Carlos A. Guanche, MD

• Southern California Orthopedic Institute
• Van Nuys, California

However 3 menstrual cycles in 6 weeks purchase 20 mg nolvadex, first delivery of the virus postnatally triggered an immune response that completely blocked transgenic protein expression after a third virus injection women's health tips for losing weight generic 10mg nolvadex fast delivery. Fetal gene transfer is still subject to immunologic barriers relating to differences in biodistribution womens health daily generic nolvadex 20 mg with visa, timing and level of transgenic protein expression women's health clinic waco tx order 20 mg nolvadex visa. Designing less immunogenic vectors and immune conditioning before gene delivery women's health boutique houston purchase 20mg nolvadex overnight delivery, a less desirable option pregnancy xmas ornament generic 20 mg nolvadex, could partially overcome the problems. Maternal immunoglobulin G antibodies can cross the placental barrier and theoretically prevent long-term expression. Targeting vectors to organs or specific tissues is the ultimate goal and will most likely require the use of several combined approaches. Choosing an appropriate route of delivery will help to direct the therapy to the right organ6 (Table 46. Ultrasonogram (A) and diagram (B) of a sheep fetus at 114 days of gestation in longitudinal section. A 20-gauge spinal needle is inserted into the fetal thorax between the third and fourth ribs, penetrates the lung parenchyma and enters the fetal trachea just proximal to the carina. Ultrasonogram (C) and diagram (D) of a sheep fetus at 61 days of gestation in transverse section. Using pregnant sheep, ultrasound-guided injection techniques from fetal medicine practice have been adapted and new methods developed to deliver gene therapy to specific organs. For example, ultrasound-guided delivery of adenovirus vectors into the fetal sheep trachea (Video 46. More than 90% of the fetal deaths were caused by iatrogenic infection, usually with known fleece commensals. Invasive procedures such as tracheal injection had a complication rate of 6% related to blood vessel damage within the thorax. Positive X gal histochemistry (blue cells, A and F) and positive -galactosidase immunohistochemistry (brown-stained nuclei, B-E) of fetal tissues is shown. Fetuses were sampled 2 days after ultrasound-guided injection of an adenovirus vector containing the lacZ gene. Positive lacZ expression is seen in the medium sized airways (A and C) and in the trachea (B) after delivery of the vector into the midgestation fetal trachea. Positive lacZ expression is seen in the small bowel (D), rectum (E) and (F) stomach after delivery to the early-gestation fetal stomach. The unique features of fetal development that make it an attractive target for gene therapy, such as its immature immune system and rapidly dividing populations of stem cells, also mean that small perturbations in pregnancy can have significant short- and longterm consequences. Fetal growth and development result from a complex interaction between the genetic blueprint and the environment and depend on a constant, balanced supply of nutrition provided by a healthy mother, with a functional placenta and a well-developed fetoplacental circulation. Viral vector-mediated gene delivery to the mother or fetus could interfere with any stage of this sequence of events. Vector leakage with transduction and gene expression in tissues other than those desired is a risk associated with most gene delivery systems. Particularly in pregnancy, the inadvertent transduction of the male germline has been assessed in sheep, mice and monkeys. After intraperitoneal injection of retroviral vector, polymerase chain reaction on purified sperm cells from rams postnatally and immunohistochemistry on their testes revealed very low numbers of transduced germ cells, particularly if vector was injected in the mid and late trimesters. The ability of adenoviruses to infect human trophoblast cells in vitro is related to the state of trophoblast differentiation. This is probably due in part to the lack of coxsackie adenovirus receptor expression on the syncytiotrophoblast,74 thus rendering it resistant to maternal adenovirus infection and limiting maternal to fetal transplacental transmission. Many viral vectors are toxic at high concentrations, mainly through their immunogenic properties. A severe reaction was observed in a human trial of adult gene therapy for ornithine transcarbamylase deficiency in which in one case, a systemic inflammatory response was fatal. Expression of a therapeutic gene at a particular stage in fetal development may be damaging to the fetus. Intrauterine procedures such as those performed under ultrasound guidance carry a finite but definitive risk for miscarriage, infection and preterm labour. Earlier gene transfer may be beneficial because there are profound increases in the numbers of circulating T cells observed between 12 and 14 weeks of fetal life. Clinical Translation of Fetal Gene Therapy Preclinical testing in animal models of disease will be an important step before clinical translation is realised. There is no ideal animal model, and a balance is needed, taking into consideration the gestational development of the organ to be targeted and how that relates to the human, the type of placentation, fetal size, number and lifespan, parturition and the fetal and maternal immune response. Toxicology studies will be needed using animals such as the pregnant rabbit, in which reproductive toxicology is commonly performed, with good historical datasets. Guidelines and regulations, such as those described by the Committee for Medicinal Products for Human Use of the European Medicines Agency, will be considered when planning preclinical study protocols. Two models are available, cultured villous explants or perfused whole placental cotyledons. Villi isolated from placental lobules are cultured in net-wells submerged in growth medium. After 1 day of culture, the syncytiotrophoblast is routinely shed in vitro and then regenerates through the differentiation of underlying cytotrophoblast cells 2 days later. Placental perfusion preserves cellular and tissue architecture whilst allowing a dual fetal- and maternal-side haemodynamic compartment to be maintained. Movement of substances such as adenovirus vector, applied to the maternal or fetal side of the placenta, can be studied in the opposite side of the placenta using this model, over a 5- to 9-hour time period after delivery of the placenta. Phase I human trials face hurdles because of difficulties in testing pregnant women in whom toxicologic studies are usually contraindicated. This can be difficult when the decision to participate in a fetal gene therapy trial will occur close to the time of prenatal diagnosis of the condition. Because the risks involve the mother, fetus and possibly future progeny, parents will also be required to consent their offspring and themselves to lifelong follow-up. One criticism levelled at fetal gene therapy is a belief that couples pregnant with an affected child would be unlikely to proceed with prenatal therapy and would opt for a termination instead. The literature review on the ethics and legality of experimental treatments in pregnant women concluded that there were no ethical or legal objections to the intervention or to a trial of this intervention. To treat severe combined immune deficiency, haematopoietic stem cells collected from the bone marrow of patients can be gene corrected ex vivo and transplanted autologously into the donor, resulting in complete cure of the disease. Fetal liver or blood sampling at an early gestational age carries a significant risk for miscarriage, but pluripotent stem cells can be readily derived from fetal samples collected at amniocentesis82 or chorionic villus sampling,83,84 procedures that have a low fetal mortality rate. Women were generally interested in participating in clinical trials that conferred a potential benefit to their unborn children. Gene transfer to developing fetuses targets rapidly expanding stem cell populations that are inaccessible after birth. In animal models of congenital disease, the functionally immature fetal immune system does not respond to the product of the introduced gene, and therefore immune tolerance can be induced. For the treatment to be acceptable, it must be safe for both the mother and fetus and preferably avoid germline transmission. Currently, fetal gene therapy remains an experimental procedure, but it is rapidly moving into the clinic with the potential of a first-in-woman study within the next 2 years to treat fetal growth restriction. Treatment of poor placentation and the prevention of associated adverse outcomes-what does the future hold Recombinant adeno-associated virus-mediated in utero gene transfer gives therapeutic transgene expression in the sheep. Fetal Stem Cells and Regenerative Medicine Principles and Translational Strategies. Effect of amniotic fluid on cationic lipid mediated transfection and retroviral infection. Comparing zinc finger nucleases and transcription activator-like effector nucleases for gene targeting in Drosophila. Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy. Rescue of enzyme deficiency in embryonic diaphragm in a mouse model of metabolic myopathy: Pompe disease. Prolonged expression of a lysosomal enzyme in mouse liver after Sleeping Beauty transposonmediated gene delivery: implications for nonviral gene therapy of mucopolysaccharidoses. A single injection of an adeno-associated virus vector into nuclei with divergent connections results in widespread vector distribution in the brain and global correction of a neurogenetic disease. Sonographic heat generation in vivo in the gravid long-tailed macaque (Macaca fascicularis). Systemic gene delivery in large species for targeting spinal cord, brain, and peripheral tissues for pediatric disorders. The effects of sildenafil citrate (Viagra) on uterine blood flow and well being in the intrauterine growth-restricted fetus. Gene therapy and gene transfer projects of the 7th Framework Programme for Research and Technological Development of the European Union. Combining keratinocyte growth factor transfection into the airways and tracheal occlusion in a fetal sheep model of congenital diaphragmatic hernia. Differential short-term transduction efficiency of adult versus newborn mouse tissues by adenoviral recombinants. Humoral immune response to recombinant adenovirus and adeno-associated virus after in utero administration of viral vectors in mice. Widespread and efficient marker gene expression in the airway epithelia of fetal sheep after minimally invasive tracheal application of recombinant adenovirus in utero. Clinically applicable procedure for gene delivery to fetal gut by ultrasound-guided gastric injection: toward prenatal prevention of early-onset intestinal diseases. Targeting the respiratory muscles of fetal sheep for prenatal gene therapy for Duchenne muscular dystrophy. Gene therapy progress and prospects: fetal gene therapy-first proofs of concept-some adverse effects. Lentiviral vector gene transfer into fetal rhesus monkeys (Macaca mulatta): lung-targeting approaches. The developmental stage determines the distribution and duration of gene expression after early intra-amniotic gene transfer using lentiviral vectors. Functional analysis of various promoters in lentiviral vectors at different stages of in vitro differentiation of mouse embryonic stem cells. Intrauterine viral infection at the time of second trimester genetic amniocentesis. Factors determining the risk of inadvertent retroviral transduction of male germ cells after in utero gene transfer in sheep. Transduction of human trophoblast cells by recombinant adenoviruses is differentiation dependent. Differential expression of the coxsackievirus and adenovirus receptor regulates adenovirus infection of the placenta. Lessons learned from the gene therapy trial for ornithine transcarbamylase deficiency. In vivo delivery of recombinant viruses to the fetal murine cochlea: transduction characteristics and long-term effects on auditory function. Oncogenesis following delivery of a nonprimate lentiviral gene therapy vector to fetal and neonatal mice. Lentivirus-mediated gene transfer to the central nervous system: therapeutic and research applications. Placental mesenchymal stem cells as potential autologous graft for pre- and perinatal neuroregeneration. Autologous transplantation of amniotic fluidderived mesenchymal stem cells into sheep fetuses. Guideline on the Quality, Non-clinical and Clinical Aspects of Gene Therapy Medicinal Products. Altered cell kinetics is cultured placental villous explants in pregnancies complicated by preeclampsia and intrauterine growth restriction. Ethics and ethical evaluation of a proposed clinical trial with maternal uterine artery vascular endothelial growth factor gene therapy to treat severe early onset fetal growth restriction in pregnant. Early intra-amniotic gene transfer using lentiviral vector improves skin blistering phenotype in a murine model of Herlitz junctional epidermolysis bullosa. This concept is most commonly known as the developmental origins of health and disease. Environmental, genetic and epigenetic factors, as well as interactions among these factors, underlie this association. Contemporary research in this field grew following on from the seminal work of David Barker and colleagues in England in the 1980s. Barker found that the geographical pattern of adult ischaemic heart disease mortality matched that of infant mortality several decades earlier. Attributed to Hippocrates, Airs, Waters and Places describes the association between an adverse environment during pregnancy and the ongoing health of the offspring, noting that: In the first place women who happen to be with child, and whose accouchement should take place in springs. Kermack and Forsdahl During the 20th century, a link between early life and adult health was proposed by several researchers. In his analysis of trends in mortality across geographical regions of England and Wales, Barker found that the areas with the highest mortality rates due to ischaemic heart disease were the same as those that had the highest rates of infant mortality decades earlier. The association with low birth weight does not necessarily reflect a causal role of abnormal fetal growth in the development of disease but, rather, abnormal fetal growth is but one measure of an abnormal intrauterine environment, exposure to which induces phenotypic variation leading to increased disease risk. Developmental plasticity is a well-recognised phenomenon in nonhuman species, with substantial animal evidence of the environmental impact upon gene expression and phenotype. For example, brain development takes place over a longer period than cardiac development, and environmental impacts only result in changes to cardiac structure when present during earlier development compared with those which may produce neurologic changes. For example, although structural development of the fetal heart is complete relatively early in gestation, late insults may alter terminal cardiac myocyte differentiation, leading to more subtle functional changes. The physiological regulation of metabolism and inflammation is relatively late to develop and is therefore subject to environmental influences for much of the early life period and more susceptible to perturbations resulting in later disease. Gluckman and Hanson20 describe an important distinction in this observation, that between developmental adaptation and developmental disruption.

Risk of stroke in asymp tomatic persons with cervical arterial bruits: a population study in Evans County breast cancer north face order 20mg nolvadex with mastercard, Georgia menopause zits nolvadex 20 mg on line. Captopril renography in the diagnosis of renal artery stenosis: accuracy and limitations menopause estrogen nolvadex 10 mg on-line. Duplex ultrasound scan ning in the diagnosis of renal artery stenosis: a prospective evaluation breast cancer pink purchase generic nolvadex. The utility of duplex ultrasound scanning of the renal arteries for diagnosing significant renal artery stenosis [see comment] menstruation for 2 weeks purchase 10 mg nolvadex mastercard. Noninvasive screening for renal artery stenosis: comparison of renal artery and renal hilar duplex scanning menstrual after menopause purchase nolvadex 20mg amex. Stent angioplasty of severe athero sclerotic ostial renal artery stenosis in patients with diabetes mellitus and nephrosclerosis. Four-year follow-up of Palmaz Schatz stent revascularization as treatment for atherosclerotic renal artery stenosis. Validation of Renal Duplex Ultrasound in Detecting Renal Artery Stenosis Post Stenting. The effect of cigarette smoking on exercise capacity in patients with intermittent claudication. Effects on the risk of peripheral vascular complications, myocardial infarction and mortality. Blood oxygen level de pendent magnetic resonance imaging identifies cortical hypoxia in severe renovascular disease. Relation between peripheral vascular complications and lo cation of the occlusive atherosclerosis in the legs. Epidemiology of some periph eral arterial findings in diabetic men and women: experiences from the Framingham Study. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent dia betes mellitus. Lp(a) lipopro tein is an independent, discriminating risk factor for premature peripheral atherosclerosis among white men. Prevalence of hyper homocyst(e) inemia in patients with peripheral arterial occlusive disease. Blood viscosity, fibrinogen, and activation of coagulation and leu kocytes in peripheral arterial disease and the normal population in the Edinburgh Artery Study. Plasma concentration of C-reactive protein and risk of developing peripheral vascular disease. Diagnosis and treatment of chronic arterial insufficiency of the lower extremities: a critical review. The ratio of ankle and arm arterial pressure as an independent predictor of mortality. Mortality over a period of 1 0 years in patients with peripheral arterial disease. Ankle-arm index as a marker of atherosclerosis in the Cardiovascular Health Study. Color flow Doppler ultrasonog raphy: comparison with peripheral arteriography for the investi gation of peripheral vascular disease. Limi tations of ultrasonic duplex scanning for diagnosing lower limb ar terial stenoses in the presence of adj acent segment disease. Value of color duplex sonog raphy for evaluation of tibioperoneal arteries in patients with femoropopliteal obstruction: a prospective comparison with an terograde intraarterial digital subtraction angiography. Ankle/ arm pressure index in asymptomatic middle-aged males: an in dependent predictor of ten-year coronary heart disease mortality. A comparison of common femoral waveform analysis with aorto-iliac duplex scanning in assessment of aorto-iliac disease. Duplex scanning for diagnosis of aortoiliac and femoropopli teal disease: a prospective study. Magnetic res onance imaging of angiographically occult runoff vessels in periph eral arterial occlusive disease. Value of duplex scanning compared with angiography and pressure mea surement in the assessment of aortoiliac arterial lesions. The potential for low er extremity revascularization without contrast arteriography: experience with magnetic resonance angiography. Does correction of stenoses identified with color duplex scanning improve infrainguinal graft patency A comparison of techniques for improved visualization of the arteries of the distal lower extremity. Because most cardiac symptoms are precipitated by exertion or some other stress, however, it may also be important to assess hemodynamic performance during some form of stress such as muscular exercise, pharmacologic intervention. Such an evaluation enables the physician to assess the cardiovascular reserve and the relationship (if any) Patients with significant heart disease may have entirely nor mal hemodynamics when assessed in the resting state during Muscular exercise, both dynamic and isometric, has been studied extensively in the cardiac catheterization laboratory, understood. There are maj or differences between the hemo dynamic responses to dynamic exercise (done either in the cise, and these two types of exercise are discussed separately. This is accompanied by an increase in both oxy Some material in this chapter was developed for previous editions by Drs. Because carbohydrate metabolism produces more carbon dioxide than fat metabo lism does, the respiratory quotient (ratio of carbon dioxide production to 0 consumption) rises from a resting value of 2 0. The delivery of bloodborne oxygen and glucose to working skeletal muscle is enhanced in the pres ence of normal vasculature by a reduction in skeletal muscle vascular resistance mediated by metabolic byproducts and by sympathetically mediated vasoconstriction elsewhere, which causes a redistribution of blood away from the renal and splanchnic beds to the exercising muscle. This formula may be used to calculate the predicted cardiac index for a given level of 0 consumption (X), and 2 the predicted cardiac index may then be compared with sured in an individual patient is appropriate to the level of exercise and increased oxygen uptake. O; minute ventilation increases ing muscle is insufficient, anaerobic metabolism of glucose develops, causing metabolic acidosis and an increase in respi tion to increase oxygen supply. When the intensity and dura 2 tion of exercise are such that oxygen delivered to the exercis. It is best to conduct exercise studies in the catheterization laboratory in out of proportion to 0 consumption. Beyond this anaerobic 2 threshold, the accumulation of hydrogen ions usually causes can be sustained for several minutes. This approach permits to determine whether the increase in cardiac output is appro priate for the increase in 0 consumption occurring at that 2 particular level of exercise. An exercise factor < 6 indicates a sub normal response in cardiac output; like exercise index of < 0. Patients who are unable to generate an adequate increase in cardiac output during dynamic exercise may also increase their arterial pressure, that in this circumstance systemic vas cular resistance does not decline and may actually increase. This equation can be used to calculate a predicted car diac index by measuring 0 consumption during dynamic 2 exercise. Several investigators examining the responses of cardiac see below), but increased sympathetic nervous system activity appears to be the most significant factor leading to enhanced upright dynamic exercise and tends to increase linearly in relation to 0 consumption. During dynamic supine exercise 2 in the catheterization laboratory, tachycardia is the predomi nant factor in increasing cardiac output. Tachycardia exerts a positive inotropic effect (the so-called treppe phenomenon, stantial decrease in the resistance of the systemic vasculature. Heart rate increases consistently during both supine and Exercise Factor Another way of using this relationship between cardiac out put and 0 consumption involves calculation of the exercise 2 factor, which is the increase in cardiac output with exercise divided by the corresponding increase in 0 consumption: 2 of supine exercise in normal subj ects and showed that the increase in cardiac output is caused primarily by an increase in heart rate with a negligible contribution by increased stroke volume. During repeat exercise when heart rate is held output, stroke volume, and heart rate to a given intensity constant, there is a comparable increase in cardiac output caused by a marked increase in stroke volume7. Therefore, to adequately interpret the response to rate is artificially increased by electrical pacing in the absence of dynamic exercise, however, cardiac output remains supine exercise in the catheterization laboratory, it is impor tant to recognize that the increase in cardiac output in nor mal young subj ects is caused by a proportionate increase in depressed, an appropriate increase in cardiac output relative heart rate. In contrast, studies of older normal subj ects or patients with atypical chest pain diastolic filling and end-diastolic fiber tension, leading to an increase in stroke volume by means of the Frank-Starling mechanism. Normal men and women can achieve U pright Versus Supine Exercise the contributions of heart rate and stroke volume to cardiac output differ in supine and upright bicycle exercise. However, normal women generally achieve increases in stroke volume during upright exercise through an increase in end-diastolic vol ume without an increase in ej ection fraction, whereas nor est when they are standing4. When subj ects are in the upright end-systolic volume, some enhancement of left ventricular end-diastolic volume, and an increase in stroke volume as well as heart rate. During erect bicycle exercise, most normal subj ects dem onstrate an increase in ej ection fraction and reduction in cated by the effects of chronic -adrenergic blockade. Studies of the hemodynamic effects of chronic -adrenergic block ade on graded exercise in hypertensive but otherwise healthy young adults have shown that no impairment of maximal exercise capacity (maximal 02 consumption) or cardiac out put response occurs during chronic -adrenergic blockade. For these reasons, strong consideration should be given to discontinu ation of -adrenergic blocking drugs at least 24 hours before catheterization if analysis of the hemodynamic response to dynamic exercise is planned to assess the adequacy of cardio vascular reserve. In normal subj ects, multiple adjustments occur to accommodate an increased transmitral flow into the left ventricle in the face of an abbre viated diastolic filling period and to maintain low pressures throughout diastole. Exercise is associated with a progressive acceleration of isovolumetric relaxation so that enhanced diastolic filling occurs with minimal change in mitral valve opening pressure. There was an upward shift in cardiovascular disease (control) and 5 patients with an aki been reported by Carroll et al. In patients with coronary artery disease, a transient but striking upward during episodes of ischemia. These findings with exercise properties limit the capacity to recruit the Frank-Starling mechanism during exercise. Four of these patients were elderly with a medical history remarkable only for chronic hypertension. Accordingly, these patients clearly have "pure" diastolic heart failure: Efforts to treat their heart failure by improving systolic function. During exercise, the cardiac index increased appropriately in relation to the increase in 0 consumption, 2 yielding an exercise index of l. Because her ej ection frac tion was only moderately depressed and her hemodynamic pic reserve and that her ability to increase cardiac output depended heavily on use of the Frank-Starling mechanism. Exercise tolerance in patients with congestive heart failure is highly variable and correlates poorly with ej ection fraction. His chest radiograph showed cardiomegaly with no evi density, "uncoupling" of the 13-receptor and adenylate cyclase activity, and deficient production of cyclic adenosine 2 monophosphate. Supine bicycle exercise was associated with a marked rise in both left and right heart filling pressures and a marginal ability to increase cardiac output appropriately in relation to his increase in 02 consumption. Gradients across the atrioventricular and semilunar valves may become apparent during exercise and may reach levels that account for the clinical symptoms of the patient. Some other patients are limited not by the inability to deliver oxygen to illary wedge pressure associated with exercise (Table 20. An example of the hemodynamic changes during supine dynamic exercise in a patient with moderate mitral stenosis is especially useful when the resting transvalvular gradient or estimated valve area has borderline significance. Ll cardiac output these data are compatible with mild mitral stenosis and illus trate the changes in the diastolic pressure gradient across the 2,800 mitral valve required to produce an increase in cardiac output appropriate to the increased oxygen requirements of strenu ous exercise. This vari rpm 20 W 1 0 W/3 greater flow may force the stenotic leaflets to open wider), deficient data, or computational errors inherent in the assump ance is usually small and may be related to actual changes in the degree of valvular obstruction. Dynamic exercise testing is especially valuable in such patients because the qualitative assessment of valvular insuf ficiency from angiograms may be unreliable and does not cor relate well with the extent of functional impairment. The patient was able to increase cardiac output normally, but mean pulmonary cap illary wedge pressure increased from 18 to 30 mmHg, with cle exercise. N ext, the system for measuring 0 consumption is 2 put in place (see Chapter l l). Alternatively, cardiac output can be assessed with the use of an indicator dilution technique. Manometers are zeroed once again, all pressures are then redisplayed, and the recording speed is slowed (to 5 to 10 mm/second). Exercise is then begun with all pressures displayed continuously on With the patient resting quietly and feet positioned on the bicycle, all manometers are zeroed, phasic and mean pressures are recorded at 25 or 50 mrn/second speed and at artery) blood oxygen saturation content should be at hand. A sufficient number of syringes for measuring systemic arterial and mixed venous (pulmonary the monitor and recorded at slow speed. At each 1 -minute interval, a brief recording of all three phasic pressures at a recording speed of 25 to 50 mrn/second is accomplished, after sures are returned to mean and the recording speed is slowed to 5 to 10 mm/second. Continuous observation and recording Performing a Dynamic Exercise Test Dynamic exercise during cardiac catheterization is eas ily performed with a bicycle ergometer while the patient is supine. A protocol detailing the exercise test should be pre pared beforehand to ensure that all essential data are obtained (Table 20. The duration and intensity of the exercise must be tailored to fit the needs of the individual patient. Little additional diagnostic information can Precautions should be taken during exercise to ensure Performing an Isometric Exercise Test untary contraction strength. A partially inflated sphygmoma nometer cuff or a specially designed handgrip dynamometer Isometric exercise is most commonly performed as sustained handgrip. The subj ect is first tested to evaluate maximal vol be obtained by continuing the exercise to the point of produc ing pulmonary edema. This testing may be done before cardiac catheter ization and well before the actual handgrip test. Cardiac output is most easily determined for this form of exercise by the indicator dilution method. The precise nature of this reflex is not completely understood, but it appears to require afferent neural impulses from the exercis ing extremity and may be related to inhibition of vagal activ ity. Although the cardiac output response may be blunted, the anticipated responses in heart rate and blood pressure are not blocked by administration of propranolol, indicating that more is involved than a simple increase in -adrenergic stimulation. It is important that the patient not do a Val salva maneuver during handgrip exercise and that the respi ratory pattern be closely observed. Valsalva maneuver may be avoided simply by engaging the patient in conversation during the test. We have used 50% maximal voluntary con traction for 3 minutes, with repeat measurements of pressures and cardiac output beginning at 2. Hemodynamic Response the hemodynamic response to isometric handgrip exercise has been studied in a series of normal subj ects and patients with heart disease 22 In normal adult subj ects, heart rate, sys temic arterial pressure, and cardiac output increase, whereas systemic vascular resistance shows no change, indicating that the increase in systemic arterial pressure is caused by the increased cardiac output rather than by a vasoconstric tor response. Moreover, they found that the degree of pacing stress needed to produce ischemia, defined in terms cise in pathologic states.

Sodium co-transport of amino acids occurs in the same manner as for glucose menstrual xx purchase nolvadex with mastercard, except that it uses a different set of transport proteins womens health jacksonville nc cheap nolvadex express. At least five amino acid transport proteins have been identified women's health low testosterone symptoms purchase 10mg nolvadex fast delivery, each of which is responsible for transporting one subset of amino acids with specific molecular characteristics menopause the musical detroit purchase nolvadex 20 mg line. Sodium co-transport of glucose and amino acids occurs especially through the epithelial cells of the intestinal tract and the renal tubules of the kidneys to promote absorption of these substances into the blood menstrual nausea vomiting order nolvadex 10mg without prescription. Other important co-transport mechanisms in at least some cells include co-transport of potassium menopause japan order nolvadex 20 mg with mastercard, chloride, bicarbonate, phosphate, iodine, iron, and urate ions. Sodium Counter-Transport of Calcium and Hydrogen Ions Two especially important counter-transporters. Sodium-calcium counter-transport occurs through all or almost all cell membranes, with sodium ions moving to the interior and calcium ions to the exterior; both are bound to the same transport protein in a countertransport mode. This mechanism is in addition to the primary active transport of calcium that occurs in some cells. An especially important example is in the proximal tubules of the kidneys, where sodium ions move from the lumen of the tubule to the interior of the tubular cell and hydrogen ions are counter-transported into the tubule lumen. As a mechanism for concentrating hydrogen ions, counter-transport is not nearly as powerful as the primary active transport of hydrogen ions that occurs in the more distal renal tubules, but it can transport extremely large numbers of hydrogen ions, thus making it a key to hydrogen ion control in the body fluids, as discussed in detail in Chapter 31. These mechanisms are also how the same substances are reabsorbed from the glomerular filtrate by the renal tubules. Numerous examples of the different types of transport discussed in this chapter are provided throughout this text. Connective tissue Na+ Diffusion Active transport Na+ Osmosis Active transport Osmosis Bibliography Agre P, Kozono D: Aquaporin water channels: molecular mechanisms for human diseases. Fischbarg J: Fluid transport across leaky epithelia: central role of the tight junction and supporting role of aquaporins. Transport of this type occurs through the following: (1) intestinal epithelium; (2) epithelium of the renal tubules; (3) epithelium of all exocrine glands; (4) epithelium of the gallbladder; and (5) membrane of the choroid plexus of the brain, along with other membranes. The basic mechanism for transport of a substance through a cellular sheet is as follows: (1) active transport through the cell membrane on one side of the transporting cells in the sheet; and then (2) either simple diffusion or facilitated diffusion through the membrane on the opposite side of the cell. This figure shows that the epithelial cells are connected together tightly at the luminal pole by means of junctions. The brush border on the luminal surfaces of the cells is permeable to both sodium ions and water. Therefore, sodium and water diffuse readily from the lumen into the interior of the cell. Then, at the basal and lateral membranes of the cells, sodium ions are actively transported into the extracellular fluid of the surrounding connective tissue and blood vessels. This action creates a high sodium ion concentration gradient across these membranes, which in turn causes osmosis of water. Thus, active transport of sodium ions at the basolateral sides of the epithelial cells results in the transport not only of sodium ions but also of water. Some cells, such as nerve and muscle cells, generate rapidly changing electrochemical impulses at their membranes, and these impulses are used to transmit signals along the nerve or muscle membranes. This article reviews the basic mechanisms whereby membrane potentials are generated at rest and during action by nerve and muscle cells. Again, the membrane potential rises high enough within milliseconds to block further net diffusion of sodium ions to the inside; however, this time, in the mammalian nerve fiber, the potential is about 61 millivolts positive inside the fiber. Later in this chapter, we show that many of the rapid changes in membrane potentials observed during nerve and muscle impulse transmission result from such rapidly changing diffusion potentials. The Nernst Equation Describes the Relationship of Diffusion Potential to the Ion Concentration Difference Across a Membrane. Let us assume that the membrane in this case is permeable to the potassium ions but not to any other ions. Because of the large potassium concentration gradient from the inside toward the outside, there is a strong tendency for potassium ions to diffuse outward through the membrane. As they do so, they carry positive electrical charges to the outside, thus creating electropositivity outside the membrane and electronegativity inside the membrane because of negative anions that remain behind and do not diffuse outward with the potassium. Within about 1 millisecond, the potential difference between the inside and outside, called the diffusion potential, becomes great enough to block further net potassium diffusion to the exterior, despite the high potassium ion concentration gradient. In the normal mammalian nerve fiber, the potential difference is about 94 millivolts, with negativity inside the fiber membrane. This time, the membrane is highly permeable to the sodium ions but is impermeable to all other ions. Diffusion of the positively charged sodium ions to the inside membrane that exactly opposes the net diffusion of a particular ion through the membrane is called the Nernst potential for that ion, a term that was introduced in Chapter 4. The magnitude of the Nernst potential is determined by the ratio of the concentrations of that specific ion on the two sides of the membrane. The greater this ratio, the greater the tendency for the ion to diffuse in one direction and therefore the greater the Nernst potential required to prevent additional net diffusion. The following equation, called the Nernst equation, can be used to calculate the Nernst potential for any univalent ion at the normal body temperature of 98. When using this formula, it is usually assumed that the potential in the extracellular fluid outside the membrane remains at zero potential, and the Nernst potential is the potential inside the membrane. Also, the sign of the potential is positive (+) if the ion diffusing from inside to outside is a negative ion, and it is negative (-) if the ion is positive. Thus, when the concentration of positive potassium ions on the inside is 10 times that on the outside, the log of 10 is 1, so the Nernst potential calculates to be -61 millivolts inside the membrane. B, Establishment of a diffusion potential when the nerve fiber membrane is permeable only to sodium ions. Note that the internal membrane potential is negative when potassium ions diffuse and positive when sodium ions diffuse because of opposite concentration gradients of these two ions. The Goldman Equation Is Used to Calculate the Diffusion Potential When the Membrane Is Permeable to Several Different Ions. When a membrane is per- meable to several different ions, the diffusion potential that develops depends on three factors: (1) the polarity of the electrical charge of each ion; (2) the permeability of the membrane (P) to each ion; and (3) the concentration (C) of the respective ions on the inside (i) and outside (o) of the membrane. The reason for this phenomenon is that excess positive ions diffuse to the outside when their concentration is higher inside than outside the membrane. This diffusion carries positive charges to the outside but leaves the nondiffusible negative anions on the inside, thus creating electronegativity on the inside. That is, a chloride ion gradient from the outside to the inside causes negativity inside the cell because excess negatively charged chloride ions diffuse to the inside while leaving the nondiffusible positive ions on the outside. Fourth, as explained later, the permeability of the sodium and potassium channels undergoes rapid changes during transmission of a nerve impulse, whereas the permeability of the chloride channels does not change greatly during this process. Therefore, rapid changes in sodium and potassium permeability are primarily responsible for signal transmission in neurons, which is the subject of most of the remainder of this chapter. In some cells, such as the cardiac pacemaker cells discussed in Chapter 10, the membrane potential is continuously changing, and the cells are never "resting". In many other cells, even excitable cells, there is a quiescent period in which a resting membrane potential can be measured. Table 5-1 shows the approximate resting membrane potentials of some different types of cells. The membrane potential is obviously very dynamic in excitable cells such as neurons, in which action potentials occur. However, even in nonexcitable cells, the membrane potential (voltage) also changes in response to various stimuli, which alter activities for the various ion transporters, ion channels, and membrane permeability for sodium, potassium, calcium, and chloride ions. The resting membrane potential is, therefore, only a brief transient state for many cells. First, sodium, potassium, and chloride ions are the most important ions involved in the development of membrane potentials in nerve and muscle fibers, as well as in the neuronal cells. The concentration gradient of each of these ions across the membrane helps determine the voltage of the membrane potential. Second, the quantitative importance of each of the ions in determining the voltage is proportional to the membrane permeability for that particular ion. If the membrane has zero permeability to sodium and chloride ions, the membrane potential becomes entirely dominated by the concentration gradient of potassium ions alone, and the resulting potential will be equal to the Nernst potential for potassium. The same holds true for each of the other two ions if the membrane should become selectively permeable for either one of them alone. The arithmetic sign of Vdf (positive or negative) and the valence of the ion (cation or anion) can be used to predict the direction of ion flow across the membrane, into or out of the cell. For cations such as Na+ and K+, a positive Vdf predicts ion movement out of the cell down its electrochemical gradient, and a negative Vdf predicts ion movement into the cell. For anions, such as Cl-, a positive Vdf predicts ion movement into the cell, and a negative Vdf predicts ion movement out of the cell. Also, the direction of ion flux through the membrane reverses as Vm becomes greater than or less than Veq; hence, the equilibrium potential (Veq) is also called the reversal potential. Note the alignment of negative charges along the inside surface of the membrane and positive charges along the outside surface. The lower panel displays the abrupt changes in membrane potential that occur at the membranes on the two sides of the fiber. Measuring the Membrane Potential the method for measuring the membrane potential is simple in theory but often difficult in practice because of the small size of most of the cells and fibers. The micropipette is impaled through the cell membrane to the interior of the fiber. Another electrode, called the indifferent electrode, is then placed in the extracellular fluid, and the potential difference between the inside and outside of the fiber is measured using an appropriate voltmeter. This voltmeter is a highly sophisticated electronic apparatus that is capable of measuring small voltages despite extremely high resistance to electrical flow through the tip of the micropipette, which has a lumen diameter usually less than 1 micrometer and a resistance of more than 1 million ohms. For recording rapid changes in the membrane potential during transmission of nerve impulses, the microelectrode is connected to an oscilloscope, as explained later in the chapter. As long as the electrode is outside the neuronal membrane, the recorded potential is zero, which is the potential of the extracellular fluid. Then, as the recording electrode passes through the voltage change area at the cell membrane (called the electrical dipole layer), the potential decreases abruptly to -70 millivolts. Moving across the center of the fiber, the potential remains at a steady -70-millivolt level but reverses back to zero the instant it passes through the membrane on the opposite side of the fiber. To create a negative potential inside the membrane, only enough positive ions to develop the electrical dipole layer at the membrane itself must be transported outward. Therefore, transfer of an incredibly small number of ions through the membrane can establish the normal resting potential of -70 millivolts inside the nerve fiber, which means that only about 1/3,000,000 to 1/100,000,000 of the total positive charges inside the fiber must be transferred. Also, an equally small number of positive ions moving from outside to inside the fiber can reverse the potential from -70 millivolts to as much as +35 millivolts within as little as 1/10,000 of a second. Rapid shifting of ions in this manner causes the nerve signals discussed in subsequent sections of this chapter. That is, the potential inside the fiber is 70 millivolts more negative than the potential in the extracellular fluid on the outside of the fiber. The K+ leak channels also leak Na+ ions into the cell slightly but are much more permeable to K+. Active Transport of Sodium and Potassium Ions Through the Membrane-the Sodium-Potassium (Na+-K+) Pump. Note that this is an electrogenic pump because three Na+ ions are pumped to the outside for each two K+ ions to the inside, leaving a net deficit of positive ions on the inside and causing a negative potential inside the cell membrane. The Na+-K+ pump also causes large concentration gradients for sodium and potassium across the resting nerve membrane. B, When the membrane potential is caused by diffusion of both sodium and potassium ions. C, When the membrane potential is caused by diffusion of both sodium and potassium ions plus pumping of both these ions by the Na+-K+ pump. The ratios of these two respective ions from the inside to the outside are as follows: Na+ inside /Na+ outside = 0. As discussed later, this differential in permeability is a key factor in determining the level of the normal resting membrane potential. Because of the high ratio of potassium ions inside to outside, 35:1, the Nernst potential corresponding to this ratio is -94 millivolts because the logarithm of 35 is 1. Therefore, if potassium ions were the only factor causing the resting potential, the resting potential inside the fiber would be equal to -94 millivolts, as shown in the figure. Intuitively, one can see that if the membrane is highly permeable to potassium but only slightly permeable to sodium, the diffusion of potassium contributes far more to the membrane potential than the diffusion of sodium. In the normal nerve fiber, the permeability of the membrane to potassium is about 100 times as great as its permeability to sodium. Using this value in the Goldman equation, and considering only sodium and potassium, gives a potential inside the membrane of -86 millivolts, which is near the potassium potential shown in the figure. Each action potential begins with a sudden change from the normal resting negative membrane potential to a positive potential and ends with an almost equally rapid change back to the negative potential. The lower panel shows graphically the successive changes in membrane potential over a few 10,000ths of a second, illustrating the explosive onset of the action potential and the almost equally rapid recovery. The resting stage is the resting membrane Na+-K+ pump is shown to provide an additional contribution to the resting potential. This figure shows that continuous pumping of three sodium ions to the outside occurs for each two potassium ions pumped to the inside of the membrane. The pumping of more sodium ions to the outside than the potassium ions being pumped to the inside causes a continual loss of positive charges from inside the membrane, creating an additional degree of negativity (about -4 millivolts additional) on the inside, beyond that which can be accounted for by diffusion alone. However, additional ions, such as chloride, must also be considered in calculating the membrane potential.

Once inside the lysosomes pregnancy exhaustion purchase 10 mg nolvadex overnight delivery, the organelles are digested menstruation migraines cheapest generic nolvadex uk, and the nutrients are reused by the cell women's health issues in thrombosis and haemostasis 2013 nolvadex 10mg. Autophagy contributes to the routine turnover of cytoplasmic components; it is a key mechanism for tissue development menstruation occurs in response to generic nolvadex 10mg with amex, cell survival when nutrients are scarce breast cancer buy nolvadex overnight delivery, and maintenance of homeostasis women's health jokes proven 20 mg nolvadex. In liver cells, for example, the average mitochondrion normally has a life span of only about 10 days before it is destroyed. Chapter 2 the Cell and Its Functions Proteins Synthesis by the Rough Endoplasmic Reticulum. As discussed in Chapter 3, protein molecules are synthesized within the structures of the ribosomes. The ribosomes extrude some of the synthesized protein molecules directly into the cytosol, but they also extrude many more through the wall of the endoplasmic reticulum to the interior of the endoplasmic vesicles and tubules into the endoplasmic matrix. These lipids are rapidly incorporated into the lipid bilayer of the endoplasmic reticulum, thus causing the endoplasmic reticulum to grow more extensive. It provides the enzymes that control glycogen breakdown when glycogen is to be used for energy. It provides a vast number of enzymes that are capable of detoxifying substances, such as drugs, that might damage the cell. It achieves detoxification by processes such as coagulation, oxidation, hydrolysis, and conjugation with glycuronic acid. These structures are formed primarily of lipid bilayer membranes, similar to the cell membrane, and their walls are loaded with protein enzymes that catalyze the synthesis of many substances required by the cell. The products formed there are then passed on to the Golgi apparatus, where they are further processed before being released into the cytoplasm. First, however, let us note the specific products that are synthesized in specific portions of the endoplasmic reticulum and Golgi apparatus. This is especially true for the formation of large saccharide polymers bound with small amounts of protein; important examples include hyaluronic acid and chondroitin sulfate. A few of the many functions of hyaluronic acid and chondroitin sulfate in the body are as follows: (1) they are the major components of proteoglycans secreted in mucus and other glandular secretions; (2) they are the major components of the ground substance, or nonfibrous components of the extracellular matrix, outside the cells in the interstitial spaces, which act as fillers between collagen fibers and cells; (3) they are principal components of the organic matrix in both cartilage and bone; and (4) they are important in many cell activities, including migration and proliferation. In a highly secre- Glycosylation Transport vesicles tory cell, the vesicles formed by the Golgi apparatus are mainly secretory vesicles containing proteins that are secreted through the surface of the cell membrane. These secretory vesicles first diffuse to the cell membrane and then fuse with it and empty their substances to the exterior by the mechanism called exocytosis. Formation of proteins, lipids, and cellular vesicles by the endoplasmic reticulum and Golgi apparatus. Processing of Endoplasmic Secretions by the Golgi Apparatus-Formation of Vesicles. As substances are formed in the endoplasmic reticulum, especially proteins, they are transported through the tubules toward portions of the smooth endoplasmic reticulum that lie nearest to the Golgi apparatus. At this point, transport vesicles composed of small envelopes of smooth endoplasmic reticulum continually break away and diffuse to the deepest layer of the Golgi apparatus. Inside these vesicles are synthesized proteins and other products from the endoplasmic reticulum. The transport vesicles instantly fuse with the Golgi apparatus and empty their contained substances into the vesicular spaces of the Golgi apparatus. Also, an important function of the Golgi apparatus is to compact the endoplasmic reticular secretions into highly concentrated packets. As the secretions pass toward the outermost layers of the Golgi apparatus, the compaction and processing proceed. Finally, both small and large vesicles continually break away from the Golgi apparatus, carrying with them the compacted secretory substances and diffusing throughout the cell. When a glandular cell is bathed in amino acids, newly formed protein molecules can be detected in the granular endoplasmic reticulum within 3 to 5 minutes. Within 20 minutes, newly formed proteins are already present in the Golgi apparatus and, within 1 to 2 hours, the proteins are secreted from the surface of the cell. This fusion increases the expanse of these membranes and replenishes the membranes as they are used up. For example, the cell membrane loses much of its substance every time it forms a phagocytic or pinocytotic vesicle, and the vesicular membranes of the Golgi apparatus continually replenish the cell membrane. In summary, the membranous system of the endoplasmic reticulum and Golgi apparatus are highly metabolic and capable of forming new intracellular structures and secretory substances to be extruded from the cell. In the human body, essentially all carbohydrates are converted into glucose by the digestive tract and liver before they reach the other cells of the body. Similarly, proteins are converted into amino acids, and fats are converted into fatty acids. Inside the cell, they react chemically with oxygen under the influence of enzymes that control the reactions and channel the energy released in the proper direction. The details of all these digestive and metabolic functions are provided in Chapters 63 through 73. The last two phosphate radicals are connected with the remainder of the molecule by high-energy phosphate bonds, which are represented in the formula shown by the symbol. Furthermore, the high-energy phosphate bond is very labile, so that it can be split instantly on demand whenever energy is required to promote other intracellular reactions. This released energy is used to energize many of converted by enzymes in the cytoplasm into pyruvic acid (a process called glycolysis). The pyruvic acid derived from carbohydrates, fatty acids from lipids, and amino acids from proteins is eventually converted into the compound acetyl-coenzyme A (CoA) in the matrix of mitochondria. This substance, in turn, is further dissolved (for the purpose of extracting its energy) by another series of enzymes in the mitochondrion matrix, undergoing dissolution in a sequence of chemical reactions called the citric acid cycle, or Krebs cycle. These chemical reactions are so important that they are explained in detail in Chapter 68. In this citric acid cycle, acetyl-CoA is split into its component parts, hydrogen atoms and carbon dioxide. The carbon dioxide diffuses out of the mitochondria and eventually out of the cell; finally, it is excreted from the body through the lungs. The hydrogen atoms, conversely, are highly reactive; they combine with oxygen that has also diffused into the mitochondria. The processes of these reactions are complex, requiring the participation of many protein enzymes that are integral parts of mitochondrial membranous shelves that protrude into the mitochondrial matrix. The initial event is the removal of an electron from the hydrogen atom, thus converting it to a hydrogen ion. In addition to synthesizing proteins, cells make phospholipids, cholesterol, purines, pyrimidines, and many other substances. For example, a single protein molecule might be composed of as many as several thousand amino acids attached to one another by peptide linkages. Other cells perform mechanical work in other ways, especially by ciliary and ameboid motion, described later in this chapter. Two other types of movement-ameboid locomotion and ciliary movement-occur in other cells. This type of movement gets its name from the fact that amebae move in this manner, and amebae have provided an excellent tool for studying the phenomenon. Typically, ameboid locomotion begins with the protrusion of a pseudopodium from one end of the cell. The pseudopodium projects away from the cell body and partially secures itself in a new tissue area; then the remainder of the cell is pulled toward the pseudopodium. The membrane of this end of the cell is continually moving forward, and the membrane at the left-hand end of the cell is continually following along as the cell moves. This partially accounts for their relatively rapid spreading from one part of the body to another, known as metastasis. Basically, this results from the continual formation of new cell membrane at the leading edge of the pseudopodium and continual absorption of the membrane in the mid and rear portions of the cell. The first is attachment of the pseudopodium to surrounding tissues so that it becomes fixed in its leading position while the remainder of the cell body is being pulled forward toward the point of attachment. This attachment is caused by receptor proteins that line the insides of exocytotic vesicles. When the vesicles become part of the pseudopodial membrane, they open so that their insides evert to the outside, and the receptors now protrude to the outside and attach to ligands in the surrounding tissues. At the opposite end of the cell, the receptors pull away from their ligands and form new endocytotic vesicles. Then, inside the cell, these vesicles stream toward the pseudopodial end of the cell, where they are used to form new membrane for the pseudopodium. The second essential effect for locomotion is to provide the energy required to pull the cell body in the direction of the pseudopodium. Much of the actin is in the form of single molecules that do not provide any motive power; however, these molecules polymerize to form a filamentous network, and the network contracts when it binds with an actin-binding protein such as myosin. This is what occurs in the pseudopodium of a moving cell, where such a network of actin filaments forms anew inside the enlarging pseudopodium. Contraction also occurs in the ectoplasm of the cell body, where a preexisting actin network is already present beneath the cell membrane. An important initiator of ameboid locomotion is the process called chemotaxis, which results from the appearance of certain chemical substances in the tissues. Any chemical substance that causes chemotaxis to occur is called a chemotactic substance. Most cells that exhibit ameboid locomotion move toward the source of a chemotactic substance-that is, from an area of lower concentration toward an area of higher concentration. Although the answer is not certain, it is known that the side of the cell most exposed to the chemotactic substance develops membrane changes that cause pseudopodial protrusion. This movement occurs mainly in two places in the human body, on the surfaces of the respiratory airways and on the inside surfaces of the uterine tubes (fallopian tubes) of the reproductive tract. In the nasal cavity and lower respiratory airways, the whiplike motion of motile cilia causes a layer of mucus to move at a rate of about 1 cm/min toward the pharynx, in this way continually clearing these passageways of mucus and particles that have become trapped in the mucus. In the uterine tubes, cilia cause slow movement of fluid from the ostium of the uterine tube toward the uterus cavity; this movement of fluid transports the ovum from the ovary to the uterus. Often, many motile cilia project from a single cell-for example, as many as 200 cilia on the surface of each epithelial cell inside the respiratory passageways. Each cilium is an outgrowth of a structure that lies immediately beneath the cell membrane, called the basal body of the cilium. The flagellum of a sperm is similar to a motile cilium; in fact, it has much the same type of structure and same type of contractile mechanism. The flagellum, however, is much longer and moves in quasisinusoidal waves instead of whiplike movements. Other types of cells can also move by ameboid locomotion under certain circumstances. For example, fibroblasts move into a damaged area to help repair the damage, and even the germinal cells of the skin, although ordinarily completely sessile cells, move toward a cut area to repair the opening. Cell locomotion is also especially important in the development of the embryo and fetus after fertilization of an ovum. For example, embryonic cells often must migrate long distances from their sites of origin to new areas during the development of special structures. Fourth, during forward motion of the cilium, the double tubules on the front edge of the cilium slide outward toward the tip of the cilium, whereas those on the back edge remain in place. If the front tubules crawl outward while the back tubules remain stationary, bending occurs. The cilia of some genetically abnormal cells do not have the two central single tubules, and these cilia fail to beat. Therefore, it is presumed that some signal, perhaps an electrochemical signal, is transmitted along these two central tubules to activate the dynein arms. The cilium moves forward with a sudden, rapid whiplike stroke 10 to 20 times per second, bending sharply where it projects from the surface of the cell. The rapid, forward-thrusting, whiplike movement pushes the fluid lying adjacent to the cell in the direction that the cilium moves; the slow dragging movement in the backward direction has almost no effect on fluid movement. As a result, the fluid is continually propelled in the direction of the fast-forward stroke. Because most motile ciliated cells have large numbers of cilia on their surfaces, and because all the cilia are oriented in the same direction, this is an effective means for moving fluids from one part of the surface to another. In the kidneys, for example, primary cilia are found in most epithelial cells of the tubules, projecting into the tubule lumen and acting as a flow sensor. In response to fluid flow over the tubular epithelial cells, the primary cilia bend and cause flow-induced changes in intracellular calcium signaling. Defects in signaling by primary cilia in renal tubular epithelial cells are thought to contribute to various disorders, including the development of large fluid-filled cysts, a condition called polycystic kidney disease. Bibliography Alberts B, Johnson A, Lewis J, et al: Molecular Biology of the Cell, 6th ed. First, the nine double tubules and two single tubules are all linked to one another by a complex of protein cross-linkages; this total complex of tubules and cross-linkages is called the axoneme. Insall R: the interaction between pseudopods and extracellular signalling during chemotaxis and directed migration. The mystery of membrane organization: composition, regulation and roles of lipid rafts. The genes control cell function by determining which structures, enzymes, and chemicals are synthesized within the cell. Because the human body has approximately 20,000 to 25,000 different genes that code for proteins in each cell, it is possible to form a large number of different cellular proteins. The total number of different proteins produced by the various cell types in humans is estimated to be at least 100,000. Some of the cellular proteins are structural proteins, which, in association with various lipids and carbohydrates, form structures of the various intracellular organelles discussed in Chapter 2. However, most of the proteins are enzymes that catalyze different chemical reactions in the cells.

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