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E. Tufail, M.A., M.D., Ph.D.

Deputy Director, Perelman School of Medicine at the University of Pennsylvania

All signal transduction systems receive an input signal (the stimulus) and then process that information to produce an output signal (the response). In general, an increase in the stimulus signal leads to an increase in the response signal. The precise relationship between stimulus and response can, however, be different in different systems. In signaling systems where little information processing occurs, there is a simple relationship between the stimulus and response. Consider, for example, a hypothetical system in which the stimulus is a small ligand that reversibly binds and activates a protein kinase, whose enzyme activity is the response (Figure 3-18). In this system, a linear increase in stimulus leads initially to a linear increase in the response. As the stimulus rises to high levels, however, the binding sites on the kinase become saturated and there is less response for a given increase in stimulus. More complex signaling systems have information-processing steps between stimulus and response, and are therefore able to convert a simple graded stimulus into a more abrupt, switch-like response. These systems respond poorly to small amounts of stimulus, but as the stimulus increases they suddenly begin to respond more and more strongly before reaching a plateau at which increasing the stimulus has little effect. These systems are termed ultrasensitive because they respond so effectively at intermediate stimulus concentrations where the curve is steepest. In some cases it can be so steep that the system behaves essentially like a binary switch. These switches will generally be reversible: that is, when stimulus is reduced the system returns to the off state. Such switches are therefore analogous to a buzzer that stays on only when the stimulus (a finger pushing a button) is maintained. Consider, for example, our simple system composed of a ligand that binds to a protein kinase; now modify the system slightly by adding a small amount of an inhibitor that reversibly binds and inactivates the stimulatory ligand (see Figure 3-19). At low stimulus concentrations, this inhibitor binds all the stimulatory ligand and reduces kinase activation, resulting in a poor response. But as ligand concentration increases, ligand molecules begin to outnumber the inhibitor molecules and the response abruptly increases. If this affinity is extremely high (not shown here), the inhibitor will completely block the response at low ligand concentrations, and when the concentration of ligand exceeds that of the inhibitor, a hyperbolic response will occur. Bistability is required for an effective binary switch Now imagine a version of our model signaling system in which the kinase can be activated by phosphorylation even if it has not bound the stimulatory ligand. One kinase molecule activated by ligand binding is therefore able to phosphorylate and activate more kinase molecules (Figure 3-20). Also assume that the system contains a phosphatase that dephosphorylates and inactivates the phosphorylated kinase. The impact of the positive feedback will vary a great deal depending on the relative rates of the various binding, phosphorylation and dephosphorylation reactions. If these rates are balanced correctly, then this system can generate a switch-like response curve like that shown in Figure 3-20. At low ligand concentrations, ligand-activated kinase will phosphorylate other kinases at a rate that is not sufficient to overcome the opposing phosphatase activity, resulting in a simple linear response. At some threshold level of stimulus, however, there will be enough kinase activity to stimulate significant kinase phosphorylation, and the resulting activated kinases will then phosphorylate more inactive kinases, in a repeated cycle, until the entire kinase population is active. The system thereby generates a maximum signal in response to a small increase in stimulus.

Syndromes

• 2 months
• Osteosarcomas
• Headache - severe
• Blood clots in the legs that may travel to the lungs
• Injury to the abdominal tissue
• Heartburn
• Selenium deficiency

In addition, diarrheal diseases caused by a variety of infectious agents, including Entamoeba histolytica, Giardia lamblia, Cryptosporidium parvum and Cyclospora cayatenensis, round out the list of miseries to be dealt with by all those living in poverty in the less developed world. The seemingly simple employment of basic sanitation, safely sequestering feces and urine away from our drinking water and food supply, remains high on the list of things to do in those countries in which these two human by-products serve as the only source of fertilizer. Political instability of vast regions of Africa and the Middle East has led to the re-emergence of many infectious diseases, including leishmaniasis and African trypanosomiasis. This vi has been largely due to environmental destruction, abandonment of control programs, and forced migration of tens of thousands of individuals from regions that were relatively safe in which to live, to places that no one should have to occupy, no matter how short the duration. These seemingly intractable situations require more than vaccines and drugs to affect a cure. Social equity, economic development, and long-term planning are the drugs of choice. The interplay of immunosuppression caused by this disease and the impact on other parasitic diseases is still poorly understood, and requires careful monitoring. As access to antiretroviral therapy improves due to the Global Fund and other non-governmental entities, new clinical syndromes are likely to emerge due to parasites behaving differently in hosts with an ever-changing immune status. It is our intent that readers of this text will be adequately armed with basic knowledge of parasites and the clinical disease states they cause, to allow them to join in a global effort already underway that has everything to do with improving the fitness and survival of the vast majority of the human species. Cutaneous Leishmaniasis Leishmania (L) major Leishmania (L) tropica Leishmania (L) mexicana 4. Visceral Leishmaniasis Leishmania (L) donovani Leishmania (L) infantum Leishmania (L) infantum chagasi 6. African Trypanosomiasis Trypanosoma brucei rhodesiense Trypanosoma brucei gambiense 7. The Malarias Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae Plasmodium knowlesi 10. Toxoplasma gondii iv v 1-8 9-10 11-22 23-30 31-42 43-50 51-60 61-72 73-88 89-96 97-128 129-140 141-154 viii 12. Naeglaria fowleri Acanthamoeba castellani Cytoisospora belli Blastocystis hominis Dientamoeba fragilis 15. Nematodes of Minor Medical Importance Manzonella ozzardi Mansonella perstans 155-168 169-174 175-194 195-198 199-200 201-208 209-216 217-226 227-240 241-252 253-266 267-278 279-290 291-298 299-304 305-312 ix Mansonella streptocerca Dirofilariaimmitis Capillaria hepatica Capillaria philippinensis Oesophagostomum bifurcum 313-328 27. Tapeworms of Minor Medical Importance Hymenolepis nana Hymenolepis diminuta Dipylidium caninum 32. Juvenile Tapeworm infections of Humans Echinococcus granulosus Echinococcus multilocularis Mesocestoides spp. The Schistosomes Schistosoma mansoni Schistosoma japonicum Schistosoma haematobium Schistosoma mekongi Schistosoma intercalatum 34. Paragonimus westermani 329-330 331-338 339-354 355-362 363-372 373-388 389-390 391-418 419-426 427-434 435-442 x 37. Procedures for Collecting Clinical Specimens for Diagnosing Protozoan and Helminthic Parasites Appendix B. Eukaryotic Parasites Eukaryotic parasites encompass subsets of organisms within the protozoan and helminth (parasitic worm) groups. In addition, medically important arthropods have been included in discussions of eukaryotic parasites, since so many of these pathogens are transmitted to humans by arthropod vectors. From a biological perspective, a phylogenetic presentation of eukaryotic parasitic organisms would undoubtedly satisfy those specialists who strictly adhere to the zoological literature, while most medical students and practicing clinicians would have little or no use for this information. The physician is more inclined to group them according to their syndromes, if they were to classify them at all. We have settled upon a compromise, in which these organisms are encountered by the reader in a somewhat biologically correct order, together with an outline of their classification and clinical presentations. Nonetheless, it is in some sense intellectually satisfying to review parasitic organisms with a semblance of evolutionary precision, allowing each student to learn about them in a sequence that most experts in the field of parasitology have agreed upon, going from the single-cell parasites to the worms and beyond. We present protozoans first, followed by the helminths, and finally round out the synopsis with medically relevant arthropods. The last half of the twentieth century has been a remarkable one for the communitybased control of pathogenic organisms. New vaccines and antibiotics have also helped reduce the incidence of numerous pathogenic organisms. At the same time, it has also heralded the emergence and re-emergence of a wide spectrum of infectious agents: viruses. Viewed from an evolutionary perspective, humans represent a highly successful system of essential niches, of which an astonishingly wide variety of eukaryotes have been able to take advantage.

As blood calcium levels rise, cell membrane permeability to sodium is decreased, and the responsiveness of the nervous system is reduced. In contrast, abnormally low blood calcium levels may be caused by parathyroid hormone deficiency, called hypoparathyroidism, which may develop following injury or surgery involving the thyroid gland. Low blood calcium increases membrane permeability to sodium, resulting in muscle twitching, cramping, spasms, or convulsions. Severe deficits can paralyze muscles, including those involved in breathing, and can be fatal. When blood calcium levels are high, calcitonin is produced and secreted by the parafollicular cells of the thyroid gland. As discussed earlier, calcitonin inhibits the activity of osteoclasts, reduces the absorption of dietary calcium in the intestine, and signals the kidneys to reabsorb less calcium, resulting in larger amounts of calcium excreted in the urine. The adrenal glands have a rich blood supply and experience one of the highest rates of blood flow in the body. They are served by several arteries branching off the aorta, including the suprarenal and renal arteries. Blood flows to each adrenal gland at the adrenal cortex and then drains into the adrenal medulla. Adrenal hormones are released into the circulation via the left and right suprarenal veins. The cortex can be subdivided into additional zones, all of which produce different types of hormones. The adrenal gland consists of an outer cortex of glandular tissue and an inner medulla of nervous tissue. The cortex itself is divided into three zones: the zona glomerulosa, the zona fasciculata, and the zona reticularis. It is really an extension of the autonomic nervous system, which regulates homeostasis in the body. The medulla is stimulated to secrete the amine hormones epinephrine and norepinephrine. Physical stresses include exposing the body to injury, walking outside in cold and wet conditions without a coat on, or malnutrition. Psychological stresses include the perception of a physical threat, a fight with a loved one, or just a bad day at school. If the stress is not soon relieved, the body adapts to the stress in the second stage called the stage of resistance. If a person is starving for example, the body may send signals to the gastrointestinal tract to maximize the absorption of nutrients from food. If the stress continues for a longer term however, the body responds with symptoms quite different than the fightor-flight response. During the stage of exhaustion, individuals may begin to suffer depression, the suppression of their immune response, severe fatigue, or even a fatal heart attack. Adrenal Cortex the adrenal cortex consists of multiple layers of lipid-storing cells that occur in three structurally distinct regions. Which hormone produced by the adrenal glands is responsible for the mobilization of energy stores Hormones of the Zona Glomerulosa the most superficial region of the adrenal cortex is the zona glomerulosa, which produces a group of hormones collectively referred to as mineralocorticoids because of their effect on body minerals, especially sodium and potassium. It is important in the regulation of the concentration of sodium and potassium ions in urine, sweat, and saliva. For example, it is released in response to elevated blood K+, low blood Na+, low blood pressure, or low blood volume. In response, aldosterone increases the excretion of K+ and the retention of Na+, which in turn increases blood volume and blood pressure. Renin then catalyzes the conversion of the blood protein angiotensinogen, produced by the liver, to the hormone angiotensin I. The cells of the zona fasciculata produce hormones called glucocorticoids because of their role in glucose metabolism. The most important of these is cortisol, some of which the liver converts to cortisone. Their overall effect is to inhibit tissue building while stimulating the breakdown of stored nutrients to maintain adequate fuel supplies.

Diseases

• Schimke syndrome
• Arginemia
• Anomic aphasia
• Microcephaly microcornea syndrome Seemanova type
• Cataract Hutterite type
• XYY syndrome
• Bartsocas Papas syndrome
• Spherophakia brachymorphia syndrome
• GTP cyclohydrolase deficiency