrogen and chloride ions, and these ions do not recombine in solution (note the one-way arrow in the preceding reaction). In the case of lactic acid, however, only a fraction of the lactic acid molecules in solution release hydrogen ions at any instant. Therefore, if a 1 mol/L solution of lactic acid is compared with a 1 mol/L solution of hydrochloric acid, the hydrogen ion concentration will be lower in the lactic acid solution than in the hydrochloric acid solution. Hydrochloric acid and other acids that are completely or nearly completely ionized in solution are known as strong acids, whereas carbonic and lactic acids and other acids that do not completely ionize in solution are weak acids. The acidity of a solution thus refers to the free (unbound) hydrogen ion concentration in the solution; the greater the hydrogen ion concentration, the greater the acidity. The brackets around the symbol for the hydrogen ion in the following formula indicate concentration: pH log [H1] Hydrogen Ions and Acidity As mentioned earlier, a hydrogen atom consists of a single proton in its nucleus orbited by a single electron. The most common type of hydrogen ion (H1) is formed by the loss of the electron and is, therefore, a single free proton. In the reactions shown, bicarbonate and lactate are bases because they can combine with hydrogen ions (note the two-way arrows in the two reactions). Also, note that by convention, separate terms are used for the acid forms - lactic acid and carbonic acid - and the bases derived from the acids - lactate and bicarbonate. By combining with As an example, a solution with a hydrogen ion concentration of 1027 mol/L has a pH of 7. Note that as the acidity increases, the pH decreases; a change in pH from 7 to 6 represents a 10-fold increase in the hydrogen ion concentration. The extracellular fluid of the body has a hydrogen ion concentration of about 4 3 1028 mol/L (pH 5 7. Most intracellular fluids have a slightly greater hydrogen ion concentration (pH 7. As we saw earlier, the ionization of carboxyl and amino groups involves the release and uptake, respectively, of hydrogen ions. Chemical Composition of the Body 29 If the electrical charge on a molecule is altered, its interaction with other molecules or with other regions within the same molecule changes, and thus its functional characteristics change. In the extracellular fluid, hydrogen ion concentrations beyond the 10-fold pH range of 7. Even small changes in the hydrogen ion concentration can produce large changes in molecular interaction. For example, many enzymes in the body operate efficiently within very narrow ranges of pH. Should pH vary from the normal homeostatic range due to disease, these enzymes work at reduced rates, creating an even worse pathological situation. We turn now to a description of the molecules essential for life in all living organisms, including humans. These are the carbon-based molecules required for forming the building blocks of cells, tissues, and organs; providing energy; and forming the genetic blueprints of all life. In some cases, such large molecules form when many identical smaller molecules, called subunits or monomers (literally, "one part"), link together. The structure of any polymer depends upon the structure of the subunits, the number of subunits bonded together, and the three-dimensional way in which the subunits are linked. Most of the organic molecules in the body can be classified into one of four groups: carbohydrates, lipids, proteins, and nucleic acids (Table 2. We will consider each of these groups separately, but it is worth mentioning here that many molecules in the body are made up of two or more of these groups. For example, glycoproteins are composed of a protein covalently bonded to one or more carbohydrates. Carbohydrates Although carbohydrates account for only about 1% of body weight, they play a central role in the chemical reactions that provide cells with energy. One of the properties of the carbon atom that makes life possible is its ability to form four covalent bonds with other atoms, including with other carbon atoms. Because carbon atoms can also combine with hydrogen, oxygen, nitrogen, and sulfur atoms, a vast number of compounds can form from relatively few chemical elements. The simplest sugars are the monomers called monosaccharides (from the Greek for "single sugars"), the most abundant of which is glucose, a six-carbon molecule (C6H12O6). Glucose is often called "blood sugar" because it is the major monosaccharide found in the blood. Five carbon atoms and an oxygen atom form a ring that lies in an essentially flat plane.

The active transport of Na1 antibiotic nasal spray for sinusitis generic nitrofurantoin 100 mg line, as previously described virus cleaner order discount nitrofurantoin, results in a decrease in the Na1 concentration on one side of an epithelial layer (the luminal side in our example) and an increase on the other antibiotics for acne is it safe discount 100 mg nitrofurantoin with amex. These changes in solute concentration are accompanied by changes in the water concentration on the two sides because a change in solute concentration bacteria nitrogen cycle discount nitrofurantoin 100 mg on line, as we have seen antibiotics resistant bacteria best order nitrofurantoin, produces a change in water concentration bacteria jokes for kids buy 100mg nitrofurantoin otc. Therefore, net movement of solute across an epithelium is accompanied by a flow of water in the same direction. If the epithelial cells are highly permeable to water, large net movements of water can occur with very small differences in osmolarity. The active transport of Na1 across the cells and into the surrounding interstitial spaces produces an elevated osmolarity in this region and a decreased osmolarity in the lumen. This leads to the osmotic flow of water across the epithelium in the same direction as the net solute movement. The water diffuses through water channels in the membrane and across the tight junctions between the epithelial cells. It is also the major way in which water is absorbed from the intestines into the blood (Chapter 15). Simple diffusion is the movement of molecules from one location to another by random thermal motion. The net flux between two compartments always proceeds from higher to lower concentrations. Diffusion equilibrium is reached when the concentrations of the diffusing substance in the two compartments become equal. The magnitude of the net flux J across a membrane is directly proportional to the concentration difference across the membrane Co 2 Ci, the surface area of the membrane A, and the membrane permeability coefficient P. Nonpolar molecules diffuse through the hydrophobic portions of membranes much more rapidly than do polar or ionized molecules because nonpolar molecules can dissolve in the fatty acyl tails in the lipid bilayer. Ions diffuse across membranes by passing through ion channels formed by integral membrane proteins. The diffusion of ions across a membrane depends on both the concentration gradient and the membrane potential. The flux of ions across a membrane can be altered by opening or closing ion channels. The mediated transport of molecules or ions across a membrane involves binding the transported solute to a transporter protein in the membrane. Changes in the conformation of the transporter move the binding site to the opposite side of the membrane, where the solute dissociates from the protein. The binding sites on transporters exhibit chemical specificity, affinity, and saturation. The magnitude of the flux through a mediated-transport system depends on the degree of transporter saturation, the number of transporters in the membrane, and the rate at which the conformational change in the transporter occurs. Facilitated diffusion is a mediated-transport process that moves molecules from higher to lower concentrations across a membrane by means of a transporter until the two concentrations become equal. Active transport is a mediated-transport process that moves molecules against an electrochemical gradient across a membrane by means of a transporter and an input of energy. Secondary active transport uses the binding of ions (often Na1) to the transporter to drive the secondary-transport process. In secondary active transport, the downhill flow of an ion is linked to the uphill movement of a second solute either in the same direction as the ion (cotransport) or in the opposite direction of the ion (countertransport). Osmosis is the diffusion of water across a membrane from a region of higher water concentration to a region of lower water concentration. The osmolarity - total solute concentration in a solution - determines the water concentration: the higher the osmolarity of a solution, the lower the water concentration. Osmosis across a membrane that is permeable to water but impermeable to solute leads to an increase in the volume of the compartment on the side that initially had the higher osmolarity, and a decrease in the volume on the side that initially had the lower osmolarity. Application of sufficient pressure to a solution will prevent the osmotic flow of water into the solution from a compartment of pure water. Net water movement occurs from a region of lower osmotic pressure to one of higher osmotic pressure. Because water comes to diffusion equilibrium across cell membranes, the intracellular fluid has an osmolarity equal to that of the extracellular fluid. Na1 and Cl2 ions are the major effectively nonpenetrating solutes in the extracellular fluid; potassium ions and various organic solutes are the major effectively nonpenetrating solutes in the intracellular fluid. During endocytosis, regions of the plasma membrane invaginate and pinch off to form vesicles that enclose a small volume of extracellular material. The three classes of endocytosis are (i) fluid endocytosis, (ii) phagocytosis, and (iii) receptor-mediated endocytosis. Most endocytotic vesicles fuse with endosomes, which in turn transfer the vesicle contents to lysosomes for digestion by lysosomal enzymes. Potocytosis is a special type of receptor-mediated endocytosis in which vesicles called caveolae deliver their contents directly to the cytosol. Exocytosis, which occurs when intracellular vesicles fuse with the plasma membrane, provides a means of adding components to the plasma membrane and a route by which membraneimpermeable molecules, such as proteins the cell synthesizes, can be released into the extracellular fluid. In epithelial cells, the permeability and transport characteristics of the apical and basolateral plasma membranes differ, resulting in the ability of cells to actively transport a substance between the fluid on one side of the cell and the fluid on the opposite side. The active transport of Na1 through an epithelium increases the osmolarity on one side of the cell and decreases it on the other, causing water to move by osmosis in the same direction as the transported Na1. Water crosses membranes by (a) diffusing through the lipid bilayer, and (b) diffusing through protein channels in the membrane. What determines the direction in which net diffusion of a nonpolar molecule will occur? In what ways can the net solute flux between two compartments separated by a permeable membrane be increased? Why are membranes more permeable to nonpolar molecules than to most polar and ionized molecules? When considering the diffusion of ions across a membrane, what driving force, in addition to the ion concentration gradient, must be considered? Describe the mechanism by which a transporter of a mediatedtransport system moves a solute from one side of a membrane to the other. What determines the magnitude of flux across a membrane in a mediated-transport system? Describe the direction in which sodium ions and a solute transported by secondary active transport move during cotransport and countertransport. If two solutions with different osmolarities are separated by a water-permeable membrane, why will a change occur in the volumes of the two compartments if the membrane is impermeable to the solutes but no change in volume will occur if the membrane is permeable to solutes? Why do sodium and chloride ions in the extracellular fluid and potassium ions in the intracellular fluid behave as though they were nonpenetrating solutes? What change in cell volume will occur when a cell is placed in a hypotonic solution? How do the mechanisms for actively transporting glucose and Na1 across an epithelium differ? By what mechanism does the active transport of Na1 lead to the osmotic flow of water across an epithelium? Soon after, her leg muscles began cramping and she felt slightly sick to her stomach. Thinking she was losing too much fluid, she stopped for a moment at a water station and drank several cups of water, then continued on. After another 2 miles, she became nauseated and consumed a full 20-ounce bottle of water; a mile later, she began to feel confused and disoriented and developed a headache. At that point, she became panicked that she would not finish the race; even though she did not feel thirsty, she finished yet another bottle of water. Twenty minutes later, she collapsed, lost consciousness, and was taken by ambulance to a local hospital. During the hour before the race, she drank two 20-ounce bottles of water (about 1. As she ran, she was careful to drink a cup of water (5­10 ounces) at each water station, roughly each mile along the course. Perspiration is a dilute solution of several ions, particularly Na1 (the other major ones being Cl2 and K1). The result of excessive sweating is that the total amount of water and Na1 in the body becomes depleted. Our patient was exercising very hard and for a very long time but was not losing as much fluid as she had anticipated because of the cold weather. She was wise to be aware of the potential for fluid loss, but she was not aware that drinking pure water in such quantities could significantly dilute her body fluids. As the concentration of Na1 in her extracellular fluid decreased, the electrochemical gradient for Na1 across her cells - including her muscle and brain cells - also decreased as a consequence. As noted in this chapter and described in detail in Chapters 6 and 9, the electrochemical gradient for Na1 is part of what regulates the function of skeletal muscle and brain cells. Many types of cells, including those of the brain, are seriously damaged when they swell due to water influx. It is even worse in the brain than elsewhere because there is no room for the brain to expand within the skull. As brain cells swell, the fluid pressure in the brain increases, compressing blood vessels and restricting blood flow. When blood flow is reduced, oxygen and nutrient levels decrease and metabolic waste products build up, further contributing to brain cell malfunction. Thus, the combination of water influx, increased pressure, and changes in the electrochemical gradient for Na1 all contributed to the mental disturbances and subsequent loss of consciousness in our patient. This might happen, for example, when someone is dehydrated, as was described earlier in this chapter. In the case of our subject, however, this hormone was counterproductive, because she was already overhydrated. The decrease in urine production caused by nauseainduced increases in antidiuretic hormone only made things worse. The treatment is an intravenous infusion of an isotonic solution of NaCl to bring the total levels of Na1 in the body fluids back toward normal. At the same time, however, the extracellular fluid volume is reduced with a diuretic (a medication that increases urine production). As you will learn in Chapters 6 and 8, a seizure is uncontrolled, unregulated activity of the neurons in the brain; one potential cause of a seizure is a large imbalance in extracellular ion concentrations in the brain. In our patient, gradual restoration of Na1 levels and treatment for the nausea and headache were sufficient to save her life, but careful monitoring of her progress over the course of a 24-hour hospital stay was required. The cells would first swell but then be restored to normal volume after a brief period of time. Diffusion of a solute through a membrane is considerably quicker than diffusion of the same solute through a water layer of equal thickness. Lipid-soluble solutes diffuse more readily through the phospholipid bilayer of a plasma membrane than do watersoluble ones. They can open and close depending on the presence of any of three types of "gates. If a small amount of urea were added to an isoosmotic saline solution containing cells, what would be the result? The cells would first shrink but then be restored to normal volume after a brief period of time. The rate of facilitated diffusion of a solute is limited by the number of transporters in the membrane at any given time. In considering diffusion of ions through an ion channel, which driving force/forces must be considered? Give two examples from this chapter that illustrate the general principle that controlled exchange of materials occurs between compartments and across cellular membranes. Another general physiological principle states that physiological processes are dictated by the laws of chemistry and physics. How does this relate to the movement of solutes through lipid bilayers and its dependence on electrochemical gradients? When diffusion equilibrium is reached, what will the concentration of solute in each compartment be in case A and in case B? When the extracellular concentration of the amino acid alanine is increased, the net flux of the amino acid leucine into a cell is decreased. If a transporter that mediates active transport of a substance has a lower affinity for the transported substance on the extracellular surface of the plasma membrane than on the intracellular surface, in what direction will there be a net transport of the substance across the membrane? Assume that a membrane separating two compartments is permeable to urea but not permeable to NaCl. If compartment 1 contains 200 mmol/L of NaCl and 100 mmol/L of urea, and compartment 2 contains 100 mmol/L of NaCl and 300 mmol/L of urea, which compartment will have increased in volume when osmotic equilibrium is reached? What will happen to cell volume if a cell is placed in each of the following solutions? Characterize each of the solutions in question 7 as isotonic, hypotonic, hypertonic, isoosmotic, hypoosmotic, or hyperosmotic. By what mechanism might an increase in intracellular Na1 concentration lead to an increase in exocytosis? If we assume that the rate of conformational change stays constant, then the greater the number of transporters, the greater the maximal flux that can occur. An isoosmotic solution of a penetrating solute, however, would only partially restore blood volume because some water would enter the intracellular fluid by osmosis as the solute enters cells. This would reduce the rate of Na1 diffusion into the cell through the Na1 channel on the lumen side because the diffusion gradient would be smaller. The secondary structure includes all the helical regions in the lipid bilayer, shown in (a) and (b). The operation of control systems requires that cells be able to communicate with each other, often over long distances.

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Volume expansion caused by high diet sodium is a key factor in driving urine calcium excretion antibiotic resistance kit order 50 mg nitrofurantoin visa, so management of hypercalciuria should include a reduction of dietary sodium bacteria en el estomago sintomas buy nitrofurantoin 50mg online, and therefore sodium excretion antibiotics and xanax side effects buy nitrofurantoin 100 mg cheap, to 100­120 mmol/day antibiotics for acne names 50mg nitrofurantoin for sale. Sodium excretion is still an accurate measure of diet sodium intake even when the patient is on diuretics when you need antibiotics for sinus infection buy nitrofurantoin 100 mg with mastercard, once the patient has been on a stable dose for 2 weeks antibiotics for dogs how long order genuine nitrofurantoin line. However, the urine sodium excretion will reflect the volume status of the patient, which is more germane to the risk of stone formation than the dietary sodium. Phosphorus Approximately 10­15% of calcium stones have calcium phosphate as their major component, and many calcium oxalate contain small amounts of calcium phosphate as the stone nidus [23]. As urine pH rises, the fraction of phosphate existing as monohydrogen phosphate increases, which is the form of phosphate that crystallizes with calcium. Magnesium Approximately 40­50% of dietary magnesium is absorbed from the diet and in steady-state conditions is then excreted in the urine. Hypomagnesuria (<60 mg/day) is felt to be a risk factor for stone formation and usually represents inadequate dietary intake of magnesium or reduced absorption due to intestinal malabsorption [24]. Low urine magnesium is often a better indicator of body stores than serum magnesium levels. Very high magnesium excretion may be an indication of use of magnesium-containing laxatives, and should be noted in any patient in whom diarrhea is suspected of being a cause of stone formation. Sulfate and urea Urine sulfate and urea are both waste products of protein metabolism. Sulfate is only generated by metabolism of sulfur-containing amino acids, which are present in highest concentration in animal flesh and in lower concentrations in vegetable protein. However, in the vast majority of people, sulfate and urea excretion are highly correlated. Sulfate provides an estimate of animal protein intake and is an indicator of dietary acid load, as sulfur amino acids are oxidized to sulfuric acid, which is excreted as sulfate [25]. Since protein intake is strongly associated with purine intake, high protein intake often lead to hyperuricosuria. High-protein diets used for weight loss, such as the Atkins diet, have been associated with an increased risk of urolithiasis [26]. When urine pH is less than 6 and ammonium excretion is high, this suggests the presence of an acid load, usually from a high-protein diet or chronic diarrhea [25]. When acidosis is of short duration, ammonium excretion may only be mildly elevated as a few days are required to reach maximal 24 types of Urinary Stones and their Medical Management levels. Effectiveness of alkali therapy can be monitored by changes in pH and suppression of ammonium production. As supersaturation increases, the risk of nucleation and growth of crystals increases. Urinary stone disease in adults with celiac disease: prevalence, incidence and urinary determinants. Hypomagnesiuric hypocitraturia: an apparent new entity for calcium nephrolithiasis. Effect of low-carbohydrate high-protein diets on acid­base balance, stone-forming propensity, and calcium metabolism. Finally, uric acid stones have been described during a recent outbreak of kidney stones in children related to consumption of melaminecontaminated infant formula [8]. Lifestyle interventions Correction of low urine pH is the cornerstone of therapy in uric acid nephrolithiasis. One limiting side-effect is the development of hyperkalemia, which is primarily seen in patients with underlying chronic kidney disease. A potential complication of xanthine oxidase inhibition in patients with significant hyperuricosuria is the formation of xanthine stones [36] due to xanthinuria resulting from the inhibition of xanthine to uric acid conversion. Periodic re-evaluation of stone size/stone burden is recommended [38], although ultrasound is preferred over non-contrast Ct which is rarely indicated for follow-up. Shock wave lithotripsy and laser lithotripsy are also effective, although radiocontrast material is needed for stone visualization [41,42]. Ammonium urate stones Ammonium urate stones (also described as ammonium acid urate stones) are a rare cause of nephrolithiasis in industrialized countries but are endemic in some countries, particularly in Asia [45]. Summary and conclusions Uric acid stones contribute significantly to the burden of urolithiasis, in particular in stone formers with diabetes, gout or the metabolic syndrome. An overly acidic urine is the key pathogenetic factor in the genesis of uric acid stones, and the major target of therapy. Uric Acid Stones 33 Key points · the metabolic syndrome and its individual features including diabetes and obesity are associated with an increased risk of uric acid stone formation. Characterization of melamine-associated urinary stones in children with consumption of melamine-contaminated infant formula. Urinary calculi composed of uric acid, cystine, and mineral salts: differentiation with dual-energy Ct at a radiation dose comparable to that of intravenous pyelography. Utility of oral dissolution therapy in the management of referred patients with secondarily treated uric acid stones. Efficacy of in vitro stone fragmentation by extracorporeal, electrohydraulic, and pulsed-dye laser lithotripsy. Overview Kidney stones are very common, affecting up to 12% of men and 5% of women in industrialized countries [1], including 900,000 people in the United States each year [2]. Furthermore, over the last 2­3 decades the incidence around the world has increased; for example, it increased nearly three-fold in Germany (0. Since the pathogenesis of most calcium stones remains undefined, it is clear that new knowledge is required to identify Urinary Stones: Medical and Surgical Management, First Edition. Further, urinary proteins such as osteopontin or tamm­Horsfall protein are likely to play a crucial role in CaOx deposition once plaque is exposed to the urinary space [15]. However, the important protein(s) are likely to differ depending on the exact pathogenesis. Net Gi absorption and renal excretion of urinary substances are under genomic influence. Studies suggest that subtle cases of incomplete distal RtA (inability to completely acidify the urine but without systemic acidosis) might be uncovered if ammonium chloride loading was employed [21]. Although protocols were previously advocated to differentiate between patients that have a renal leak of calcium versus intestinal hyperabsorption, it is now appreciated that this strategy is neither clinically necessary nor useful. Overall heritability of urinary calcium excretion has been estimated at ~40% [28]. However, hypercalciuria appears to be a polygenic disorder [29] and the exact molecular defect(s) contributing to it in the majority of stone formers remain undefined. A small subset of hypercalciuric stone formers will have primary hyperparathyroidism. Other important diagnoses to exclude include sarcoidosis and excessive intake of vitamin d and/or calcium antacids. Hyperoxaluria "Mild" hyperoxaluria (40­70 mg/24 h) has been reported in up to 20­30% of idiopathic CaOx stone formers [30] although the mechanism(s) and pathogenic importance for stone formation remain unclear. Whether hyperoxaluria could result from polymorphisms in the three genes implicated in primary hyperoxaluria (alanine glyoxylate transferase [37], glycolate reductase/hydroxypyruvate reductase [38], and 4-hydroxy-2-oxoglutarate aldolase [39]) is unknown. Hypocitraturia Low levels of urinary citrate, an important inhibitor of crystallization, have been identified in 19­63% of patients with calcium urolithiasis [42]. Urinary citrate excretion is predominantly determined by the prevailing acid­base status within proximal tubular cells [43], which in the absence of systemic acidosis is most critically dependent on the net absorption of alkali from the diet [44]. Stones without clear risk factors Occasionally active stone formers are identified that have no clear urinary risk factors in a standard metabolic profile. More recently, two large prospective studies containing both men and women [60,61] have identified specific dietary components that correlated with subsequent stone events. Calcium pills, on the other hand, may slightly increase stone risk 3 lower sodium intake 4 moderate protein intake (0. Potassium citrate is preferred, to limit sodium loads, but must be used in caution in patients with chronic kidney disease. Although no randomized trials have been completed, two effects of the medication should be helpful: increase of urinary pyrophosphate, a crystallization inhibitor, and lowering of urinary calcium, perhaps via inhibition of vitamin d hydroxylation. Calcium Stones 43 Key points Major causes of calcium stones CaOx Hypercalciuria Hyperoxaluria Hypocitraturia Hyperuricosuria Low urine volume CaP High urine pH Low urine citrate Hypercalciuria Components of a diet plan for calcium stones High fluid intake (urine output >2 L/day) Normal dietary calcium (1200 mg/day); no calcium pills Moderate protein (0. Oxalate content of soybean seeds (Glycine max: Leguminosae), soyfoods, and other edible legumes. Pyridoxine effect in type i primary hyperoxaluria is associated with the most common mutant allele. A prospective study of the intake of vitamins C and b6, and the risk of kidney stones in men. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones [see comments]. Randomized prospective study of a nonthiazide diuretic, indapamide, in preventing calcium stone recurrences. Randomized double-blind study of potassium citrate in idiopathic hypocitraturic calcium nephrolithiasis. Struvite stones account for 5% of all renal stones, and because of their association with urinary tract infection, gender prevalence favors females by a ratio of 2:1 [2,3]. Foreign bodies in the urinary tract, including suture material or retained ureteral stents or catheters, can also result in bacterial colonization of the urine and a propensity to form struvite stones [4]. Along with low pH and the presence of various salts, the presence of urea is one of the main factors 50 types of Urinary Stones and their Medical Management that reduces bacterial growth and survival in the urinary tract. Diagnosis and features A definitive diagnosis of struvite calculus is made by urine microscopy or with stone composition ­ either by evaluating a stone which was spontaneously passed by the patient or one which was extracted during endourological or surgical procedures. While efforts have been made to determine stone subtype based on radiographic findings, to date there are no studies which have reported the accurate differentiation of struvite calculi from calcareous stones using plain radiography, computed tomography (Ct), or ultrasound. Once attached to the urothelial cells, the bacteria produce and secrete a thick capsular polysaccharide layer that connects neighboring bacteria, resulting in irreversible adhesion and the formation of a coherent bacterial biofilm on the urothelial surface [17]. Struvite Stones 51 As a result of urease activity, the pH within the polysaccharide layer increases, resulting in the crystallization of struvite and apatite in the immediate vicinity of the biofilm and leading to the formation of nidi for subsequent stone formation [18,19,20]. However, urease activity, although responsible for struvite crystal formation, is not enough to trigger the formation of clinically relevant stones as this process involves additional factors that hold these crystals together to form a mature stone. O-Antigen compositions that bound calcium and magnesium weakly were associated with increased crystallization rates (due to increased supersaturation), while those that bound large amounts of these cations inhibited crystallization [27,28]. As the pH of the surrounding urine increases due to the actions of urease, the forming stone provides a surface for further bacterial attachment and subsequent biofilm formation. Of note, a murine model of struvite urolithiasis was recently reported ­ the authors created cutaneous vesicostomies in megabladder mice and a majority of experimental animals (>85%) formed struvite calculi. Effects on renal function the potential deleterious effects of struvite calculi on renal function are well known. A significant decrease in recurrence of struvite calculi was shown, but significant side-effects were also noted, including headache, deep venous thrombosis, tremulousness, and pulmonary embolism [35,36,37]. Hydroxyurea is another urease inhibitor which has not been studied in a randomized trial [35]. Chronic antibiotic suppression has also been suggested in patients with struvite calculi. An alternative approach is to treat the patient with a course of perioperative antibiotics for 1­2 weeks after struvite stone removal, but to reserve the decision on chronic suppression for patients who have recurrent infection after stone removal. Certainly in patients in whom complete stone removal is not possible because of co-morbidities or stone complexity, chronic antibiotic therapy may be useful in slowing the rate of struvite stone growth [15]. Struvite Stones 53 Irrigation chemolysis in select patients, typically those unfit for endourological treatment and/or those who have had significant side-effects of pharmacotherapy, irrigation chemolysis has been used effectively to treat struvite calculi [39,40]. With specific reference to struvite calculi, an emphasis is placed on complete stone removal, as residual fragments can serve as nidi for recurrent stone formation. As described above, the thick exopolysaccharide layer formed on the stone by bacteria and the stone matrix itself make these stones difficult to treat with antibiotics and urease inhibitors alone. Even small residual stone fragments will harbor bacteria which may then break free, multiply, and lead to the formation of additional struvite calculi. Postoperative, culture-specific antibiotics after removal of struvite calculi are often given for 5­7 days in the absence of infectious complications, though there are no randomized trials which have evaluated this practice. When performing endourological procedures, it is important to obtain both renal pelvic and stone culture in patients with known or suspected struvite calculi. Unique ability of the Proteus mirabilis capsule to enhance mineral growth in infectious urinary calculi. Crystallization of urine mineral components may depend on the chemical nature of Proteus endotoxin polysaccharides. Struvite urolithiasis and chronic urinary tract infection in a murine model of urinary diversion. Stone and pelvic urine culture and sensitivity are better than bladder urine as predictors of urosepsis following percutaneous nephrolithotomy: a prospective clinical study. A genetic disorder should always be considered during evaluation of kidney stones in children and in unusual adult cases. Also, Lesch­Nyhan syndrome which is associated with uric acid stones, and xanthinuria which results in formation of xanthine stones. Genetic Causes of Kidney Stones 59 However, many of the monogenic disorders causing kidney stones have an autosomal recessive pattern of inheritance which may not be readily apparent in the family history. A severe disease course as evidenced by frequent hospital admissions and urological interventions may suggest a genetic cause, and nephrocalcinosis should always prompt a search for a genetic disorder. When viewed by polarized light microscopy (right panel), the medium-sized cystals appear yellow in colour and produce a central Maltese cross pattern. Cystine stones, which are less dense than calcium stones on Ct images, frequently grow very large and can form staghorn calculi. Diagnosis Cystinuria should be suspected in patients presenting with their first kidney stone in childhood or adolescence. Maintaining an alkaline urine at all times is desirable for the most significantly affected individuals. Cystine stones are often not amenable to being fragmented by shock wave lithotripsy, but can be effectively broken up by laser treatment administered through ureteroscopy [9]. Clinical features Most patients present with manifestations of nephrolithiasis and recurrent stone passage is characteristic of the disorder [2].

An important example is the phenomenon of generation of electrical signals in neurons reflects the altered conformation of membrane proteins (ion channels) through which ions can diffuse between extracellular and intracellular fluid infection prevention society purchase cheapest nitrofurantoin and nitrofurantoin. Similarly virus in jamaica discount nitrofurantoin 50mg online, changes in the rate of glucose secretion by the liver induced by the hormone epinephrine reflect the altered activity and concentration of enzymes in the metabolic pathways for glucose synthesis do you need antibiotics for sinus infection buy nitrofurantoin 50mg low cost. Finally antibiotic resistant gonorrhea 2015 best purchase for nitrofurantoin, muscle contraction induced by the neurotransmitter acetylcholine results from the altered conformation of contractile proteins virus 87 buy nitrofurantoin 100mg amex. The diverse sequences of events that link receptor activation to cellular responses are termed signal transduction pathways antibiotics how long generic nitrofurantoin 50 mg with visa. The "signal" is the receptor activation, and "transduction" denotes the process by which a stimulus is transformed into a response. Signal transduction pathways differ between lipidsoluble and water-soluble messengers. As described earlier, the receptors for these two broad chemical classes of messenger are in different locations - the former inside the cell and the latter in the plasma membrane of the cell. The rest of this chapter describes the major features of the signal transduction pathways that these two broad categories of receptors initiate. Chemically, these hormones are all hydrophobic, and the steroid receptors constitute the steroid-hormone-receptor superfamily. Although plasma membrane receptors for a few of these messengers have been identified, most of the receptors in this superfamily are intracellular. In a few cases, the inactive receptors are located in the cytosol and move into the nucleus after binding their hormone. Most of the inactive receptors, however, already reside in the cell nucleus, where they bind to and are activated by their respective ligands. In both cases, receptor activation leads to altered rates of the transcription of one or more genes in a particular cell. The activated receptor complex then functions in the nucleus as a transcription factor, defined as a regulatory protein that directly influences gene transcription. In some cases, the unbound receptor is in the cytosol rather than the nucleus, in which case the binding occurs there, and the messenger-receptor complex moves into the nucleus. In many cases, however, two messenger-receptor complexes must bind together in order to activate a gene. Second, in some cases, the transcription of a gene or genes may be decreased rather than increased by the activated receptor. Cortisol, for example, inhibits transcription of several genes whose protein products mediate inflammatory responses that occur following injury or infection; for this reason, cortisol has important anti-inflammatory effects. Pathways Initiated by Water-Soluble Messengers Water-soluble messengers cannot readily enter cells by diffusion through the lipid bilayer of the plasma membrane. Instead, they exert their actions on cells by binding to the extracellular portion of receptor proteins embedded in the plasma membrane. Water-soluble messengers include most peptide and protein hormones, neurotransmitters, and paracrine­autocrine compounds. On the basis of the signal transduction pathways they initiate, plasma membrane receptors can be classified into the types listed in Table 5. Receptors that themselves function as enzymes, such as receptor tyrosine kinases C. G-protein-coupled receptors that activate G proteins, which in turn act upon effector proteins - either ion channels or enzymes - in the plasma membrane receptors are often referred to as first messengers. Second messengers, then, are substances that enter or are generated in the cytoplasm as a result of receptor activation by the first messenger. The second messengers diffuse throughout the cell to serve as chemical relays from the plasma membrane to the biochemical machinery inside the cell. There are many different protein kinases, and each type is able to phosphorylate only specific proteins. The important point is that a variety of protein kinases are involved in signal transduction pathways. These pathways may involve a series of reactions in which a particular inactive protein kinase is activated by phosphorylation and then catalyzes the phosphorylation of another inactive protein kinase, and so on. Different proteins respond differently to phosphorylation; some are activated and some are inactivated (inhibited). As described in Chapter 3, other enzymes do the reverse of protein kinases; that is, they dephosphorylate proteins. These enzymes, termed protein phosphatases, also participate in signal transduction pathways, but their roles are less understood than those of the protein kinases and will not be described further in this chapter. In addition, when the channel is a Ca21 channel, its opening results in an increase by diffusion in cytosolic Ca21 concentration. Increasing cytosolic Ca21 is another essential event in the transduction pathway for many signaling systems. Receptors That Function as Enzymes the receptors in the second category of plasma membrane receptors listed in Table 5. The typical sequence of events for receptors with intrinsic tyrosine kinase activity is as follows. The binding of a specific messenger to the receptor changes the conformation of the receptor so that its enzymatic portion, located on the cytoplasmic side of the plasma membrane, is activated. This results in autophosphorylation of the receptor; that is, the receptor phosphorylates some of its own tyrosine residues. The newly created phosphotyrosines on the cytoplasmic portion of the receptor then serve as docking sites for cytoplasmic proteins. The bound docking proteins then bind and activate other proteins, which in turn activate one or more signaling pathways within the cell. The common denominator of these pathways is that they all involve activation of cytoplasmic proteins by phosphorylation. Most of the receptors with intrinsic tyrosine kinase activity bind first messengers that typically influence cell proliferation and differentiation, and are often called growth factors. There is one physiologically important exception to the generalization that plasma membrane receptors with inherent enzyme activity function as protein kinases. As described in Chapter 7, receptors that function both as ligand-binding molecules and as guanylyl cyclases are abundantly expressed in the retina of the eye, where they are important for processing visual inputs. This Control of Cells by Chemical Messengers 125 Receptors That Are Ligand-Gated Ion Channels In the first type of plasma membrane receptor listed in Table 5. Because the opening of ion channels has been compared to the opening of a gate in a fence, these types of channels are known as ligand-gated ion channels. They are particularly prevalent in the plasma membranes of neurons, as you will learn in Chapter 6. The opening of ligand-gated ion channels in response to binding of a first messenger results in an increase in the net diffusion across the plasma membrane of one or more types of ions specific to that channel. Note that the receptor exists in two conformations in the unbound and bound states. It is the binding of the first messenger to its receptor that triggers the conformational change that leads to opening of the channel. Note: Conformational changes also occur in panels b­d but only the bound state is shown for simplicity. Nitric oxide is a lipid-soluble gas produced from the amino acid arginine by the action of an enzyme called nitric oxide synthase, which is present in numerous cell types including the cells that line the interior of blood vessels. As you will learn in Chapter 12, the ability of certain blood vessels to dilate is an important part of the homeostatic control of the circulation of blood and of blood pressure. Receptors That Interact with Cytoplasmic Janus Kinases Recall that in the previous category, the receptor itself has intrinsic enzyme activity. The binding of a first messenger to the receptor causes a conformational change in the receptor that leads to activation of the janus kinase. Different receptors associate with different members of the janus kinase family, and the different janus kinases phosphorylate different target proteins, many of which act as transcription factors. One significant example of signals mediated primarily via receptors linked to janus kinases are those of the cytokines - proteins secreted by cells of the immune system that play a critical role in immune defenses (Chapter 18). In essence, then, a G protein serves as a switch to couple a receptor to an ion channel or to an enzyme in the plasma membrane. The G protein may cause the ion channel to open, with a resulting change in electrical signals or, in the case of Ca21 channels, changes in the cytosolic Ca21 concentration. Alternatively, the G protein may activate or inhibit the membrane enzyme with which it interacts. Such enzymes, when activated, cause the generation of second messengers inside the cell. This cleavage renders the alpha subunit inactive, allowing it to recombine with its beta and gamma subunits. There are several subfamilies of plasma membrane G proteins, each with multiple distinct members, and a single receptor may be associated with more than one type of G protein. Moreover, some G proteins may couple to more than one type of plasma membrane effector protein. In this way, a firstmessenger-activated receptor, via its G-protein couplings, can call into action a variety of plasma membrane proteins such as ion channels and enzymes. To illustrate some of the major points concerning G proteins, plasma membrane effector proteins, second messengers, and protein kinases, the next two sections describe the two most common effector protein enzymes regulated by G proteins - adenylyl cyclase and phospholipase C. In addition, the subsequent portions of the signal transduction pathways in which they participate are described. This causes Gs to activate its effector protein, the membrane enzyme called adenylyl cyclase (also known as adenylate cyclase). Recall that Control of Cells by Chemical Messengers 127 G-Protein-Coupled Receptors the fourth category of plasma membrane receptors in Table 5. Bound to the inactive receptor is a protein complex located on the cytosolic surface of the plasma membrane and belonging to the family of proteins known as G proteins. The binding of a first messenger to the receptor changes the conformation of the receptor. This dissociation allows the activated alpha subunit to link up with still another plasma membrane protein, either an ion channel or an enzyme. Not shown in the figure is the existence of another regulatory protein, Gi, which certain receptors can react with to cause inhibition of adenylyl cyclase. Chapter 5 protein kinases phosphorylate other proteins - often enzymes - by transferring a phosphate group to them. Again, recall that each of the various protein kinases that participate in the multiple signal transduction pathways described in this chapter has its own specific substrates. While it is active, a single enzyme molecule is capable of transforming into product not one but many substrate molecules, let us say 100. At each of the two subsequent enzyme-activation steps in our example, another 100-fold amplification occurs. Therefore, the end result is that a single molecule of the first messenger could, in this example, cause the generation of 1 million product molecules. This helps to explain how hormones and other messengers can be effective at extremely low extracellular concentrations. To take an actual example, one molecule of the hormone epinephrine can cause the liver to generate and release 108 molecules of glucose. For example, the enzyme catalyzing the rate-limiting step in glycogen synthesis is inhibited by phosphorylation. This explains how epinephrine inhibits glycogen synthesis at the same time it stimulates glycogen breakdown by activating the enzyme that catalyzes the latter response. Not mentioned thus far is the fact that receptors for some first messengers, upon activation by their messengers, inhibit adenylyl cyclase. Control of Cells by Chemical Messengers 129 (the subscript i denotes "inhibitory"). This common cellular feature highlights the general principle that most physiological functions are controlled by multiple regulatory systems, often working in opposition. Phospholipase C, Diacylglycerol, and Inositol Trisphosphate In this system, a G protein called Gq is activated by a receptor bound to a first messenger. Activated Gq then activates a plasma membrane effector enzyme called phospholipase C. Because the concentration of Ca21 is much greater in the endoplasmic reticulum than in the cytosol, Ca21 diffuses out of this organelle into the cytosol, significantly increasing cytosolic Ca21 concentration. However, it is worth noting that one of the actions of Ca21 is to help activate some forms of protein kinase C (which is how this kinase got its name - C for "calcium"). This is known as direct G-protein gating of plasma membrane ion channels because the G protein interacts directly with the channel. All the events occur in the plasma membrane and are independent of second messengers. This receptor is a ligand-gated ion channel that, when opened, allows the release of calcium ions from the endoplasmic reticulum into the cytosol. Common Mechanisms by Which Stimulation of a Cell Leads to an Increase in Cytosolic Ca21 Concentration I. To generalize, the indirect G-protein gating of ion channels utilizes a secondmessenger pathway for the opening or closing of the channel. The physiology of Ca21 as a second messenger requires an analysis of two broad questions: (1) How do stimuli cause the cytosolic Ca21 concentration to increase? Note that, for simplicity, our two questions are phrased in terms of an increase in cytosolic concentration. By means of active-transport systems in the plasma membrane and cell organelles, Ca21 is maintained at an extremely low concentration in the cytosol. Consequently, there is always a large electrochemical gradient favoring diffusion of Ca21 into the cytosol via Ca21 channels found in both the plasma membrane and the endoplasmic reticulum. A stimulus to the cell can alter this steady state by influencing the active-transport systems and/or the ion channels, resulting in a change in cytosolic Ca21 concentration. The most common ways that receptor activation by a first messenger increases the cytosolic Ca21 concentration have already been presented in this chapter and are summarized in the top part of Table 5. The common denominator of Ca21 actions is its ability to bind to various cytosolic proteins, altering their conformation and thereby activating their function.