Wei Dong Gao, M.B., M.D., M.S., Ph.D.

• Associate Professor of Anesthesiology and Critical Care Medicine

https://www.hopkinsmedicine.org/profiles/results/directory/profile/0016624/wei-dong-gao

This initial set of guidelines will provide a standardized terminology for the evaluation and classification of kidney disease; the proper monitoring of kidney function from initial injury to end stage; a logical approach to stratification of kidney disease by risk factors and comorbid conditions; and consequently a basis for continuous care and therapy throughout the course of chronic kidney disease medicine 600 mg meclizine 25 mg without a prescription. While considerable effort has gone into the development of the guidelines during the past 24 months 85 medications that interact with grapefruit order 25 mg meclizine otc, and great attention has been paid to detail and scientific rigor moroccanoil treatment order 25mg meclizine with amex, it is only their incorporation into clinical practice that will assure their applicability and practical utility 2c19 medications effective 25 mg meclizine. In a voluntary and multidisciplinary undertaking of such magnitude, numerous others have made valuable contributions to these guidelines but cannot be individually acknowledged here. In the United States, there is a rising incidence and prevalence of kidney failure, with poor outcomes and high cost. Increasing evidence, accrued in the past decades, indicates that the adverse outcomes of chronic kidney disease, such as kidney failure, cardiovascular disease, and premature death, can be prevented or delayed. Earlier stages of chronic kidney disease can be detected through laboratory testing. Treatment of earlier stages of chronic kidney disease is effective in slowing the progression toward kidney failure. Initiation of treatment for cardiovascular risk factors at earlier stages of chronic kidney disease should be effective in reducing cardiovascular disease events both before and after the onset of kidney failure. Unfortunately, chronic kidney disease is ``under-diagnosed' and ``under-treated' in the United States, resulting in lost opportunities for prevention. One reason is the lack of agreement on a definition and classification of stages in the progression of chronic kidney disease. A clinically applicable classification would be based on laboratory evaluation of the severity of kidney disease, association of level of kidney function with complications, and stratification of risks for loss of kidney function and development of cardiovascular disease. The Work Group charged with developing the guidelines consisted of experts in nephrology, pediatric nephrology, epidemiology, laboratory medicine, nutrition, social work, gerontology, and family medicine. An Evidence Review Team, consisting of nephrologists and methodologists, was responsible for assembling the evidence. Defining chronic kidney disease and classifying the stages of severity would provide a common language for communication among providers, patients and their families, investigators, and policy-makers and a framework for developing a public health approach to affect care and improve outcomes of chronic kidney disease. More reliable estimates of the prevalence of earlier stages of disease and of the population at increased risk for development of chronic kidney disease 2. Evaluation of factors associated with a high risk of progression from one stage to the next or of development of other adverse outcomes 5. The Work Group did not specifically address evaluation and treatment for chronic kidney disease. However, this guideline contains brief reference to diagnosis and clinical interventions and can serve as a ``road map,' linking other clinical practice guidelines and pointing out where other guidelines need to be developed. The first three of these, on bone disease, dyslipidemia, and blood pressure management are currently under development. Other guidelines on cardiovascular disease in dialysis patients and kidney biopsy will be initiated in the Winter of 2001. This report contains a summary of background information available at the time the Work Group began its deliberations, the 15 guidelines and the accompanying rationale, suggestions for clinical performance measures, a clinical approach to chronic kidney disease using these guidelines, and appendices to describe methods for the review of evidence. The guidelines are based on a systematic review of the literature and the consensus of the Work Group. The target population includes individuals with chronic kidney disease or at increased risk of developing chronic kidney disease. In particular, the classification of stages of disease and principles of diagnostic testing are similar. A subcommittee of the Work Group examined issues related to children and participated in development of the first six guidelines of the present document. A separate set of guidelines for children will have to be developed by a later Work Group. The target audience includes a wide range of individuals: those who have or are at increased risk of developing chronic kidney disease (the target population) and their families; health care professionals caring for the target population; manufacturers of instruments and diagnostic laboratories performing measurements of kidney function; agencies and institutions planning, providing or paying for the health care needs of the target population; and investigators studying chronic kidney disease. There will be only brief reference to clinical interventions, sufficient to provide a basis for other clinical practice guidelines relevant to the evaluation and management of chronic kidney disease. Executive Summary 3 Classification of Chronic Kidney Disease Table 3 shows the classification of stages of chronic kidney disease, including the population at increased risk of developing chronic kidney disease, and actions to prevent the development of chronic kidney disease and to improve outcomes in each stage. The word ``kidney' is of Middle English origin and is immediately understood by patients, their families, providers, health care professionals, and the lay public of native English speakers. On the other hand, ``renal' and ``nephrology,' derived from Latin and Greek roots, respectively, commonly require interpretation and explanation. Currently, there is no uniform classification of the stages of chronic kidney disease. A review of textbooks and journal articles clearly demonstrates ambiguity and overlap in the meaning of current terms. The Work Group concluded that uniform definitions of terms and stages would improve communication between patients and providers, enhance public education, and promote dissemination of research results. In addition, it was believed that uniform definitions would enhance conduct of clinical research. Adverse outcomes of kidney disease are based on the level of kidney function and risk of loss of function in the future. Many disciplines in medicine, including related specialties of hypertension, cardiovascular disease, diabetes, and transplantation, have adopted classification systems based on severity to guide clinical interventions, research, and professional and public education. Providers and patients are familiar with the concept that ``the kidney is like a filter. In addition, expressing the level of kidney function on a continuous scale allows development of patient and public education programs that encourage individuals to ``Know your number! Rather, it is a learned term, which allows the ultimate expression of the complex functions of the kidney in one single numerical expression. Conversely, numbers are an intuitive concept and easily understandable by everyone. No clinical practice guideline, irrespective of the rigor of its development, can accomplish its intended improvement in outcome without an implementation plan. The process has been set in motion in parallel with that of development of the guidelines. Evidence model for stages in the initiation and progression of chronic kidney disease, and therapeutic interventions. Thick arrows between ellipses represent factors associated with initiation and progression of disease that can be affected or detected by interventions: susceptibility factors (black); initiation factors (dark gray); progression factors (light gray); and end-stage factors (white). It is anticipated that clinical practice guidelines for interventions to reduce adverse outcomes in patients with chronic kidney disease can be based on this model. This line of logic allows for the ultimate construction of a list of modifiable risk factors at each stage of chronic kidney disease, as shown in Table 5. A detailed explanation of these methods is provided in Part 10, Appendices 1 and 2; Table 6 provides a brief listing of the steps involved in this approach. Applicability Applicability (also known as generalizability or external validity) addresses the issue of whether the study population is sufficiently broad so that the results can be generalized to the population of interest at large. The study population is typically defined by the inclusion and exclusion criteria. A designation for applicability was assigned to each article, according to a three-level scale. Results Results are represented by prevalence levels, proportions (percents) for categorical variables, mean levels for continuous variables, and associations between study measures. Executive Summary 9 the specific meanings of these symbols are explained in the footnotes of tables where they appear. Some informative studies reported only single point estimates of study measures (eg, mean data) rather than associations. Where data on associations were limited, evidence tables provide these point estimates. Studies that provide data on associations and studies that provide only point estimates are listed and ranked separately, with shading used to distinguish them (as in the table, Example of Format for Evidence Tables). Quality Methodological quality (or internal validity) refers to the design, conduct, and reporting of the clinical study. Because studies with a variety of types of design were evaluated, a three-level classification of study quality was devised: Strength of Evidence Each rationale statement has been graded according the level of evidence on which it is based. The reader is referred to specific pages for rationale, evidence tables and references. The goal of Part 4 is to create an operational definition and classification of stages of chronic kidney disease and provide estimates of disease prevalence by stage, to develop a broad overview of a ``clinical action plan' for evaluation and management of each stage of chronic kidney disease, and to define individuals at increased risk for developing chronic kidney disease. Studies of disease prevalence were evaluated as described in Appendix 1, Table 147. Earlier stages of chronic kidney disease can be detected through routine laboratory measurements.

Of course treatment refractory discount 25mg meclizine with visa, calibration with a second pH standard such as the 1:1 phosphate buffer (pH = 6 treatment anal fissure discount meclizine 25 mg. These included stability and compatibility with biological fluids and a temperature coefficient which more closely approximates that of whole blood than does the phosphate buffer [2] medicine 10 day 2 times a day chart order 25 mg meclizine with visa. This buffer should be considered a secondary standard until more extensive studies of the liquid junction problem are completed medications quotes generic meclizine 25 mg without prescription. While their data indicate liquid junction problems with these instruments, the interpretation of their findings is not unequivocal, since they also find pH errors when a physiologic phosphate buffer is measured. The pH errors with the Tris buffers are somewhat larger but also exhibit both positive and negative deviations from the expected values. While the Tris buffer may not be suitable for use as a primary standard, Ladenson, et at. It also proved to be convenient and effective in monitoring the performance of these analyzers. It is obvious that much more extensive research must be carried out to elucidate the nature and magnitude of this problem. Whereas the Tris buffer may eventually prove to be unsuitable as a pH standard, there are many other possible materials for use as clinical pH buffers, such as the materials in the list published in 1966 by Good, et at. One of these, tris(hydroxymethyl)methylglycine ("Tricine"), was the subject of a recent study by Bates and coworkers [6] who found that a solution consisting of 0. 0 One very important area of development is the use of these electrodes in automatic, multi -electrolyte clinical analyzers. As in the case of the pH electrode, standards are also required for the reliable application of these sensors [7]. In considering the certification of ion activity standards, one important difference exists in regard to the measurement process. This consideration requires that more reliance be placed on the activity scales and theoretical conventions used in calculating the single-ion activities. The details of this ion activity scale have been reviewed by Bates [10] and will not be repeated here. As in the case of the pH scale, it is necessary to make certain extra-thermodynamic assumptions. The "conventional" step in the hydration treatment is the assignment of hydration numbers to individual ionic species. The hydration numbers are calculated from smoothed values of Y ^x the hydration number for the electrolyte and 0 using the Stokes-Robinson hydration theory. For the present scale, the hydration number for the chloride ion was taken to be Ionic zero, and the other ionic hydration numbers are referred to this convention [10]. One way to avoid this latter difficulty is to prepare ionic activity buffers which can extend the low activity limit by several orders of magnitude. Not only was the response linear and approximately Nernstian over 25 decades of concentration, but whereas the response time of the electrode in unbuffered silver ion solutions increased with decreasing concentration, in the silverbuffered solutions, the electrode response was almost immediate, i. While the concept of "metal buffers" is not new, their use in the calibration of ionselective electrodes has been studied primarily by workers in Denmark and Hungary [12-17]. In Denmark, Blum and Fog developed water-soluble buffers for copper which avoid the slowness of solution equilibration inherent in precipitate- type buffers which involve heterogeneous equilibria [12]. In Hungary, Havas, Kaszas, and Varsanyi have reported [16] the development of mixed precipitate buffers for the halides (including fluoride) and silver ion. They demonstrated their technique with iodide and silver and also indicated that sulfide, fluoride and thiocyanate could be generated electrochemically Although the solutions are not buffered, an advantage of such a procedure is that it could be automated and is more reproducible than the serial dilution method. Great care must be exercised, however, in applying either the "pure" electrolyte or buffered standards to the calibration of ion-selective electrodes below the point where the pure electrolyte response begins to deviate from linearity. It is clear that much more work is required to develop ion activity standards which will be suitable for most applications and acceptable to everyone. Standards for the Future As the requirements of clinical laboratories and available instrumentation become more refined, data for salt effects and medium effects on electrolytes and gases are needed to provide the basis for the development and certification of the required standards and quality control materials. We plan to obtain data for ionic equilibrium processes in saline media, to develop accurate methods for determining ion concentrations and gas tensions, and to develop multicomponent standards for calibration of the clinical instruments used for the determination of pH, dissolved gases, and electrolytes in various biological fluids. Ultimately such standards may contain all of the major ionic constituents, complexing agents, and non-electrolytes at levels approximating those in the real samples. Only when such standards are available will it be feasible to calibrate multi-parameter clinical instruments conveniently and with some assurance of the consistency and comparability of data obtained in different laboratories. As far as the major ionic constituents are concerned, the first step in this direction has already been taken [18]. The primary purpose of this system is to cause a constant temperature water bath to cycle through a preprogrammed set of temperatures and to record the data when the bath temperature and potentials read from the measurement cells pass certain stability and control requirements. A centrally the temperature-controlled emf measurement system is diagrammed in figure 1. The data communications system consists of four main parts: (1) the digital data bus, (2) the computer interface, (3) the laboratory logic box interface, and (4) the laboratory control console. The computer interface connects the the computer to the laboratory via the digital data bus and laboratory interface. The laboratory interface contains the logic circuitry by a multi-level time-sharing scheme. Data necessary to connect as many as four experimental systems to the digital data bus. I In performing a pH certification, the first requirement is to prepare the buffer solutions As specified in the pH certificates, the carefully and measurement cells with utmost care. For buffers in the neutral and basic regions, carbon dioxide must also be removed from the water prior to dissolution the hydrogen gas is purified of oxygen by passage through a catalytic of the buffer salts. Details of the preparation of the platinized (or palladized) platinum and the silver/silver chloride electrodes can be found in references [20] and [21]. View of the measurement facility including the water bath, instrument rack and laboratory logic box interface (open on rear wall). Another view, figure 5, shows the entire electronics rack Briefly, the equipment in cells on the laboratory bench top. Close-up view of the instrument rack with thermostated standard cells on the laboratory bench to the right. The functions multiplexed include: temperature (platinum resistance), standard resistor (calibration), standard emf cells (calibration), and up to ten measurement cells. The control console permits communication with the computer via a series of thumbwheel switches which enter all of the required input parameters. The control console also includes a set of pushbuttons which are used to set up, start (send), and terminate the experiment, as well as indicator lights which signal operations (data acquisition, operate, auto, ete. The remainder of the equipment in the rack constitutes the Mueller bridge system for manual checking of the water bath temperature via the second platinum resistance thermometer shown in figure 3. When the bath temperature achieves the nominal value, within certain preset control limits as indicated by the platinum resistance thermometer, the input multiplexer automatically switches through the readout positions. After a programmed time delay, the multiplexer recycles through the positions and compares the values to the previous sets of data. After three cycles, if the data agree within the requisite control limits, the computer sets the temperature control to the next sequence value and the operation is repeated. If any of the values exceed the control limits, an out-of-range message is printed next to the incorrect value and, following two more cycles, the computer proceeds to the next sequence temperature after again flagging the out-of-range value. Depending on the temperature value or the direction of the temperature change, the computer turns on the refrigeration unit or an auxiliary heater. After the temperature sequence is completed, the routine is automatically terminated. The data reduction consists of a series of operations including correcting the experimental emf values to the standard partial pressure of hydrogen, calculating the acidity functions, extrapolating to zero molality of added chloride to obtain the limiting acidity functions, evaluating the chloride ion activity coefficient using the Bates-Guggenheim pH convention, and finally calculating the pa^ values. These experimental values are then smoothed with respect to temperature by the method of least squares to give the certified pH(S) values. Reference Electrodes (Academic Press, New York, 255 National Bureau of Standards Special Publication 450.

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The details of this system are relatively complex treatment high blood pressure quality 25mg meclizine, and a textbook of immunology should be consulted medicine of the prophet cheap 25mg meclizine mastercard. This results in cell lysis and generation of peptide or polypeptide fragments that are involved in various aspects of inflammation (chemotaxis medicine river animal hospital 25 mg meclizine otc, phagocytosis symptoms pneumonia buy 25 mg meclizine with visa, etc). The system has other functions, such as clearance of antigen-antibody complexes from the circulation. Activation of the complement system is triggered by one of two routes, called the classic and the alternative pathways. The first involves interaction of C1 with antigenantibody complexes, and the second (not involving antibody) involves direct interaction of bacterial cell surfaces or polysaccharides with a component designated C3b. Gabay C, Kushner I: Acute-phase proteins and other systemic responses to inflammation. Rational management of these conditions requires a clear understanding of the bases of blood clotting and fibrinolysis. It forms at the site of an injury or abnormal vessel wall, particularly in areas where blood flow is rapid (arteries). It morphologically resembles the clot formed in a test tube and may form in vivo in areas of retarded blood flow or stasis (eg, veins) with or without vascular injury, or it may form at a site of injury or in an abnormal vessel in conjunction with an initiating platelet plug. This separation of clotting factors and platelets is artificial, since both play intimate and often mutually interdependent roles in hemostasis and thrombosis, but it facilitates description of the overall processes involved. These processes encompass blood clotting (coagulation) and involve blood vessels, platelet aggregation, and plasma proteins that cause formation or dissolution of platelet aggregates. In hemostasis, there is initial vasoconstriction of the injured vessel, causing diminished blood flow distal to the injury. Then hemostasis and thrombosis share three phases: (1) Formation of a loose and temporary platelet aggregate at the site of injury. Both Intrinsic & Extrinsic Pathways Result in the Formation of Fibrin Two pathways lead to fibrin clot formation: the intrinsic and the extrinsic pathways. Initiation of the fibrin clot in response to tissue injury is carried out by the extrinsic pathway. How the intrinsic pathway is activated in vivo is unclear, but it involves a negatively charged surface. The intrinsic and extrinsic pathways converge in a final common pathway involving the activation of prothrombin to thrombin and the thrombin-catalyzed cleavage of fibrinogen to form the fibrin clot. The events depicted below factor Xa are designated the final common pathway, culminating in the formation of cross-linked fibrin. In addition, thrombin and factor Xa feedback-activate at the two sites indicated (dashed arrows). Factor V Activated by thrombin; factor Va is a cofactor in the activation of prothrombin by factor Xa. The numbers indicate the order in which the factors have been discovered and bear no relationship to the order in which they act. Tissue factor these factors are usually not reCa2+ ferred to as coagulation factors. It results in the production of factor Xa (by convention, activated clotting factors are referred to by use of the suffix a). In vivo, the proteins probably assemble on endothelial cell membranes, whereas glass or kaolin can be used for in vitro tests of the intrinsic pathway. Protein S Acts as a cofactor of protein C; both proteins contain Gla (-carboxyglutamate) residues. ThromboProtein on the surface of endothelial modulin cells; binds thrombin, which then activates protein C. This in turn cleaves an Arg-Ile bond in factor X (56 kDa) to produce the twochain serine protease, factor Xa. For assembly of the tenase complex, the platelets must first be activated to expose the acidic (anionic) phospholipids, phosphatidylserine and phosphatidylinositol, that are normally on the internal side of the plasma membrane of resting, nonactivated platelets. The activation of prothrombin, like that of factor X, occurs on the surface of activated platelets and requires the assembly of a prothrombinase complex, consisting of platelet anionic phospholipids, Ca2+, factor Va, factor Xa, and prothrombin. Activation of factor X provides an important link between the intrinsic and extrinsic pathways. The Ca2+ is bound to anionic phospholipids of the plasma membrane of the activated platelet. The release of the fibrinopeptides by thrombin generates fibrin monomer, which has the subunit strucXa Glan 1 2 A ture (.)2. The removal of the fibrinopeptides exposes binding sites that allow the molecules of fibrin monomers to aggregate spontaneously in a regularly staggered array, forming an insoluble fibrin clot. It is the formation of this insoluble fibrin polymer that traps platelets, red cells, and other components to form the white or red thrombi. This initial fibrin clot is rather weak, held together only by the noncovalent association of fibrin monomers. Levels of Circulating Thrombin Must Be Carefully Controlled or Clots May Form Once active thrombin is formed in the course of hemostasis or thrombosis, its concentration must be carefully controlled to prevent further fibrin formation or platelet activation. The site of the catalytically active serine residue is indicated by the solid triangle. The A and B chains of active thrombin (shaded) are held together by the disulfide bridge. Diagrammatic representation (not to scale) of fibrinogen showing pairs of A, B, and chains linked by disulfide bonds. This is the basis for the use of heparin in clinical medicine to inhibit coagulation. Thrombin is involved in an additional regulatory mechanism that operates in coagulation. A genetic deficiency of either protein C or protein S can cause venous thrombosis. A: Thrombin-induced cleavage of Arg-Gly bonds of the A and B chains of fibrinogen to produce fibrinopeptides (left-hand side) and the and chains of fibrin monomer (right-hand side). These proteins, all of which are synthesized in the liver, are dependent on the Ca2+binding properties of the Gla residues for their normal function in the coagulation pathways. The coumarins act by inhibiting the reduction of the quinone derivatives of vitamin K to the active hydroquinone forms (Chapter 45). Thus, the administration of vitamin K will bypass the coumarin-induced inhibition and allow maturation of the Gla-containing factors. Heparin and warfarin are widely used in the treatment of thrombotic and thromboembolic conditions, such as deep vein thrombosis and pulmonary embolus. Fibrin Clots Are Dissolved by Plasmin As stated above, the coagulation system is normally in a state of dynamic equilibrium in which fibrin clots are constantly being laid down and dissolved. Plasmin, the serine protease mainly responsible for degrading fibrin and fibrinogen, circulates in the form of its inactive zymogen, plasminogen (90 kDa), and any small amounts of plasmin that are formed in the fluid phase under physiologic conditions are rapidly inactivated by the fastacting plasmin inhibitor, 2-antiplasmin.

Cleavage of these propeptides may occur within crypts or folds in the cell membrane symptoms stroke discount meclizine 25 mg on-line. Once the propeptides are removed medications restless leg syndrome 25mg meclizine otc, the triple helical collagen molecules treatment zit discount meclizine 25mg with mastercard, containing approximately 1000 amino acids per chain osteoporosis treatment purchase 25 mg meclizine overnight delivery, spontaneously assemble into collagen fibers. The same cells that secrete collagen also secrete fibronectin, a large glycoprotein present on cell surfaces, in the extracellular matrix, and in blood (see below). Fibronectin binds to aggregating precollagen fibers and alters the kinetics of fiber formation in the pericellular matrix. Diseases caused by mutations in collagen genes or by deficiencies in the activities of posttranslational enzymes involved in the biosynthesis of collagen. However, its breakdown is increased during starvation and various inflammatory states. A Number of Genetic Diseases Result From Abnormalities in the Synthesis of Collagen About 30 genes encode collagen, and its pathway of biosynthesis is complex, involving at least eight enzyme-catalyzed posttranslational steps. Ehlers-Danlos syndrome comprises a group of inherited disorders whose principal clinical features are hyperextensibility of the skin, abnormal tissue fragility, and increased joint mobility. Electron microscopy reveals characteristic abnormalities of the structure of the basement membrane and lamina densa. This collagen forms delicate fibrils that anchor the basal lamina to collagen fibrils in the dermis. These anchoring fibrils have been shown to be markedly reduced in this form of the disease, probably resulting in the blistering. Epidermolysis bullosa simplex, another variant, is due to mutations in keratin 5 (Chapter 49). However, it is due to a deficiency of ascorbic acid (Chapter 45) and is not a genetic disease. These signs reflect impaired synthesis of collagen due to deficiencies of prolyl and lysyl hydroxylases, both of which require ascorbic acid as a cofactor. Some of the prolines of tropoelastin are hydroxylated to hydroxyproline by prolyl hydroxylase, though hydroxylysine and glycosylated hydroxylysine are not present. However, the major cross-links formed in elastin are the desmosines, which result from the condensation of three of these lysine-derived aldehydes with an unmodified lysine to form a tetrafunctional crosslink unique to elastin. Elastin exhibits a variety of random coil conformations that permit the protein to stretch and subsequently recoil during the performance of its physiologic functions. The mutations, by affecting synthesis of elastin, probably play a causative role in the supravalvular aortic stenosis often found in this condition. A number of skin diseases (eg, scleroderma) are associated with accumulation of elastin. Fragmentation or, alternatively, a decrease of elastin is found in conditions such as pulmonary emphysema, cutis laxa, and aging of the skin. It affects the eyes (eg, causing dislocation of the lens, known as ectopia lentis), the skeletal system (most patients are tall and exhibit long digits [arachnodactyly] and hyperextensibility of the joints), and the cardiovascular system (eg, causing weakness of the aortic media, leading to dilation of the ascending aorta). Most cases are caused by mutations in the gene (on chromosome 15) for fibrillin; missense mutations have been detected in several patients with Marfan syndrome. Fibrillin is a large glycoprotein (about 350 kDa) that is a structural component of microfibrils, 10- to 12-nm fibers found in many tissues. Fibrillin is secreted (subsequent to a proteolytic cleavage) into the extracellular matrix by fibroblasts and becomes incorporated into the insoluble microfibrils, which appear to provide a scaffold for deposition of elastin. Of special relevance to Marfan syndrome, fibrillin is found in the zonular fibers of the lens, in the periosteum, and associated with elastin fibers in the aorta (and elsewhere); these locations respectively explain the ectopia lentis, arachnodactyly, and cardiovascular problems found in the syndrome. Other proteins (eg, emelin and two microfibril-associated proteins) are also present in these microfibrils, and it appears likely that abnormalities of them may cause other connective tissue disorders. A number of proteins, collectively known as attachment proteins, are involved; these include talin, vinculin, an actin-filament capping protein, and -actinin. Talin interacts with the receptor and vinculin, whereas the latter two interact with actin. The interaction of fibronectin with its receptor provides one route whereby the exterior of the cell can communicate with the interior and thus affect cell behavior. It consists of two identical subunits, each of about 230 kDa, joined by two disulfide bridges near their carboxyl terminals. The amino acid sequence of the fibronectin receptor of fibroblasts has been derived, and the protein is a member of the transmembrane integrin class of proteins (Chapter 51). The integrins are heterodimers, containing various types of and polypeptide chains. In that structure, the basal lamina is contributed by two separate sheets of cells (one endothelial and one epithelial), each disposed on opposite sides of the lamina; these three layers make up the glomerular membrane. Laminin (about 850 kDa, 70 nm long) consists of three distinct elongated polypeptide chains (A, B1, and B2) linked together to form an elongated cruciform shape. The collagen interacts with laminin (rather than directly with the cell surface), which in turn interacts with integrins or other laminin receptor proteins, thus anchoring the lamina to the cells. This is explained by two sets of facts: (1) the pores in the glomerular membrane are large enough to allow molecules up to about 8 nm to pass through. The normal structure of the glomerulus may be severely damaged in certain types of glomerulonephritis (eg, caused by antibodies directed against various components of the glomerular membrane). A number of them have been characterized and given names such as syndecan, betaglycan, serglycin, perlecan, aggrecan, versican, decorin, biglycan, and fibromodulin. They vary in tissue distribution, nature of the core protein, attached glycosaminoglycans, and function. The amount of carbohydrate in a proteoglycan is usually much greater than is found in a glycoprotein and may comprise up to 95% of its weight. Hyaluronic acid affords another exception because there is no clear evidence that it is attached covalently to protein, as the definition of a proteoglycan given above specifies. Dark field electron micrograph of a proteoglycan aggregate in which the proteoglycan subunits and filamentous backbone are particularly well extended. Biosynthesis of Glycosaminoglycans Involves Attachment to Core Proteins, Chain Elongation, & Chain Termination A. An O-glycosidic bond between xylose (Xyl) and Ser, a bond that is unique to proteoglycans. The synthesis of the core proteins occurs in the endoplasmic reticulum, and formation of at least some of the above linkages also occurs there. The repeating disaccharide is similar to that found in hyaluronic acid, containing B. Summary of structures of glycosaminoglycans and their attachments to core proteins. The presence of link trisaccharides (Gal-Gal-Xyl) in the chondroitin sulfates, heparin, and heparan and dermatan sulfates is shown. The protein molecule of the heparin proteoglycan is unique, consisting exclusively of serine and glycine residues. They are inherited in an autosomal recessive manner, with Hurler and Hunter syndromes being perhaps the most widely studied. In addition, some of them interact with certain adhesive proteins such as fibronectin and laminin (see above), also found in the matrix. This latter ability attracts water by osmotic pressure into the extracellular matrix and contributes to its turgor. The term "mucolipidosis" is retained because it is still in relatively widespread clinical usage, but it is not appropriate for these two latter diseases since the mechanism of their causation involves mislocation of certain lysosomal enzymes. Genetic defects of the catabolism of the oligosaccharide chains of glycoproteins (eg, mannosidosis, fucosidosis) are also described in Chapter 47. Surprisingly, only one case of an apparent genetic deficiency of this enzyme appears to have been reported. Its ability to attract water into the extracellular matrix and thereby "loosen it up" may be important in this regard.

Topics that fall outside of biology (the "study of life") include how metamorphic rock is formed and how planetary orbits function 9 medications that can cause heartburn purchase meclizine 25mg otc. You might also become thirsty and pause long enough for a cool drink medicine with codeine generic meclizine 25 mg on line, which will help to restore the water lost during perspiration symptoms yeast infection buy meclizine 25 mg cheap. The electrons are not shared between the atoms schedule 8 medications list generic meclizine 25mg without a prescription, but rather are associated more with one ion than the other. Ionic bonds are strong bonds, but are weaker than covalent bonds, meaning it takes less energy to break an ionic bond compared with a covalent one. This system is able to absorb hydrogen and hydroxide ions to prevent changes in pH and keep cells functioning properly. Glycogen is stored in animals in the liver and in muscle cells, whereas starch is stored in the roots, seeds, and leaves of plants. Starch has two different forms, one unbranched (amylose) and one branched (amylopectin), whereas glycogen is a single type of a highly branched molecule. Phospholipids and steroids are important components of animal cell membranes, as well as plant, fungal, and bacterial membranes. For example, in sickle cell anemia, the hemoglobin chain has a single amino acid substitution-the amino acid glutamic acid in position six is substituted by valine. Because of this change, hemoglobin molecules form aggregates, and the disc-shaped red blood cells assume a crescent shape, which results in serious health problems. The sugar and the phosphate are on the outside of the helix and the nitrogenous bases are in the interior. A ribonucleotide contains ribose (the pentose sugar), one of the four nitrogenous bases (A,U, G, and C), and the phosphate group. Small cells have no need for organelles and therefore do not need to expend energy getting substances across organelle membranes. Large cells have organelles that can separate cellular processes, enabling them to build molecules that are more complex. After the vesicle passes through the Golgi apparatus and fuses with the plasma membrane, it turns inside out. While the bones of the two correspond, the parts serve different functions in each organism and their forms have adapted to follow that function. In centrioles, two rings of nine microtubule "triplets" are arranged at right angles to one another. Plasmodesmata, which a plant cell needs for transportation and communication, are able to allow movement of really large molecules. It also allows the motion of membrane components, required for some types of membrane transport. Increasing or decreasing temperature increases or decreases the energy in the medium, affecting molecular movement. The denser a solution is, the harder it is for molecules to move through it, causing diffusion to slow down due to friction. Living cells require a steady supply of nutrients and a steady rate of waste removal. If the distance these substances need to travel is too great, diffusion cannot move nutrients and waste materials efficiently to sustain life. A baby developing from a fertilized egg is an endergonic process; enthalpy decreases (energy is absorbed) and entropy decreases. Sand art being destroyed is an exergonic process; there is no change in enthalpy, but entropy increases. A ball rolling downhill is an exergonic process; enthalpy decreases (energy is released), but there is no change in entropy. Muscle cells also must repair muscle tissue damaged by exercise by building new muscle. However, a spontaneous reaction need not occur quickly or suddenly like an instantaneous reaction. It may occur over long periods due to a large energy of activation, which prevents the reaction from occurring quickly. After the earthquake, the system became much more disordered and had higher entropy. In general, this reduces the production of superfluous products and conserves energy, maximizing energy efficiency. Interestingly, one of the worst side effects of this drug is hyperthermia, or overheating of the body. Milk sickness is rare today, but was common in the Midwestern United States in the early 1800s. Harvesting energy from the bonds of several different compounds would result in energy deliveries of different quantities. A red blood cell would lose its membrane potential if glycolysis were blocked, and it would eventually die. Moreover, Q is the only component of the electron transport chain that is not a protein. Ubiquinone and cytochrome c are small, mobile, electron carriers, whereas the other components of the electron transport chain are large complexes anchored this OpenStax book is available for free at cnx. Anaerobic respiration uses all three parts of cellular respiration, including the parts in the mitochondria like the citric acid cycle and electron transport; it also uses a different final electron acceptor instead of oxygen gas. Cell-surface receptors, however, are embedded in the plasma membrane, and their ligands do not enter the cell. Binding of the ligand to the cell-surface receptor initiates a cell signaling cascade and does not directly influence the making of proteins; however, it may involve the activation of intracellular proteins. Therefore, they respond to different ligands, and the second messengers activate different pathways. If a kinase is mutated so that it cannot function, the cell will not respond to ligand binding. Human gametes have 23 chromosomes, one each of 23 unique chromosomes, one of which is a sex chromosome. Microtubules are polymers of the protein tubulin; therefore, it is the mitotic spindle that is disrupted by these drugs. Without a functional mitotic spindle, the chromosomes will not be sorted or separated during mitosis. Some cells are only triggered to enter G1 when the organism needs to increase that particular cell type. The M checkpoint confirms the correct attachment of the mitotic spindle fibers to the kinetochores. The cell cycle can speed up as a result of the loss of functional checkpoint proteins. The cells can lose the ability to self-destruct and eventually become "immortalized. The sister chromatids that are formed during synthesis are held together at the centromere region by cohesin proteins. As the cell enters prophase I, the nuclear envelope begins to fragment, and the proteins holding homologous chromosomes locate each other. The four sister chromatids align lengthwise, and a protein lattice called the synaptonemal complex is formed between them to bind them together. The synaptonemal complex facilitates crossover between non-sister chromatids, which is observed as chiasmata along the length of the chromosome. As prophase I progresses, the synaptonemal complex breaks down and the sister chromatids become free, except where they are attached by chiasmata. At this stage, the four chromatids are visible in each homologous pairing and are called a tetrad. In anaphase I, the homologous chromosomes are pulled apart and move to opposite poles. The fused kinetochore formed during meiosis I ensures that each spindle microtubule that binds to the tetrad will attach to both sister chromatids. Random alignment during metaphase I leads to gametes that have a mixture of maternal and paternal chromosomes. If the round pea parent is heterozygous, there is a one-eighth probability that a random sample of three progeny peas will all be round. They cannot carry it because an individual needs two X chromosomes to be a carrier. The gene that is interfering is referred to as epistatic, as if it is "standing upon" the other (hypostatic) gene to block its expression. The predicted frequency of recombinant offspring ranges from 0% (for linked traits) to 50% (for unlinked traits).

Additional information:

• Cyclopentolate
• Atenolol