I. Sanuyem. Barber-Scotia College.

The release of cy- blood levels of IGF-1 and its uptake into the tokines near the time of an acute injury prednisone 10mg cheap, for Biologic Adaptations and Neural Repair 107 example 40 mg prednisone otc, may make the environment unsafe for rons cheap prednisone 5 mg without a prescription. When the stem cells were transplanted new cell survival discount prednisone 20mg free shipping, proliferation or migration purchase prednisone 5mg visa, as into the striatum, cortex, hippocampus, and ol- well as set off a series of cellular cues that lead factory bulb of adult mice, the cells migrated to delayed cell death or inhibition of axonal re- and differentiated extensively only in the generation. In contrast, embry- erebral grafts have partially restored a variety onic neuronal precursors and adult precursors of sensorimotor and cognitive skills in animal that were grown in vitro before transplantation models of injury, but methodologies must take have been more efficient at migration and dif- into account many factors (Table 2–8). Neural pro- be able to take on the cell type characteristics genitor cells from embryonic human forebrain of their neighbors. Given that they can prolif- tissue have remarkable potential for adaptabil- erate and migrate, they may also serve as trans- ity in a new environment. When implanted into port vehicles for a variety of genetically engi- the hippocampus and subventricular zone of neered proteins (Table 2–9). Many immunosuppression and neuropro- stores and bone marrow offer an intriguing tection strategies are being tried. Embryonic stem cells, a cocktail of the growth factor GDNF was com- so far, seem more flexible than stem cells found bined with a caspace inhibitor of apoptosis to in adult tissues, but the gap appears to be clos- enhance the survival of dopamine neurons ing. The way the donor material is prepared from fetal ventromesencephalic tissue. These techniques are improving, tion that has been rapidly expanded to supply but the results of transplantation are rather un- as many cells as needed. For example, neural stem cells hand, neural precursor cells, such as human from the subventricular zone preferentially mi- mesencephalic precursors that make dopamine, grate to the olfactory bulb and form interneu- may require a cocktail of growth factors, cy- Table 2–9. Neural Stem or Precursor Cells as Delivery Vehicles POTENTIAL CAPABILITIES Cell replacement in a circuit Provide extracellular matrix products Contact with intact cells, altering their activity Provide anti-inhibitory molecules for axonal growth Myelination cone extension Provide diffusable molecules (e. Clinicians can also help put replication into the neurons of choice in large the potential of stem cell research for mollify- numbers. Genes can also be delivered directly ing neurologic disease into the context of the into neurons by infecting them with a virus that disabilities caused by these diseases in millions carries the message for cells to produce a neu- of people. The remark- been genetically engineered to transport spe- able effects of exercise have implications cific genes or cells into the nervous system. It is structs may provide the substances missing in difficult enough to show an exercise-dose to genetic diseases that affect the CNS. Also, tent cells are potentially useful for repairs, re- reducing stress-induced glucorcorticoids and placements, and to transport genes for trophic adding growth factors may lead to greater pro- factors, proteins, and neurotransmitters. Basic researchers must still pursue genes that produce specific neurotrophins or how the myriad genetic, molecular, and envi- other molecules that can diffuse toward cells ronmental factors that continue to be identi- in need of nurture and toward axons that may fied come to regulate proliferation, migration, be coaxed to regenerate. Sophisticated tech- differentiation, and incorporation of newly niques for gene therapy allow both direct and minted neurons. At the moment, the state-of- cell-mediated transfer of therapeutic genes the-art cannot quite define the identity of in into the CNS. Greater knowledge of the endogenous boundary, they migrate better than Schwann regulators of natural neurogenesis may even- cells,146 elicit axonal regeneration in rat spinal tually lead to proactive self-repair strategies cord,147 and form a thin layer of myelin over manipulated by clinicians. Clinicians can These include adrenal medulla autotransplan- do a great service for stem cell research by tation, dopaminergic neurons from human fe- making sure that lay people understand just tuses, a human teratocarcinoma cell line, com- what comprises a blastocyst from which ES mitted dopaminergic neurons from embryonic Biologic Adaptations and Neural Repair 109 midbrain expanded in vitro, immortalized pro- than 10% of human fetal substantia nigral cells genitor cells given a gene or other factor for survive grafting; approximately 25% are dam- dopaminergic differentiation, and other clever aged by manipulation, and another 25% are manipulations. Reports suggested that graft dead before implantation, even when the sur- survival in animal models of induced Parkin- geon immediately deploys the cells. Some grafts in ro- gather large numbers of cells came from the dents have been placed in the substantia nigra apparent success of implanting fetal pig cells where a small percentage of neurons have sent into rodents and then into humans. No clinical cultured mesencephalic tissue cells from 4 em- gains were described 18 months later. Fiber outgrowth tal precursor cells, striatal cells, and human from the transplant, demonstrated by PET donor cells from the lateral ventricle of fetuses scanning, occurred in most of these cases. At into rats and primate models of HD has led to postmortem examination of two subjects, the human trials. Hopes have been high, in part dopamine neurons generated dendrites from 2 because the dominant region of pathology in to 3 mm from the cell body. Unfortunately, this neurodegenerative disease, which is 15% of these subjects developed dystonia and caused by increased cytosine, adenine, guani- dyskinesias. Effects of age, severity of disease, eight donors of embryonic striatal tissue.

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As isolated systems generic prednisone 10 mg line, networks in culture allow quantitative purchase prednisone 20mg without a prescription, repeated pharmaco- logical manipulations over long periods of time trusted 5mg prednisone. In this domain buy prednisone 5 mg free shipping, response repeat- ability is remarkable because the networks react to molecules introduced into the medium proven 10 mg prednisone, which simultaneously a¤ects all target receptors or other binding sites. These network properties immediately suggest the development of massively parallel systems for systematic screening and evaluation of compounds for toxicity and neuroactive and pharmacological potential. Finally, as a consequence of their pharmacological sen- sitivity and reliable neurophysiological responses, networks can be used to provide early warning of the presence of chemical toxicants. The networks represent broad- band sensors that react to known and unknown compounds that have the capability of altering the performance of nervous system functions. Long-Term Contact between Neural Networks and Microelectrode Arrays 203 Keefer, E. Hickman The objective of our research e¤orts is to learn how to handle and prepare cells to serve as components for microdevices and engineered tissues, and then to demon- strate the practicality of this approach by manipulating them to build hybrid systems and engineer functional tissues. Since it will be necessary to predict the outputs of the neuronal circuits in the test-beds, which will depend on geometry, synapse placement, and cell pheno- type(s), we have modeled various circuit configurations as well. The ability to control the surface composition of an in vitro system, as well as other variables, such as growth media and cell preparation, plays an important role in creating a defined sys- tem for fabricating a hybrid device and in vitro evaluation of surface modifications and their e¤ect on cellular materials. We have reproducibly created patterned neuronal circuits and shown that we can successfully measure the signals from these circuits in our defined in vitro culture sys- tem (Das et al. We have also modeled modes of cell- cell communication that could be monitored and investigated the electrical properties of the neuronal circuits in contact with the designed biological interfaces in these sys- tems (Peterson, 2001; Jung et al. One application of this concept is for drug development or new biomedical diagnostics. These function- based test-beds could also detect drug e‰cacy or toxicity through e¤ects ranging from the obvious (cell death) to those that are more subtle (impairment of function). This wide range of responses can be measured because cells and the networks they form are exceedingly sensitive to certain changes in their environment. We have developed surface chemistry that can be used to create templates that en- able the patterning of discrete cells and networks of cells in culture (Stenger et al. This advance allows the construction of a test-bed that measures changes in the po- tential of cells and/or their processes. Thus, any changes in the electrical signals upon exposure to a compound could be detected. Hickman under development include ion-sensitive electrodes (Solsky, 1990; Uhlig et al. Most assays rely on the fact that the agonist is known and are targeted for a specific compound. Preliminary work has been reported on measuring signals from neurons using solid-state devices (Regher et al. It would be beneficial to develop sensors to function as precursors to these epidemiological studies. In vitro cell cultures of embryonic rat tissue have been used to study rudimentary cellular organization and communication. Neurons in culture are generally disorga- nized in the sense that the connections between the cells are not controllable. Histor- ically, this has made it di‰cult to relate specific signals to specific functions, as well as to make the system reproducible. If one could control the connections between liv- ing neurons, new paradigms in in vitro cellular networks could be realized. A major benefit would come from sorting out all of these complex connections and arrange- ments and making them reproducible. We are using a reductionist approach to in vitro cellular networks by using the minimum number of neurons to construct simple reproducible circuits and connecting them to silicon devices. These new hybrid neu- roelectric devices can then be connected in a multitude of configurations, much like the components and devices that comprise computational devices. The most di‰cult tasks in developing the fabrication protocol are controlling the placement of neurons, the processes, and the number and placement of synapses. Building a network composed of neurons into the preferred synaptic configuration requires high-resolution surface patterns that guide the geometry and outgrowth of the elements of the circuit. The use of hippocampal neurons is of particular interest for studies of cell-cell communication because the hippocampus is thought to play a central role in learning and memory function. It is known that the ability of neuronal processes to extend to their targets is dependent on adhesion to underlying substrata, which in vivo appears to be spatially and temporally patterned. The ability to culture mammalian neurons on patterned substrata would allow the investigation, and pos- sible control, of the factors involved in the formation of basic neuronal circuits.

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Gui Zhi Tang not only regulates and harmonizes the constructive and defensive buy prednisone 40 mg with amex, it also warms and frees the flow of the bladder channel purchase prednisone 40mg without prescription. Yi Zhi Ren and Tu Si Zi are added to warm the kidneys and secure and contain buy cheap prednisone 20 mg. From The Treatment of 43 Cases of Pediatric Enuresis Combining Jin Suo Gu Jing Wan (Golden Lock Essence- securing Pills) with Liu Wei Di Huang Wan (Six Flavors Rehmannia Pills) by Zou Shi-chang purchase prednisone 10 mg online, Ji Lin Zhong Yi Yao (Jilin Chinese Medicine & Medicinals) cheap prednisone 5mg on line, 1998, #5, p. Twenty-five cases were between the ages of 5-10, and 18 cases were between the ages of 10-16 years old. These children had enuresis as much as 2-3 times per night and as little as 3-4 times per week. Among the patients, 18 cases had frequent urination during the day, and 14 cases had urgency of urination, fatigued spirit, and lack of strength. Their tongues were pale with thin, white fur, and their pulses were fine and weak. Treatment method: Five to 10 year-olds took five grams of Jin Suo Gu Jing Wan (Golden Lock Essence-securing Pill) two times per day; 10-16 year-olds took eight grams two times per day. At the same time, 5-10 year-olds took three grams of Liu Wei Di Huang Wan (Six Flavors Rehmannia Pills) two times per day; 10-16 year-olds took 56 Treating Pediatric Bed-wetting with Acupuncture & Chinese Medicine five grams of Liu Wei Di Huang Wan two times per day. Study outcomes: In general, after approximately seven days of treatment, the child was able to wake to urinate and the frequency of enuresis was reduced. Most times, it took 20-30 days of taking medicinals to stop the enuresis. Among the 43 patients, the longest a patient took the medicinals was 30 days and the shortest length of time was 10 days. Therefore, the author believes the appropriate treatment to stop enuresis is to strengthen, regulate, and supplement the kidneys and secure and contain. Jin Suo Gu Jing Wan secures the kidneys and astringes the essence and, therefore, can be used to treat enuresis due to kidney vacuity. Jin Suo Gu Jing Wan and Liu Wei Di Huang Wan are available in ready-made form from many different companies in North America and Europe. From The Treatment of 126 Cases of Pediatric Enuresis with Shao Yao Gan Cao Tang Jia Wei (Peony & Licorice Decoction with Added Flavors) by Wang Shi-biao, Zhe Jiang Zhong Yi Za Zhi (Zhejiang Journal of Chinese Medicine), 1992, #2, p. Forty-four cases were between 3-5 years old, 69 cases were 6-8 years old, 13 cases were 9-13 years old. The frequency of enuresis ranged from two times per week to five times per night, with the majority of patients having enuresis 1-2 times per night. Eighty-two cases were Chinese Research on the Treatment of Pediatric Enuresis 57 difficult to wake when called, 43 cases had a tongue with red sides, 34 cases had a red tongue, and 14 cases had a pale tongue. The tongue fur was thin and yellow in 57 cases, slimy in 26 cases, and peeled in 12 cases. The pulse was bowstring in 96 cases, fine in 14 cases, and slippery and rapid in 16 cases. Treatment method: The basic formula administered in this study consisted of: Bai Shao (Radix Paeoniae Albae), 15-60g mix-fried Gan Cao (Radix Glycyrrhizae), 9g Fu Pen Zi (Fructus Rubi), 9g Yi Zhi Ren (Fructus Alpiniae Oxyphyllae), 9g Shan Yao (Radix Dioscoreae), 9g Gui Zhi (Ramulus Cinnamomi), 3-6g If there was severe qi vacuity, nine grams of Dang Gui (Radix Angelicae Sinensis) and five grams of Wu Wei Zi (Fructus Schisandrae) were added. If the child was difficult to wake, nine grams of uncooked Ma Huang (Herba Ephedrae) and five grams of mix-fried Yuan Zhi (Radix Polygalae) were added. If there was chronic or severe enuresis, 20 grams of Qian Shi (Semen Euryalis) and 20-30 grams of Ying Su Ke (Pericarpium Papaveris Somniferi) were added. Each day, one packet of these medicinals was decocted in water for 30-60 minutes and administered orally. Study outcomes: One hundred thirteen cases were cured, 10 cases improved, and three cases got no improvement. From Modified Gui Zhi Jia Long Gu Mu Li Tang (Cinnamon Twig Plus Dragon Bone & Oyster Shell Decoction) in the Treatment of 104 Cases with the Pattern of Lower Origin Vacuity Cold by Cheng Li-chang, An Hui Zhong Yi Lin Chuang Za Zhi (Anhui Clinical Journal of Chinese Medicine), 1999, # 2, p. Forty-two cases were between 3-5 years old, 31 cases were between 6-8 years old, 15 cases were between 9-11 years old, and 16 cases were between 12-14 years old. The course of disease was 1-3 years in 54 cases, 4-6 years in 37 cases, and 7-9 years in 13 cases. These children were all unable to contain themselves, with enuresis during sleep that was frequent and copious and more than one time each evening. Other signs and symptoms included lack of strength, a somber white facial complexion, fear of cold, cold limbs, lack of warmth in the extremities, low back and knee aching and limpness, somewhat less than normal intelli- gence, usually long, clear urination, a pale tongue with thin, white fur, and a fine, deep or slow, deep pulse.

During nor- mal conduction generic 20 mg prednisone free shipping, the electrical impulse moves freely down the conduction system until it reaches recently excited tissue that Conductivity is refractory to stimulation buy prednisone 10mg mastercard. The SA node then recovers purchase 5 mg prednisone otc, fires spontaneously generic 40mg prednisone, Conductivity is the ability of cardiac tissue to transmit elec- and the conduction process starts over again generic prednisone 5 mg with amex. Although the electrophysiology of a single tion means that an impulse continues to reenter an area of the myocardial cell can assist understanding of the process, the or- heart rather than becoming extinguished. For this to occur, derly, rhythmic transmission of impulses to all cells is needed the impulse must encounter an obstacle in the normal con- for effective myocardial contraction. The obstacle is usually an area of damage, Normally, electrical impulses originate in the SA node and such as myocardial infarction. The damaged area allows con- are transmitted to atrial muscle, where they cause atrial con- duction in only one direction and causes a circular movement traction, and then to the AV node, bundle of His, bundle of the impulse (Fig. The normal heart Indications for Use can maintain an adequate cardiac output with ventricular rates ranging from 40 to 180 beats per minute. The diseased heart, Antidysrhythmic drug therapy commonly is indicated in the however, may not be able to maintain an adequate cardiac out- following conditions: put with heart rates below 60 or above 120. To convert atrial fibrillation (AF) or flutter to normal usually categorized by rate, location, or patterns of conduction. When the ventricular rate is so fast or irregular that car- diac output is impaired. Decreased cardiac output leads ANTIDYSRHYTHMIC DRUGS to symptoms of decreased systemic, cerebral, and coro- nary circulation. Atropine for bradydysrhythmias is discussed in if not quickly terminated. For example, ventricular Chapter 21; digoxin and its use in treating atrial fibrillation tachycardia may cause cardiac arrest. These drugs are described in the following sections and listed in Drugs at a Glance: Mechanisms of Action Antidysrhythmic Drugs. Clinical use of antidysrhythmic drugs for tachydysrhyth- Drugs used for rapid dysrhythmias mainly reduce automatic- mias has undergone significant changes. One change is that ity (spontaneous depolarization of myocardial cells, including the goal of drug therapy is to prevent or relieve symptoms or ectopic pacemakers), slow conduction of electrical impulses prolong survival, not just suppress dysrhythmias. This change through the heart, and prolong the refractory period of myo- resulted from studies in which clients treated for some dys- cardial cells (so they are less likely to be prematurely activated rhythmias had a higher mortality rate than clients who did not by adjacent cells). Several different groups of drugs perform receive antidysrhythmic drug therapy. They are classified according to rate was attributed to prodysrhythmic effects (ie, worsening their mechanisms of action and effects on the conduction sys- existing dysrhythmias or causing new dysrhythmias). Additionally, all, there is decreasing use of class I drugs (eg, quinidine) and some drugs have characteristics of more than one classification. Another change is the greater use of nonpharmacologic CLASSIFICATIONS AND management of dysrhythmias. These methods include de- INDIVIDUAL DRUGS stroying dysrhythmogenic foci in the heart with radio waves (radiofrequency catheter ablation) or surgical procedures Class I Sodium Channel Blockers and implanting devices for sensing, cardioverting, defibril- lating, or pacing (eg, the implantable cardioverter–defibrillator Class I drugs block the movement of sodium into cells of or ICD). This results in a membrane- CHAPTER 52 ANTIDYSRHYTHMIC DRUGS 761 BOX 52–1 TYPES OF DYSRHYTHMIAS Sinus dysrhythmias are usually significant only if they are severe ication) and to prevent stroke or other thromboembolic complica- or prolonged. Tachycardia increases the workload of the heart tions (eg, with aspirin, warfarin, or both). Sinus tachycar- Nodal dysrhythmias may involve tachycardia and increased dia may cause anginal pain (myocardial ischemia) by two related workload of the heart or bradycardia from heart block. One mechanism involves increased myocardial oxy- cardia or bradycardia may decrease cardiac output. The other mechanism involves a shortened dias- volves impaired conduction of the electrical impulse through the tole so that coronary arteries may not have adequate filling time AV node. With first-degree heart block, conduction is slowed, but between heartbeats. With second-degree heart block, every second, dium is required at the same time that a decreased blood supply is third, or fourth atrial impulse is blocked and does not reach the ven- delivered. Thus, atrial and ventricular rates dif- Sinus tachycardia may be caused by numerous conditions such fer. Mobitz type I has been as- asthma remedies and nasal decongestants), and lifestyle drugs sociated with individuals with inferior wall myocardial infarction such as alcohol, caffeine, and nicotine. Thus, the initial assessment (MI) or digoxin toxicity and usually does not require temporary of a client with sinus tachycardia should include a search for pacing because it is transient in nature. The rate usually may be slowed by treating the clients with anterior wall MI, may progress to third-degree block, underlying cause or by stimulating the vagus nerve (eg, by carotid and often requires cardiac pacing because it is associated with a sinus massage or Valsalva maneuver).

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