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Tetracyclines The tetracyclines are a large group of drugs with a common basic structure and activity order diltiazem with a mastercard. Tetracyclines are classified as short acting (chlortetracycline purchase diltiazem 180 mg free shipping, tetracycline 60mg diltiazem visa, oxytetracycline), intermediate acting (demeclocycline and methacycline), or long-acting (doxycycline and minocycline) based on serum half-lives. They are active against for many gram-positive and gram-negative bacteria, including anaerobes, rickettsiae, chlamydiae, mycoplasmas, and are active against some protozoa. The main mechanisms of resistance to tetracycline is decreased intracellular accumulation due to either impaired influx or increased efflux by an active transport protein pump. Pharmacokinetics: Tetracyclines mainly differ in their absorption after oral administration and their elimination. A portion of an orally administered dose of tetracycline remains in the gut lumen, modifies intestinal flora, and is excreted in the feces. Absorption occurs mainly in the upper small intestine and is impaired by food (except doxycycline and minocycline); by divalent cations (Ca2+, Mg2+, Fe2+) or Al3+; by dairy products and antacids, which contain multivalent cations; and by alkaline pH. They are distributed widely to tissues and body fluids except for cerebrospinal fluid. Minocycline reaches very high concentrations in tears and saliva, which makes it useful for eradication of the meningococcal carrier state. Tetracyclines cross the placenta to reach the fetus and are also excreted in milk. Doxycycline, in contrast to other tetracyclines, is eliminated by nonrenal mechanisms. Clinical uses: A tetracycline is the drug of choice in infections with Mycoplasma pneumoniae, chlamydiae, rickettsiae, and some spirochetes. They are used in combination regimens to treat gastric and duodenal ulcer disease caused by Helicobacter pylori. They may be employed in various gram-positive and gram-negative bacterial infections, including Vibrio infections. A tetracycline in combination with an aminoglycoside is indicated for plague, tularemia, and brucellosis. Adverse reactions Gastrointestinal adverse effects: Nausea, vomiting, and diarrhea are the most common and these effects are attributable to direct local irritation of the intestinal tract. Tetracyclines suppress susceptible coliform organisms and causes overgrowth of Pseudomonas, Proteus, staphylococci, resistant coliforms, clostridia, and Candida. This can result in intestinal functional disturbances, anal pruritus, vaginal or oral candidiasis, or enterocolitis (associated with Clostridium difficile) with shock and death. It causes discoloration, and enamel dysplasia; they can also be deposited in bone, where it may cause deformity or growth inhibition. If the drug is given to children under 8 years of age for long periods, similar changes can result. They are hepato and nephrotoxic drug, the also induce sensitivity to sunlight (demeclocycine) and vestibular reactions (doxycycline, and minocycline). Erythromycin Erythromycin is poorly soluble in water but dissolves readily in organic solvents. Antimicrobial Activity: Erythromycin is effective against gram-positive organisms, especially pneumococci, streptococci, staphylococci, and corynebacteria. Mycoplasma, Legionella, Chlamydia trachomatis, Helicobacter, Listeria, Mycobacterium kansasii, and Mycobacterium scrofulaceum are also susceptible. Gram-negative organisms such as Neisseria species, Bordetella pertussis, Treponema pallidum, and Campylobacter species are susceptible. Pharmacokinetics: Erythromycin base is destroyed by stomach acid and must be administered with enteric coating. Clinical Uses: Erythromycin is the drug of choice in corynebacterial infections (diphtheria, corynebacterial sepsis, erythrasma); in respiratory, neonatal, ocular, or genital chlamydial infections; and in treatment of community-acquired pneumonia because its spectrum of activity includes the pneumococcus, Mycoplasma, and Legionella. Erythromycin is also useful as a penicillin substitute in penicillin-allergic individuals with infections caused by staphylococci, streptococci, or pneumococci. Adverse Reactions Gastrointestinal Effects: Anorexia, nausea, vomiting, and diarrhea. Liver Toxicity: Erythromycins, particularly the estolate, can produce acute cholestatic hepatitis (reversibile). It increases serum concentrations of oral digoxin by increasing its bioavailability. Clarithromycin and erythromycin are virtually identical with respect to antibacterial activity except that clarithromycin has high activity against H. Clarithromycin penetrates most tissues, with concentrations equal to or exceeding serum concentrations. The advantages of clarithromycin compared with erythromycin are lower frequency of gastrointestinal intolerance and less frequent dosing. Azithromycin The spectrum of activity and clinical uses of azithromycin is identical to those of clarithromycin. Clindamycin Clindamycin is active against streptococci, staphylococci, bacteroides species and other anaerobes, both grampositive and gram-negative. Clinical uses: Clindamycin is used for the treatment of severe anaerobic infection caused by Bacteroides. It is used for prophylaxis of endocarditis in patients with valvular heart disease who are undergoing certain dental procedures. Clindamycin plus primaquine is an effective for moderate to moderately severe Pneumocystis carinii pneumonia. Adverse effects: Diarrheas, nausea, and skin rashes, impaired liver functions are common. Severe diarrhea and enterocolitis is caused by toxigenic C difficile (infrequently part of the normal fecal flora but is selected out during administration of oral antibiotics). Pharmacokinetics: Aminoglycosides are absorbed very poorly from the intact gastrointestinal tract. The kidney clears aminoglycosides, and excretion is directly proportionate to creatinine clearance. Ototoxicity can manifest itself either as auditory damage, resulting in tinnitus and high-frequency hearing loss initially; or as vestibular damage, evident by vertigo, ataxia, and loss of balance.

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The An abnormal finding in the test of station is if the feet patient then must indicate whether one or two stimuli are are placed far apart diltiazem 60 mg on-line. Which of the following could be a multimodal subtests that are sometimes considered a separate set of integrative area? What term describes the inability to lift the arm above understanding language generic 60 mg diltiazem otc, both from another person and the the level of the shoulder? Without olfactory sensation to complement gustatory of the cranial nerve exam for the vestibulocochlear nerve? Learning to ride a bike is a motor function dependent major language areas is most likely affected and what is the on the cerebellum buy cheap diltiazem 60 mg on-line. Similarly, certain cells send chemical signals to other cells in the body that influence their behavior. This long-distance intercellular communication, coordination, and control is critical for homeostasis, and it is the fundamental function of the endocrine system. In the human body, two major organ systems participate in relatively “long distance” communication: the nervous system and the endocrine system. Neural and Endocrine Signaling The nervous system uses two types of intercellular communication—electrical and chemical signaling—either by the direct action of an electrical potential, or in the latter case, through the action of chemical neurotransmitters such as serotonin or norepinephrine. When an electrical signal in the form of an action potential arrives at the synaptic terminal, they diffuse across the synaptic cleft (the gap between a sending neuron and a receiving neuron or muscle cell). Once the neurotransmitters interact (bind) with receptors on the receiving (post-synaptic) cell, the receptor stimulation is transduced into a response such as continued electrical signaling or modification of cellular response. The target cell responds within milliseconds of receiving the chemical “message”; this response then ceases very quickly once the neural signaling ends. In this way, neural communication enables body functions that involve quick, brief actions, such as movement, sensation, and cognition. These signals are sent by the endocrine organs, which secrete chemicals—the hormone—into the extracellular fluid. Hormones are transported primarily via the bloodstream throughout the body, where they bind to receptors on target cells, inducing a characteristic response. As a result, endocrine signaling requires more time than neural signaling to prompt a response in target cells, though the precise amount of time varies with different hormones. For example, the hormones released when you are confronted with a dangerous or frightening situation, called the fight-or-flight response, occur by the release of adrenal hormones—epinephrine and norepinephrine—within seconds. What is the secondary messenger made by adenylyl cyclase during the activation of liver cells by epinephrine? The same hormone may play a role in a variety of different physiological processes depending on the target cells involved. It is also important in breastfeeding, and may be involved in the sexual response and in feelings of emotional attachment in both males and females. In general, the nervous system involves quick responses to rapid changes in the external environment, and the endocrine system is usually slower acting—taking care of the internal environment of the body, maintaining homeostasis, and controlling reproduction (Table 17. So how does the fight-or-flight response that was mentioned earlier happen so quickly if hormones are usually slower acting? It is the fast action of the nervous system in response to the danger in the environment that stimulates the adrenal glands to secrete their hormones. As a result, the nervous system can cause rapid endocrine responses to keep up with sudden changes in both the external and internal environments when necessary. Endocrine and Nervous Systems Endocrine system Nervous system Signaling mechanism(s) Chemical Chemical/electrical Primary chemical signal Hormones Neurotransmitters Distance traveled Long or short Always short Response time Fast or slow Always fast Environment targeted Internal Internal and external Table 17. The primary function of these ductless glands is to secrete their hormones directly into the surrounding fluid. The endocrine system includes the pituitary, thyroid, parathyroid, adrenal, and pineal glands (Figure 17. For example, the pancreas contains cells that function in digestion as well as cells that secrete the hormones insulin and glucagon, which regulate blood glucose levels. The hypothalamus, thymus, heart, kidneys, stomach, small intestine, liver, skin, female ovaries, and male testes are other organs that contain cells with endocrine function. Moreover, adipose tissue has long been known to produce hormones, and recent research has revealed that even bone tissue has endocrine functions. The ductless endocrine glands are not to be confused with the body’s exocrine system, whose glands release their secretions through ducts. As just noted, the pancreas also has an exocrine function: most of its cells secrete pancreatic juice through the pancreatic and accessory ducts to the lumen of the small intestine. Other Types of Chemical Signaling In endocrine signaling, hormones secreted into the extracellular fluid diffuse into the blood or lymph, and can then travel great distances throughout the body. An autocrine (auto- = “self”) is a chemical that elicits a response in the same cell that secreted it. Local intercellular communication is the province of the paracrine, also called a paracrine factor, which is a chemical that induces a response in neighboring cells. Although paracrines may enter the bloodstream, their concentration is generally too low to elicit a response from distant tissues. A familiar example to those with asthma is histamine, a paracrine that is released by immune cells in the bronchial tree. Another example is the neurotransmitters of the nervous system, which act only locally within the synaptic cleft. Endocrinologists—medical doctors who specialize in this field—are experts in treating diseases associated with hormonal systems, ranging from thyroid disease to diabetes mellitus. Endocrine surgeons treat endocrine disease through the removal, or resection, of the affected endocrine gland. Patients who are referred to endocrinologists may have signs and symptoms or blood test results that suggest excessive or impaired functioning of an endocrine gland or endocrine cells. The endocrinologist may order additional blood tests to determine whether the patient’s hormonal levels are abnormal, or they may stimulate or suppress the function of the suspect endocrine gland and then have blood taken for analysis. Some endocrine disorders, such as type 2 diabetes, may respond to lifestyle changes such as modest weight loss, adoption of a healthy diet, and regular physical activity. Other disorders may require medication, such as hormone replacement, and routine monitoring by the endocrinologist.

Nevertheless discount 60 mg diltiazem otc, it is believed that the func- tion of neutrophils goes beyond their microbicidal ability buy diltiazem 60mg with mastercard. Therefore purchase discount diltiazem online, these cells are thought to contribute to the control of infection through the production of chemoki- nes (Riedel 1997), the induction of granuloma formation (Ehlers 2003) and the transference of their own microbicidal molecules to infected macrophages (Tan 2006). On the other hand, neutrophils have recently been ascribed a role in the develop- ment of the pathology, rather than the protection of the host. This event seems to be influenced by the differential expression of molecules which are chemoattractant to 5. Evidently, a more precise definition of the role played by neutrophils during infection will depend on an evaluation of the kinetics and magnitude of the response that these cells have in the early stages of the dis- ease. Mast cells Mast cells are effector cells with a relevant role in allergic reactions (Woodbury 1984, Miller 1996, Galli 1999, Williams 2000); and are also critical for the devel- opment of a T helper 2 (Th2) response (Galli 1999, Metcalfe 1997). They are found in the mucosa of the respiratory, gastrointestinal, and urinary tracts and can also be observed in the vicinity of blood and lymph vessels. Besides this interaction between IgE and the antigen, other agents are able to in- duce the activation of mast cells and the liberation of cytokines and other media- tors. The locations where mast cells are usually found are common gateways for infec- tious agents and there is evidence of these cells being excellent mediators of the inflammatory response (Williams 2000, Metcalfe 1997). At least in bacterial infec- tions by Klebsiella pneumoniae and Escherichia coli, mast cells are required for the triggering of innate immunity (Malaviya 1996, Malaviya 2001). In addition, due to their strategic distribution within the lung, mast cells have a fundamental role in the 160 Immunology, Pathogenesis, Virulence defense of the host against mycobacteria. An early study showed an increased number of mast cells and their degranulation in the lungs of animals experimentally infected with M. The presence of mast cells has also been described in the duodenum and the ileum of cows infected with Mycobacte- rium paratuberculosis, a microorganism that causes granulomatous enteropathic lesions (Lepper 1988). Indeed, alveolar macrophages have been shown to play an essential role in the elimination of particles that enter the organism through the airways; and have long been considered the first cell population to interact with the tubercle bacillus. More macrophages are recruited afterwards from the bloodstream, and are in charge of maintaining the infection in the host (Dannenberg 1991, Dannenberg 1994). Though it is unknown if the bacteria interact with one or more of these receptors during in vivo infection, the results of in vitro experiments suggest that the macrophage response depends on the type of receptor with which the bacteria interact. Their interaction with Fc receptors increases the production of reactive oxygen intermediates and allows the fusion of the bacteria-containing phagosomes with lysosomes (Armstrong 1975). The interactions of mycobacteria with members of the Toll-like receptor family have been studied for some years. Regardless of the receptor with which the bacteria interact, it has been observed that the cellular cholesterol present in the macrophage cell membrane is an essen- tial molecule for the internalization of the bacteria (Gatfield 2000). It is believed that cellular cholesterol works as a direct anchorage point for the bacterium and stabilizes its interaction with the macrophage membrane. Once the bacteria enter the macrophage, they generally locate themselves in the mycobacterial phagosome (Armstrong 1971, Armstrong 1975). This structure de- rives from the plasma membrane and presents some cell surface receptors (Russell 1996, Hasan 1997). In contrast to normal phagocytosis, during which the phagoso- mal content is degraded upon fusion with lysosomes, the mycobacteria block this process (Armstrong 1971, Armstrong 1975). This inhibition depends on an active process induced by viable mycobacteria, since dead bacilli can be easily found in lysosomal compartments (Armstrong 1971, Armstrong 1975). Besides having a different morphology, the vacuoles in which the bacteria reside present “early” endosomal compartment markers instead of the characteristic “late” endosomes (Hasan 1997, Clemens 1996, Baker 1997). These events show both molecules to be importantly associated in the mycobacterial mechanisms for survival (Gatfield 2000). In contrast, the role played by the reactive oxygen intermediates during infection has not been completely explained, though it is known that hydro- gen peroxide produced by macrophages activated by cytokines has a mycobacteri- cidal activity (Walter 1981). Dendritic cells bind antigens via C-type lectin receptors and Fcγ/Fcε receptors, and internalize them by endocy- tosis (Engering 1997, Fanger 1996, Jiang 1995). Immune response against Mycobacterium tuberculosis 163 receptors with which mycobacteria seem to interact. Once the antigens have been captured and internalized, dendritic cells become mature (indicated by phenotypical and functional changes) and efficiently migrate to peripheral lymph nodes. Components of the mycobacterial cell wall were also shown to inhibit the phenotypical maturation of dendritic cells induced by lipopolysaccharides. In particular, the enhanced virulence ascribed to Beijing strains might well be related to their inability to stimulate dendritic cell maturation (Lopez 2003, Ebner 2001). Natural killer cells Natural killer cells play a very important role in the development of the innate immune response. For a long time, the study of this cell population was focused on their role in viral and tumoral diseases. More recently, however, increasing interest has arisen in their eventual function in several bacte- rial infections. Human natural killer cells have been shown to have an enhanced cytotoxicity for macrophages infected with M. Immune response against Mycobacterium tuberculosis 165 detrimental role, at least in the late phase of mouse experimental infection (Suga- wara 2002). Epithelial cells Alveolar macrophages have been considered for a long time to be the first cell population to interact with M. However, the number of epithelial cells in the alveoli is 30 times higher than the number of macrophages and thus, the likelihood that they are the first cells exposed to the infecting bacilli is similarly higher. In addi- tion, several in vitro studies have characterized the interaction between epithelial cells and M. Obviously, in vivo experiments are necessary to better understand the role played by alveolar epithe- lial cells in M. Defensins A conspicuous element of the innate immune response against microorganisms is a group of small endogenous antimicrobial peptides known as defensins (Diamond 1998). These cationic peptides, consisting of approximately 30 to 50 amino acids, are present in myeloid and epithelial cells of all animal species. They were shown to display antibacterial (Gabay 1989, Ganz 1985, Selsted 1987), antifungal (Selsted 1985), and antiviral (Daher 1986) activities. These molecules are classified as al- pha, beta, and theta defensins based on the position of cysteine residues and the number of disulfur bonds (Bals 2000, Hoover 2000, Lehrer 1993). In phagocytic cells, defensins represent the main microorganism destruction components inde- pendent of oxygen metabolism (Miyakawa 1996, Ogata 1992). Allegedly, these peptides break the membrane of several microorganisms and some of them are even able to pass through the cytoplasmic membrane and enter the infected cell (Ganz 2003, Rivas-Santiago 2006).