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It grows Agastache can be prepared alone as a tea serpina 60 caps sale, incorpo- wild on sunny hillsides and along roads 60 caps serpina mastercard, but also can be rated into a lotion purchase serpina 60caps with amex, or prepared as a pill cheap 60caps serpina mastercard. ORGANIZATIONS Biennial—Biennial plants take two years to com- American Association of Oriental Medicine (AAOM) buy generic serpina 60caps. Qi—Qi is the Chinese term for the vital life force Tish Davidson that permeates the body. According to traditional Chinese medicine, qi collects in channels in the body and can be moved and redirected through treatments and therapies. Aging strongly aromatic, but lose this quality with prolonged Definition boiling (over 15 minutes). Starting at what is commonly called middle age, op- erations of the human body become more vulnerable to The best know formulas using agastache are agas- daily wear and tear. There is a general decline in physical, tache formula and Huo Xiang Zheng Qi Wan, or agas- and possibly mental, functioning. It is given as treatment for er, the upward limit of the life span can be as high as 120 gastrointestinal upsets with chills, fever, and diarrhea. During the latter half of life, an individual is more Huo Xiang Zheng Qi Wan regulates qi and treats prone to problems with the various functions of the body, seasonal gastric disorders, especially those occurring and to a number of chronic or fatal diseases. This formula is commercial- vascular, digestive, excretory, nervous, reproductive, and ly available in both tablet and liquid form. Precautions Description Agastache has a long history of use with no substan- Human beings reach a peak of growth and develop- tial reported problems. Although there are quite a few age-related changes that tax the body, disability is Side effects not necessarily a part of aging. Health and lifestyle fac- No side effects have been reported with the use of tors, together with the genetic makeup of the individual, agastache. Body functions that are most often affected by age include: • Hearing, which declines especially in relation to the Interactions highest pitched tones. Agastache is often used in conjunction with other • The proportion of fat to muscle, which may increase by herbs with no reported interactions. Typically, the total padding of body been used almost exclusively in Chinese medicine, there fat directly under the skin thins out and accumulates are no studies of its interactions with Western pharma- around the stomach. There are several theories on why the aging body • Sensations of taste and smell, which decrease. It may be that several factors work to- gether or that one particular factor is the culprit in a • Cardiovascular and respiratory systems, with changes given individual. These theories include: leading to decreased oxygen and nutrients throughout the body. The aging of the cells for each individual is programmed • Nervous system, which experiences changes that result into the genes, and there is a preset number of possible in less efficient nerve impulse transmission, reflexes that rejuvenations in the life of a given cell. Human cells maintain their own seed of and sexual hormones are particularly affected. Protects cell mem- aging, is based on the fact that ongoing chemical reac- branes against damage. As time goes on, more cells die or that selenium may play a role in reducing cancer risk. May help in treating cancer, colds and flu, arthritis, and immune • Immunological theory. The dosage should be decreased if down, the body is more apt to have autoimmune reac- this occurs. Studies show that B12 may help reduce mental symptoms, such as confusion, Diagnosis memory loss, and depression. Many problems can arise due to age-related changes • Coenzyme Q10 may be helpful in treating heart disease. Although there is no individual test to mea- Up to 75% of cardiac patients have been found to lack sure these changes, a thorough physical exam and a this heart enzyme. When older people become ill, the first signs of disease are often Hormones nonspecific. Further exams should be conducted if any The following hormone supplements may be taken of the following occur: to prevent or treat various age-related problems.

The “fight-or-flight” response is promoted by the thetic and parasympathetic divisions of the autonomic a purchase serpina 60caps without a prescription. Clinical depression is associated with abnormal sero- Understanding Concepts tonin levels 60caps serpina. Differentiate between the terms in each of the fol- neurotransmitter from the synapse can control the disor- lowing pairs: der serpina 60caps. What effect does this have on action poten- along a myelinated fiber differ from conduction along an unmyelinated fiber? The Senses Taste from the tongue receptors Smell from receptors in the upper nasal cavities The sensory system protects a person by detecting General senses changes in the environment cheap serpina 60 caps with mastercard. An environmental change Pressure cheap serpina 60 caps on-line, temperature, pain, and touch from recep- becomes a stimulus when it initiates a nerve impulse, tors in the skin and internal organs which then travels to the central nervous system (CNS) Sense of position from receptors in the muscles, ten- by way of a sensory (afferent) neuron. A stimulus be- dons, and joints comes a sensation—something we experience—only when a specialized area of the cerebral cortex interprets the nerve impulse it generates. Many stimuli arrive from The Eye and Vision the external environment and are detected at or near the In the embryo, the eye develops as an outpocketing of the brain. The skull bones form the walls of the eye orbit (cavity) Sensory Receptors and protect more than half of the posterior part of the The part of the nervous system that detects a stimulus is eyeball. The eyelids can be closed to keep harmful materials out of the eye, and blinking helps The free dendrite of a sensory neuron, such as the re- to lubricate the eye. If the muscle becomes weaker with afferent neuron, such as those for touch and temperature age, the eyelids may droop and interfere with vision, a A specialized cell associated with an afferent neuron, condition called ptosis. A thin membrane, the conjunctiva (kon-junk-TI-vah), Receptors can be classified according to the type of lines the inner surface of the eyelids and covers the visible stimulus to which they respond: portion of the white of the eye (sclera). These include pressure Eyelashes Eyebrow receptors in the skin, receptors that monitor body posi- tion, and the receptors of hearing and equilibrium in the ear, which are activated by the movement of cilia on specialized receptor cells. Any receptor must receive a stimulus of adequate in- Upper eyelid tensity, that is, at least a threshold stimulus, in order to (superior respond and generate a nerve impulse. The choroid may be compared to the dull black lining of Tears, produced by the lacrimal (LAK-rih-mal) glands a camera in that it prevents incoming light rays from scat- (Fig. As tears flow across the The blood vessels at the posterior, or fundus, of the eye from the lacrimal gland, located in the upper lateral 11 eye can reveal signs of disease, and visualization of part of the orbit, they carry away small particles that these vessels with an ophthalmoscope (of-THAL- may have entered the eye. An excess of tears causes cells known as rods and cones, which generate the nerve a “runny nose”; a greater overproduction of them re- impulses associated with vision. With age, the lacrimal glands produce less secretion, but tears still may overflow onto the cheek if the nasolacrimal ducts Checkpoint 11-2 What are the names of the tunics of the eye- ball? Pathway of Light Rays and Refraction As light rays pass through the eye to- ward the retina, they travel through a series of transparent, colorless parts de- scribed below and seen in Figure 11-3. On the way, they undergo a process known as refraction, which is the bending of light rays as they pass from one substance to another substance of different density. Note the three tunics, the refractive parts of the eye (cornea, rior continuation of the sclera, but it aqueous humor, lens, vitreous body), and other structures involved in vision. The aqueous (A-kwe-us) humor, a watery fluid that fills The rods are highly sensitive to light and thus function much of the eyeball anterior to the lens, helps maintain in dim light, but they do not provide a sharp image. It is during this because it is elastic and its thickness can be adjusted to time that the rods are beginning to function, a change that focus light for near or far vision. When you are able to see The vitreous (VIT-re-us) body is a soft jellylike sub- again, images are blurred and appear only in shades of stance that fills the entire space posterior to the lens gray, because the rods are unable to differentiate colors. If a person is lacking in vitamin A, he Retina or she may have difficulty seeing in dim light because there is too little Photoreceptor light to activate the rods, a condi- cells tion termed night blindness. THE SENSORY SYSTEM 227 muscles connected with each eye orig- Comparison of the Rods and Cones of the inate on the bones of the orbit and in- Table 11•1 Retina sert on the surface of the sclera (Fig. These muscles pull on the eye- Number About 120 million in About 6 million in ball in a coordinated fashion so that each retina each retina both eyes center on one visual field. Distribution Toward the periphery Concentrated at the This process of convergence is neces- (anterior) of the center of the retina sary to the formation of a clear image retina Stimulus Dim light Bright light on the retina. Having the image come Visual acuity (sharpness) Low High from a slightly different angle from Pigments Rhodopsin (visual Pigments sensitive to each retina is believed to be important purple) red, green, or blue for three-dimensional (stereoscopic) Color perception None; shades of gray Respond to color vision, a characteristic of primates. When an ophthalmologist (of-thal-MOL-o-jist), a Checkpoint 11-5 What is the function of the extrinsic muscles physician who specializes in treatment of the eye, exam- of the eye?

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Coherence by itself is not convincing evidence of a causal connection between two oscillations buy 60caps serpina with mastercard. In this case purchase serpina 60 caps without a prescription, the phase spectrum between the motor ECoG and EMG showed a constant delay between cortex and muscle; the delay was 16 msec for deltoid buy generic serpina 60 caps on line,39 a value that is very similar to that obtained by transcranial magnetic stimulation (TMS) of the motor cortex 60caps serpina fast delivery. Stationary rats show a fine 9-Hz tremor of the jaw and/or vibrissae safe serpina 60 caps, not to be confused with the large 7-Hz vibrissal sweep of exploratory sniffing. Semba and Komisaruk postulate that the function of synchrony between mu rhythm and vibrissal tremor may be to increase the gain of sensory input, facilitating reception of sensory input. Copyright © 2005 CRC Press LLC Recording MEG in humans performing sustained wrist movements, Marsden and coworkers observed corticomuscular coherence only during isometric postural contractions, not phasic movements. Both 10- and 20-Hz com- ponents in the MEG were coherent with EMG and showed the same dipoles to estimate the source in sensorimotor cortex. Again the close relationship between mu and beta rhythms in the rolandic cortex was confirmed. Other studies have also noted corticomuscular coherence at 10 Hz, in some subjects, during steady muscle contrac- tion. An MEG study by Gross and coworkers has found a correlation between 6–9 Hz oscillations in the motor cortex and the pulsatile subcomponents of slow finger movements. During slow and continuous index finger flexion–exten- sion, EMG was significantly coherent with the contralateral sensorimotor cortex at a peak frequency of 7 Hz. Analysis of the direction of coupling between the coherent oscillations indicated that motor cortex led muscle (efferent drive), but muscle led somatosensory cortex (afferent drive). Further analysis of coherences among brain regions identified a ring of zones contributing to the 6–9 Hz activity in the motor cortex, all showing significant phase synchronization. The direction of coupling ran from the cerebellum to the thalamus to the “premotor” cortex (which looks like it might actually be prefrontal) to the motor cortex and back to the cerebellum. Indeed, it has already been shown that movements performed together, combined eye and hand tracking of a visual target, are coherent at 8 Hz. Gastaut also noted that mu oscillations were actually much rarer than beta rhythms in the rolandic cortex. Since then, mu ERD with movement onset or somatosensory stimulation has been universally seen in EEG, MEG, and ECoG recorded in humans. However, there are conflicting findings; indeed the ease of finding mu ERD virtually proves that it is far more widespread than the sensorimotor zone being activated. Using a subdural recording grid, they found a difference between the early and late phases of a motor response. In the early phase, mu ERD occurred in a diffuse spatial pattern that was Copyright © 2005 CRC Press LLC bilateral and not somatotopically specific. Movement amplitude influ- enced the magnitude, duration, and extent of the spatial distribution of mu power changes. The authors concluded that the overall changes in mu activity reflect shifts in the functional state of neuronal ensembles involved in the initiation and execution of motor tasks. Using EEG recording, Andrew and Pfurtscheller found two alpha band rhythms in the rolandic area. Both rhythms appeared to be generated within the rolandic area; they were not volume conducted. It is confusing, however, because the lower frequency is the one that corresponds to the original 9-Hz defi- nition of mu rhythm, not the 12-Hz component. Both before and after EMG onset, phase coherence showed a lead of anterior areas on more posterior regions. This suggests that mu oscillations are still functioning in the processes of motor preparation and execution, and that mu ERD simply reflects a much more focused Copyright © 2005 CRC Press LLC and controlled expression of the oscillation. In a report on LFPs in the motor cortex of monkeys performing a maintained precision grip, Jackson and coworkers pre- sented a spectrogram (their Figure 2) that indicated a modest relative increase in mu power before and at the time of movement onset. A brief mu oscillation can arise from more than one mechanism, so caution is necessary. Nevertheless, the gross picture of mu ERD may mask a more complex pattern at the level of functional clusters of neurons. In an analysis of human EEG–EMG phase coherence, Feige, Aertsen, and Kristeva-Feige also found corticomuscular synchronization in the 2–14 Hz range during brief finger movements.

However many minor antigenic mark- Clinical chemistry results showed her serum liver ers that can cause immunological incompatibility enzymes (LDH generic serpina 60 caps free shipping, ALT) and bilirubin level to be ele- differ between individuals trusted 60caps serpina. Such reactions usually occur when reaction is diagnosed cheap serpina 60 caps fast delivery, treatment with corticoste- immunologically competent cells are introduced roids serpina 60 caps sale, such as prednisone and prednisolone purchase serpina 60 caps on-line, is usu- into an immunocompromised host. Lazo and Jennifer Rubin Grandis Most drugs used today are designed to treat symp- tient in a phase I gene therapy protocol. Notable stimulated a substantial review of the oversight mecha- exceptions include cytotoxic chemotherapeutic agents, nisms in human gene transfer research. One of the first as described in Chapter 56, and agents that restore or successes of gene therapy was reported in 2000, when modulate hormone function, as outlined in Chapter 57. The first disease-associated gene, -globin, was C transgene expression in T- and NK cells was de- cloned over 25 years ago. It is now theoretically possible tected and T-, B-, and NK-cell counts and function were to isolate, sequence, and analyze genes causally associ- comparable to those of age-matched controls. Moreover, with the com- orous approach to investigating the safety and efficacy plete sequencing of the human genome, many of the es- of gene transfer will ensure that clinical strategies em- timated 100,000 human genes may become candidates ploying genetic manipulation are rationally incorpo- for genetic manipulations. GENE THERAPY: DEFINITION Germ cell gene therapy will require considerable dis- AND GOALS cussion about ethical issues and extensive information before it can be applied to humans, but somatic cell gene The broadest definition of human gene therapy includes therapy in humans is now being extensively explored. Principles of proved by the Office of Biotechnology Activities (OBA, gene therapy include transfer of one or more transgenes formerly the Recombinant DNA Advisory Committee) to prevent a disease, prevent an adverse consequence of of the National Institutes of Health. Although most of the controversy and excitement have With few exceptions, gene therapy was considered centered on the transfer of functional genes, the thera- safe if not particularly effective until the death of an 18- peutic potential of genes that abrogate aberrant func- year-old man in 1999, the first fatal outcome for a pa- tion (e. A second approach seeks permanent alteration of the genotype of the cell, Infectious leading to a modified phenotype that prevents or alters disease 7% a disease state. Theoretically, mutated or nonfunctional genes could be excised and replaced, and new genes with desired Monogenic functions could be permanently inserted into the diseases 12% genome. Because of the Cancer 63% technical difficulties associated with the delivery of nu- cleic acid–based products selectively to specific target cells in vivo, more experimental information is available FIGURE 58. During the past 5 years in the United States more than 500 human gene therapy clinical trials have been approved by the Office of Biotechnology Activities of the National ANTISENSE Institutes of Health. In the first, cleotide that is in the reverse orientation (antisense) to a genetic material is introduced into cells to alter the cel- portion of a target messenger RNA (mRNA) species, is lular phenotype but not the genotype. This is typified by introduced into a cell and a DNA–RNA duplex is formed the transfer of unintegrated DNA, antisense oligomers, by complementary Watson-Crick base pairing. In this regard, gene therapy has many of of protein synthesis then may result from the rapid DNA Insert Vector Antisense Oligomer Integration into genome hnRNA Sense mRNA hnRNA Antisense mRNA DNA RNA Nucleus duplex RNA RNA duplex Ribonuclease H Cell FIGURE 58. Cells and or- plexes designed to bind to a particular transcription fac- ganisms protect themselves against foreign DNA and tor and prevent its normal function are another ap- RNA by producing nucleases that degrade phosphodi- proach examined in the context of NF B blockade. Chemical modifi- These strategies, like antisense itself, do not require in- cation of the phosphodiester moiety can produce nucle- tegration into the genome, and thus they share the phar- ase-resistant oligomers. In the two most common macological problems of absorption, distribution, me- chemical analogues, the backbone phosphate is replaced tabolism, and elimination of any traditional drug not either with a methyl group to form a methyl phosphonate based on nucleic acid. These modifications grant extra stability to the oligonucleotides, allowing for a longer half-life in vivo. GENE EXCISION AND REPLACEMENT The antisense RNA can also be generated within cells after delivery via a plasmid or attenuated virus Diseases at a genetic level can result from several containing a suitable promoter that controls expression causes, including (1) mutation in a gene, (2) loss of ex- of the antisense strand using methods of gene insertion pression of a gene, (3) elevated expression of a gene, or described later (Fig. In sense strategies, several related approaches have been each case, gene replacement or excision therapy might considered. Theoretically, the disease gene could be re- zymes capable of degrading complementary mRNA placed through a homologous recombination event. Oli- Depending on the design of the replacement gene, it gomers designed to interact with genes directly via also would be possible to engineer stop codons or non- Hoogsteen hydrogen binding in a triplex formation sense sequences into the internal domains of a gene to have been suggested as a means of disrupting transcrip- ensure loss of protein production. Excision of an entire O Base O O P O O n DNA Transcription O Base O O P S O n Phosphorothioate Definition of symbols: Triplex Decoy duplex O Base Oligomer O O DNA Transcription P factor CH3 O n Methylphosphonate FIGURE 58. This strategy, however, requires ex- GENE ADDITION tremely efficient and specific homologous recombina- tion events in the target cell population. Such strategies A more practical approach has been to permit the in- have allowed for the development of knockout animals, troduced genes to integrate into the genome in a site- but to date have not been practical for human somatic nonspecific manner. Ongoing investigations are exploring function to provide a missing or mutated gene product the feasibility of inducible vectors, use of the cre-lox sys- (Fig. This is the approach of most current gene tem, or cell type specific promoters to optimize gene ex- therapy protocols and is exemplified by the development pression in target cells. ADA is in the presence of systemic administration of a nontoxic a reasonable target for these reasons: (1) It is an auto- prodrug.

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