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Efficiency of farabloc in reduction of delayed onset muscle soreness Zhang, Jian 1998

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The Efficiency of Farabloc in Reduction of Delayed Onset Muscle Soreness by Jian Zhang B.M., Shanghai Second Medical University, 1982 A THESIS PROPOSAL SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES SCHOOL OF HUMAN KINETICS We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA June 1998 © Jian Zhang ^ggg in presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. 1 further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives. It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. Department of l4u^D>^ kftvMl'cA The University of British Columbia Vancouver, Canada Date ^^AAT^ • 3 ^ ^ / DE-6 (2/88) Abstract Farabloc is made of a series of ultra thin steel threads woven into a linen fabric. It is based on the same principle as the "Farady Cage" to shield external electromagnetic influences. The product was shown in previous research to have a beneficial effect on the reduction of phantom limb pain. However, whether this product can be used in muscle pain is still a question.• The aim of this study is to test the efficiency of Farabloc in reducing delayed onset muscles- soreness (DOMS). It was proposed that Farabloc therapy would reduce exercise induced muscle soreness following injury. The first hypothesis is that exercise induced muscle soreness causes a local inflammatory response in the quadriceps muscle and Farabloc therapy will reduce the inflammatory response and pain sensation. The second hypothesis is that using Farabloc will accelerate the return of eccentric strength, reduced by DOMS. The experiment created DOMS,utlizing exercise on a Biodex unit, with a single blind crossover design and assessed the effectiveness of Farabloc on response of inflammation, strength and pain. Twenty subjects were divided into two groups—A group and B group. Both groups were treated by Farabloc or placebo in two experimental stages. All subjects were tested in a single blind design and covered their entire thigh area with either a 2 layer Farabloc or placebo wrap immediately following exposure to the noxious exercise. Pain was measured utlizing a visual analog scale and strength was measured on the BIODEX unit. Muscle damage and response of inflammation assessed by blood assay of creatine kinase (CK), leukocyte, neutrophil, myoglobin and malondialdehyde (MDA). Tests were taken at intervals over 5 days. Each stage of the experiment had four periods consisting of rest, exercise, treatment and post treatment. To consider the correlation between the variables statistical analyses used three separate two way MANOVA with repeated measures and one ANOVA with repeated measures on the parameters of different time periods. Significant defferences have found between stage 1 A group (farabloc treatment) and B group (placebo treatment) for the MANOVA analyses for pain and strength testing (p<0.001), CK with myglobin tests (p<0.001) and the MANOVA of WBC with neutrophil tests (p=0.003), and also the ANOVA analyses for MDA. In stage 2 the MANOVA of pain and strength testing (p=0.221), CK with myglobin (p=0.460) and leukocyte with neutrophil (p=0.204) had no significant differences between B group (Farabloc) and A group (placebo) but there was significant difference in ANOVA of MDA test between the two groups. The crossover studies showed there were significant differences between Farabloc treatment and placebo treatment in both groups (p<0.05) except for the MANOVA analyses for leukocyte with neutrophil in A group. It was concluded that the Farabloc appears to positively effect the recovery from exercise-induced muscle soreness. TABLE OF CONTENTS ABSTRACT i i TABLE OF CONTENTS iv LIST OF TABLES vi LIST OF FIGURES vii ACKNOWLEDGMENT viii I. Introduction 1 II. The Mechanism of Muscle Pain 1 III. Delayed Onset Muscle Soreness (DOMS) 4 IV. The Traditional Treatment of Muscle Pain 8 V. The Possible Mechanism of Farabloc in the Relief of Delayed Onset Muscle Soreness--A New Concept of Treatment... 12 VI. Rational 19 VII. Hypothesis and Assumption 21 1. Hypothesis 21 2 .Assumptions 22 VIII. Methodology 22 1. Purpose 22 2 . subj ects 24 3 .Observation Process and Exercise Method 24 4.Muscle Soreness Evaluation 26 5 . Single Blind Test 27 6 . Biochemical Measurement .21 A.The Assay of Myglobin Concentration. 28 B.The Assay of Creatine Phosphokinase 2 8 C . The Assay of . Leukocytes and Neutrophil 2 8 D.The Assay of Malondiadehyde Concentration 2 9 7 . Statistical Analyses 30 IV IX. Results .31 X. Discussion 45 1. Delayed Onset Muscle Soreness 45 2.Effect of Farabloc on DOMS 48 XI. Summary 53 References 54 Appendix 64 Statistical analyses output LIST OF TABLES Table 1 3 3 Table 2 33 VI LIST OF FIGURES Figure 1 18 Figure 2 19 Figure 3. 23 Figure 4 26 Figure 5 34 Figure 6 35-36 Figure 6-1 (a&b) 35 Figure 6-2 (b&c) 36 Figure 7 37-44 Figure 7-1 (a&b) 37 Figure 7-1 (c&d) 38 Figure 7-2 (a&b) 39 Figure 7-2 (c&d) 40 Figure 7-3 (a&b) 41 Figure 7-3 (c&d) 42 Figure 7-4 (a&b) 43 Figure' 7-4 (c&d) 44 Figure 8 52 VII ACKNOWLEDGMENT I would like to thank Drs. Doug Clement, Don Mckenzie, Jack Taunton and Tim Inglis for their advice in the various stages of putting this thesis together. I would also like to Dr. Angela Belcastro and those who have assisted me at different stages of this research. The most valuable learning experience though has been through my association with Dr. Doug Clement. He provided me with the inspiration the thesis topic, was unfailing in his enthusiasm and support and, at all time, he was willing to discuss with me the numerous questions and problems that I encountered. His time, effort and thorough knowledge was very much needed and appreciated, and also his example as a scientist • has left a lifelong impression Funding for thesis work was provided by Foarabloc Development Corp. VIII I. Introduction Farabloc was invented twenty years ago in Germany to combat phantom limb .pain after amputations. Farabloc consists of a special woven mesh which is made of stainless steel fibers and a nylon thread, based on the concept of electric field shielding. In 1985 Bach first reported that Farabloc was shown to have a beneficial effect on the treatment of phantom limb pain. Further studies done by Bach (1987) confirmed that Farabloc was effective in the therapy of phantom limb pain, but also rheumatic pain and other painful syndromes. More recently a doiible blind cross-over study once again showed that the product was impressive in reducing phantom limb pain (Conine et.al. 1993). However, whether this product can be used in deep somatic pain (muscle pain) still needs investigation. Therefore, the purpose of this study is to examine the effect of Farabloc in relieving delayed onset muscle soreness. The etiological mechanism of muscle pain and delayed onset muscle soreness are described, traditional treatment is reviewed and the possible mechanism of Farabloc in relieving muscle pain is discussed and our experimental design and method is outlined. II. The Mechanism of Muscle Pain In deep somatic pain, a tissue: threatening stimulus is picked up by specific nociceptors which are located in the endings of sensory nerves in skeletal muscle. These sensory nerve endings of skeletal muscle respond to strong mechanical force and to noxious chemicals and. mediators (e.g. K+, hyperosmolal saline bradykinin/ histamine, and serotonin). Some endings discharge impulses when the muscle becomes hypoxic, especially when it is actively contracting, providing a physiological basis for the pain of claudication. The nociceptors of these endings are connected to the nociceptive neurons in the dorsal horn of the spinal cord (Mense and Meyer 198.5, Hoheisel and Mense 1996)'., The axons project to the-, thalamus and other supra spinal centers presumably concerned with deep'.pain (Willis 1958). Muscle pain, however, differs distinctly from cutaneous pain., The subjective sensation of deep somatic pain is described as diffuse and difficult to locate while skin pain is more anatomically specific. The difficulty of localizing muscle pain could be due to the fact that muscle tissue has a low innervation density (Feindel et al. 1948) or has afferent fibers with large receptive fields; however available experimental data do not.support, this assumption (Mitchell and Schmidt 1983,- Mense and Meyer 1985) . A mechanical injury or unaccustomed exercise often, causes, unpleasant sensations in the muscle or. even pain.' The muscle sometimes".exhibits local tenderness. The unpleasant sensation or muscle pain is likely caused by an over-sensitivity of the muscle nociceptors and other, mechanosensitive receptor endings. 'The over-sensitivity is.due to the release of endogenous substances from the damaged tissue which lowers the mechanical' threshold of nociceptive endings into a sensitive range. The result is that even some weak stimuli are able to excite nociceptors and elicit muscle pain (Mense and Meyer 1988, Mense 1981,)-. Muscle pain may become chronic soreness; the exact mechanisms are unknown. The source may originate both in the peripheral tissue and in the central nervous system. In the, periphery, each lesion is likely to induce the release of endogenous sensitizing and pain-inducing substances. The main actions of these substances on blood capillaries are vasodilation and increase in vascular permeability; in high' concentrations, these substances are capable of producing local edema. The ischaemia is in turn a powerful promoting factor for the release of pain-inducing substances. In skeletal muscle, ischaemia will lead to a lack of ATP, the failure of the calcium pump and induce contracture which may compress blood vessels and amplify the ischaemia (Simons 1988). It is hypothesized that the swelling of muscle fibers during activity leads to increasing tissue pressure and disturbances in microcirculation. An experiment found that the capillaries of the affected area were not blocked but dilated. The swelling mainly involved the interstitial space (Peeze Binkhorst et.al 1989). This data suggest that changes in microcirculation are not the primary cause for muscle damage. However, when the microcirculation is damaged, this leads to metabolic changes and free radical formation (Zerba et al. 1990) which may activate proteolytic enzymes (Appell et al. 1992). On the other hand, reactive oxygen species are generated during ischaemia/hypoxia and subsequent reperfusion/reoxygenation in skeletal muscle. The presently accepted mechanism for this, process is that, during hypoxia, xanthine is formed from the degradation of ATP, and, during the reoxygenation, xanthine dehydrogenase is converted to xanthine oxidase, which then generates oxygen radical and uric acid from xanthine (McCord 1985). During ischaemia, the muscle may suffer a temporary ATP imbalance. This imbalance causes a malfunctioning of ion pumps and thus, an increase of intracellular calcium. Protease becomes activated with increasing intracellular Ca++ which converts xanthine dehydrogenase to xanthine oxidase. Therefore, temporary ATP imbalance leads to.a metabolic stress and simulates ischemia and reperfusion condition. The net result is the increase of oxygen free radicals which induce the disruption of phospholipid layers and lipid peroxidation and hence Skeletal muscle is injured and muscle soreness will occur (Zerba et al. • 1990) . III. Delayed Onset Muscle Soreness (DOMS) DOMS is the feeling of pain, tenderness, deep ache, and stiffness in muscle that begins several hours after exercise. The soreness is commonly associated with an intense bout of unaccustomed exercise that involves a significant eccentric component (Clarkson & Tremblay 1988) . The severity of DOMS is variable, ranging from mild discomfort to extreme soreness that limits the normal use of muscle (Jones et.al. 1986). The onset of DOMS occurs in the first 24 hours following exercise, and peak will be at 48 to 72 hours (Clarkson et al. 1992). In the case of extreme severity, peak soreness may be delayed as long as 4 to 5 days post-exercise (Jones et al. 1986). DOMS may disappear anytime from 48 hours to 2 weeks later, depending on the severity. Several studies have identified the eccentric component of exercise as the stimulus that causes disruption or damage to muscle tissue and subsequently initiating DOMS (Komi & Buskirk 1972). Eccentric muscle actions involve actively resisting lengthening of the muscle and are characterized by high tension on muscle fibers and connective tissue. High-force eccentric actions have been demonstrated to contribute to the muscle damage associated with DOMS (Clarkson et al. 1986; Friden et al. 1989). Having studied human biopsy samples, Newham et al. (1983) found that the high tension of eccentric muscle action caused microlesions and ultrastructural damage in muscle fibers, and therefore eliciting DOMS. It is generally agreed that this damage to the muscle ultrastructure is responsible for the coincident pain. One hypothesis to explain DOMS is that damage to muscle ultrastructure initiates an inflammatory response (Smith 1991). An acute inflammatory reaction involves local and systemic responses following heavy exercise. There is rather strong evidence that calcium plays a pivotal role for inducing the acute inflammatory responses (Duan et al. 1990). It is assumed that the mechanical overloading induces an increase in intracellular calcium concentration which may trigger a chain of events (Armstrong 1990). There is also evidence that free radical formation contributes to these responses (Maugham et al. 1989). These responses include pain, swelling, elevation in white blood cell count particularly the neutrophils, increased intramuscular and circulating levels of acute phase mediators and the accumulation of monocytes (Clarkson et al. 1992; Smith et al. 1989; Cannon et al. 1989; Round et al. 1987). After local damage, the initial- injury mediated by the activation of lysosomal enzymes from neutrophils and other cells appears to exacerbate the process (Weiss 1989). The lesion then increases in size. The systemic reaction (acute phase reaction--APR) appears to be initiated by a group of substances i.e. interleukin-I, which may be released by the macrophage at the site of injury (Dinarello 1985). One response to the increase in interleukin-I levels is the production of acute phase proteins (APP) by the liver at 6-8 hours post injury (Colditz 1988; Colley et al. 1983). The overall process is quite similar to classical inflammation except that inflammatory cells, particularly monocytes, appear in the tissue later than it would be expected relative to pain (Smith 1991). Since the cellular response does not parallel the symptoms, other factors must contribute, to the perception of soreness. The alternative hypothesis to explain the sensation of DOMS is that something other than inflammatojry mediators stimulates or sensitizes pain receptors, perhaps intracellular metabolites or by-products of proteolysis i.e. histamine, acetycholine, bradykinin, potassium and prostaglandin of the E series (PGE) (Moncada et al. 1978). PGE is the most likely an important intracellular metabolite in raising muscle pain (Bomalaski et al. 1983; Moncada et al. 1978). It does not directly cause pain but instead sensitizes nociceptors thus producing a state of hyperalgesia (Berbrrich et al. 1988; Moncada et.al. 1978). In this condition, previously benign chemical, mechanical, or thermal stimuli may activate "pain" fibers. In addition, protein-associated ions may sensitize nociceptors which respond dramatically to mechanical or other stimuli (Friden et al. 1989).. Also a number of enzymes, . ions and molecular compounds released by damaged- muscle cells can sensitize or stimulate pain receptors. However, this hypothesis seems to be in conflict with observations that prostaglandin inhibiting drugs do not alleviate the perception of soreness (Donnelly et al. 1988; Kuipers et al. 1985). Additionally, free O2 radical production and lipid peroxidation increase during exercise (Jenkins 1988) and potentially play a role in the initiation of muscle injury. Greater relative reduction of the respiratory pathways in muscles during eccentric exercise could lead to increased production of oxygen radicals. Free radicals with unpaired electrons are highly reactive with the poly-unsaturated fatty acids (PUFA) of plasma membranes (Jenkins 1988) . In reacting with the PUFA, free radicals change the structure and disrupt the plasma membrane by lipid peroxidation (Weiss 1986) . This disruption is associated with exercise-induced muscle damage and soreness (Manghan et al. 1989; Weiss 1986) and the activation of neutrophils and macrophages (Fantone & Ward 1982) . IV. The Traditional Treatment of Muscle Pain During the past twenty years, the majority of sports medicine research has dealt with major injuries to bones, ligaments and cartilage. Only in recent years, have some studies focused on soft tissue injuries that are more frequent than any other injuries in sports medicine.(Woo & Buckwatter 1988). Injury to the muscle fibers can be divided into three different groups. The first group consists of acute, stretch-induced muscle injuries. The second group includes acute blunt trauma to the muscle such as a muscle contusion. The third group encompasses injuries to the muscle because of repetitive motion often termed exercise-induced muscular injury (Almekinders 1993). The first group of muscle injuries is thought to occur during a sudden tension increase within'the muscle-tendon unit. This injury often happens because of a stretching force generated by antagonistic muscles and accompanied by a contraction of the affected muscle itself (Miller 1977; Brewer 1960). This injury can result in a partial or complete rupture of the-muscle fibers within the muscle belly. Group two injuries (blunt trauma) are a common injury not only in contact sport but also in many other sports because of accidental contact with other players or equipment. The direct contusion causes a necrosis and haematoma of muscle fibers because of disrupted blood vessels. The subsequent response appears identical to the inflammatory response (Kvist et al. 1974) . The third group involves injuries to the muscle because of repetitive .motion, often termed exercise-induced muscular injury. These repetitive motion injuries are usually associated with endurance sports and multisports events. This injury is most likely to occur in sports that require many eccentric contraction of the muscle (Asmussen 1956) . Clinically, the group three injury becomes delayed onset muscle soreness (DOMS) and pain usually peaks at approximately 48 hours following the injury (Newham et al. 1987). Traditionally, the early treatments of muscular injuries have been aimed at decreasing the initial inflammatory response. The inflammatory response consists of vasodilatation with extravasation of blood and blood products into the surrounding tissue. It is followed by the recruitment of inflammatory cells such as leukocytes and macrophages to the affected area. This response results clinically in increased swelling, redness, pain and impaired function. Therefore, treatment is often advocated to decrease this response. Initial anti-inflammatory methods consist of cryotherapy, physical mobilities and the use of nonsteroidal anti-inflammatory medication. Rest, ice, compression and elevation (RICE) are traditionally recommended for initial treatment for acute soft tissue muscle injuries (Kellet 1986). This treatment may only be needed for several hours in a mild grade I muscle strain or up to two or three days for a severe Grade II strain. Grade III strain.without surgical repair may need several weeks of relative immobilization. Application of cryotherapy has been advocated to decrease the swelling by inducing vasoconstriction of the blood vessels in the injured area (Kalenak 1975). Cooling also results in slowing of the local metabolism and may decrease the extent of injury. In addition, it can have an analgesic effect by slowing nerve conduction of sensory nerve fibers (Starkey 1976). Although cryotherapy is beneficial to muscle injuries, contraindications to the use of cryotherapy include conditions.such as Raynaud's phenomenon, cold, allergy, C2ryoglobulinema and paroxysmal cold hemoglobinuria. The problem of frostbite is virtually eliminated by wrapping ice in cloth and limiting exposure to a maximum duration of 20-30 minutes. 10 The use of non-steroidal anti-inflammatory drugs (NSAIDs) or anti-prostaglandin medications has become increasingly common in recent years. Numerous medications are currently available that share a common property, namely the inhibition of prostaglandin production (i.e. aspirin and ibuprofen). Prostaglandins are a group of fatty acid-derived mediators of the inflammatory response. A decrease in their production through inhibition of cyclo-oxygenase by NSAIDs is thought to also inhibit the inflammatory response (Vane- 1971) . Intramuscular injection of NSAIDs were able to reduce prostaglandin levels within the muscle but this did not result in decreasing edema or increasing strength (Almekinders 1991). It was postulated that other mediators were able to continue the inflammatory response. Inflammatory mediators such as histamine, serotonin and oxygen radicals are not inhibited by NSAIDs and may be responsible for an inflammatory response even in the presence of NSAIDs. In addition, NSAIDs may-increase the production of pro-inflammatory leukotrienes by blocking the cyclo-oxygenase pathway. Fatty acid metabolites are forced in a different pathway which is controlled by lipoxygenase while lipoxygenase is not inhibited by NSAIDs. Increased level of leukotrienes have been found in the presence of NSAIDs (Almekinders et al. 1992). Finally, the partial inhibition of . prostaglandins may enhance the anti-inflammatory effects (Belch 1989), but a total inhibition of all prostaglandins may have a negative effect. 11 A variety of manual and electrical procedures appear to be gaining popularity in treating a range of soft tissue pathology. Although some studies suggested that these treatments, which include neuroprobe (Paris et al. 1983), ultrasound (Maskulolowe and Monzos 1977), electric muscle stimulation (EMS) (Houston 1983), acupuncture and acupressure, have some beneficial effect, the mechanism is poorly understood. V. The Possible Mechanism of Farabloc in the Relief of Delayed Onset Muscle Soreness--A New Concept of Treatment According to the inventor, Farabloc is made of a series of ultrathin steel threads woven, in a specific pattern, into a linen fabric. It is based on the same principle as the "Farady Cage" to shield external electric field influences. Dr. Twidale (1991) suggested that " Farabloc, as an electrically conductive fabric, can relieve pain and muscle spasm by allowing negatively charged ions to leave the body into the fabric, instead of building up within the body waiting to be neutralized by biochemical changes by the natural defenses of the body." As a physiological point, most pain nociceptors fall into two classes. 1) A? mechanical nociceptors which are innervated by small myelinated axons and discharge only when subjected to intense mechanical, but not to thermal or chemical, stimuli. 2) Multimodal C fiber nociceptors, on the other hand, respond not 12 only to intense mechanical stimuli at the same thresholds but also respond to noxious thermal and chemical stimuli. These endings are also activated by locally applied chemical agents such as histamine, acetylcholine, bradykinin, and K+ and H+ (Brown 1989) . When somatic, tissues are injured, Multimodel C fiber nociceptors are excited by endogenous substances. These nociceptors may discharge'continuously and produce further tissue pain. From a physiologic perspective, discharge from nerve endings creates an impulse producing nerve cell membrane excitation. Ionic channels play an important role in nerve cell membrane excitation. Cell membranes are comprised of mostly lipids and some proteins. Lipids serve as structural components of the membranes and provide the matrix in which proteins assume their physical geometries and relationship. Proteins determine the function of cell membranes (Singer & Nicolson 1971). Nerve cells have electrical potentials in the order of 10-100 mV recorded across their surfaces, with the inside negative and the outside positive. The potentials are related to the distributions of ions between the intra- and intercellular milieu, and to the affinities of surface charge for ions. In nerve cells, the resting potential is typically determined by the ratio of K+ to Na+ in the extracellular medium. These cells are excitable because an electrical or chemical stimulus can induce a rapid alteration in the potential. The normal resting potential is quickly restored. The action potential is ' , 13 accompanied, by movements of ions, typically K-*- and Na"*" (Hille 1989). It is anticipated that electromagnetic fields (EMF) are likely to have an effect on nerve cell potentials•and on excitability of nerves (Papatheofanis 1987). Plonsey (1982) lucidly summarized the fundamental interactions between electromagnetic fields and excitable tissues. Depending on Plonsey's derivation which comes from Ohm's law, the relationship between intensities of extracellular and intracellular EMF sources may be determined. By varying the electric fields of extracellular for specific tissues or subcellular organelles or structures, a wide range of magnetic field intensities may be derived for specific systems. Therefore, electrical potentials- (ionic channels) of cells are influenced by the EMF of the natural environment. It is speculated that intracellular EMF which is normally influenced by the EMF of the environment will be changed when tissues are covered by Farabloc. The nociceptors of damaged tissue maybe shielded by Farabloc from geoelectromagnetism. This change possibly increases cell resting potential and the ionic channels may not be opened when nerve cells receive a stimulus. One possible mechanism for the effect of electric field shielding on membrane permeability may involve the alteration of metalic ions at the catalytic site and its effect on membrane proteins at an ion port. When EMF is shielded,. the membrane protein of ion transfer could be modified so that no ion exchange could occur and no membrane excitation could be obtained under this condition (Figure 1). The changes in protein conformation due to 14 magnetic fields, has also be discussed by a mathematical model (Lorrain and Corson 1970). The result will stop the endings of C fibers from picking up pain stimuli, also reducing the discharge of nerve cells and blocking the pain signals to the central nervous system. One of the chief characteristics of living systems, from an electrical point of view, is that they are typically, made of conductive mobile ions. Conductivity (cf') is a measure of the ease with which free charges can migrate through the material under the influence of an electrical field. By contrast, if an exogenous electrical field can induce or modulate significant charge separations (i.e. polarizations) the material will have a high permittivity (g_' ) . The passive electrical properties of living systems are completely characterized by their frequency-dependent conductivity and permittivity (Fishman 1985) . When frequency is increased, permittivity falls and,conductivity rises, in a series of steps known as dispersions. The electric characterization of the cell membrane is similar to a dipolar billiard ball. The cell membrane contains a permanent dipole moment because it has two (or more) of opposite signs separated in space. At the low frequency electric field, the permittivity of the membrane is increased and conductivity is decreased indicating that the membrane is easily charged and has high polarization. Most cells experience a modification of the membrane potential that is extremely small when exposed to 15 extracellular electric fields below lOOkHz.' Even fields as large as ImV/cm will alter the transmembrane potentials by no more than a few microvolts for the largest of these cells (Mcleod 1992). At low frequency the admittance of the cell membranes is very low, such,that they behave as nonconductions suspended in a conducting medium and most of the current flowing in the suspension must flow round the cells. In this situation, cell excitation is lower (Tseng & Astumian 1986). Therefore, the alternating nature of the electrical field means the dipole (molecule) seeks to rotate to a suitable position in the cell membrane (Pethig 1979). This modification of the proteins induces channels of ions in cell membranes to be closed. According to characteristics of electromagnetic shielding high-frequency electromagnetic fields will be easily shielded, but not low-frequency magnetic fields (Lee 1990) . When Farabloc covers damaged tissue,, cells will be only influenced by lower-frequency electromagnetic fields. Nociceptors have high permittivity and high threshold voltage which cause the difficult depqlarization of cell membranes. Permeability of cells is very low and resting potential is high, because the membrane proteins of ion transfer modify to a suitable position which close the channel of ions. All these conditions will reduce the excitation of nerve cells and decrease pain sensation. 16 . In addition, many biochemical reactions, especially inflammatory processes, involving molecules with one or more, unpaired electrons, called radical and triplet molecules, have a non-zero electron spin. The orientation of this spin can be influenced by a stationary or alternating magnetic field component. When such molecules, typically oxygen and iron, play a decisive role in a biochemical chain reaction, the reaction •yield can be strongly influenced by electromagnetic fields (Grundler et al. 1992). An applied electromagnetic field may alter the electrical properties of the iron complexes which are present in the fatty acid oxygenases or in iron-oxygen complexes to form lipid hydroperoxides. When the inflammatory events continue, more iron and other metal ions are also released at the site allowing more nonenzymatic formation of hydroperoxides as a result of reactions with the fatty acid in the cellular debris (Papatheofanis 1987). Activation of iron by electromagnetic fields might result in an aggressive iron-oxygen complex that attacks membrane phospholipids and eventually causes disruption of the cell membrane. Inflammation promotes cellular'release of chemical agents such as histamine, acetylcholine, K""" and H+. These agents stimulate the nociceptors of C fibres and elicit tissue soreness. If inflammation is reduced, tissue soreness will be relieved. Farabloc, as an electromagnetic shield which blocks external geomagnetic influences, might decrease inflammatory reaction through blocking the generation of 5-hydroper-oxyeicosatetraenoic acid (5-HPETE) and polyunsaturated fatty acid (PUFA) (Figure 2). The mechanism of Farabloc could block the following two reactions: . 17 1) Fe'* + O, ^ [Fe^* 0,] ^ [Fe'* 6',] . This reaction produces the superoxide O2 from a variety of enzymatic and nonenzymatic sources in vivo and the perferryl ion a very powerful oxidizing; and 2) ROOH + Fe'" ->. ROO" + H" + Fe'" The perferrly ion can also act as an initiator of lipid peroxidation. •  , Glycolipid Outer layer Inner layer Glycoprotei Ion channels Phospholipid Fig.l Biomembrane and ion channels is modified by magnetic field. Arrows suggest general movement of metal ions (M) and alteration in conformation after magnetic fields change. 18 PUFA Phospholipase Arachkjonic acid Oxygen Lipoxygenase Fe"-Fe"^SrM Q *— fCitO^^^'^^ OOH Y=-~^ k^^-^.^COOH 5.HPETE Leukotrienes Inflammation Fig.2 Model of Farabloc reduced inflammatory react ion. VI. Rational Given the evidence of muscle pain and DOMS, plus the proposals illustrating the mechanism of Farabloc in the relief of DOMS we present two hypotheses. 1) The first hypothesis is that exercise induced muscle soreness will cause a local inflammatory response in the quadriceps and Farabloc therapy will reduce the inflammatory response and pain sensation. We believe that part of the pain caused by DOMS occurs due to an acute inflammatory response occurring in the eccentricly-exercised muscle or muscles (Armstrong et al. 1983; Clarkson and Tremblay 1988; Miles and Clarkson 1994). A literature review by Smith suggests that similarities in pain, swelling, loss of 19 function in acute inflammation and DOMS are due to a general response of the body to a stressful or traumatic insult (Smith 1990). In the first two hours following injury, neutrophil activity is increased in the circulation and predominates at the site of the injury (Smith 1990). Approximately 6-12 hours later, other white blood cells enter the injury area and increase in number over the first 24 hours. The white blood cell numbers peak at approximately 48 hours and are severely reduced by 72 hours post exercise (Smith 1990). It also appears that in DOMS, serum creatine kinase (CK) and myoglobin (Mb) increase in 4 to 24 hours (Balnave and Thompson 1993), and serum malondialdehyde (MDA) peaks between 6 to 24 hours (Maughan et al. 1989). Therefore, to measure the inflammatory response and lipid peroxidation, Mb, CK, leukocytes, neutrophil and MDA in the times of 0, 2, 6, 24 and 48 hours post exercise were chosen. In both acute inflammation and strenuous muscular exercise there may be a delay in the onset of pain or soreness. The pain measurement should be started at 24 hours post-exercise. The visual analogue scale (VAS) to monitor pain perception was used in this study because this method provides, a simple and adequate measure of pain intensity (Zusman 1986) . Session to session (24 hours or more) reliability of VAS for experimental pain has been established at r=0.97 (Price et al. 1983) so we assume we will receive accurate results from the subjects completing a VAS over consecutive days from 24 hours to 120 hours post-exercise. 20 2) The second hypothesis is Farabloc therapy will accelerate the return of eccentric strength, reduced below baseline levels by DOMS. Recently, a study of muscle function and evidence of leukocytes in DOMS had done by Dr. Maclntyre (1994) as her Ph.D. thesis. Her results showed that greatest decline in eccentric torque was at 24 hours after eccentric exercise and it did take 96 hours to return to pre-exercise levels. Eccentric strength was tested at 0 (baseline), each 24 hours to 96 hours because objective outcomes of eccentric exercise are more accurate parameters than a DOMS score in recovery studies (Rodenburg et•al. 1993). Because of a lack of correlation between DOMS and other outcomes of eccentric exercise, many authors suggested the measurement of functional and biochemical measure is preferred for DOMS. when one plans a study to investigate whether differences exist between groups (Rodenburg et al. 1993). VII. Hypothesis and Assxjiitption 1• Hypothesis It is hypothesized that the use of Farabloc would have a statistically significant effect on the relief of delayed onset muscle soreness and the return of eccentric strength of the quadriceps muscle following exposure to noxious exercise stress. As well the inflammatory markers myoglobin, CK, leukocyte. 21 neutrophil and MDA will be decreased in the FARABLOC treated group if the damage of the muscle is limited. 2. Assumptions 1) Assume 200 eccentric contractions will cause a similar insult in all subjects used. 2) Assume that subjects will give their maximal effort on the BIODEX, and will accurately report their pain rating at the specified time. 3) Assume subjects will not exercise intensely before or immediately (up to 24 hours) after the DOMS protocol. 4) Assume the subjects respond honestly about the average amount exercise they perform in a week. VIII. Methodology 1. Purpose The main goal of this study was to examine the efficacy of Farabloc in the treatment of delayed onset muscle soreness. The delayed onset muscle soreness of the quadriceps was created by exercise on the BIODEX machine. All subjects were tested in a single blind and cross over design (Figure 3). All subjects covered their entire thigh area with either a 2 layer FARABLOC or placebo wrap immediately following exposure to the noxious exercise. Pain was measured by visual analog scale, strength was measured by the BIODEX, muscle .damage was assessed by blood assay of creatine phosphokinase, leukocyte,-neutrophil, 22 myoglobin and lipid peroxidation assessed by blood assay of malondialdehyde (MDA) over 5 days. The experiment was divided into two stages (Farabloc and placebo) with four periods in each stage as follows: 1) rest period 2) exercise period (muscle pain creating period) 3) treatment period (placebo and Farabloc treatment) 4) post treatment period. Farabloc Placebo 5 days Group B n = 1 0 8-12 weeks wash out 5 days Group A n = 1 0 variables Pain-(VAS) 0, 24, 48, 72, 96 hours Strength-(EST) • 0,. 24, 48, 72, 96 hours Inflammation-(CK, WBC, Neutr, Mb, MDA) 0, 2, 6, 24, 48 hours Figure 3. cross over design. 23 2. Subjects 10 untrained male and 10 untrained female volunteers age 20-38 years served as experimental subjects. Individuals who exercise less than once a week were considered untrained. The experimental and control groups have an equal number of randomly assigned males and females. Subjects excluded from participation in our study included athletes who were actively weight training, running and jogging, most team sports (basketball, volleyball, football, soccer, etc.) and skiing because these activities involve repetitive eccentric loading of the quadriceps. Also .subjects who have experienced delayed onset muscle soreness to their quadriceps in the last three months or who have had past history of severe joint injury or arthritis or other chronic illnesses were excluede. Any subject taking analgesic or prescription drugs was also excluded. 3. Observation Process and Exercise Method All subjects were divided into two groups—A group and B group. A group was treated as a Farabloc group and B group was treated as a placebo group in stage one. After 8 to 12 weeks recovery period both of them were treated reversely. 1)Prior to exercise: after resting in a chair for ten minutes, subjects had a record ta:ken of their heart rate and blood pressure for medical reasons. It would screen out the siibject who has any abnormalities and disease which is dangerous 24 in heavy exercise. A sample of venous blood (4ml) was taken from the antecubital fossa. 2)Exercise session: After a further ten minutes, the subjects undertook a practice session to acquaint themselves with the eccentric exercise. The BIODEX Dynamometer arm was set to the proper distance for each subject and line up the center of the subject's knee with the middle of the rotational axis of the BIODEX. This session included force adjustment, pre-exercise eccentric strength test and 20 sets of 10 repetition heavy muscle endurance work. During the,strength tests, subjects performed three submaximal and, one maximal contraction, followed by 4 maximal contractions at 30° per second through a 60° range at a long muscle length (105°-45° of knee flexion) . The data was collected during the four maximal contractions and saved onto a disk and subsequently analyzed as the average eccentric torque of the knee extensors over repetitions 2 through 4. The values were taken as baseline mean torque value. A one minute rest was interposed between the warm-up contractions and 4 maximal repetitions. Each repetition lasted no less than 10 seconds. The heavy exercise set lasted about 100 seconds with a 10 second recovery..Total heavy exercise required about 40 minutes. The FARABLOC or placebo thigh wrap was then applied. 3)Two hours and six hours after the exercise session venous blood samples were taken again. At twenty four hours, an 25 evaluation of muscle soreness was done. Subjects were asked to quantify on a visual analog scale their muscle pain. Prior to reapplication of Farabloc or Placebo thigh wrap, a eccentric strength test was repeated and venous blood samples (4ml) .were withdrawn. The Farabloc or Placebo thigh wrap was constructed in double layers which covered the entire thigh. The treatment period consisted of 5 days. 4)Forty eight hours after exercise: the muscle soreness evaluation, eccentric strength test and venous blood sampling were repeated. Subjects repeated their evaluation and eccentric strength test at 72 and 96 hours post exercise. 4. Muscle Soreness Evaluation The perception of delayed muscular soreness wasevaluated by using a visual analog scale (range 1-10, l="not sore at all",10="extremely sore") (Figure 4). Subjects responded to the magnitude of the soreness felt by marking a line on the visual analog scale. No soreness worst soreness Figure 4. Visual analog scale 26 5. Single Blind Test For the purpose of this test, placebo fabric, identical to Farabloc in color, thickness, and texture but without the wire mesh was obtained. The research team could distinguish the • Farabloc from the placebo fabric because of subtle differences in texture but the subjects were blinded to the proposed activity of the fabric. The design is a single blind pattern using either Farabloc or placebo during the treatment period. One of the.researchers screened the referred candidates for the inclusion and exclusion criteria. Researchers obtained the informed consent and-explained the experimental procedures. 6. Biochemical Measurement Serum enzyme activities are increased by physical exercise and muscle damage. Creatine phosphokinase (CPK), lactate dehydrogenase-2 (LDH-2) and pyruvate kinase (PK) which serum activities have been measured in athletes, are increased during and after exercise (Noakes 1987). C-reactive protein (Strachan et al. 1984), myoglobin (Roxin et al. 1984) or carbonic . andydrase III (Osterman et al. 1985), may be more sensitive indices of muscle damage. Because the normal range of CPK and myoblobin are highly variable, leukocyte and neutrophil levels were measured in our study as extra indices of muscle damage. Malondialdehyde (MDA) was determined as an index of lipid peroxidation which is increased in the process of free radical 27 damage secondary to severe eccentric exercise induced muscle stress. A. The Assay of Myoglobin Concentration' Blood samples were drawn by venepuncture from the ante cubital fossa region of.the arm. The blood was allowed-to clot for 10 min at room temperature in a serum separation tube and then centrifuged for-10 min at 1000 g to separate the serum. After separation all serum samples were frozen at -20°C until analysis of myoglobin concentration. ,Serum myoglobin concentration was measured by.radioimmunoassay using lodine^^i-labelled myoglobin, with a Nucleair Medical Systems Inc.- test kit (Nuclear Medical Systems Inc. Newport Beach CA) '. B. The Assay of Creatine Phosphokinase Blood samples were drawn.by venepuncture and treated the same as myoglobin. CPK activity was assessed in duplicate samples by measuring the rate, of NADP reduction in the coupled assay system at 340 nmMml vol, 25°C, as described by the method of Szasz et.al. (1976) with a. Sigma test kit. Serum and whole blood hemoglobin levels were determined to ensure that hemolysis and hemoconcentration did not affect the serum enzyme levels. C. The Assay of Leukocytes and Neutrophil Complete white blood cell counts (total leukocytes) and differential counts of white blood cells for neutrophils were 28 •.assessed by a routine blood count, Diluting a well-mixed sample of blood in a weak acid'(i.e. 2% acetic acid) ;solution lyses the red cells, leaving the white cells to be counted in a counting chamber (haemocytometer) of known volume; the nuclei of the white cells were visualized by the addition of a stain, gentian violet to the diluting fluid. Absolute polymorphonuclear' neutrophil counts were calculated from the total WBC and percent of cell count from the differential count. Differentia:!- count were performed on a blood film. D. The Assay of Malondiadehyde Concentration •'• Blood samples were obtained the same as for myoglobin. Malondiadehyde (in serum) reacts with the thiobarbituric acid (TBA) to yield a fed pigment absorbing at 535 nm. MDA has been identified as the product of lipid peroxidation. The TBA reaction is advantageous in its high sensitivity, but disadvantageous in its low specificity. To determine specifically lipid peroxides in serum or plasma, they were precipitated along with serum or plasma protein to remove water-soluble TBA-reactive substance and the reaction was carried out at pH 3 or lower, where sialic acid cannot react with TBA. To increase the sensitivity, the reaction product was determined fluorometrically. The standard"procedure was summarized by Yagi (1987) as follows: „ •, • , 1) Twenty microliters of serum was mixed with 4.0ml of N/12 H2SO4, 29 2) To this mixture, 0.5ml of 10%.phosphotungstic acid was added and mixed. After standing at room temperature for 5 min, the mixture was centrifuged at 3000 rev./min for 10 min. 3) The supernatant was discarded, and the sediment' was mixed with 2.0ml of N/l2 H2SO4 and 0.3ml of 10% phosphotungstic acid. The mixture was centrifuged at 3000 rev./min for 1 min. 4) The sediment was suspended in 4.0ml of distilled water, and 1.0ml of TBA reagent (a mixture of equal volumes of 0.67% TBA aqueous solution and glacial acetic acid) was added. The reaction mixture was heated at 95°C for 60 min in an oil bath. 5) After cooling with tap water,- 5.0ml of n-butanol was added and the mixture was shaken vigorously. 6) After centrifugation at 3000 rev./min for 15 min, the n-butanol layer was taken for fluorometric measurement at 553 nm with excitation at 515 nm. 7) By taking the fluoresence intensity as f and that of the standard solution, which is obtained by reacting 0.5 nmol of tetramethoxypropane with TBA by step 4-6 as F, the lipid peroxide level ( Lp ) can be expressed in terms of MDA: f 1-0 f Lp(serum) = 0.5 x — x = ^^ x 15(nmol I ml) F 0.02 F 7. Statistical Analyses For the pain perception scores averages of the group were calculated for each day. Hypotheses concerning the differences between pain, EST and blood chemical demonstration of results. 30 which are significant at testing by using all, individual values. A two way MANOVA with repeated measure (2x5 multivariate mixed model) was performed on the data of pain evaluation and . eccentric strength test. Two separate two way MANOVA with repeated measure were performed on the data of myglobin with CPK and WBC with neutrophil tests because we believe they have correlation in their physiological effects. An individual ANOVA was perfoinned on the data of MDA test because there is very low relationship of this variable with others. A discrimination function test was made for an assessment of the relative contribution of the criteria variables to the resultant group differences. Post-hoc comparisons will be made with Scheffe-type contrasts and stepdown analysis. The significant level was set at p<0.05. IX. Results After both eccentric exercise sessions, all subjects complained of muscle soreness and stiffness. Significant changes from baseline were found among the measurements of pain with the visual analog scale., eccentric strength test and biochemical tests as a function of time. The visual analog scale and the eccentric strength test showed their largest changes after 24 hours and biochemical tests showed an initial increase 2 hours after exercise, but showed even larger increases before 24 hours. The perceived muscle soreness values aire presented in Figure 5. These values represent the muscle group demonstrating 31 the greatest soreness level for each subject. A significant decrease was found from placebo treatment to Farabloc treatment for the tests between A group and B group in stage one, B group and A group in stage two and the tests between stage one and stage two for A group also between stage one and stage two for B group. The visual analog scales at 24 hours averaged 41.4mm when subjects were using placebo materials, but subjects using Farabloc materials revealed only 23.2mm on average (Figure 4). Figure 5 also presents the change in eccentric strength for each group over the two treatments. The mean value of eccentric strength at 24 hours was 118.85feet-LB i^ the subjects with placebo materials but 139. Tlfg^ t-LB i^ the subjects with Farabloc materials (Table 1). The average values of biochemical tests in 24 hours are also showed in Table 1. The results of statistical analysis of MANOVA between two groups showed that the visual analog scales were lower in the subjects when they wear Farabloc materials and eccentric strength tests were lower in the subjects when they used placebo materials (Figure 6). These results revealed significant' differences between two groups in the first experimental section (p<0.05) and crossover studies in both groups (p<0.05), but no significant differences were demonstrated in the second section between the two groups (p>0.05). The biochemical tests (Figure 7) were also significantly lower in the subjects using Farabloc materials. The MANOVA analyses for CK and myglobin showed 32 significant differences in the- first experimental section (A group with Farabloc vs B group with placebo) and two crossover studies,, but no significant differences were seen-in the second section (B group with Farablac vs A group with placebo). The tests of WBC and neutrophil showed significant differences in the first study section but no significant differences were seen in the second study section and in the both crossover studies of A or B group. The ANOVA results of MDA were significantly lower in ail studies (Table 2). Table 1. The mean values of all tests in 24 hours A g r o u p ( s t a g e 1) B g r o u p ( s t a g e 2) A g r o u p ( s t a g e 2) B g r o u p ( s t a g e 1) F a v e r a g e P a v e r a g e F F P P VAS (mm) 2 2 . 5 23 . 9 3 5 . 6 4 7 . 1 23 . 2 4 1 . 4 EST (feet-lb) 1 4 3 . 0 3 1 3 6 . 3 8 1 2 3 . 1 6 1 1 4 . 5 4 1 3 9 . 7 1 1 1 8 . 8 5 CPK (U/L) 64 . 6 1 1 0 9 . 5 2 1 0 3 . 7 4 3 7 8 . 4 9 8 7 . 0 7 2 4 1 . 2 1 WBC (XIOVL) 7 . 3 7 7 . 4 7 7 . 6 2 8 . 0 4 7 . 4 2 7 . 8 3 MUETR (XIOVD 2 . 2 2 2 . 5 2 . 3 6 2 . 7 5 2 . 3 6 2 . 5 6 MAD (nmol/ml) 1 . 9 9 2 . 1 5 2 . 2 2 2 . 7 2 2 . 0 7 2 . 4 7 MB (ng/ml) 4 8 . 6 1 5 9 . 6 4 5 7 . 8 2 7 5 . 0 8 5 4 . 1 3 6 6 . 4 5 Table 2. P values of T square comparing farabloc to placebo treatment. * significance p<0.05 Stage 1 Stage 2 Crossover Crossover Farabloc Group A Group B Group A Group B Placebo Group B Group A Group A Group B Strength & Pain P value of T p<0.001 * p=0.221 p=0.043 * p=0.004 * CKand Myglobin P value of T^ p<0.001 * p=0.460 p<0.001* p=0.005 * WBC and Neutrophil P value of T p=0.003* p=0.063 p=0.176 p=0.075 MDA P value of T^ p<0.001* p<0.001* p<0.001* p<0.001* 33 241.21 139.71 23. 41.4 m nfarabloc ^placebo 66.45 54.1 7.42 7.83 2.56 2.36 2.07 2.47 VAS EST CK WBC N U E T R MAD MB Figure 5. The average values of all tests in 24 hours. The unit of VAS is mm; the unit of EST is feet-lb. The units of CK MB and MAD are U/L, ng/ml and nmol/ml. The units of WBC and Neutrophil are xlO^ /L 34 260 240 220 200 180 160 140 120 100 80 60 40 20 0 -•-Fest (A) -®-Pest(B) -& Fvas (A) -•— Pvas (B) 48 hours 96 a. VAS and EST tests between A group and B group in stage 1 E E •o c CD 0} 220 200 180 160 140 120 100 80 60 40 20 0 -Fesf (B) Pest (A) Fvas (B) - Pvas (A) 24 48 h o u r s 72 96 b. VAS and EST tests between A group and B group in stage 2 Figure 6-1 (a & b) The results of pain visual analog scales (VAS) and eccentric strength tests (EST) between A group and B group in stage 1 and stage 2. 35 E E T3 C CD XI 1 260 -, 240 7 220 -200 -180 -160 -140 -.120 -100 -•80 -60 -40 -20 -0 -t 1—=:— - * ' • - = - ' 0 . " -a— -:-r^-:'--.::^^^..X.:-24 48 hours _____ -II-€^~ - = = * 72 -•-Fest ^ Pest A Fvas -^— Pvas B ::==-i 96 c. VAS and EST tests between.stage 1 and stage 2 In A group. d. VAS and EST tests between stage 1 and stage 2 in B group Figure 6-2 (c & d) The results of pain visual analog scales (VAS) and eccentric strength tests (EST) between stage 1 and stage 2 in same group. Figure 6. The results of pain visual analog scales (VAS) and eccentric strength tests (EST).. 36 1100 1000 900 800 700 600 500 400 300 -200 100 0 -farabloc (A) placebo (B) 10 20 30 hours 40 50 a. CK level between A group and B group in stage 1 12 11 10 9 8 7 6 -5 4 ^ 3 2 -1 0 --farabloc (WBC) (A) -placebo (WBC) (B) -farabloc (Neutr) (A) - placebo (Neutr) (B) 20 30 50 hours b. WBC and Neutrophil between A group and B group in stage 1 37 100 80 60 20-40 50 hours c. Myglobin between A group and B group in stage 1 4.0 3.5 -3.0 2.5 2.0 1.5 -1.0 0.5 0.0 • farabloc (A) - placebo (B) s—*-~$ ^  10 20 30 50 hours d. MDA between A group and B group in stage 1 Figure 7-1. Biochemical tests between A group (farabloc) and B group (placebo) in stage 1 38 500 -, 450 400 350 300 250 200 H 150 100 50 0 10 20 30 40 — I 50 hours a. CK level between A group and B group in stage 2 10 9 8 7 6 5 4 ,3 2 1 0 - • - f a r a b l o c (WBC) (B) — ® - placebo (WBC) (A) A farabloc (Neutr) (B) —•— placebo (Neutr) (A) 10 20 30 40 50 hours b. WBC and Neutrophil between A group and B group in stage 2 39 100 90 8 0 -7 0 -6 0 -5 0 -40 3 0 -2 0 -10 0 20 30 40 hours c. Myglobin between A group and B group in stage 2 3.0 2.5 2.0 -1.5 1.0 0 . 5 -0.0 — I — 10 20 30 — I — 40 hours 50 50 d. MDA between A group and B group in stage 2 Figure 7-2. Biochemical tests between A group (placebo) and B group (farabloc) in stage 2 40 240 220 200 180 160 140 120 100 80 60 40 20 0 -•— farabloc -®— placebo 10 20 30 — I — 40 50 hours a. CK level of A group between stage 1 (farabloc) and stage 2 (placebo) 11 10 - • - f a r a b l o c (WBC) ®—placebo (WBC) A farabloc (Neutr) —W~ placebo (Neutr) 10 20 30 40 50 hours b. WBC and Neutrophil level of A group between stage 1 (farabloc) and stage 2 (placebo) 41 110 100 90 80 70 60 -50 -40 -30 -20 -10 0 hours c. Myglobin level of A group between stage 1 (farabloc) and stage 2 (placebo) 2.5 2.0 1.5 1.0 0.5 0.0 -•—farabloc -® placebo S'" 10 20 30 40 hours d. MDA level of A group between stage 1 (farabloc) and stage 2 (placebo) Figure 7-3. Biochemical tests of A group between stage 1 (farabloc) and stage 2 (placebo) 42 1000 -800 -600 -400 -200 -0 -c < / / / l / ' / / / / -) ^ ^ 1 \ i.^ \~^^^ ""\^  "^^^ -^  — • — farabloc — Q placebo ^ ~ ~ ~ ^ 1 ~ '~" '—^^- - r • " ~ - — . -~~-~-4 r— I hours a. CK level of B group between stage 1 (placebo) and stage 2 (farabloc) 12 -| 11 -10 -9 -8 -7 -6 -5 -4 -3 -2 -1 -0 - • - • - f a r a b l o c (WBC) ® placebo (WBC) -A—fa rab loc (Neutr) - • — placebo (Neutr) 20 30 40 50 . hours b. WBC and Neutrophil level of B group between stage 1 (placebo) and stage 2 (farabloc) 43 120 110 100 90 80 70 60 50 40 30 20 10 0 hours c. Myglobin level of B group between stage 1 (placebo) and stage 2 (farabloc) 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 - farabloc - placebo j ' " 10 20 30 40 hours d. MDA level of B group between stagl (placebo) and stage 2 (farabloc) Figure 7-4. Biochemical tests of B group between stage 1 (placebo) and stage 2 (farabloc) F i g u r e 7 . B i o c h e m i c a l t e s t s compared for . a l l c o n d i t i o n s 44 X. Discussion 1. Delayed Onset Muscle Soreness The present study confirms the finding of others (Kuipers et al. 1985, Schwane et al. 1983, William et al. 1985 ) that eccentric exercise elicits a delayed onset muscle soreness with maximal severity experienced 24-48 hours after exercise. Kuipers et al. reported greatest soreness at 48 hours, but the study of William et al. (1985) had a higher soreness values at 42 hours postexercise with no indication that peak values had been achieved at this time. In present study, the highest soreness values in most subjects were recorded 24 hours postexercise. In 1983, Schwane et al. examined serum CK levels following 45 minutes of downhill running and they reported greatest soreness at 24 hours. Therefore, utilizing different exercise regimens will have different time points of peak soreness in the delay onset muscle soreness. We have found that the soreness ratings were quite variable among subjects, with some subjects reporting almost no soreness and others reporting almost maximal soreness. This finding is consistent with other studies (Newham et al. 1983, Schwan et al. 1983), yet no explanation presently exists for this phenomenon. A remarkable finding was that using Farabloc caused significantly less muscle soreness'in all subjects after the eccentric bout. Therefore the Farabloc seemed to affect the sensations of muscle soreness. Previous studies have indicated (Schwane & Armstrong 1983) that.a single bout of eccentric exercise can effectively prevent muscle damage during 45 a second test. This suggests a training effect from the first" exercise stage. In our experiment this effect was considered, therefore the wash out period between two sessions was over 8 weeks. In the present study the magnitude of the CPK response in placebo treatment was smaller than that found after downhill running by William et al. (1985), perhaps due to differences in exercise methods. William et. al. measured CPK activity at' 0, 6, 18 and 42 hours postexercise, whereas in our study CK was assessed at 0, 2, 6, 24 and 48 hours. If our CK samples were assessed at 18 hours, it is, possible that.magnitude of change for CK may have been similar to that reported by William et al.. Consistent with previous results (Newham et al. 1983, Schwane et al. 1983,) CK activity did not return to resting values by 48 hours. Although serum myoglobin levels have been routinely used •in the diagnosis of myocardial infarction, few studies have assessed serum myoglobin levels following exercise (William et al. 1985) . The results of this study showed that the peak myoglobin response was at 6 hours compared with 2, 24, and 48 hours. The earlier peak for myoglobin may be due to its smaller molecular size (Rodenburg et al. 1994). Rowland (1980) suggested that the plasma membrane permeable to muscle proteins may vary because of the difference in size and charge. 46 In an attempt to. explain the observed formation of edema after muscular exercise, Brendstrup (1962) supposed that it was provoked by an increase in capillary permeability for macromolecules, as found in inflammatory conditions. Changes indicative of muscle inflammation were reported, after downhill running of rats (Armstrong et al. 1980). However, in humans suffering from delayed onset muscle soreness, there are two conflicting results,. In the studies of Schwane et al (1983) and Bobbert et al. (1986), increases in peripheral white blood cell counts were not found. They thought the formation of edema is perhaps caused by Z-band disruption leading to formation of degraded protein contents and release of protein-bound ions. Cline(1975) and Kelleit (1986) believed that peripheral white blood cell counts are increased during the delayed onset muscle soreness. In this study, a little response of white blood cells and neutrophils were found in 2-6 hours after exercise. But the most studies found the white blood count in perpheral blood did not affect the changes in intracellular. Therefore, the results of future research in histological and histochemical changes accompanying the development of delayed onset muscle soreness might provide more insight. Several studies have reported (Dillard et al. 1978, Stanley et al. 1985, Lovlin et al. 1987) that, following an exhaustive exercise, serum malonaldehyde (MDA) increased. The findings in this, study agree with their results. During maximal 47 exercise, the activity of free radical scavenging enzymes may be compromised and substrates that generate free radicals would accumulate. That free radical accumulation may occur during exhaustive exercise is indicated in a study of muscle tissue from.marathon runners by Corbucci et al. (1984). Our study indicated that MDA accumulation would continue at least 8 hours after exercise. 2. Effect of Farabloc on DOMS Farabloc treatment had a positive effect on pain, strength and inflammatory biochemical tests either on the comparison between A and B groups in both experimental stages or on the comparing between subjects themselves in farabloc and placebo treatments. Statistical significance was present in all comparisons except in stage 2 evaluation of Group B Farabloc verses Group A placebo of pain and strength. Training effects not controlled by the washout period may have been a factor.. Although most of the results of the biochemical tests were found to be significantly different between Farabloc and placebo treatments with MANOVA, the working mechanism of Farabloc is still unexplained. According to the inventor, Farabloc acts as a Faraday Cage to shield the nerve endings in the tissue from electromagnetic fields. But why are there significant differences in the tests between Farabloc and placebo treatments?. One possible explanation is that a Faraday Cage may only shield higher frequency electrostatic sources but not lower 48 frequency sources. This situation means that tissues were exposed only to lower frequency electrical fields. As previously noted, if the frequency is lowered the permittivity rises and conductivity falls, in a series of steps known as dispersions. Most researchers believe that the electric characterization of the cell membrane is similar to a dipolar billiard ball. The cell membrane contains a permanent dipole moment because it has two (or more) opposite signs separated in space. At the low frequency electric field, the permittivity of the membrane is increased and conductivity is decreased therefore the membrane of the cells is easily charged and has high polarization (Figure 8). At low frequency fields, the admittance of the cell membranes is very low, such that they behave as nonconductors suspended in a conducting medium and most of the current flowing in the suspension must flow round the cells and the dipole (molecule) of the cell membrane which controls the channel seeks to rotate to a suitable position in the cell membrane (Pethig 1979). This modification of the proteins induces ionic channels in cell membrane to be closed. In this situation, the permittivity of the nerve cell membrane is increased and membrane has high polarization, therefore nerve cells have lower activity and the cells excitation are lower (Tsong & Astumian 1986) . The frequency (in Hz) at which the transition of conductivity and permittivity is half-completed is known as the 49 characteristic frequency (fc) and is related to the relaxation time . W by the relation fc=l/ (2'fft-) . This formula is very helpful to understand why Farabloc can relieve the pain. As the frequency rises, fewer and fewer ions have time to charge up the membranes before the field changes direction. Thus the electrical charge for a given exciting voltage decreases and the cell membrane potential will be smaller than its potential at lower frequency field. Therefore, cells are easier to be depolarized at higher frequency field. Another explanation of the possible effects of Farabloc is that when tissue is exposed to a lower frequency field the reaction of free radicals would decrease (McLauchlan 1992). In an inflammatory process, unpaired electrons, called radical and triplet molecules, have a; non-zero electron spin. The orientation of this spin can be influenced by a stationary or alternating electromagnetic field component. The Einstein's equation of the kinetic energy of the ejected electrons (mgv2=h»/ -VJQ) suggests that electron ejection is highly related with frequency. This concept indicates free radical interactions will be influenced by an increase in the frequency electromagnetic field. Acconding to the McLauchlan's (1992) model, very low . static magnetic fields cause triplet pairs to break and form singlets. As the field is increased two of the three triplet states become entirely decoupled from the singlet state. Research also supports the concept of free radical interactions 50 which may be of special significance to biomolecular with millimeter wave electromagnetic fields. Illinger (1981) found the resonant vibrational or rotational interactions of free radicals may occur with molecules or portions of molecules at frequencies within the range 10-1,000 GHz which could be shielded by the action of Farabloc. Only.at very high frequencies, infrared and above radiation, does the photon quantum energy suffice to ionize atoms or to dissociate molecules. Below the mid-infrared frequency of f=6THz the photon energy -hV is smaller than the thermal energy kT=l/40eV, which is the average energy in every molecular degree of freedom (Grundler et.al. 1992) . Any field effect with energy which the primary interaction generates an excitation should be greater than average thermal energy (kT) inherent in any system. Therefore we believe that free radical reaction and inflammatory process are influenced by high frequency fields. If high frequency fields are shielded by Farabloc, free radical reaction and inflammation will decrease and pain will be relieved. To answer the questions raised by the results of the present study is a more difficult task. More research is needed to fully understand if and how Farabloc influences recovery from muscle tissue damage. It can be concluded that the Farabloc appears to positively influence recovery from exercise-induced muscle soreness but the exact mechanism is not fully understood. 51 Enviromental Electric Field (E) Electric Shield Polarisation ^ + -inflamation markers AAA p^"^  strength No shield j^Excitation of memebrane t high excitation muscle injury A y low excitation strength pain inflamation markers C>sJ in Farabloc Shield high frequency electric field ybxcitation of membrane Figure 8. Theoretical bioelectric effect of Farabloc. Farabloc may shield higher frequency electric fields but not lower frequency fields, hence the flow of current around the cells at lower frequency fields. This may reduce the excitation of the cell membrane by increasing the relative polarisation as shown in the right hand portion. XI. Summary In the present study, we used a single blind crossover design with measurements of seven variables to determine whether Farabloc can influence the degree of muscle damage. The delayed onset muscle soreness model was used. The present study showed that Farabloc is effective in reducing muscle soreness. The results of multivariate analysis of variance showed differences between Farabloc treatment and placebo treatment. In practical terms, the use of Farabloc had a positive effect on muscle pain and muscular strength. Further studies are needed to define the optimum electrical frequency interval to influence the recovery of the tissue damage. Physics tests should be done to reveal the nature of Fairabloc. Finally, an animal study could be done to further understand the effects of Farabloc on biological systems-. 53 References Almekinders, L.C. 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NUMBER OF WITHIN CELLS NUMBER OF BETWEEN CELLS 10 2 20 CELL STATISTICS FACTOR group FACTOR T FACTOR group LEVEL FARABLOC LEVEL Tl T2 T3 ' T4 T5 LEVEL PLACEBO VARIATE a b a b a b a b a b COUNT 10 10 10 10 10 10 10 10 10 10 MEAN MAXIMUM 144.2900 217.3000 0.0700 0.4000 143 .0300 229.4000 2.2500 3.2000 160.9400 255.3000 1.8100 3 .6000 172.7800 282.6000 1.0100 2.5000 167.4000 244.6000 0.3700-1.2000 STDERROR MINIMUM 16.2062 52.6000 0.0473 0.0000 18.9471 71.1000 0.2600 0.7000 21.4918 66.0000 0.3456 0.4000 22.8843 68.0000 0.2622 0.0000 18.3196 71.9000 0.1257 0.0000 STD_ 51 0 59 0 67 1 72 0 57 0 _DEV 2486 1494 9161 8223 9630 0929 3664 8293 9316 3974 WTD_ 144 0 143 2 160 1 172 1 167 0 _MEAN 2900 0700 0300 2500 9400 8100 7800 0100 4000 3700 FACTOR LEVEL VARIATE COUNT MEAN STDERROR MAXIMUM MINIMUM STD DEV WTD MEAN Tl 10 138.4200 226.8000 10 0.1200 18.4082 64.6000 0.0917 58.2118 0.2898 138.4200 0.1200 65 T2 T3 T4 T5 0.9000 10 114.5400 10 10 10 10 10 10 10 216.4000 4.7100 9.7000 125.3300 233.0000 4.8100 7.0000 135.4600 254.8000 2.5000 4.3000 135.5200 244.9000 1.1600 2.0000 0.0000 14.0264 73.7000 0.8380 1.2000 17.0838 64.4000 0.4658 2.0000 18.1003 81.4000 0.3636 0.0000 16.4460 87.8000 0.2638 0.0000 44.3553 2.6501 54 .0238 1.4731 57.2382 1.1499 52.0070 0.8343 114.5400 4.7100 125.3300 4.8100 135.4600 2.5000 135.5200 1.1600 ANALYSIS INSTRUCTIONS Analysis Procedure=Factorial./ WITHIN EFFECT: OBS: WITHIN CASE MEAN EFFECT VARIATE STATISTIC DF g: group -ALL-TSQ= 32.9777 15.57 17 0.0001 ERROR SS= MS = SS = MS = 271849 15102 35 1 70850198 76158344 18979973 95498887 Group B (Farabloc) vs Group A (placebo) FILE='A:\farabloc.DAT'. /BETWEEN FACTORS ARE GROUP. CODE(GROUP) ARE 1,2. NAMES(GROUP) ARE FARABLOC,PLACEBO. /WITHIN FACTORS ARE T,VARIATES. CODES(T) ARE 1,2,3,4,5. NAMES(T) ARE Tl,T2,T3,T4,T5. CODES(VARIATES) ARE 1,2. NAMES(VARIATES) ARE a,b. NUMBER OF CASES READ. . NUMBER OF WITHIN CELLS NUMBER OF BETWEEN CELLS 20 10 2 CELL STATISTICS 66 FACTOR group FACTOR T FACTOR group FACTOR T LEVEL FARABLOC LEVEL Tl T2 T3 T4 T5 LEVEL PLACEBO LEVEL Tl T2 T3 T4 T5 VARIATE a b a b a b a b a b VARIATE a b a b a b a b a b COUNT 10 10 .10 10 10 10 10 10 10 10 COUNT 10 10 10 10 / 10 10 10 10 10 10 MEAN MAXIMUM 139.9100 220.4000 0.1000 0.5000 13S.3800 238.8000 2.3900 5.7000 146.6000 237.9000 1.7700 4.8000 151.1600 241.6000 1.0900 2.7000 155.8600 242.9000 0.4400 1.0000 MEAN MAXIMUM 147.7400 214.8000 0.0900 0.5000 123.1300 212.8000 3.5600 4.8000 137.6000 236.1000 2.9800 5.4000 147.1700 247.8000 1.5600 3 .4000 145.0200 253.0000 1.1300 4.2000 • STDERROR MINIMUM 14.1772 91.0000 0.0558 0.0000 15.2453 88.2000 0.5769 0.1000 15.7410 84.2000 0.5031 0.0000 14 .4043 107.3000 0.3244 0.0000 14 .1761 112.6000 0.1176 0.0000 STDERROR MINIMUM 15.6839 81.3000 0.0605 0.0000 17.2006 63.3000 0.3655 1.5000 17.4059 81.5000 0.4341 0.7000 19.1429 88.6000 0.3351 0.0000 20.0127 79.2000 0.3862 0.0000 STD_ 44 0 48 1 49 1 45 1 44 0 STD_ 49 0 54 1 55 1 60 1 63 1 _DEV 8322 1764 2100 8242 7775 5910 5503 0257 8286 3718 _DEV 5969 1912 3931 1559 0422 3726 5352 0596 2858 2212 WTD_ 139 0 136 2 146 1 151 1 155 0 WTD_ 147 0 123 3 137 2 147 1 145 1 _MEAN 9100 1000 3800 3900 6000 7700 1600 0900 8600 4400 _MEAN 7400 0900 1300 5600 6000 9800 1700 5600 0200 1300 ANALYSIS INSTRUCTIONS 67 g: group -ALL TSQ= 3 .49938 1.65 17 0.2209 ERROR SS= MS= SS = MS= 233373 12965 64 3 39037165 18835398 70100032 59450002 Group A: Stage 1 (Farabloc) vs Stage 2 (placebo) FILE='A:\crosovf.DAT'. /BETWEEN FACTORS ARE GROUP. CODE(GROUP) ARE 1,2. NAMES(GROUP) ARE FARABLOC,PLACEBO. /WITHIN FACTORS ARE T,VARIATES. CODES(T) ARE 1,2,3,4,5. NAMES(T) ARE Tl,T2,T3,T4,T5. CODES(VARIATES) ARE 1,2. NAMES(VARIATES) ARE a,b. REMAINING NUMBER OF CASES 2 0 NUMBER OF WITHIN CELLS 10 NUMBER OF BETWEEN CELLS 2 CELL STATISTICS FACTOR LEVEL group FARABLOC FACTOR LEVEL VARIATE COUNT MEAN STDERROR MAXIMUM MINIMUM STD DEV WTD MEAN Tl T2 T3 T4 ' b 10 10 10 10 10 10 10 10 144.2900 217.3000 0.0700 0.4000 143.0300 229.4000 2.2500 3.2000 160.9400 255.3000 1.8100 3.6000 172.7800 282.6000 1.0100 16.2062 52.6000 0.0473 0.0000 18.9471 71.1000 0.2600 0.7000 21.4918 66.0000 0.3456 0.4000 22.8843 68.0000 0.2622 51.2486 144.2900 0.1494 0.0700 59.9161 143.0300 0.8223 2.2500 67.9630 160.9400 1.0929 1.8100 72.3664 172.7800 0.8293 I.'OIOO 68 FACTOR group FACTOR T T5 LEVEL PLACEBO LEVEL Tl T2 T3 T4 T5 a b VARIATE a b a b a b a b a b 10 ~ 10 COUNT 10 10 10 10-10 10 10 10 10 10 2.5000 167.4000 244.6000 0.3700 1.2000 MEAN MAXIMUM 147.7400 214.8000 0.0900 0.5000 123.1300 212.8000 3.5600 . 4.8000 137.6000 236.1000 2.9800 5.4000 147.1700 247.8000 1.5600 3.4000 145.0200 253.0000 1.1300 4.2000 0.0000 18.3196 71.9000 0.1257 0.0000 STDERROR MINIMUM 15.6839 81.3 0'00 0.0605 0.0000 17,2006 63 .3000 0.3655 1.5000 17.4059 81.5000 0.4341 0.7000 19.1429 88.6000 0.3351 0.0000 20.0127 79.2000 0.3862 0.0000 57 b STD_ 49 0 54 1 55 1 60 1 63 1 9316 3974 _DEV 5969 1912 3931 1559 0422 3726 5352 0596 2858 2212 167.4000 0.3700 WTD_MEAN 147.7400 0.0900 123 .1300 3.5600 137.6000 2.9800 147.1700 1.5600 145.0200 1.1300 ANALYSIS INSTRUCTIONS g: group -ALL-TSQ= 8.06550 3 .81 2, 17 0.0430 ERROR SS= 300175.57640397 MS= 16676.42091133 SS = MS= 32.47700100 1.80427783 Group B: Stage 1 (placebo) vs Stage 2 (Farabloc) FILE='A:\crosovl.DAT'. /BETWEEN FACTORS ARE GROUP. CODE(GROUP) ARE 1,2. NAMES(GROUP) ARE FARABLOC,PLACEBO. /WITHIN FACTORS ARE T,VARIATES. CODES(T) ARE 1,2,3,4,5. NAMES(T) ARE Tl,T2,T3,T4,T5. 69 CODES(VARIATES) ARE 1,2. NAMES(VARIATES) ARE a,b. REMAINING NUMBER OF CASES . . . . NUMBER OF WITHIN CELLS 10 NUMBER OF BETWEEN CELLS 2 20 CELL STATISTICS FACTOR group ==> FACTOR T FACTOR group ==> FACTOR T LEVEL FARABLOC LEVEL Tl T2 T3 T4 T5 LEVEL PLACEBO LEVEL Tl T2 T3 VARIATE a b a b a b a b a b VARIATE a b a b a b COUNT 10 10 10 10 10 10 10 10 10 10 COUNT 10 10 10 10 . 10 10 MEAN MAXIMUM 139.9100 220.4000 0.1000 0.5000 136.3800 238.8000 2.3900 5.7000 146.6000 237.9000 1.7700 4.8000 151.1600 241.6000 1.0900 2.7000 155.8600 242.9000 0.4400 1.0000 MEAN MAXIMUM 138.4200 226.8000 0.1200 0.9000 114.5400 216.4000 4.7100 9.7000 125.3300 233.0000 4.8100 7.0000 STDERROR MINIMUM 14.1772 91.0000 0.0558 0.0000 15.2453 88.2000 0.5769 0.1000 15.7410 84 .2000 0.5031 0.0000 14 .4043 107.3000 0.3244 0.0000 14 .1761 112 .6000 0.1176 0.0000 STDERROR MINIMUM 18.4082 64.6000 0.0917 0.0000 14.0264 73.7000 0.8380 1.2000 17.0838 64.4000 0.4658 2.0000 STD_ 44 0 48 1 49 1 45 1 44 0 STD_ 58 0 44 2 54 1 _DEV 8322 1764 2100 8242 7775 5910 5503 02 5 7 8286 3718 _DEV 2118 2898 3553 6501 0238 4731 WTD_ 139 0 136 2 146 1 151 1 155 0 WTD_ 138 0 114 4 125 4 _MEAN 9100 1000 3800 3900 6000 7700 1600 0900 8600 4400 _MEAN 4200 1200 5400 7100 3300 8100 70 T4 T5 10 10 10 10 135 254 2 4 135 244 1 2 4600 8000 5000 3000 5200 9000 1600 0000 18 81 0 0 16 87 0 0 1003 4000 3636 0000 4460 8000 2 63 8 0000 57 1 52 0 2382 1499 0070 8343 135 2 135 1 4600 5000 5200 1600 ANALYSIS INSTRUCTIONS g: group -ALL-TSQ= 16.9551 8.01 2, 17 0.0035 ERROR ss= MS= SS= MS= 205047 11391 67 3 52246967 52902609 41379905 74521106 71 Group A (Farabloc) vs Group B (placebo) file='A:\avsb.data' /between /within factors are group, code(group) are 1,2. names(group) are farabloc, placebo, factors are times,variates. codes(times) are 1,2,3,4,5. names(times) are tl,t2,t3,t4,t5 . codes(variates) are 1,2. names(variates) are ck,mb. NUMBER OF CASES READ. 20 NUMBER OF WITHIN CELLS NUMBER OF BETWEEN CELLS 10 2 CELL STATISTICS FACTOR group FACTOR times FACTOR group FACTOR LEVEL farabloc LEVEL tl t2 t3 t4 t5 LEVEL placebo LEVEL VARIATE ck mb ck mb ck mb ck mb ck mb VARIATE COUNT 10 10 10 10 10 10 10 10 10 10 COUNT MEAN MAXIMUM 28.1500 39.5000 21.2200 26.6000 92.1800 110.5000 48.5000 63.2000 91.9200 130.6000 67.5200 90.1000 64.6100 99.8000 48.6100 61.2000 49.3600 86.3000 24.0000 30.2000 MEAN MAXIMUM STDERROR MINIMUM 2.3383 18.8000 1.0990 15.8000 5.9527 55.6000 2.9688 36.2000 9.1362 53 .3000 4.6817 46.3000 8.4264 26.2000 2.7513 36.2000 6.9204 20.1000 1.3139 20.1000 STDERROR MINIMUM STD_ 7 3 18 9 28 14 26 8 21 4 STD_ _DEV 3945 4752 8241 3881 8911 8049 6465 7004 8843 1548 _DEV WTD_ 28 21 92 48 91 67 64 48 49 24 WTD_ _MEAN 1500 2200 1800 5000 9200 5200 6100 6100 3600 0000 _MEAN 72 times tl t2 t3 t4 t5 ck mb ck mb ck mb ck mb ck mb 10 10 10 10 10 10 10 10 10 10 40 66 26 33 364 984 77 101 669 052 105 120 378 733 75 96 180 340 38 78 5000 3000 4600 0000 3900 2000 '8400 3000 8700 3000 7700 3000 4900 9000 0800 3000 8700 3000 1200 2000 4 16 1 21 88 110 3 63 83 233 3 81 79 97 4 56 31 55 4 22 8840 4000 2146 9000 7403 3000 7601 1000 0765 6000 6578 2000 1168 0000 3063 6000 9780 6000 8847 3000 15 3 280 11 262 11 250 13 101 15 4447 8408 6214 8904 7109 5671 1894 6178 1234 4469 40 26 364 77 669 105 378 75 180 38 5000 4600 3900 8400 8700 7700 4900 0800 8700 1200 ANALYSIS INSTRUCTIONS g: group ERROR VARIATE -ALL ck mb TSQ= SS = MS = SS= MS= STATISTIC 42.7861 1.7106024E+6 1.7106024E+6 12864.096223 12864.096223 ck mb SS= MS = SS = MS = 1.106485253E+6 61471.40294787 6153.43751003 341.85763945 20.20 27.83 37.63 DF 17 0.0000 18 0.0001 18 0.0000 Group B (Farabloc) vs Group A (placebo) file='A:\bvsa.data' /between /within factors are group. code(group) are 1,2. names(group) are farabloc, placebo. factors are times,variates. codes(times) are 1,2,3,4,5. names(times) are tl,t2,t3,t4,t5. 73 codes(variates) are 1,2. names (variates) are ck,tTib. NUMBER OF CASES READ. . 2 0 NUMBER OF WITHIN CELLS 10 NUMBER OF BETWEEN CELLS 2 CELL STATISTICS FACTOR LEVEL group farabloc ==> I FACTOR LEVEL VARIATE COUNT MEAN STDERROR STD_DEV WTD_MEAN MAXIMUM MINIMUM times tl ck 10 37.0400 3.5841 11.3340 37.0400 65.1000 24.6000 mb 10 25.7000 1.1858 3.7500 25.7000 30.0000 19.2000 t2 ck 10 161.2400 32.8881 104.0014 161.2400 360.2000 56.2000 mb 10 65.1500 3.0543 9.6584 65.1500 78.3000 46.4000 t3 ck 10 241.5100 63.6843 201.3875 241.5100 606.8000 38.9000 mb 10 76.9600 5.6458 17.8535 76.9600 101.6000 35.0000 t4 ck 10 109.5200 24.9219 78.8100 109.5200 320.1000 37.2000 mb 10 59.6400 2.1651 6.8468 59.6400 68.2000 46.2000 t5 Gk 10 80.7500 22.4534 71.0040 80.7500 274.7000 28.1000 mb 10 30.3000 2.2236 7.0315 30.3000 45.0000 20.1000 FACTOR LEVEL group placebo FACTOR LEVEL VARIATE COUNT MEAN STDERROR STD_DEV WTD_MEAN MAXIMUM MINIMUM times tl ck 10 28.8600 2.8966 9.1600 • 28.8600 44.2000 16.2000 mb 10 21.6400 0.9573 3.0274 21.6400 27.1000 17.3000 t2 ck 10 127.1600 11.3649 35.9391 127.1600 217.5000 96.2000 mb 10 64.7500 3.5856 11.3387 64.7500 80.1000 40.1000 t3 ck 10 160.4800 20.2055 63.8953 160.4800 260.4000 70.5000 mb 10 86.0100 3.6098 11.4150 86.0100 74 t4 t5 Ck mb ck mb 10 10 10 10 99.1000 103.7400 173.6000 57.8200 73.1000 83.1100 156.2000 28.6800 35.1000 61.2000 13 .0689 24.6000 3.5273 38.3000 9.9483 45.5000 1.2717 21.6000 41.3275 11.1544 31.4593 4.0216 103.7400 57.8200 83.1100 28.6800 ANALYSIS INSTRUCTIONS EFFECT group ERROR VARIATE P-ALL ck TSQ= SS = MS = SS = MS = STATISTIC 1.72284 16055.425318 16055.425318 1.322499 1.322499 ck mb ss= MS= SS= MS= 309804 17211 2324 129 24672414 34704023 68459763 14914431 DF 0.81 2, 17 0.459E 0.93 1, 18 0.3469 0.01 1, 18 0.9205 Group A: Stage 1 (Farabloc) vs Stage 2 (placebo) file='A:\groupa.data' /between /within factors are group. code(group) are 1,2. names(group) are farabloc, placebo. factors are times,variates. codes(times) are 1,2,3,4,5. names(times) are tl,t2,t3,t4,t5. codes(variates) are 1,2. names(variates) are ck,mb. NXmBER OF CASES READ NUMBER OF WITHIN CELLS 10 NUMBER OF BETWEEN CELLS 2 20 CELL STATISTICS FACTOR LEVEL 75 group farabloc FACTOR times FACTOR group FACTOR times LEVEL tl t2 t3 t4 t5 LEVEL placebo LEVEL tl t2 t3 t4 t5 VARIATE ck mb ck mb ck mb ck mb ck mb VARIATE ck mb ck mb ck mb ck mb ck mb COUNT 10 10 10 10 10 10 10 10 10 10 COUNT 10 10 10 10 10 10 10 10 10 10 MEAN MAXIMUM 28.1500 39.5000 21.2200 26.6000 92.1800 110.5000 48.5000 63 .2000 91.9200 130.6000 67.5200 90.1000 64.6100 99.8000 48.6100 61.2000 49.3600 86.3000 24.0000 30.2000 MEAN MAXIMUM 28.8600 44.2000 21.6500 27.1000 127.1600 217.5000 64.7200 80.1000 160.4800 260.4000 86.0100 99.1000 103.7400 173.6000 57.8200 73.1000 83.1600 156.2000. 28.6800 35.1000 STDERROR MINIMUM 2.3383 18.8000 1.0990 15.8000 5.9527 55.6000 2.9688 36.2000 9.1362 53 .3000 4.6817 46.3000 8.4264 26.2000 2.7513 36.2000 6.9204 20.1000 1.3139 20.1000 STDERROR MINIMXJM 2.8966 16.2000 0.9569 17.3000 11.3649 96.2000 3.5897 40.1000 20.2055 70.5000 3.6098 61.2000 13 .0689 24.6000 3.5273 38.3000 9.9514 45.5000 1.2717 21.6000 STD_ 7 3 18 9 28 • 14 26 8 21 4 STD_ 9 3 35 11 63 11 41 11 31 4 _DEV 3945 4752 8241 3881 8911-8049 6465 7004 8843 1548 DEV 1600 0259 9391 3515 8953 4150 3275 1544 4690 0216 WTD_ 28 21 92 48 91 67 64 48 49 24 WTD_ 28 21 127 64 160 86 103 57 83 28 _MEAN 1500 2200 1800 5000 9200 5200 6100 6100 3600 0000 _MEAN 8600 6500 1600 7200 4800 0100 7400 8200 1600 6800 ANALYSIS INSTRUCTIONS EFFECT VARIATE -ALL STATISTIC DF 76 ERROR Ck mb ck mb TSQ= SS = MS = SS = MS = 27.5317 31392 31392 2403 2403 752373 752373 940S21 940621 ss= MS = SS = MS= 43941.04036032 2441.16890891 2918.91176716 162.16176484 13.00 2, 17 0.0004 12.86 1, 18 0.0021 14.82 1, 18 0.0012 Group B: Stage 1 (placebo) vs Stage 2 (Farabloc) file='A:\groupb.data' /between /within factors are group, code(group) are 1,2. names(group) are farabloc, placebo, factors are times,variates. codes(times) are 1,2,3,4,5. names(times) are tl,t2,t3,t4,t5. codes(variates) are 1,2. names(variates) are ck,mb. NUMBER OF CASES READ NUMBER OF WITHIN CELLS 10 NUMBER OF BETWEEN CELLS 2 20 CELL STATISTICS FACTOR group = = > FACTOR LEVEL farabloc LEVEL times tl t2 t3 VARIAl Ck mb ck mb ck mb "E COUNT 10 10 10 10 10 10 MEAN MAXIMUM 37.0400 65.1000 25.7000 30.0000 161.2400 360.2000 65.1500 78.3000 241.5100 606.8000 76.9600 STDERROR MINIMUM 3.5841 24 .6000 1.1858 19.2000 32.8881 56.2000 3 .0543 46.4000 63 .6843 38.9000 5.6458 STD_ 11 3 104 9 201 17 _DEV 3340 7500 0014 6584 3875 8535 WTD_ 37 25 161 65 241 76 _MEAN 0400 7000 2400 1500 5100 9600 77 t4 t5 ck mb ck nib FACTOR LEVEL group placebo 10 10 10 10 101.6000 109.5200 320.1000 59.6400 68.2000 80.7500 274.7000 30.3000 45.0000 35.0000 24.9219 37.2000 2.1651 46.2000 22.4534 28.1000 2.2236 20.1000 78.8100 6.8468 71.0040 7.0315 109.5200 59.6400 80.7500 30.3000 FACTOR times LEVEL tl t2 t3 t4 t5 VARIATE Ck mb Ck mb ck mb ck mb ck mb COUNT 10 10 10 10 10 10 10 10 10 10 MEAN MAXIMUM 40.5000 66.3000 26.4600 33.0000 364 .3900 984 .2000 77.8400 101.3000 669.8700 1052.3000 105.7700 120.3000 378.4900 733 .9000 75.0800 96.3000 180.8700 340.3000 38.1200 78.2000 STDERROR MINIMUM 4.8840 16.4000 1.2146 21.9000 88.7403 110.3000 3.7601 63.1000 83.0765 233.6000 3.6578 81.2000 79.1168 97.0000 4.3063 56.6000 31.9780 55.6000 4.8847 22.3000 STD_ 15 3 280 11 262 11 250 13 101 15 _DEV 4447 8408 6214 8904 7109 5671 1894 6178 1234 4469 WTD_ 40 26 364 77 669 105 378 75 180 38 _MEAN 5000 4600 3900 8400 8700 7700 4900 0800 8700 1200 ANALYSIS INSTRUCTIONS FF g: ECT VARIATE group -ALL ck mb TSQ= SS = MS = SS = MS = STATISTIC 15.8722 1.0081365E+6 1.0081365E+6 4292.870610 4292 .870610 DF ERROR ck mb SS= 1.372347534E+6 MS= 76241.52969033 SS= 5560.80953608 7.50 13 .22 13 .90 1, 17 0.0046 18 0.0019 18 0.0015 78 MS = 308.93385312 Group A (Farabloc) vs Group B (placebo) file='A:\avsb.data'. /between /within factors are group. code(group) are 1,2. names(group) are farabloc, placebo. factors are times,variates. codes(times) are 1,2,3,4,5. names(times) are tl,t2,t3,t4,t5. codes(variates) are 1,2. names(variates) are wbc,neu. NUMBER OF CASES READ NIMBER OF WITHIN CELLS 10 NUMBER OF BETWEEN CELLS 2 20 CELL STATISTICS FACTOR group FACTOR times FACTOR group LEVEL farabloc LEVEL tl , t2 t3 t4 t5 LEVEL placebo VARIATE wbc neu wbc neu wbc neu wbc neu wbc neu COUNT 10 10 10 10 10 10 10 10 10 10 MEAN MAXIMUM 7.2400 7.9000 2.2500 2.7000 7.7300 8.1000 2.4800 2.9000 7.4800 8.1000 2.3800 2.8000 7.3700 7.8000 2.2200 2.6000 7.2200 7.6000 2.1700 2.6000 STDERROR MINIMUM 0.1408 6.8000 0.0764 2.0000 0.1221 6.9000 0.0772 2.2000 0.1356 6.7000 0.0917 2.0000 0.0989 6.8000 0.0533 2.0000 0.1083 6.7000 0.0684 2.0000 STD_DEV 0.4452 0.2415 0.3860 0.2440 0.4290 0.2898 0.3129 0.1687 0.3425 0.2163 WTD_MEAN 7.2400 2.2500 7.7300 2 .4800 7.4800 2.3800 7.3700 2.2200 7.2200 2.1700 FACTOR LEVEL VARIATE COUNT MEAN STDERROR STD DEV WTD MEAN 79 times tl t2 t3 t4 t5 wbc wbc wbc wbc wbc 10 10 10 10 10 10 10 10 10 10 MAXIMUM 7 7 2 3 8 9 3 4 9 11 3 4 8 8 2 3 7 8 2 3 4100 9000 6000 1000 5500 8000 2600 60 0,0 5500. 5000 6700 9000 0400 7000 7500 2000 6500 2000 5600 2000 MINIMUM 0 6 0 2 0 7 0 2 0 7 0 2 0 7 0 2 0 6 0 2 1178 8000 0931 1000 2825 2000 2099 3000 4083 6000 2708 4000 1536 1000 1276 1000 1462 8000 1087 0000 0.3725 0.2944 0.8935 0.6637 1.2912 0.8564 0.4858 0.4035 0.4625 0.3438 7.4100 2.6000 8.5500 3.2600 9.5500 3.6700 8.0400 2.7500 7.6500 2.5600 ANALYSIS INSTRUCTIONS EFFECT VARIATE STATISTIC DF g: group -ALL wbc neu -TSQ= SS = MS = ss= MS = 18.1615 17.305601 17.305601 11.155601 11.155601 ERROR wbc SS = MS= SS= MS= 24.72080105 1.37337784 11.79280043 0.65515558 l.5f 12.60 17.03 17 0.0027 18 0.0023 18 0.0006 Group B (Farabloc) vs Group A (placebo) file='A:\bvsa.data'. /between /within factors are group, code(group) are 1,2. names(group) are farabloc, placebo, factors are times,variates. codes(times) are 1,2,3,4,5. names(times) are tl,t2,t3,t4,t5. codes(variates) are 1,2. names(variates) are wbc,neu. 80 NUMBER OF CASES READ NUMBER OF WITHIN CELLS 10 NUMBER OF BETWEEN CELLS 2 20 CELL STATISTICS FACTOR group = = > FACTOR times LEVEL farabloc LEVEL tl t2 t3 t4 t5 VARIATE wbc neu wbc neu wbc neu wbc neu wbc neu COUNT 10 10 10 10 10 10 10 10 10 10 MEAN MAXIMUM 7.3400 8.0000 2.5400 3.0000 7.9000 9.2000 2.8400 3.8000 7.8500 9.3000 2.9000 4.2000 7.4700 8.2000 2.6000 3.1000 7.2100 7.8000 2.5200 3.0000 STDERROR MINIMUM 0.1267 6.9000 0.0897 2.1000 0.2333 6.9000 • 0.1384 2 .3000 0.2668 6.8000 0.2113 2.2000 0.1687 6.7000 0.1095 2.1000 0.1509 6.3000 0.0917 2.1000 STD_ 0 0 0 0 0 0 0 0 0 0 _DEV 4006 2836 7379 4377 8436 6683 5334 3464 4771 2898 WTD_ 7 2 7 2 7 2 7 2 7 2 _MEAN 3400 5400 9000 8400 8500 9000 4700 6000 2100 5200 FACTOR LEVEL group placebo FACTOR times LEVEL tl t2 t3 t4 VARIAT wbc neu wbc neu wbc neu wbc neu E COUNT 10 10 10 10 10 10 10 10 MEAN MAXIMUM 7.2100 8.0000 2.3300 2.9000 8.2200 9.0000 2.7600 3.1000 7.9000 8.8000 2.6700 3.0000 7.6200 8.3000 2.3500 STDERROR MINIMUM 0.1362 6.8000 0.'0716 2.1000 0.1775 7.4000 0.0499 2.6000 0.1571 7.2000 0.0831 2.2000 0.1504 7.0000 0.0806 STD_ 0 0 0 0 0 0 0 0 _DEV 4306 2263 5613 1578 4967 2627 4756 2550 WTD_ 7 2 8 2 7 2 7 2 _MEAN 2100 3300 2200 7600 9000 6700 6200 3500 81 t5 wbc neu 10 10 2 7 8 2 2 8000 3700 1000 2200 6000 2 0 6 0 2 1000 1476 7000 0512 1000 ANALYSIS INSTRUCTIONS EFFECT VARIATE STATISTIC DF ERROR wbc ss= MS = SS = MS = 21 1 6 0 22740316 17930018 68819974 37156665 Group A: Stage 1 (Farabloc) vs Stage 2 (placebo) file='A:\groupa.data'. /between /within factors are group. code(group) are 1,2. names(group) are farabloc, placebo. factors are times,variates. codes(times) are 1,2,3,4,5. names(times) are tl,t2,t3,t4,ts. codes(variates) are 1,2. names(variates) are wbc,neu. NUMBER OF CASES READ. 20 NUMBER OF WITHIN CELLS 10 NUMBER OF BETWEEN CELLS 2 SUMMARY STATISTICS FOR VARIATE(S): 0.4668 7.3700 0.1619 2.2200 : group -ALL wbc neu -TSQ= SS = MS= SS= MS= 6 91085 0.302500 0.302500 1.144900 1.144900 3.26 0.26 3 .08 2, 1, 1, 17 18 18 0.0632 0.6187 0.0962 CELL STATISTICS FACTOR group ==> FACTOR LEVEL farabloc LEVEL VARIATE COUNT MEAN MAXIMUM STDERROR MINIMUM STD DEV WTD MEAN 82 times FACTOR group FACTOR times tl t2 t3 t4 t5 LEVEL placebo LEVEL tl t2 t3 t4 t5 wbc neu wbc neu wbc neu wbc neu wbc neu VARIATE wbc neu wbc neu wbc neu wbc neu wbc neu 10 10 10 10 10 10 10 10 10 10 COUNT 10 10 10 10 10 10 10 10 10 10 7.2400 7.9000 2.2500 2.7000 7.7300 8.1000 2.4800 2.9000 7.4800 8.1000 , 2.3800 2.8000 7.3700 7.8000 2.2200 2.6000 7.2200 7.6000 .2.1700 2.6000 MEAN MAXIMUM 7.2100 8.0000 2.3300 2.9000 8.2200 9.0000 2.7600 3.1000 7.9000 8.8000 2.6700 3 .0000 7.6200 8.3000 2.3500 2.8000 7.3700 8.1000 2.2200 2.6000 0.1408 6.8000 0.0764 2.0000 0.1221 6.9000 0.0772 2.2000 0.1356 6.7000 0.0917 2.0000 0.0989 6.8000 0.0533 2.0000 0.1083 6.7000 0.0684 2.0000 STDERROR MINIMUM 0.1362 6.8000 0.0716 2.1000 0.1775 7.4000 0.0499 2.6000 0.1571 7.2000 0.0831 2.2000 0.1504 7.0000 0.0806 2.1000 0.1476 6.7000 0.0512 2.1000 0.4452 0.2415 0.3860 0.2440 0.4290 0.2898 0.3129 0.1687 0.3425 0.2163 STD_DEV 0.4306 0.2263 0.5613 0.1578 0.4967 0.2627 0.4756 0.2550 0.4668 0.1619 7.2400 2.2500 7.7300 2 .4800 7.4800 2.3800 7.3700 2.2200 7.2200 2.1700 WTD_MEAN 7.2100 2.3300 8.2200 2.7600 7.9000 2.6700 7.6200 2.3500 7.3700 2.2200 ANALYSIS INSTRUCTIONS EFFECT VARIATE STATISTIC g: group TSQ= 4.08707 SS= 1.638400 -ALL-wbc DF 1.93 17 0.1756 83 MS= 1.638400 2.2£ 1, 18 0.1488 ERROR wbc SS= MS= 0.688900 0.688900 ss= MS= SS= MS= 12 0 3 0 95000259 72000014 03620021 16867779 4.08 1, 18 0.0584 Group B: Stage 1 (placebo) vs Stage 2 (Farabloc) file='A:\groupb.data'. /between /within factors are group. code(group) are 1,2. names(group) are farabloc, placebo. factors are times,variates. codes(times) are 1,2,3,4,5. names(times) are tl,t2,t3,t4,t5 . codes(variates) are 1,2. names(variates) are wbc,neu. NUMBER OF CASES READ NUMBER OF WITHIN CELLS 10 NUMBER OF BETWEEN CELLS 2 .20 CELL STATISTICS FACTOR group FACTOR times LEVEL farabloc LEVEL tl t2 t3 t4 VARIATE wbc neu wbc neu wbc neu wbc COUNT 10 10 10 10 10 10 10 MEAN MAXIMUM 7.3400 • 8.0000 2.5400 3.0000 7.9000 9.2000 2 .8400 3.8000 7.8500 9.3000 2.9000 4.2000 7.4700 STDERROR MINIMUM 0.1267 6.9000 0.0897 2.1000 0.2333 6.9000 0.1384 2.3000 0.2668 6.8000 0.2113 2.2000 0.1687 STD_ 0 0 0 0 • 0 0 0 _DEV 4006 2836 7379 4377 8436 6683 5334 WTD_ 7 2 7 2 7 2 7 _MEAN 3400 5400 9000 8400 8500 9000 4700 84 FACTOR group t5 wbc 10 10 10. LEVEL placebo 8.2000 2.6000 3.1000 7.2100 7.8000 2.5200 3.0000 7000 1095 1000 1509 3000 0917 1000 0.3464 2.6000 0.4771 7.2100 0.2898 2.5200 FACTOR times LEVEL tl VARIATE wbc t2 t3 t4 t5 wbc wbc wbc wbc COUNT 10 10 10 10 10 10 10 .10 10 10 MEAN MAXIMUM 7.4100 7.9000 2.6000 3.1000 8.5500 9.8000 3.2600 4.6000 9.5500 11.5000 3.6700 4.9000 8.0400 8.7000 2.7500 3.2000 7.6500 8.2000 2.5600 3.2000 STDERROR MINIMUM 0.1178 6.8000 0.0931 2.1000 0.2825 7.2000 0.2099 2.3000 0.4083 7.6000 0.2708 2.4000 0.1536 7.1000 0.1276 2.1000 0.1462 6.8000 0.1087 2.0000 STD_ 0 0 0 0 1 0 0 0 0 0 _DEV 3725 2944 8935 6637 2912 8564 4858 4035 4625 3438 WTD_ 7 2 8 3 9 3 8 2 7 2 _MEAN 4100 6000 5500 2600 5500 6700 0400 7500 6500 5600 ANALYSIS INSTRUCTIONS EFFECT VARIATE g: group -ALL wbc neu TSQ= SS = MS = SS = MS = STATISTIC 6 .42007 11.764902 11.764902 2.073600 2.073600 ERROR wbc SS = MS = SS= MS= 32 1 15 0 98820162 83267787 44479995 85804444 DF 3.03 2, 17 0.0748 6.42 1, 18 0.020E 2.42 1, 18 0.1375 85 Group A (Farabloc) vs Group B (placebo) file='A:\avsb.data' /group /design /end codes(group) are 1,2. names(group) are farabloc, placebo. dependent=mdal,mda2,mda3,mda4,mdaS. level=5. name=time. Orthogonal. grouping=group. NUMBER OF CASES READ. 20 GROUP STRUCTURE group farabloc placebo CELL MEANS COUNT 10 10 FOR 1-ST DEPENDENT VARIABLE group = farabloc placebo time MARGINAL mdal mda2 mda3 mda4 mda5 1.92000 2.06600 2.02100 1.99200 1.95300 1.93400 2 .69700 3.02000 2.72600 2.50400 1.92700 2.38150 2 .52050 2.35900 2.22850 MARGINAL COUNT 1.99040 10 2.57620 10 2 .28330 20 STANDARD DEVIATIONS FOR 1-ST DEPENDENT VARIABLE group = farabloc placebo time mdal rada2 mda3 mda4 mda5 1 2 3 4 5 0 0 0 0 0 15239 16939 19029 15245 16425 0 0 0 0 0 17665 42919 35861 48736 45191 86 ANALYSIS OF VARIANCE FOR mdal mda2 mda3 1-ST DEPENDENT VARIABLE mda4 mdaS SOURCE MEAN group 1 ERROR t(l) t(l)g ERROR t(2) t(2)g ERROR t(3) t(3)g ERROR t(4) t(4)g ERROR time tg 2 ERROR SUM OF SQUARES 521.34588 8.57904 5.46685 0.67396 0.69266 1.22360 3.08910 1.78082 0.45947 0.24012 0.05478 0.62347 0.02862 0.08627 0.54344 4.03181 2.61453 2.84998 D.F. 1 1 18 1 1 18 ^ 1 1 18 1 1 18 1 1 18 4 4 72 MEAN SQUARE 521.34588 8.57904 0.30371 0.67396 0.69266 0.06798 3.08910 1.78082 0.02553 0.24012 0.05478 0.03464 0.02862 0.08627 0.03019 1.00795 0.65363 0.03958 F 1716 28 9 10 121 69 6 1 0 2 25 16 57 25 91 19 02 76 93 58 95 86 46 51 TAIL PROB. 0.0000 0.0000 0.0056 0.0050 0.0000 0.0000 0.0169 0.2246 0.3431 0.1082 0.0000 0.0000 SOURCE MEAN group t(l) t(l)g t(2) t(2)g t(3) t(3)g t(4) t(4)g GREENHOUSE HUYNH GEISSER FELDT PROB . PROB . time tg 0.0000 0.0000 0.0000 0.0000 ERROR TERM EPSILON FACTORS FOR DEGREES OF FREEDOM ADJUSTMENT GREENHOUSE-GEISSER 0.7382 HUYNH-FELDT, 0.9479 87 Group B (Farabloc) vs Group A (placebo) file='A:\bvsa.data' /group /design /end codes(group) are 1,2. names(group) are farabloc, placebo. dependent=mdal,mda2,mda3,mda4,radaS. level=5. name=time. Orthogonal. grouping=group. NUMBER OF CASES READ. GROUP STRUCTURE group COUNT farabloc placebo 10 10 20 CELL MEANS FOR 1-ST DEPENDENT VARIABLE group = farabloc placebo time MARGINAL mdal mda2 mda3 mda4 mdaS 1.89600 2.15800 2.37100 2.15300 2.04100 .95300 ,28700 ,32500 ,22600 ,08900 92450 22250 34800 18950 06500 MARGINAL COUNT 2.12380 10 ,17600 10 .14990 20 STANDARD DEVIATIONS FOR 1-ST DEPENDENT VARIABLE group time mdal 1 mda2 2 mdaS 3 mda4 4 mdaS 5 farabloc 0.12002 0.23522 0.43725 0.39331 0.38197 placebo 0.13458 0.18655 0.26709 0.17102 0.10060 88 ANALYSIS OF VARIANCE FOR mdal mda2 mda3 1-ST DEPENDENT VARIABLE mda4 mda5 SOURCE MEAN group 1 ERROR t(l) t(l)g ERROR t(2) t(2)g ERROR t(3) t(3)g ERROR t(4) t(4)g ERROR time tg 2 ERROR SUM OF SQUARES 462.20699 0.06812 4.11850 0.12301 0.00274 0.91165 1.82092 0.00357 0.85757 0.08528 0.00530 0.29836 0.05271 0.06846 0.34011 2.08191 0.08007 2.40769 D.F. 1 1 18 1 1 18 1 1 18 1 1 18 1 1 18 4 4 72 MEAN SQUARE 462.20699 0.06812 0.22881 0.12301 0.00274 0.05065 . 1.82092 0.00357 0.04764 0.08528 0.00530 0.01658 0.05271 0.06846 0.01889 0.52048 0.02002 0.03344 F 2020 0 2 0 38 0 5 0 2 3 15 0 09 30 43 05 22 07 15 32 79 62 56 60 TAIL PROB. 0.0000 0.5920 0.1365 0.8188 0.0000 0.7874 0.0359 0.5786 0.1122 0.0731 0.0000 0.6648 SOURCE MEAN group t(l) t(i)g t(2) t(2)g t(3) t(3)g t(4) t(4)g GREENHOUSE HUYNH GEISSER FELDT PROB. PROB. time tg 0.0000 0.5854 0.0000 0.6183 ERROR TERM EPSILON FACTORS FOR DEGREES OF FREEDOM ADJUSTMENT GREENHOUSE-GEISSER 0.6075 HUYNH-FELDT 0.7482 89 Group A: Stage 1 (Farabloc) vs Stage 2 (placebo) file='A:\groupa.data'. /group codes(group) are 1,2. names(group) are farabloc, placebo, /design dependent=mdal,mda2,mda3,mda4,mda5. level=5.. name=time. Orthogonal. grouping=group. /end NUMBER OF CASES READ GROUP STRUCTURE . group farabloc placebo CELL MEANS COUNT 10 10 20 FOR 1-ST DEPENDENT VARIABLE group = farabloc placebo time MARGINAL mdal mda2 mda3 mda4 mdaS 1.92000 2.06600 2.02100 1.99200 1.95300 1.95300 2.28700 2.32500 2.22600 2.08900 1.93650 2.17650 2.17300 2.10900 2.02100 MARGINAL COUNT 1.99040 10 2.17600 10 2.08320 20 STANDARD DEVIATIONS FOR 1-ST DEPENDENT VARIABLE mdal mda2 mda3 mda4 mdaS group time 1 2 3 4 5 farabloc 0.15239 0.16939 0.19029 0.15245 0.16425 placebo 0.13458 0.18655 0.26709 0.17102 0.10060 ANALYSIS OF VARIANCE FOR 1-ST DEPENDENT VARIABLE -90 mdal mda2 SOURCE MEAN group 1 ERROR t(l) t(l)9 ERROR t(2) t(2)g ERROR t(3) t(3)g ERROR t(4) t(4)g ERROR time tg 2 ERROR mda3 mda4 mda5 SUM OF SQUARES 433.97222 0.86118 1.73663 0.020,60 0.02398 0.11124 0.73339 0.18772 0.41325 D. 1 1 18 1 1 18 1 1 18 F. 0.09636 1 0.00296 1 0.27154 18 0 0 0 0 0 0 00613 00214 18503 85649 21681 98107 1 1 18 4 4 72 MEAN SQUARE 433.97222 0.86118 0.09648 0.02060 0.02398 0.00618 0.73339 0.18772 0.02296 0.09636 0.00296 0.01509 0.00613 0.00214 0.01028 0.21412 0.05420 0.01363 F 4498 8 3 3 31 8 6 0 0 0 15 3 07 93 33 88 94 18 39 20 60 21 71 98 TAIL PROB. 0.0000 0.0079 0.0845 0.0644 0.0000 0.0104 0.0211 0.6628 0.4499 0.6538 0.0000 0.0057 SOURCE MEAN group t(l) t(l)g t(2) t{2)g t(3) t(3)g t(4) t(4)g time tg GREENHOUSE HUYNH GEISSER FELDT PROB. PROB. 0.0000 0.0171 0.0000 0.0103 ERROR TERM EPSILON FACTORS FOR DEGREES OF FREEDOM ADJUSTMENT GREENHOUSE-GEISSER 0.6483 HUYNH-FELDT 0.8091 91 Group B: Stage 1 (placebo) vs Stage 2 (Farabloc) file='A:\groupb.data'. /group /design /end codes(group) are 1,2. names(group) are farabloc, placebo. dependent=mdal,mda2,mda3,mda4,mdaS. level=5. name=time. Orthogonal. grouping=group. NUMBER OF CASES READ. . . GROUP STRUCTURE group farabloc placebo CELL MEANS group COUNT 10 10 FOR farabloc i-ST DEPENDENT VARIABLE MARGINAL placebo 20 time mdal mda2 mda3 mda4 mdaS 1.89600 2.15800 2.37100 2.15300 2.04100 1.93400 2.69700 3.02000 2.72600 2.50400 1.91500 2.42750 2.69550 2.43950 2.27250 MARGINAL COUNT 2.12380 10 2.57620 10 2.35000 20 STANDARD DEVIATIONS FOR 1-ST DEPENDENT VARIABLE group = farabloc placebo time mdal mda2 mda3 mda4 mda5 1 2 3 4 5 0 0 0 0 0 12002 23522 43725 39331 38197 0 0 0 0 0 17665 42919 35861 48736 45191 ANALYSIS OF VARIANCE FOR mdal mda2 mda3 1-ST DEPENDENT VARIABLE mda4 mdaS 92 SOURCE MEAN group 1 ERROR t(l)-t(i)g ERROR t{2) t{2)g ERROR t(3) t(3)g ERROR t(4) t(4)g ERROR time tg 2 ERROR SUM OF SQUARES 552.25000 5.11664 7.84872 1.05706 0.39073 2.02401 5.06527 0.70802 0.90379 0.22244 0.06372 0.65028 0.22759 0.00020 0.69852 6.57236 1.16268 4.27660 p.F. 1 1 18 1 1 18 1 1 18 1 1 18 1 1 18 4 4 72 MEAN SQUARE 552.25000 5.11664 0.43604 1.05706 0.39073 0.11245 5.06527 0.70802 0.05021 0.22244 0.06372 0.03613 0.22759 0.00020 0.03881 1.64309 0.29067 0.05940 F 1266 11 9 3 100 14 6 1 5 0 27 4 51 73 40 47 88 10 16 76 86 01 66 89 TAIL PR:OB. 0.0000 0.0030 0.0067 0.0787 0.0000 0.0014 0.0232 0.2007 0.0262 0.9435 0.0000 0.0015 SOURCE MEAN group t(l) t(i)g t(2) t(2)g t(3) t(3)g t(4) t(4)g GREENHOUSE HUYNH GEISSER FELDT PROB . PROB . time tg 0.0000 0.0074 0.0000 0.0038 ERROR TERM EPSILON FACTORS FOR DEGREES OF FREEDOM ADJUSTMENT GREENHOUSE-GEISSER 0.6318 HUYNH-FELDT 0.7843 93 

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