By J. Phil. Columbus College of Art and Design. 2018.

These cells continuously travel through blood and IL-2 order zithromax 100 mg free shipping antibiotics for dogs diarrhea, -3 buy 100mg zithromax amex bacteria jekyll island, -4, -5, and -6, GM-CSF, and interferon gamma. The The devastating effects of acquired immunodeficiency three types of lymphocytes are natural killer cells, T cells, syndrome (AIDS) result primarily from the ability and B cells. T cells are involved in both cell-mediated but differ in the other cytokines they secrete. The TH1 and humoral immunity and are especially able to combat in- subset is responsible for many cell-mediated functions tracellular infections (eg, virus-infected cells). B cells are (eg, delayed-type hypersensitivity reactions and acti- involved in humoral immunity; they secrete antibodies that vation of cytotoxic T cells) and for the production of can neutralize pathogens before their entry into host cells. These cells are also associated with they can fulfill their immune functions, and both have pro- excessive inflammation and tissue injury. The TH2 sub- teins on their cell membrane surfaces that act as receptors set stimulates the activation and differentiation of for antigens. There are five main classes of also associated with hypersensitivity reactions. Once activated by antigen and IL-2, cytotoxic with molecules of antigen, and the antigen–antibody T cells bind to antigens on the surfaces of target cells. Activated complement After binding to antigen, the T cells are thought to de- causes an inflammatory reaction, promotes phagocyto- stroy target cells by one or more of three mechanisms. IgG also One mechanism involves the formation of holes in the crosses the placenta to provide maternally acquired anti- target cell membrane that allow fluids to enter and bodies (passive immunity) to the infant. Another is the insertion of • IgA is the main immunoglobulin in mucous mem- enzymes that break down or digest the cell. It is found in saliva, breast mechanism is to induce apoptosis (programmed cell milk, and nasal, respiratory, prostatic and vaginal se- death). It protects against pathogens and other anti- target cells, they can detach themselves and attack gens that gain access to these areas. Cytotoxic T cells are especially lethal to virus-infected • IgM constitutes approximately 10% of serum antibodies. It acts only in the bloodstream because even after destruction of all the invaders that elicited the its large molecular size prevents its movement or trans- original cytotoxic activity. It activates complement to pecially important in killing body cells that have been in- destroy microorganisms. Cytotoxic T cells also play a role in body fluids and readily enters body tissues. It is in- the destruction of transplanted organs and delayed hyper- volved in parasitic infections and hypersensitivity re- sensitivity reactions. IgE sensitizes mast An additional type of T cells, called suppressor cells, which then release histamine and other chemical T cells, has been postulated to exist and to function by mediators that cause bronchoconstriction, edema, ur- stopping the immune response (ie, decreasing the ac- ticaria, and other manifestations of allergic reactions. This activity is considered impor- of IgE is stimulated by T lymphocytes and interleukins tant in preventing further tissue damage. Small in autoimmune disorders, suppressor T cell function is amounts of IgE are present in the serum of nonallergic impaired and extensive tissue damage may result. They also regulate the intensity and duration of in the bone marrow), and migrate to the spleen, lymph the immune response by stimulating or inhibiting the acti- nodes, or other lymphoid tissue. In lymphoid tissue, the vation, proliferation, and/or differentiation of various cells cells may be dormant until exposed to an antigen. In re- and by regulating the secretion of antibodies or other cy- sponse to an antigen and IL-2 from helper T cells, B cells tokines. Although the hematopoietic cytokines described in- multiply rapidly, enlarge, and differentiate into plasma clude the immune system cytokines, the emphasis here is on cells, which then produce antibodies (immunoglobulins those that affect immune cells. Immunoglobulins are secreted formed by activated macrophages enter the bone marrow, into lymph and transported to the bloodstream for circula- where they induce the synthesis and release of other cytokines 636 SECTION 7 DRUGS AFFECTING HEMATOPOIESIS AND THE IMMUNE SYSTEM Macrophage Antigen ILs 1, 6, 11, 12 IL8 G-CSF, GM-CSF, TNF alpha M-CSF, TNF RBCs ILs 1, 6, 8, 10, 12, 15 IFNs alpha and beta WBCs TNF alpha Stem cell Neutrophils Platelets Resting TH cell Activated TH cell ILs 4, 10 IL2 ILs 3, 6, 7 ILs 3, 4, 10 ILs 3, 5 ILs 2, 12, 15 GM-CSF Antigen Resting TH cells B cell IL12 Stem cells Activated B cell TC cells ILs 2, 4, 5, 13 IFN gamma ILs 3, 4, 10, 13 IFN alpha and beta Natural TNF beta Eosinophils killer cells RBCs WBCs Platelets Mast cells B cells IL 6 Macrophages Plasma cells Antibodies (Ig G, M, A, E, D) Figure 42–2 Macrophage and T cell cytokines, their target cells, and the products of target cells. IL, interleukin; IFN, interferon; TNF, tumor necrosis factor; TH, helper T cell; TC, cytotoxic T cells; CSF, colony- stimulating factor. CHAPTER 42 PHYSIOLOGY OF THE HEMATOPOIETIC AND IMMUNE SYSTEMS 637 that activate resting stem cells to produce more granulocytes crease over approximately 6 months as maternal antibodies and monocyte–macrophages.

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Roleofthehumanfusimo- fusimotor dysfunction drives motor disturbances cheap 100 mg zithromax fast delivery virus quarantine, torsysteminamotoradaptationtask zithromax 100 mg without prescription 200 antimicrobial peptides. JournalofPhysiology but the database of spindle recordings from patients (London), 401, 77–95. Response profiles of human muscle afferents during active finger movements. Reflex changes for spindle afferents from triceps surae and the fore- inmusclespindledischargeduringavoluntarycontraction. Reflexactivationofmusclespindlesinhuman independent of the level of drive. Behavior of human muscle receptors when reliant activation drives the next clonic contraction. Journal of suggests that spinal proprioceptive reflexes do not Neurophysiology, 64, 661–70. Muscle spindle feedback during spa- There are, as yet, no published reports of recordings tially oriented movements. Experimental Brain Research, from spindle endings in patients with spinal spas- 134, 301–10. Journal of Physiology (London), 180, group II muscle afferents, contributes to the reflex 649–72. Afferent tobedominatedbymusclespindleactivityandsome andefferentactivationofhumanmusclereceptorsinvolved single-unit recordings during parkinsonian tremor. Experimental Neurol- These have revealed no evidence of selective or dis- ogy, 41, 754–68. JournalofNeurology,Neurosurgery but the question needs to be addressed quantita- and Psychiatry, 37, 1012–21. The activity of human muscle spindle endings ings from identified afferents. In International Review of Phys- ing tremor, spindle discharge occurs in two phases: iology,vol. Criticalexaminationofthecasefororagainstfusimo- stretched, a pattern similar to that seen with volun- tor involvement in disorders of muscle tone. The responses of human muscle spindle endings to ism of monosynaptic reflex reinforcement during Jendras- vibration during isometric contraction. Scandinavian Journal of soleus Ia afferents to vibration in the presence of the tonic Rehabilitation Medicine, 9, 15–23. JournalofPhysiology(London),276, of movement in a man without large myelinated sensory 159–64. Electroencephalography and Clinical Neu- vation of spindle endings in human muscles temporar- rophysiology, 89, 45–53. Journal of Physiology (London), 306, Journal of Physiology (London), 400, 101–11. Journal of Physiology (London), 339, fusimotor axons in hind-limb muscles of the cat. Supraspinal and segmental control of static activation of human fusimotor neurons. EMG studies of stretch reflexes in mation to control natural limb movements? Electroencephalography and Clinical Neurophysiol- Brain Sciences, 15, 614–32. New ity recorded with microelectrodes from human peripheral York:Academic Press. Discharge characteris- between human muscle spindle endings and motor units tics of human muscle afferents during muscle stretch and assessedusingspike-triggeredaveraging. A influences on muscle spindle activity in relaxed human leg preliminary report. Voluntary activation of human motor axons in the dle responses to stretch in normal and spastic sub- absence of muscle afferent feedback.

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It shows a diagrammatic representation of a multifunctional system to achieve long-term neuron survival and a neu- ronal interface with an electrode (pads or penetrating) while simultaneously suppressing glial proliferation purchase zithromax 100 mg virus kills kid, activation order zithromax 250mg fast delivery infection drainage, invasion, and the ensuing inflammatory response. Conformal multisite electrode arrays can be coated with specific adhesion substrates, followed by microstamping of hydrogel matrices that contain neu- ronal survival and glial suppression factors around the electrode. Hippocampal slices can be cultured on top of the electrode-adhesion substrate-hydrogel matrix to test for optimal in vitro conditions prior to in vivo analyses. Acknowledgments This work was supported by O‰ce of Naval Research grants to T. IV HARDWARE IMPLEMENTATIONS Brain-Implantable Biomimetic Electronics as a Neural Prosthesis for 1 Hippocampal Memory Function Theodore W. One of the true frontiers in the biomedical sciences is repair of the human brain: developing prostheses for the central nervous system to replace higher thought pro- cesses that have been lost through damage or disease. The type of neural prosthesis that performs or assists a cognitive function is qualitatively di¤erent than the coch- lear implant or artificial retina, which transduce physical energy from the environ- ment into electrical stimulation of nerve fibers (Loeb, 1990; Humayun et al. Instead, we consider here a neural prosthe- sis designed to replace damaged neurons in central regions of the brain with silicon neurons that are permanently implanted into the damaged region. The replacement neurons would have the same functional properties as the damaged neurons, and would receive electrical activity as inputs and send it as outputs to regions of the brain with which the damaged region previously communicated. Thus, the prosthesis being proposed is one that would replace the computational function of damaged brain areas, and restore the transmission of that computational result to other regions of the nervous system. Although the barriers to creating intracranial, electronic neural prostheses have seemed insurmountable in the past, the biological and engineering sciences are on the threshold of a unique opportunity to achieve such a goal. The tremendous growth in the field of neuroscience has allowed a much more detailed understanding of neurons and their physiology, particularly with respect to the dynamic and adap- tive cellular and molecular mechanisms that are the basis for information processing in the brain. Likewise, there have been major breakthroughs in the mathematical 242 Theodore W. Berger and colleagues modeling of nonlinear and nonstationary systems that are allowing quantitative rep- resentations of neuron and neural system functions to include the very complexity that is the basis of the remarkable computational abilities of the brain. The con- tinuing breakthroughs in electronics and photonics o¤er opportunities to develop hardware implementations of biologically based models of neural systems that allow simulation of neural dynamics with true parallel processing, a fundamental charac- teristic of the brain, and real-time computational speed. Fundamental advances in low-power designs have provided the essential technology to minimize heat gen- eration by semiconductor circuits, thus increasing compatibility with temperature- sensitive mechanisms of the brain. Finally, complementary achievements in materials science and molecular biology o¤er the possibility of designing compatible neuron/ silicon interfaces to facilitate communication between silicon computational devices and the living brain. Essential Requirements for an Implantable Neural Prosthesis In general terms, there are six essential requirements for an implantable microchip to serve as a neural prosthesis. First, if the microchip is to replace the function of a given brain tissue, it must be truly biomimetic; that is, the neuron models incorpo- rated in the prosthesis must have the properties of real biological neurons. This demands a fundamental understanding of the information-processing capabilities of neurons that is experimentally based. Second, a neural prosthesis is desired only when a physiological or cognitive function is detectably impaired (according to neurological or psychiatric criteria). Physiological or cognitive functions are the ex- pression, not of single nerve cells, but of populations of neurons interacting in the context of a network of interconnections. Thus, biologically realistic neuron models must be capable of being concatenated into network models that can simulate these phenomena. Third, the neuron and neural network models in question must be su‰ciently miniaturized to be implantable, which demands their implementation in at least microchip circuitry. Given the known signaling characteristics of neurons, such an implementation will most likely involve hybrid analog-digital device designs. Fourth, the resulting microchip or multichip module must communicate with existing, living neural tissue in a bidirectional manner. Given that both electronic and neural sys- tems generate and respond to electrical signals, this is feasible, although the region- specific, nonuniform distribution of neurons within the brain places substantial constraints on the architecture of neuron/silicon interfaces. Fifth, the variability in phenotypic and developmental expression of both struc- tural and functional characteristics of the brain will necessitate adaptation of each A Neural Prosthesis for Hippocampal Memory Function 243 prosthetic device to the individual patient. Finally, there is the critical issue of power required for the prosthetic device. Not only will supplying power be di‰cult, given implantation of a set of microchips into the depths of the brain (versus the periphery, as with a cochlear implant), but cellular and molecular mechanisms found in the brain are highly temperature sensitive, so that any solution must minimize heat generation to remain biocompatible.

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We know buy 250 mg zithromax otc virus 1918, in particular buy zithromax 100 mg otc antibiotic resistant std, that the likelihood that a specific set of clinical activities—a given process—will result in desirable outcomes depends crucially on how efficacious that process has been shown to be. Efficacy A clinical intervention is said to be efficacious if it has been shown to reli- ably produce a given outcome when other, potentially confounding, fac- tors are held constant. The efficacy of a clinical intervention is typically established through formal clinical trials or similarly systematic, controlled studies. Knowledge about efficacy is crucial to making valid judgments about quality of care based on either process or outcome measures. If we know that a given clinical intervention was undertaken in circumstances that match those under which the intervention has been shown to be effi- cacious, we can be confident that the care was appropriate and, to that extent, of good quality. A frequently asked question is whether structure, process, or outcome is the best measure of quality of care. The answer—that none of them is inher- ently better and that all depends on the circumstances (Donabedian 1988a, 2003)—often does not satisfy those who are inclined to believe that out- come measures are the superior measure. After all, they reason, outcomes address the ultimate purpose, the bottom line, of all caregiving: was the condition cured, did the patient get better? As previously mentioned, how- ever, good outcomes can result even when the care (i. The reverse is also possible: although the care was excellent, the outcome was not a good one. Besides the care provided, a number of other factors—most of them, like how frail the patient is, not within the control of clinicians—can affect outcomes and must be accounted for through risk- adjustment calculations that are seldom straightforward (Iezzoni 2003). Ultimately what a particular outcome tells us about quality of care depends crucially on whether the outcome can be attributed to the care provided. In other words, we have to examine the link between the out- come and the antecedent process and determine whether the care provided 36 The Healthcare Quality Book was appropriate—a determination that is made based on what we know about efficacy—and whether it was provided skillfully. Outcomes are there- fore very useful in identifying possible problems of quality (fingering the suspects), but not in ascertaining whether poor quality was actually pro- vided (determining guilt). The latter determination requires delving into the antecedent process of care to establish whether the care provided is actually the likely cause of the observed outcome. Criteria and Standards In practice, to assess quality using structure, process, or outcome measures we need to know what constitutes good structure, good process, or good outcomes. In other words, we need criteria and standards for those aspects of care. Definitions Criteria refer to specific attributes that are the basis for assessing quality. Standards express quantitatively what level the attributes must reach to sat- isfy preexisting expectations about quality. An example unrelated to health- care may help clarify the difference between criteria and standards. The scores are thus one of the criteria by which programs judge the quality of their applicants. However, although two programs may use the same criterion— standardized scores—to evaluate applicants, the programs may differ markedly on their standards: one program may consider applicants accept- able if they have scores above the 50th percentile, whereas scores above the 90th percentile may be the standard of acceptability at the other. Sources A shift in the way criteria and standards are derived has been occurring in the healthcare field. Prior to the 1970s, formally derived criteria and stan- dards for quality-of-care evaluations for the most part relied on consensus opinions of groups of clinicians selected for their clinical knowledge and experience and for the respect they commanded among their colleagues (Donabedian 1982). This approach to formulating criteria took for granted that in their deliberations the experts would incorporate the latest scien- tific knowledge relevant to the topic under consideration, but formal require- ments that they do so seldom existed. It was not until the mid-1970s that the importance of the scientific literature in relation to criteria and standards was highlighted, notably by Basic Concepts of Healthcare Quality 37 TABLE 2. At about the same time, Brook and his col- leagues at RAND were the first to use systematic reviews and evaluations of the scientific literature as the starting point for the deliberations of pan- els charged with defining criteria and standards for studies of quality (Brook et al. This focus on the literature—and especially on the validity of the studies within that literature—was reinforced in the 1990s by the evi- dence-based medicine movement, which seeks to put into practice what the best evidence has to say about what is and is not efficacious under a given set of clinical circumstances (Evidence-Based Medicine Working Group 1992; Sackett et al. Thus, criteria and standards have come to revolve increasingly around the strength and validity of the scientific evi- dence and less on the unaided consensus opinions of experts (Eddy 1996).

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