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Toward Replacement Parts for the Brain Toward Replacement Parts for the Brain Implantable Biomimetic Electronics as Neural Prostheses edited by Theodore W quality voveran 50mg spasms 1982. Glanzman A Bradford Book The MIT Press Cambridge 50 mg voveran spasms 1983 trailer, Massachusetts London, England ( 2005 Massachusetts Institute of Technology All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means (including photocopying, recording, or information storage and retrieval) without permission in writing from the publisher. MIT Press books may be purchased at special quantity discounts for business or sales promotional use. This book was set in Times New Roman on 3B2 by Asco Typesetters, Hong Kong, and was printed and bound in the United States of America. Library of Congress Cataloging-in-Publication Data Toward replacement parts for the brain : implantable biomimetic electronics as neural prostheses / edited by Theodore W. Loeb 2 Microelectronic Array for Stimulation of Large Retinal Tissue Areas 15 Dean Scribner, M. Taylor 3 Imaging Two-Dimensional Neural Activity Patterns in the Cat Visual Cortex using a Multielectrode Array 43 David J. Normann, and Alexei Koulakov II NEURAL REPRESENTATIONS 4 Brain Parts on Multiple Scales: Examples from the Auditory System 69 Ellen Covey 5 A Protocol for Reading the Mind 91 Howard Eichenbaum 6 Cognitive Processes in Replacement Brain Parts: A Code for All Reasons 111 Robert Hampson, John Simeral, and Sam A. Deadwyler 7 Mathematical Modeling as a Basic Tool for Neuromimetic Circuits 129 Gilbert A. Berger vi Contents 8 Real-Time Spatiotemporal Databases to Support Human Motor Skills 159 Shahram Ghandeharizadeh III NEURON/SILICON INTERFACES 9 Long-Term Functional Contact between Nerve Cell Networks and Microelectrode Arrays 177 Guenter W. Keefer, Alexandra Gramowski, and Simone Stuewe 10 Building Minimalistic Hybrid Neuroelectric Devices 205 James J. Hickman 11 The Biotic/Abiotic Interface: Achievements and Foreseeable Challenges 221 Roberta Diaz Brinton, Walid Sousou, Michel Baudry, Mark Thompson, and Theodore W. Berger IV HARDWARE IMPLEMENTATIONS 12 Brain-Implantable Biomimetic Electronics as a Neural Prosthesis for Hippocampal Memory Function 241 Theodore W. Keith Jenkins 15 Reconfigurable Processors for Neural Prostheses 335 Jose Mumbru, Krishna V. The meeting was sponsored by the National Institute of Mental Health (NIMH), the University of Southern California (USC) Alfred E. Mann Institute for Biomedical Engineering, and the USC Center for Neural Engineering. The motivation for the meeting was a growing realization among neuroscientists, engineers, and medical researchers that our society was on the threshold of a new era in the field of neural prosthetics; namely, that in the near future it would be possible to mathematically model the functional properties of dif- ferent regions or subregions of the brain, design and fabricate microchips incorporat- ing those models, and create neuron/silicon interfaces to integrate microchips and brain functions. In this manner, our rapidly increasing understanding of the com- putational and cognitive properties of the brain could work synergistically with the continuing scientific and technological revolutions in biomedical, computer, and elec- trical engineering to realize a new generation of implantable devices that could bi- directionally communicate with the brain to restore sensory, motor, or cognitive functions lost through damage or disease. Recognizing the ambitious nature of such a vision, the goal of the meeting and thus of this book, was to explore various dimensions of the problem of using biomi- metic devices as neural prostheses to replace the loss of central brain regions. The first two chapters focus on advances in developing sensory system prostheses. The re- markable success in development and clinical application of the cochlear implant, and the rapid progress being made in developing retinal and visual prostheses, pro- vide the best foundation for considering the extension of neural prostheses to central brain regions. Beyond the issues of designing multisite electrode arrays for the complex geometry and cytoar- chitecture of cortical brain (chapters 3 and 12) it is clear that neural representations of sensory receptive fields are not static, but in fact are dynamic, changing over time viii Preface and with experience (chapter 4). The limitations of using static, multisite electrode arrays to extract information from a dynamically changing population of neurons must be taken into account when designing neural prosthetic systems triggered by sensory ensemble codes. Sophisticated analyses of multielectrode recordings from the hippocampus in behaving animals (chapters 5 and 6) emphasize the complexity of neural representations typical of memory systems in the brain. Hippocampal neu- rons respond to multiple dimensions (modalities) of a given learning and memory task, with key, higher-level features distributed across populations of spatially dispa- rate cells. How to extract information from systems with such complex functional properties in real time, process that information, and then transmit the processed output back to other parts of the brain to influence cognitive function and behavior constitutes a considerable challenge. Given the multiple levels of function that characterize the nervous system (i. Chapter 8 o¤ers some practical approaches for how to organize multidimensional time series data to achieve representational schemes for sensorimotor coupling. Despite these complexities, considerable progress is being made in implementing biologically realistic neural system models in hardware.

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Phase I trials on contra- For contraception in women cheap voveran 50mg amex spasms after hemorrhoidectomy, recruitment into ceptives cheap voveran 50 mg with amex muscle relaxant glaucoma, therefore, are often also used to look Phase I trials is conducted among volunteers of at these surrogates of efficacy in addition to reproductive age, not pregnant or lactating, regu- safety issues, so that Phase I and Phase II tri- larly menstruating, identified in family planning als are combined to evaluate both safety and clinics or selected community groups, who are endocrinological endpoints. Examples of surro- IUD users or sterilised, and therefore, not at risk gates of efficacy are hormone levels as indica- of becoming pregnant. Users of other hormonal tors of inhibition of ovulation in contraceptives contraceptives than the one being studied are not for women, sperm concentration in long-acting acceptable because the method might interfere androgen–progestogen formulations for men as with the assessment of clinical and laboratory an indicator of inhibition of spermatogenesis, and parameters. Other selection criteria depend on amount of serum hCG antibodies in immunocon- the contraceptive being studied. Serological and clin- contraceptive vaccines, acute hypersensitivity to ical diagnoses of pregnancies are also conducted. These studies involve doses that activity of a steroid contained in the contra- are two or three times the initial dose. For each ceptive and its principal metabolites should dose level, a study is conducted in 10–20 healthy be described. Pharmacological action on ovarian function: Selection criteria for Phase II trials on women, the mechanism by which the contraceptive different to those mentioned for Phase I trials, are effect is attained should be described. This being currently exposed to the risk of pregnancy involves, in the first place, a description of and have proven fertility. At this stage, if the ovarian function in women with normal volunteers participating in Phase I studies are ovulatory function, measuring plasma concen- IUD users and they are willing to continue, then tration of ovarian steroids and gonadotrophins the IUD should be removed to assess efficacy. CONTRACEPTION 325 Phase IIB trials require about 50–100 subjects once-a-month preparations. The crossover design to assess efficacy and side-effects of the dosage has been used in a metabolic study to compare determined in early trials (Phase I–IIA). A Phase I trial tested When conducting Phase I/II trials, the fact that the use of progesterone as an alternative. This justifies the assessment 11 women involved one pre-treatment cycle, a of the minimum effective dose at early stages of 3-month treatment phase with an injection of development. Cyclofem every 28 days and then a 3-month When volunteers are advised on the risks and recovery phase. It confirmed that ovulation was benefits of the study in order to seek their inhibited and that inhibition of luteal activity per- informed consent, the specific risks of receiving sists after the last injection for several cycles. A comparative non-randomised study of Cyclo- fem and Mesigyna with 15 women, 8 receiv- PHASE III TRIALS ing Cyclofem and 7 Mesigyna, involved one Objectives pre-treatment cycle, three treatment cycles of 28 days and a 90-day follow-up period. The After a contraceptive is shown to be reasonably results showed that the suppressive effect of effective in Phase II trials, it is essential to com- Cyclofem was greater than Mesigyna. Specific Phase II studies on biochemical variables Design and Trial Size are conducted when required. These variables include lipid and lipoprotein metabolism, coagu- The most common design to compare meth- lation, fibrinolysis and platelet function as well as ods within each broad class of contracep- other physiological events such as vaginal blood tives has been the parallel group design, loss. This was the case for the develop- describe examples of these studies for injectable ment of OCs,5–7 injectables,18,19,22,32,33,38,55,67 326 TEXTBOOK OF CLINICAL TRIALS implants,27 IUDs,40–46 condoms68 and EC hand, the Committee for Proprietary Medicinal regimens. This Examples of comparisons of new versus standard, calculation is based on the criterion that the respectively, are the following: NET-EN ver- difference between the upper 95% confidence sus DMPA (injectables), Norplant II versus Nor- limit for the Pearl index (number of pregnancies plant (implants), steroid-releasing versus copper per 100 women-years) and the point estimate does not exceed 1. Placebo controls have been used to assess effi- Recruitment cacy of a treatment to improve the bleeding pattern disrupted by the use of progestin-only Participants in Phase III contraceptive trials are contraceptives. A In contraceptive trials, the main end-point for majority of attendants requesting contraception in efficacy is based on pregnancies, a rare event. On arrival, subjects (women or men) detect as significant a difference between groups or couples requesting or using the method under corresponding to a doubling of the rate, in a two- study are screened for eligibility. An eligibility sided 5% level test, with 80% power, is usually criterion common to contraceptive efficacy trials large (1140 for a control rate of 2%, 4700 for a is good general health, but others are specific control rate of 0. This might be their particular characteristics affect external a reason for which factorial designs have not been validity, making difficult the generalisation of commonly used in contraceptive efficacy trials. For example, a factorial design is provided by a trial compar- implants are often selected by older women.

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Hence purchase voveran 50 mg mastercard spasms left shoulder blade, few patients were likely to experience regional relapse or STATISTICAL CONSIDERATIONS other resectable recurrence cheap voveran 50 mg without a prescription muscle relaxant ibuprofen, where secondary resection and delayed adjuvant interferon could be employed. Most relapses occurred in non- Although clinical factors clearly impact on the resectable distant sites. In recent medical practice, interpretation of the three trials, our main goal is interferon is rarely employed for the treatment of to examine the statistical aspects of these trials measurable metastatic disease. We focus first ical staging of the regional nodes, and surgery on E1684 and E1690. Among STATISTICAL TESTS EMPLOYED AND all relapsed patients (n = 114 in the high-dose PRESENTATION OF RESULTS interferon arm and n = 121 in the observation control arm), 54% on high-dose interferon and One source of confusion could be due to the fact 45% on observation experienced regional recur- that one-sided p-values were presented for E1684 rence only. Retrospective data collection indi- but two-sided p-values were presented for E1690. In addition, all hazard ratios are expressed as observation TRIAL SIZE, OVERALL RESULTS arm versus treatment arm ratios. Thus, a hazard AND OTHER ASPECTS ratio >1 indicates an excess of hazard in the observation arm, or treatment advantage. To interpret the combined results E1684 and Another possible source of confusion could E1690, it is useful to compare the study param- be the fact that, in E1684, statistically signifi- eters and overall results. Since there was vival differences by the stratified logrank test not a low-dose interferon arm in E1684, only (adjusted for disease burden and presentation at the high-dose interferon and observation arms of E1690 are included in the tables. Due to the initial diagnosis versus recurrent nodal disease limitations of data availability, all randomised status) were reported (Table 2 of Ref. But patients regardless of eligibility determination are when Cox regression analysis was performed, presented for consistency. However, these hazard ratios (presented in their reciprocals as interferon over observa- tion ratios, 0. E1684 and E1690 patient disease stage observation patients in this subset. For the readers distribution who did not appreciate these details of the Cox modelling, the hazard ratios for the nodal disease Disease T4 T1-4 N+ T1-4 N+ N+ subset could have been over-interpreted as the stage N0 (occult) (overt) Recurrent Cox model treatment effects for the study as a E1684 11% 12% 14% 63% whole, which were not presented in the original E1690 26% 11% 12% 50% publication. When Study ratio 95% CI p-Value the results were presented, however, one-sided p- Relapse-free survival values less than 0. Should the true magnitude of benefit from both interferon regimens be the same, the events were analysed for E1690 from the larger power to detect both effects in the same study sample size and the fact that few events occurred was close to 0. The main known patient char- rate in the end, the overall power would increase acteristic difference was in the distribution of somewhat but would likely remain less than ade- disease stage. There were more node-negative quate for detecting reasonable effects from both patients (26% vs. The more favourable relapse and survival experiences of the obser- WHAT DOES E1694 TELL US? E1694 was designed to detect a GMK vaccine 26% and overall survival of 54% vs. As is often practiced with ing the treatment outcome, the magnitude of the superiority designs, the trial would be stopped interferon benefit was smaller in E1690 than at planned interim analyses if the hypothesised in E1684 for both relapse-free survival (hazard vaccine benefit could be definitively ruled out. Instead of in E1690 resulted in narrower confidence inter- the typical, highly stringent interim p-value vals. As offered by the authors as one plausible requirements, the GMK vaccine needed only conclusion,13 the combined evidence from these to be inferior to interferon at a fixed, one- two trials seems to indicate that, for node posi- sided p-value of 0. Survival benefit, if it vaccine inferiority but would certainly rule out exists, may be more limited. It is worth pointing out that E1690 was Considering the substantially more favourable designed with not one but two primary compar- vaccine toxicity profile, a more appropriate trial isons, comparing high-dose interferon and low- design might have sought to demonstrate the dose interferon to observation (but not to each equivalence of the two agents in their efficacy 156 TEXTBOOK OF CLINICAL TRIALS rather than the superiority of the vaccine. However, it is known that effects only when there was decisive evidence that the of prognostic factors such as disease stage can GMK vaccine was inferior to high-dose inter- easily overwhelm any treatment effects. Obviously, The predominant subcategories of high-risk if it were known that the GMK vaccine had melanoma patients are those having thick primary some level of clinical efficacy, the finding that tumours with clinically or pathologically nega- high-dose interferon was significantly better in tive nodes and those having documented involve- both disease-free and overall survival would be ment of the nodes. Among the node-positive of great clinical significance and would substan- patients, subsets include those with 1, 2 to 3 and tiate the benefits identified in the initial E1684 ≥4 nodes; patients with clinically evident ver- trial. Without this knowledge, some have main- sus microscopic nodal involvement; and patients tained the possibility of a deleterious vaccine found to have nodal involvement at the time of effect and insisted that the study cannot be used initial presentation versus those developing recur- to give information on the non-design comparison rent disease in the nodes.

Nitrofurantoin is most active against organisms causing UTI when urine pH is 5 buy voveran 50 mg low cost spasms perineum. What are potentially serious adverse effects of tetracy- How Can You Avoid This Medication Error? What is the rationale for long-term 50 mg voveran free shipping muscle relaxant 2632, low-dose administration an allergy to sulfa, and the sulfamethoxazole component is a sul- of a tetracycline for acne? You might want to ask him what type of reaction he ex- perienced when he previously took sulfa. Which tetracyclines may be given to clients with renal is an adverse side effect rather than an allergic response. What are major adverse effects of sulfonamides, and how hold the medication and call the physician. Nursing Notes: Apply Your Knowledge SELECTED REFERENCES Answer: An indwelling catheter significantly increases the inci- Chambers, H. Antimicrobial agents: Protein synthesis inhibitors dence of urinary tract infection (UTI). Limbird urine with lots of sediment also supports the presence of a UTI. Antimicrobial agents: Sulfonamides, trimethoprim- crease risk of chronic, recurrent UTIs. Discuss characteristics and clinical indications macrolide antibacterials. Apply principles of using macrolides in selected vancomycin in the treatment of pseudo- client situations. Critical Thinking Scenario You are an infection control nurse who will be providing long-term care nurses with an update on methicillin- resistant Staphylococcus aureus (MRSA). Because MRSA has been a significant problem over the last decade, especially in long-term care facilities, your goal is to increase knowledge about the development of drug resistance and appropriate measures to prevent spread of this organism. What risks are involved when vancomycin is used consistently to treat MRSA. What infection control practices are necessary to limit the spread of MRSA and other resistant organisms. OVERVIEW sues and fluids and may be bacteriostatic or bactericidal, depending on drug concentration in infected tissues. They The drugs described in this chapter are heterogeneous in are effective against gram-positive cocci, including group their antimicrobial spectra, characteristics, and clinical A streptococci, pneumococci, and most staphylococci. Some are used often; some are used only in specific are also effective against species of Corynebacterium, Tre- circumstances. The macrolides and selected miscellaneous ponema, Neisseria, and Mycoplasma and against some drugs are described in the following sections; names, routes, anaerobic organisms such as Bacteroides and Clostridia. MAC disease is an opportunistic infection that occurs mainly in people with advanced human MACROLIDES immunodeficiency virus infection. Erythromycin, the prototype, is now used less often be- The macrolides, which include erythromycin, azithromycin cause of microbial resistance, numerous drug interactions, and (Zithromax), clarithromycin (Biaxin), and dirithromycin the development of newer macrolides. Erythromycin is me- (Dynabac), have similar antibacterial spectra and mecha- tabolized in the liver and excreted mainly in bile; approxi- nisms of action. They are widely distributed into body tis- mately 20% is excreted in urine. Depending on the specific salt 548 CHAPTER 37 MACROLIDES AND MISCELLANEOUS ANTIBACTERIALS 549 Drugs at a Glance: Macrolides Usual Routes and Dosage Ranges Generic/Trade Name Adults Children Azithromycin (Zithromax) Respiratory and skin infections, PO 500 mg 6 mo and older: Acute otitis media PO, as a single dose on the first day, then 250 mg 10 mg/kg as a single dose (not to exceed once daily for 4 d. Nongonococcal urethritis 500 mg) on the first day, then 5 mg/kg and cervicitis caused by Chlamydia trachomatis, (not to exceed 250 mg) once daily for 4 d give 1 g as a single dose. Azithromycin and Mechanism of Action dirithromycin are excreted mainly in bile, and clarithromycin is metabolized to an active metabolite in the liver, which is The macrolides enter microbial cells and attach to 50S ribo- then excreted in urine. Oph- thalmic and topical preparations are discussed in Chapters 65 and 66.

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