text:
|Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Stroke treatment utilizing extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Artificial blood and other gas transport agents
|Clark, Jr.
|Perfluorochemical emulsion artificial blood
|Extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Extravascular circulation of oxygenated synthetic nutrients to treat tissue hypoxic and ischemic disorders
|Blood gas control
|Cormier et al.
|Novel fluorohydrocarbons
|Automated intravenous fluid regulating and administering apparatus
|Marx et al.
|Reference liquid for blood gas equipment
|Sorensen et al.
|Blood pressure alarm system for dialysis machines
|Tetramethylpentane blood substitutes
|Lagow et al.
|Brominated perfluorocarbon radiopaque agents
|Long, Jr.
|Method for treating cerebral edema
|Gainer, Jr.
|Method for treating spinal cord injury
|Gainer, Jr.
|Emulsification of fluorocarbon compounds for biological application as oxygen transporters
|Chabert et al.
|Non-toxic brominated perfluorocarbons radiopaque agents
|Long, Jr.
|Oxygen-transferable emulsion
|Yokoyama et al.
|Apparatus for extracorporeal treatment of blood
|Means for introducing and guiding objects into body cavities and blood vessels
|Method of treating hydrocephalus
|Long, Jr.
|Wortman et al.
|Claff et al.
This is a continuation of application Ser. No. 925,727, filed Oct. 30, 1986 now abandoned which is a division of application Ser. No. 428,900, filed Sept. 30, 1982, U.S. Pat. No. 4,758,431 which in turn is a division of Ser. No. 139,886 filed on Apr. 14, 1980, U.S. Pat. No. 4,378,797.
(a) providing an oxygenated physiologic synthetic spinal fluid of known composition;
(b) injecting said synthetic spinal fluid into at least a first portion of the cerebrospinal pathway of a mammal;
(c) withdrawing fluid comprising at least a portion of said synthetic spinal fluid from a second portion of said pathway,
whereby said withdrawn fluid is said diagnostic fluid and is used for diagnosing conditions of the central nervous system tissue of said mammal by comparing the composition of said diagnostic fluid with that of said oxygenated physiologic synthetic spinal fluid prior to injection.
Cerebrovascular accident, a disease commonly known as "stroke" remains a leading cause of death and probably constitutes the single largest category of long term disability in this country. In spite of current medical knowledge and available treatments, a major central nervous system vascular occlusion is attended by irreversible damage to the affected brain region(s). A "completed stroke" is manifest by a fixed and permanent neurological deficit. Millions of dollars have been expended in stroke research and care by Federal and private agencies without a single substantial gain in our present chemotherapeutic abilities for a completed stroke. On a clinical level, once vascular flow in any portion of the central nervous system has ceased for longer than a few minutes, a permanent "stroke" invariably follows. Accordingly, a long felt need exists to prevent permanent damage and/or reverse neurologic deficits resulting from interrupted vascular flow.
Over the years, many experiments have been conducted with materials possessing high oxygen-dissolving properties, many of which have been incorporated as constituents in "artificial blood". The concept of utilizing materials possessing high oxygen-dissolving properties for the maintenance of tissue respiration was first reported by Rodnight in 1954. See Rodnight, R.; Biochemistry Journal, Vol. 57, pg. 661. Rodnight capitalized upon the considerable oxygen solubility found in silicone oils, and sustained tissue slices by incubation in these oxygen laden oils. Approximately 12 years later, Clark reported experiments involving the total immersion of small animals in silicone oils and fluorocarbon liquids. Rats totally immersed in oxygenated silicone oil survived for one hour with no apparent ill effects, but died several hours after removal, from unknown causes. Similar experiments using synthetic fluorocarbon liquids, which dissolve about 3 times more oxygen than do the silicone oils, were performed with some success. Under these conditions, animals survived immersion in oxygenated synthetic fluorocarbon liquids and thereafter returned to apparent health. See Clark, L. C. Jr. and Gollon, F.: Science, Vol. 152, pg. 1755, (1966); and Gollon, F., Clark, L. C. Jr.,: Alabama Journal of Medical Science, Vol. 4, Pg. 336, (1967). While arterial oxygenation was reported as excellent for Clark's studies in rats, coincident impairment of carbon dioxide elimination was also reported, as was pulmonary damage from breathing flourocarbon liquids. One rat, which was observed for five days following liquid breathing, was described as being in respiratory distress and as succumbing within 15 minutes after the sub-cutaneous administration of hydrocortisone (50 mg), with copious loss of body fluid from the trachea. In this regard, Clark concluded:
These organic liquids should prove to be of value in studies of gas exchange in living tissues in animals. Organic liquids, since they can support respiration with oxygen at atmospheric pressure and have other unique qualities, may find use in submarine escape, undersea oxygen support facilities, and medical application. The pulmonary damage caused by the breathing of the organic liquids available at the present time remains a major complication of their use in man. Science, Vol. 152, pg. 1756.
Following these observations, fluorocarbon liquids were used as an incubation medium for isolated rat hearts. See Gollon and Clark, The Physiologist, Vol. 9, Pg. 191, (1966). In this work, myocardial oxygen requirements were apparently well met, however these hearts did not flourish without intermittent fluorocarbon removal and washing with oxygenated, diluted blood. This phenomen has been explained in terms of aqueous phase lack in pure fluorocarbons such that necessary ionic exchange is impeded.
More recently, considerable attention has been directed to the use of fluorocarbons as constituents of artificial blood. Sloviter, in order to overcome the problem of aqueous-metabolite fluorocarbon insolubility, made an emulsion with fluorocarbon and albumin. Sloviter's emulsion sustained the isolated rat brain by a vascular perfusion as well as did an erythrocyte suspension. See Sloviter, H. A. and Kamimoto, T.: Nature (London), Vol. 216, Pg. 458, (1967). A better emulsion was later developed comprising a detergent, "Pluronic F 68" (manufactured by the Wyandotte Chemical Corp., Wyandotte, Mich.), and fluorocarbon liquids which were properly emulsified using sonic energy. This improved emulsion permitted the replacement of most of the blood of a rat which was then reported as surviving in an atmosphere of oxygen for five to six hours. See Geyer, R. P.: Federation Proceedings, Vol. 29 No. 5, September-October, 1970; and Geyer, R. P.: Med u Ernohn, Vol. 11, Pg. 256, (1970).
Experiments have also been reported wherein fluorocarbons have been used to perfuse livers. Ten hours after in vitro fluorocarbon perfusion, the isolated liver ATP; AMP; lactate/pyruvate ratio; and a number of other metabolites were found to be as good or better than livers perfused in vitro with whole blood. See Krone, W., Huttner, W. B., Kampf, S. C., et al.: Biochemika et Biophysica Acta, Vol. 372, Pgs. 55-71, (1974). These detailed metabolic studies indicated that the organs perfused with 100% fluorocarbon liquid were redeemed "intact"; while only 75% of the whole blood infused organs maintained a similar degree of metabolic integrity. The ability of fluorocarbon perfusion to maintain cellular integrity was confirmed by electron-microscopy studies. The cells had normal mitochrondrial ultra structure after ten hours of fluorocarbon support, indicating the persistence of normal or adequate aerobic metabolism.
Fluorocarbons have also been used in experiments involving cerebral blood circulation. In Rosenblum's studies, mouse hematocrits were reduced to 10-15 by exchanging the animal's blood with a fluorocarbon solution. When the animals were respired with 100% oxygen after intravascular fluorocarbon infusions, the brains remained metabolically sound. These organs were able to reverse rising NADH levels and EEG abnormalities induced by short period nitrogen inhalation. The EEG's of fluorocarbon treated animals could be activated by the central nervous system stimulant metrazole. By these criteria, intravascular fluorocarbon does support the cerebral microcirculation and provides functions of oxygenation, metabolism and electrical activity which are normally associated with blood transport. Please refer to Rosenblum, E. I.; "Fluorocarbon Emulsions and Cerebral Microcirculation", Federation Proceedings, Vol. 34, No. 6, Pg. 1493, (May 1975).
As reported by Kontos et al., the marked vasodilation of small cerebral surface arteries which occurs in response to acute profound hypoxemia may be locally obviated by perfusing oxygen equilibrated fluorocarbon into the space under the cranial window. See Kontos, H. A., et al., "Role of Tissue Hypoxemia in Local Regulation of Cerebral Microcirculation", American Journal of Physiology, Vol. 363, Pgs. 582-591, (1978). Kontos et al. described the effect of perfusions with fluorocarbon with 100% oxygen as resulting from increased supplies of oxygen to the neural cells and consequent partial or complete relief of hypoxia, rather than to a local increase in the oxygen tension in the immediate environment of the vascular smooth muscle of the pial arterioles. Two other potential explanations for the observed action are suggested in the Kontos et al. article.
In 1977, Doss, Kaufman and Bicher reported an experiment wherein a fluorocarbon emulsion was used to partially replace cerebrospinal fluid with the intention of evaluating its protective effect against acute anoxia. According to this experiment, systemic hypoxia was produced through one minute of 100% nitrogen inhalation. A bolus of oxygenated fluorocarbon placed in the cisterna magna immediately prior to nitrogen breathing increased regional cerebrospinal fluid O2 tension by a factor of 5. During the one minute experimental period, the fluorocarbon emulsion provided twice as much brain tissue oxygen as was found in saline injected controls. Doss et al. found the anticipated regional tissue oxygenation decline attending nitrogen inhalation to be halved by the administration of the oxygen bearing fluorocarbon emulsion.
In spite of the above described experiments, there has yet to be any reported information of a practical therapeutic approach to the treatment of ischemic tissue, and particularly human ischemic central nervous system disease.
The present invention provides a novel nutrient formulation for circulation through cerebrospinal fluid pathways, and systems and methods for using same to treat central nervous tissue hypoxic-ischemic conditions. Through its use, a new diagnostic methodology is also disclosed.
The cerebrospinal fluid (CSF) pathway system, which intimately bathes and permeates brain and spinal cord tissues, constitutes a unique anatomical relationship within the body. Although it has some similarities to systemic lymphatics, its anatomical arrangement differs considerably from that of lymph. Indeed, this system has been named the "third circulation". Due to the extensive area of CSF-tissue contact over the cerebral and cord surfaces, in the miniature Virchow-Robins spaces, and cerebral ventricles, the cerebrospinal fluid system constitutes a vast, complex and intimate therapeutic avenue for access to central nervous tissue. Excepting certain infections and neoplasms where the cerebrospinal fluid is now utilized as an a treatment conduit, the cerebrospinal fluid system has not been otherwise widely exploited as an easily accessible therapeutic route and has never been used as a continuous therapeutic diagnostic circulation system in man. The present invention is predicated on the recognition that, when regional cerebral blood flow is interrupted, such as after major stroke, or is otherwise seriously impeded by profound vaso-spastic states, the cerebrospinal fluid pathway actually represents the only practical and viable anatomical route by which these tissues may be readily treated. This results from the fact that the usual vascular delivery system is either occluded or nonfunctional, and thus tissues within affected territories cannot be properly served.
In accordance with the present invention, essential cellular substrates are delivered to beleaguered ischemic brain regions by utilizing the "back door" cerebrospinal fluid delivery route. Accordingly, the present invention provides a novel nutrient emulsion, circulatory method and system which provide necessary nutrient penetration into regions suffering vascular deprivation.
It has been found that the cerebrospinal fluid to brain relationship is not characterized by the rigid and highly selective barrier mechanisms which are present at the blood-brain interface. Thus, the penetration rate of materials from cerebrospinal fluid regions to the brain relate largely to molecular size, that is, small substances penetrate deeply while large molecules move more slowly into brain substance. Although entry rates are generally inversely proportional to molecular weight, penetration is also influenced by lipid solubility and the molecular configuration of the penetrating substance. Accordingly, the present invention provides a nutrient emulsion containing essential brian nutrients including selected electrolytes, having a relatively low molecular size which, in accordance with the methods of the present invention, are caused to relatively freely diffuse from either the ventricular or subarachnoid fluid regions into the brain matter to be treated. Accordingly, the present invention provides a novel nutrient emulsion which has been purified, balanced, and perfected to fall within the narrow physiologic limits while nonetheless providing the desired nutritional characteristics referred to above.
In accordance with the preferred embodiment of the present invention, this nutrient emulsion constitutes "synthetic cerebrospinal fluid" comprising pre-selected electrolytes, glucose, amino acids, at least one oxygen-carrying component, typically a fluorocarbon, and other components which impart to the composition a pre-selected pH, buffering capability, and osmolarity. This nutrient emulsion is prepared by controlling sonication time and by properly dialyzing the material to achieve a toxic free emulsion. The resulting solution may be rapidly oxydated to O2 pressures of 650 mm of mercury by simply bubbling 100% oxygen gas through at atmospheric pressures. In a covered glass container, the resultant nutrient emulsion will not appreciably decline in its pO2 for at least two hours. As a result, a novel oxygenated nutrient emulsion is provided which is believed to exhibit exceptional therapeutic properties.
The present invention also provides a novel method and apparatus for circulating the oxygenated nutrient emulsion through cerebral spinal fluid pathways, particularly those pathways which contact brain and spinal cord tissue. According to these methods, treated tissues exhibit a substantially improved ability to resist and/or repair damage which would otherwise result from vascular occlusion. In accordance with the preferred method of the present invention, the novel oxygenated nutrient emulsion is circulated through this cerebrospinal fluid route by injecting it into brain ventricles and withdrawing it from the cisterna magna (as shown in FIG. 1, via withdrawal means 30), or the spinal subarachnoid space (as shown in FIG. 1, via withdrawal means 30b) to nourish and to treat central nervous tissues. In other instances the fluid may be injected into the subarachnoid space and withdrawn from another subarachnoid position (as shown in FIG. 2). The preferred embodiment oxygenated nutrient emulsion should be circulated to tissues to be treated in amounts sufficient to provide adequate gas exchange. Pure fluorocarbon may contain 50 ml O2 per 100 ml at one atmosphere oxygen while normal blood contains only 20 ml O2 /100 ml under the same conditions. The oxygen carrying capability per ml of the final emulsion is considerably less than that of pure fluorocarbon by reason of its content of other constituents for normalizing osmotic pressure, buffering, eletrolytes, and other physiologic balancing materials. Thus, the preferred embodiment nutrient emulsion may be charged with oxygen (100% O2 at one atmosphere) to attain pO2 tensions of 650-700 ml of mercury and an O2 content of 20 ml per 100 ml. Under rapid circulation conditions, the integral O2 exchange (fluorocarbon to tissue) has been found to be about 50%. Thus, an oxygen exchange value of ten (10) O2 /100 ml nutrient emulsion is provided by the present method.
In accordance with the preferred embodiment of the present invention, sufficient nutrient emulsion should be supplied to counteract oxygen deprivation to the affected tissue. For example, the entire supertentorial adult cat brain weighs 12 grams (plus or minus 2) and the normal metabolic consumption of oxygen of the cat brain equals 3-4 ml per 100 grams per minute. This total metabolic need may be met with the circulation rate of 6-8 mls per minute. Metabolic needs necessary to simply sustain and/or salvage tissue can be achieved by perfusion rates of one half or less of this optimum. Within these constraints an easily achieved sustenance flow rate of 20 ml/minute would be anticipated to salvage 100 gms of human brain tissue. It has been found experimentally that it is possible to supply sufficient oxygen to counteract the deprivation of the affected tissue through circulation of the nutrient emulsion through the cerebrospinal fluid route. In fact, under carefully controlled conditions, it is believed within the scope of the present invention to nourish the entire human brain using the preferred embodiment apparatus, method and substance of the present invention. In this manner, central nervous neurons deprived of major blood supply may be sustained without significant damage.
In accordance with the preferred embodiment of the present invention, a novel system is disclosed for administering and maintaining the oxygenated nutrient emulsion for delivery and circulation through the cerebrospinal route.
The preferred embodiment system of the present invention effectively carries out the circulation and equilibration of the nutrient emulsion during treatment. This system, which is diagrammatically illustrated in FIG. 1, generally comprises a reservoir containing nutrient emulsion; means for delivering the nutrient emulsion at pre-selected flow rates; an oxygenation means for equilibrating the nutrient emulsion to desired gaseous tension levels; heat exchanger and/or cooling unit means for selectively controlling the temperature of the nutrient emulsion; filtering means for cleansing the nutrient emulsion; and circulation monitoring means for insuring that desired circulation flows and pressures are maintained within the system.
The present invention also provides a method of diagnosing conditions of neurologic tissue in mammals. This novel method generally comprises providing an artificial spinal fluid of known composition, injecting that artificial spinal fluid into at least a first portion of the cerebrospinal pathway of a mammal, withdrawing a diagnostic fluid from a second portion of that pathway to create a circulation of fluid at least through a portion of said pathway, monitoring the composition of said diagnostic fluid, and comparing for at least a selected difference in the compositions of said artificial spinal and diagnostic fluids, whereby the detected differences in those compositions are at least diagnostic of neurologic tissue disposed along said portion of the cerebrospinal pathway. In accordance with the diagnostic methods of the present invention, the diagnostic fluids may be monitored for differences in oxygen content, lactic acid concentration, carbon dioxide concentration, potassium and/or sodium ion concentration, enzyme concentration, pH difference, ammonium concentrations, GABA (gamma-aminobutyric acid) and other amino acid(s) concentrations, microorganism content, bacterial count, myelin fragments, cellular fragments or organelles, malignant cells, and/or poisons.
It is also within the scope of the present invention to provide a novel nutrient liquid and/or diagnostic liquid for treating cerebrospinal tissue containing various novel specified components which is formulated using novel methodology.
It is additionally within the scope of the present invention to provide a novel apparatus for treating patients having ischemic-hypoxic tissues, including novel injection means (20a or 30a) and withdrawal means (30, 30b or 30c) comprising a novel catheter means which is particularly adapted for injecting oxygenated nutrient liquid into a cerebral ventricle without danger of substantially damaging neurologic tissue in the vicinity of that ventricle.
In addition to the methods described above, it is within the scope of the present invention to provide additional therapeutic agents to the nutrient emulsion, such as antineoplastic agents; antibiotics, and/or other therapeutic agents for use in treating the target tissue(s).
Accordingly, the primary object of the present invention is the provision of a method, substance, and system for providing early stroke treatment.
Other objects of the present invention are to provide treatments for brain and spinal cord injuries, cerebral hemorrhage, cerebral vasospasm, senility, after general hypoxia and other hypoxic-ischemic related neurological disorders.
It is a further object of the present invention to provide therapeutic treatment which may sustain the life of the brain and central nervous system tissues in case of profound shock and/or temporary cardio-respiratory failure.
It is a further object of the present invention to provide life-sustaining support to the brain and/or spinal cord tissues during the conduct of neurological or cardiovascular surgery.
Other objects of the present invention are the provision of methods which may compliment treatments of central nervous system neoplasms by either external radiation and chemotherapy by providing local tissue hyperoxygenation or drug which may enhance drug or radiation tumorocidal effects.
Further objects of the present invention include the provision of methods which are useful in treating anoxic states attending birth injury. The present method will also assist in removal of central nervous system poisons.
These and other objects of the present invention will become apparent from the following more detailed description.
FIG. 1 is a diagrammatic view of the preferred embodiment treatment system of the present invention illustrating the circulation of nutrient emulsion from a reservoir, into a cerebral ventricle, such as a lateral ventricle, through a portion of the cerebrospinal fluid pathway for output from the spinal subarachnoid space or from the cisterna magna.
FIG. 2 is a diagrammatic view of a portion of the preferred embodiment treatment system of FIG. 1 illustrating an alternate circulation route wherein oxygenated nutrient emulsion is injected into the spinal subarachnoid space and is collected from the cisterna magna;
FIG. 3 is a diagrammatic view of a portion of the preferred embodiment treatment system illustrated in FIG. 1 showing an alternate circulation route wherein oxygenated nutrient emulsion is injected into the cisterna magna for passage through the spinal subarachnoid space for withdrawal from a lumbar region.
In the following more detailed description, numerous examples have been selected for the purpose of explanation and illustration of the preferred embodiments of the present invention. One of ordinary skill in the art will readily recognize that numerous substitutions or alterations from the examples set forth may be made without departing from the spirit of the present invention, which is defined more particularly in the appended claims.
Referring now to FIG. 1, the preferred system for circulating nutrient emulsion through a cerebrospinal pathway is diagrammatically illustrated. As shown in FIG. 1, a nutrient emulsion reservoir 10 is provided for receiving and retaining nutrient emulsion, the preparation of which will be described more fully hereinafter. In accordance with the preferred system and method of the present invention, the nutrient emulsion is injected into a cerebrospinal pathway following pH adjustment and filtering, temperature adjustment, oxygenation, and adjustment of the pressure and flow rate of the nutrient input stream 19. In FIG. 1, these steps are illustrated diagrammatically at 12, 14, 16 and 18 respectively. Preferably, the nutrient input stream 19 is delivered to a ventricle of the brain, and more particular to a lateral ventricle 20 of the human brain designated generally 22. Injection of the nutrient input stream permits the oxygenated nutrient emulsion to come into contact with the subarachnoid spaces, miniature Virchow-Robins spaces, cerebral and cord surfaces, and cerebral ventricles. For the system illustrated in FIG. 1, the nutrient input stream 19 is diagrammatically illustrated as being injected into a lateral ventricle 20. Since the lateral ventricle is in fluid communication with other portions of the cerebrospinal pathway, the withdrawal of fluid from a portion of the pathway which is remote from that ventricle will create a circulation of fluid within the cerebrospinal pathway. More particularly, circulation of the nutrient input stream through at least a portion of the cerebrospinal pathway may be accomplished by withdrawing fluid (via withdrawal means 30 or 30b) from the spinal subarachnoid space, diagrammatically illustrated at 26 in FIG. 1, or alternatively, from the cisterna magna 24 (via withdrawal means 30 or 30b).
As illustrated in FIG. 1, circulation of fluid through the cerebrospinal pathway is intended to permit the treatment of at least cerebral tissues. It is within the scope of the present invention, however, to focus treatment on selected neural tissue areas, in which case alternative points of injection and withdrawal of fluid may be selected by the attending physician. For example, in the case of spinal cord injury, it is anticipated that the point of injection of oxygenated nutrient emulsion may preferably be in the lumbar, spinal subarachnoid space, with the point of withdrawal being at the cisterna magna. See FIG. 2. While the above mentioned cerebrospinal pathway injection and withdrawal points are preferred, it is within the scope of the present invention to utilize other injection and withdrawal locations, provided a substantial circulation of fluid through the area of affected neurologic tissue is established by utilizing the selected loci. As shown in FIG. 3, injection via injection means 30a into the cisterna magna and withdrawal via withdrawal means 30c from the spinal subarachnoid space is also possible.
The preferred injection means of the present invention comprises a cerebral catheter means 20a for insertion into a brain ventricle. This injection means comprises means for preventing a portion of the catheter located within a brain ventricle from damaging tissues surrounding the ventricle. In the preferred embodiment, an inflatable balloon tip may be provided for this purpose. The actual injection of nutrient emulsion into the brain ventricle is accomplished by providing an arrangement of the outlet holes disposed as series of slits radially spaced around the catheter tip. Both the injection means and withdrawal means also further comprise attachment means for attaching the catheter to the body in the vicinity of the injection or withdrawal sites. Thus the injection catheter may comprise a means for fixing at least a portion thereof with respect to the skull to insure catheter stability. The withdrawal catheter, which may have a tip with multiple perforations disposed therein, further comprises means for attaching at least a portion thereof to tissue in the region of the subarachnoid space. This attachment means may include a staple for attaching a non-collapsible portion of the catheter to a lumbar region of the skin.
It is not anticipated that the fluid which is withdrawn from the cerbrospinal pathway at the point of withdrawal will be identical in composition to the oxygenated nutrient emulsion which is injected at the injection point. By taking advantage of differences in composition which are detected in the withdrawn fluid, which may be considered to be a diagnostic fluid, the attending physician may easily monitor the physiologic condition of the neurologic tissue which is being treated. This diagnostic fluid may also be monitored to assure that treatment is proceeding according to plan. Accordingly, fluid which is withdrawn from the cerebrospinal pathway is directed to an output collection means 28 for collecting diagnostic fluid. Preferably, an output monitor 34 will continuously monitor various chemical and physical characteristics of the diagnostic fluid for such properties as flow rate, hydraulic pressure, potassium and sodium ion temperature, lactic acid concentration, gamma amino butyric acid and other amino acid concentrations, oxygen concentration, carbon dioxide concentration, enzymes, and ammonia concentration. The output of this output monitor will not only provide the attending physician with information concerning the state of the cerebrospinal tissue being treated, but also will be fed back to the monitor, control and alarm systems for at least pressure and flow rate, temperature, oxygen-carbon dioxide and chemical constituency, as described more fully hereinafter. This diagnostic system takes advantage of the fact that ischemic neurologic tissue produces higher concentrations of such materials as Gamma-aminobutyric acid (GABA), lactate ion (lactic acid), enzymes and/or LDH (lactic dehydrogenase), ammonia, and other constituents which have been determined by analyzing cerebrospinal fluids of patents subjected by disease to similar anoxic conditions.* In accordance with the system of the present invention, however, a continuous monitoring of the state of neurologic tissue is possible, since the circulation of oxygenated nutrient emulsion will produce a continuous flushing of the affected tissues regions, and thus will result in diagnostic fluid component variations which are rapidly reflective of the physiologic state of the tissues being treated. Due to the multi-point injection-withdrawal method of the present invention, dangers which are inherent in sampling natural cerebrospinal fluid at a single location are avoided by utilizing a double venting method wherein the cerebrospinal fluid pressure is at all times carefully controlled. FNT *See for example, "Rapid and Sensitive Ion-Exchange Fluorometric Measurement of G-Aminobutyric Acid in Physiological Fluids", Hare et al., Anal. Biochem., Vol. 101, 349-355 (1980) for a preferred GABA measurement method.
It is within the scope of the present invention to sterilize and reconstitute that diagnostic fluid as shown at step 32, whereupon that reconstituted diagnostic fluid may be provided as nutrient emulsion to the nutrient emulsion reservoir 10. As shown in FIG. 1, the output monitor 34 may monitor the diagnostic fluid during the sterilization and reconstitution processes and, if desired, ensure that the reconstituted fluid satisifes the requirements of the nutrient emulsion reservoir. As shown in FIG. 1, in order to ensure that appropriate degrees of oxygenation, filtration and chemical balancing, temperature adjustment, and pressure and flow rate are maintained, the nutrient input stream is monitored by various monitors, controls, and alarms, which are intended to provide a fail safe nutrient input stream. In particular, a pressure and flow rate monitor, control and alarm 38 is provided for monitoring the pressure and flow rate of the nutrient input stream, for controlling the pressure and flow rate adjustment 18 to establish desired pressures and flow rates, and for sounding an alarm in the event that the nutrient input stream exceeds or falls below preselected pressures or flow rates. If desired, this alarm may additionally disable the pumping mechanism producing flow of the nutrient input stream such that the unit "shuts down" upon detection of unacceptable input stream conditions.
Referring now to the temperature monitor, control and alarm, the temperature characteristics of the nutrient input stream are similarly detected, at least to ensure that hyperthermic states except when used as therapeutic modality are avoided. While in most instances, the nutrient input stream will be adjusted to a 37° C. temperature, it may be desired to select hypothermic temperatures in order to establish certain treatment conditions. In either event, the temperature monitor will continuously detect the temperature of the input stream, will control the temperature adjustment 14 to establish a preselected temperature, and will sound an alarm and/or disable the system in the event that a preselected temperature range is not maintained in the nutrient input stream.
Referring now to the chemical monitor, control and alarm 42, the nutrient input stream will be continuously monitored for one or more chemical or physical characteristics of the nutrient input stream, and will control the chemical balancing, filtration, etc. which is performed by the filtration and chemical balancing unit 12. The chemical monitor, control and alarm may, for example, monitor the pH, osmolarity, electrolyte component, carbohydrate component, amino acid component, or other components of the nutrient emulsion to ensure that the nutrient input stream falls within preselected stream characteristics. In the event that these characteristics do not fall within the preselected range, the alarm for unit 42 may sound and/or may disable the system to thereby prevent further injection of nutrient input stream into the cerebrospinal pathway.
Finally, an oxygen/carbon dioxide monitor, control and alarm unit 36 is provided which continuously monitors the oxygen and carbon dioxide contents of the nutrient input stream, which controls the oxygenation unit 16, and which sounds an alarm in the event that the oxygen or carbon dioxide concentrations do not fall within preselected ranges. It is anticipated that each of units 36-42 may provide continuous displays of the information monitored from the nutrient input stream, and may, if desired, enable back-up units which either manually or automatically may supplement or replace the functions of units 12-18 in the event that those units are not functioning to produce a nutrient input stream within the desired ranges. For example, it is anticipated that a manual or battery operated pump, oxygenator, filter, and pressure and flow rate adjustments will be provided to enable emergency operation of the system, since continual nutrient flow is lifesaving for the devitalized portion of the treated organ.
The preferred nutrient emulsion of the present invention is comprised of carefully formulated components which, to the extent possible while maintaining desired therapeutic activity, mimic the physical and chemical characteristics of natural cerebrospinal fluid. Generally, tissues and cells will not fair well if exposed to large volumes of non-physiologic ionic solutions. Accordingly, it has been recognized that appropriate electrolyte compositions at the tissue level are indispensable when it is considered that the circulatory method of the present invention would otherwise result in the washing and the dilution of electrolytes from the region even after short terms of circulation, to the detriment of cell membrane functions. Accordingly, in accordance with the preferred embodiment of the present invention, sodium, potassium, calcium, magnesium, and chloride ions are carefully balanced in the nutrient emulsion of the present invention to thereby create, to the degree possible, normal extra-cellular compositions. The present invention also provides a non-aqueous oxygen transfer component for selectively combining with oxygen and for transferring oxygen to the tissues to be treated. Numerous compounds are known to the art which are characterized by having a high solvent property for oxygen, carbon dioxide, and other gases. The preferred non-aqueous oxygen transfer component of the preferred nutrient liquid should exhibit when so charged, oxygen vapor pressure ranges of above 400, and preferably 600, Torr. Such oxygen transfer components should similarly not have in themselves high vapor pressures which would boil at body temperatures, nor have viscosities which are difficult if not impossible to emulsify. Generally, the preferred compounds for use as non-aqueous oxygen transfer components are fluorocarbon polymers, such as perfluorocarbons, perfluorinated alkyl polyethers, fluoroethers, fluoroamines, etc. While compounds within these groups range in molecular weight from 250 to 7000, their selection for use as non-aqueous transport components are based upon the combination of features of the proper vapor pressure, molecular weight, viscosity, emulsifiability, emulsion-stability and tissue distribution. One such fluorocarbon which has been found to be particularly suited for the non-aqueous oxygen transport component of the preferred nutrient liquid is a compound sold by the 3-M Corporation under the trademark "FC-80". FC-80 has an oxygen solubility coefficient ScO2 of 0.45 of ml O2 /ml at pO2 of 760 Torr. See Navari et al., Res. Exp. Med., 170: 169-180 (1977), which paper is specifically incorporated by reference as if fully set forth herein. It should be noted that whole blood under the same circumstances contains 0.23 ml O2 /ml. The FC-80ScO2 is linear from 760 to 200 Torr but declines quite rapidly below the lower level. The high oxygen diffusion coefficient (5.71/10-5 centimeters squared per second) indicates more than adequate FC-gas in a physiologic sense. Similar studies concerning CO2 solubility and diffusion indicate that absorption and release are described by a straight line function. From these observations, metabolic tissue CO2 accumulations should theoretically be easily removed by fluorocarbon solutions administered through a circulatory method.
Not only do fluorocarbons possess these unique physical gaseous properties but they are for the most part non-toxic. The main acute toxicity has been found to reside in free fluoride ion accumulation which occurs mainly from sonication. See, Clark et al., Fed. Proc., 34: 1468-1477 (1979). The free ion can, however, be removed by repetitive dialysis and the emulsion thereby rendered physiologically acceptable. Accordingly, the preferred embodiment nutrient liquid of the present invention, which has been dialysized and filtered through a milipore filter, has evidenced no toxicity either in short term or long term use during circulation through cerebrospinal pathways of animals. One chief advantage of the CSF circulation route is that most or all the nutrient liquid can be removed by washing at the time of treatment termination. In this way long term cellular retention as previously noted for liver and reticuloendothelial cells in vascular circulations of oxygenating liquids may be avoided.
In the preferred embodiment nutrient liquid of the present invention, an emulsification component is provided for permitting the emulsification of the nutrient component with the oxygen transfer component of that liquid. The best currently available material for this purpose is believed to be block polymer polyols, which are known to the art as "pluronics", of which, pluronic F68 has proven to be a most efficient emulsifying agent. As used in a nutrient liquid as described more fully hereinafter, the toxicity from such a pluronic detergent is negligible. At the present time, however, it is anticipated that other emulsification components which will permit the non-aqueous transfer component of the nutrient liquid to become soluble with respect to the aqueous nutrient component of the nutrient liquid may be utilized to provide solutions which have adequate physiologic perimeters. Such other means of solubilizing fluorocarbons include the formation of miceles, etc.
In the preparation of the preferred nutrient liquid, an important factor in producing an acceptable nutrient liquid is the achievement of an acceptable final osmotic pressure. The osmotic pressure of the nutrient liquid will depend upon the amount of the emulsification component, the particle size of the fluorocarbon, and the ionic composition of the aqueous nutrient component. In accordance with the preferred method of preparing the nutrient liquid of the present invention, toxic emulsification components should be removed by dialysis. Fluorocarbon particle size will be controlled by sonification time and filtering, while the ionic composition of the aqueous nutrient component will be carefully adjusted to produce a nutrient liquid possessing desired osmic characteristics. If desired, a final osmic tuning may be accomplished in accordance with the method of the present invention by adding ascorbic acid to the nutrient liquid.
In order to provide fully successful treatment of ischemic tissues, it is desirable to provide nutrient liquid for circulation around those tissues which will compensate for relative or complete deficiencies of blood transport metabolites. In addition to oxygen, other tissue metabolic requirements include glucose, amino acids, ions, hormones, vitamins, etc. While in temporary treatment conditions, it may be suitable to temporarily omit one or more vitamin, hormone, ion, or amino acid, for prolonged treatment and to produce the most desirable results, it is preferred to provide substantially all of the above mentioned metabolites in the preferred nutrient liquid. It is at least desirable to provide in the nutrient liquid all components necessary to support aerobic metabolism which will be available within the medium for use at cellular levels. Glucose deprivation of central nervous system tissue causes a serious cellular matabolic deficiency, as does the same degree of oxygen deficiency. Accordingly, by providing a total and finely adjusted mixture that has all the necessary components for total cell survival, an extremely efficient and therapeutic liquid material is provided which is ideal for circulation through the cerebrospinal pathways.
In order to illustrate the preferred method and composition of such an oxygen-nutrient material, the following example is provided:
Under conditions of replacing blood borne materials by perfusion all nutrients necessary for aerobic metabolism must be available within the medium for immediate use at cellular levels. As far as the central nervous system is concerned, glucose deprivation causes as serious a cellular metabolic deficiency as does the equivalency of oxygen lack. To achieve the desired ends we have added all known essential nutrients to the FC (fluorocarbon) emulsion. FC itself thereby serves the purpose of a gas transport system while the aqueous emulsion phase contains an array of cellular metabolic essentials. The total and finally adjusted mixture has all the necessary ingredients for total cell survival. The combination material is referred to as an oxygen-nutrient formula (Ox-N), or oxygenated nutrient emulsion.
(A) 5% Commercial grade Pluronic F68 (Basic Wynadotte).
(B) 20% W/V FC-80 (3M Corporation).
(C) Synthetic C.S.F.
Sodium Chloride--7.3 gm/L
Potassium Chloride--300 mg/L
Calcium Chloride (dehyd)--200 mg/L
Magnesium Sulfate--300 mg/L
Sodium Phosphate (hepta)--200 mg/L
Sodium Bicarbonate--190 mg/L
Adjust the pH to between 7.380-7.420 with 10% Ascorbic Acid
(D) Bacitracin Inj. 50,000 u/vial (Pharmacy) reconstitute with 10 ml saline to give a concentration of 5000 u/ml. Use 0.2 ml of each liter of perfusate to obtain a concentration of 1,000 units per liter of perfusate.
(E) Essential Amino Acids (Pool) (Sigma)
D-Glutamic Acid--11.8 mg
L-Glutamine--730.0 mg
DL-Serine--26.3 mg
D-Threonine--30.0 mg
D-Lysine--38.8 mg
D-Valine--19.0 mg
D-Leucine--14.0 mg
DL-Isoleucine--13.0 mg
D-Phenylalanine--15.0 mg
DL-Tyrosine--14.0 mg
D-Methionine--4.5 mg
Before oxygenating the fluorocarbon emulsion add 9.8* mg. Amino Acid and 200 mg Dextrose for each 100 ml of emulsion. FNT *Siegel et al. pp. 297.
(F) Steroid (Methylprednisolone sodium succinate 125 mgs. The UpJohn Company). Reconstitute the steroid with 2 ml of dilutent to obtain a concentration of 62.5 mg/ml. Add 0.5 ml of this mixture of each liter of emulsion before oxygenation (31.2 mg/L).
(G) 1N NaOH
2. Materials
(A) Sonifier Cell Disruptor (Branson) Model W185D
(B) Waring Blender for mechanical dispension of Pluronic Acid.
(C) Dialyzer tubing 7/8 in. (22 mm) (Thomas). It is necessary to dialize the emulsion to remove fluoride ions as well as other low molecular weight contaminants.
(D) Whatman Filter Paper #1 (46×57) (Thomas) The emulsion should be filtered to remove particles originating from disrupted carbon skeletons of fluorocarbon during sonication.
(E) 0.8 micron filter unit (Thomas) Sterilization is accomplished by filtering the emulsion through a micro filter.
(F) CO2 tank (Welders Supply Company) CO2 is used as a defoaming agent while sonicating.
(G) 100% O2 tank (Welders Supply Company) for saturating perfusate.
(H) Sterile Culture Flasks (Thomas) for storing perfusate.
(I) Gas Dispersion Tubes (Fisher Scientific Company) for equilibrating the emulsion with O2.
(J) Aspiratory Bottle (Thomas)
a. 250 ml capacity-cut off 21/2" from the neck with a glass cutter in order to accommodate the macrotip for sonification.
b. ##EQU1## (I) K50 Extension tubing (storeroom) Capacity approximately 2.1 ml length 50.7 centimeters (20 in.)
(L) Circulating Pump
(M) Sonification Assembly
a. Fill a container with crushed ice; one that will allow drainage of the water as the ice melts (a fish tank will do).
b. On the serrated outlet near the bottom of the aspiratory bottle connect seven lengths (140 in) of K50 extension tubing. Place the bottle in the ice bath and connect the tubing to the circulating pump.
c. Place the precooled Pluronic acid in the aspirator bottle. Drape and return extension tubing from the pump over the side of the bottle. Drape the tubes from the CO2 tank over the side of the bottle and bubble slowly. Carefully lower the macrotip into the solution and start sonification.
3. Method 20% FC-80 (5% Pluronic (F68)) (w/v)
A. Place 25 gms of F68+250 ml of artificial C.S.F. in a Warning blender and blend at a high speed for 2 minutes. The solution will become very foamy. For best results the solution should be refrigerated overnight before using. This allows the head of foam to settle and precools the solution to the proper temperature for sonification.
B. Place the precooled Pluronic acid solution in the aspirator bottle. Turn on Sonifier. With a Pasteur pipette add 58.8 mls (100 gm) of FC-80 over a 30 minute period sonifying throughout. Once added allow the mixture to sonicate for 45 minutes. Be sure that the temperature does not exceed 20° C.
C. Cut dialyzer tubing that has been presoaked in artificial C.S.F. into 60-inch strips. Fill each strip half full with the mixture. Place strips in containers filled with approximately 1000 ml, of artificial C.S.F. Refrigerate and allow to dialize for 48 hours. The dialyzing solution should be changed every twelve hours, and the emulsion checked and transferred to additional tubing since the volume is considerably increased during dialysis.
D. After dialysis filter the solution through Whatman #1 filter paper, then take the total volume. 25 gm of Pluronic acid and 58.8 ml of FC-80 should yield between 500 and 750 ml of emulsion. The former volume represets 20% FC-80 and 5% F68 w/v ratio. The emulsion should be kept in an ice bath while processing.
E. Add bacitracin to the emulsion. The pH at this point should be between 6.5 and 6.8.
F. It is necessary to adjust the electrolytes at this stage.
Unadjusted electrolytes:
It is necessary to add 696 mg NaCl/L of emulsion in order to normalize the electrolytes.
Adjusted electrolytes:
G. Using 1.0N NaOH adjust the pH to between 7.380 and 7.420, then check the osmolarity. (Range 298-317).
H. Sterilize the emulsion by filtering through 0.8 micron filter. The emulsion can be frozen at -20° C. and is stable for several months.
4. Immediately Before Using Emulsion
A. Add:
Glucose 0.8-2.5 gm/L
Amino Acid 0.098 gm/L
Steroid 31.2 mg/L
B. Warm the emulsion to 37° C. and equilibrate with 100% O2 using a gas dispersion tube for 30 minutes to obtain a pO2 of between 580-660.
C. A typical batch of FC-80 emulsion shows the following properties:
Na=131 meq/L
K=3.8 meq/L
Cl=130 meq/L
CO2 =3 meq/L
Glucose=186 mg.%
Osmolarity=311 mOsM
|Gas Characteristics After Oxygen Equilibration Unsaturated Saturated
pH 7.231 7.342
pCO2 3.7 5.7
pO2 190 640
In order to provide an indication of the efficacy of the preferred treatment methods, the following examples are provided:
For reasons of simplicity and reproducability a model continually in use in applicant's laboratory has been employed. Osterholm, J. L.; Pathophysiology of Spinal Cord Injury, C. C. Thomas, Springfield, Ill. (1978). Extensive experience with spinal cord injury in terms of standardization, quantitative histological studies, regional blood flow and biochemical parameters suggested these procedures. A primary pathophysiologic event in that model has been determined to be discrete regional ischemia. A microcirculatory flow failure within the injured region has been documented by many study techniques including microangiography, distribution of intravascular particulate materials, hydrogen-platinum flow studies, regional isotopic techniques and lactate accumulation. Recent C14 antipyrine microregional blood flow studies conducted in applicant's laboratory have accurately delineated the magnitude of ischemia in the injured cord. Within one hour the regional grey matter flow drops from the control of 44 cc/m100 gm/min to only 2 cc/100 gm/min. The white matter is also ischemic. Blood flows in these regions are depressed from 15 cc/100 gm/min to 1-2 cc/100 gm/min.
From these observations, standardized spinal cord inury causes a restricted ischemic lesion which can be easily studied and quantitated. In this rigid system, therapeutic treatment effects are readily detected by comparison with our extensive untreated injury data. It should be noted here that the mechanical injury forces used in these experiments are substantially above saturation and all wounded animals are rendered permanently paraplegic.
Experiments were carried out by continuously injecting either saline or Ox-N emulsion saturated with O2 at 1 atm into the distal subarachnoid spinal space. The outflow (withdrawal) of the diagnostic fluid was at the cisterna magna. Infusions were begun immediately after severe wounding. An infusion rate of 3 ml/minute was easily achieved, and this rate was maintained for two hours.
Prior to lumbar spinal infusion we were able to develop pO2 tensions of 535±89 mm O2 in the Ox-N emulsion by simply bubbling 100% oxygen through the solution. Upon exit at the cisterna magna after traversing the entire spinal subarachnoid space the pO2 had fallen to 243±63. The oxygen difference between entering and exit was 292±63, or a 55% decline, which is statistically significant at the P=<0.001 level. This finding indicates a rapid pO2 exhange during the thirty seconds or less transit time. For various technical reasons our initial pO2 was lower than can be achieved under idealized circumstances. More recently it has been possible to regularly attain pO2 of 650 torr. It is postulated that even better experimental results might obtain under conditions of higher O2 tension.
FC-80 is an efficient CO2 exchange and transport agent, and the emulsion therefore easily extracts tissue CO2. This is indicated by an initial emulsion pCO2 of 2.7 torr which rose to 16.0 torr after the tissue perfusion contact. This represents a 593% increase in FC-80 CO2 (P=<0.001). The emulsion also removes other acid metabolites since in some experiments the inherent buffering capacities were exceeded as the exit fluid pH exhibited a considerable depression toward the acid side (original pH 7.4, exit pH 7.0). This pH change exceeded any acid contribution by the collected CO2, and amounted to 0.248 m mole lactate/hour.
Frozen tissues were sectioned and stained (H & E, and acid phosphatase). The sections were evaluated by projection to 25± magnification and preselected lesion parameters measured by means of a compensating polar planimeter. There was considerable increase in the untreated injury cord cross sectional area (1280 mm2) which was significantly reduced in the Ox-N experiments, (869 mm2). We have assumed that this substantial cross sectional cord area increase is caused by edema fluid. In the course of other experiments, the degree of edema appearance has been quantified. It was found that net water accumulation at those post injury times ranged from 25 to 40%. The absolute reduction in cross sectional area by the Ox-N treatment is significant at the P=<0.001 level.
Using our standard sampling methodology which includes skip serial sections throughout the injury region, and analysis by quantification tecnhiques, the degree of injury induced hemorrhagic necrosis can be determined. With the perfected injury system the lesion size at any time point can be reliably predicted. The effects of saline and Ox-N circulations upon lesion size were compared to each other and to our established untreated values. The results are summarized in Table I:
|LESION SIZE 2 Hour Injuries % Grey % White % Total
Standard Injury-
(No Infusion)
Saline Circulation
Ox--N Circulation
Table I Percentages are expressed in terms of total tissue area lesioned by hemorrhagic necrosis for grey, white or total cord area two hours afte severe injury with the various treatments. (Statistical Significance P = <*0.01. The saline values are not significant)
The data indicates a highly significant degree of protection against injury lesions afforded by the Ox-N circulation treatments. The actual lesions are halved by the treatment and this remarkable stabilizing effect upon the important white matter tracts would be anticipated to substantially improve the final functional result attending severe spinal cord injury.
A technique of counting the anterior horn cells which contain visible acid phosphate histochemical reaction product has been developed in this laboratory. The procedure has been previously used to assess ischemic cellular effects in terms of cellular survival and/or lysis time.
From Table II it can be seen that untreated injury has a highly lethal effect upon anterior horn neurones. Within the two hour experimental time period, more than 97% of all cells at the injury center undergo cytoplasmic lysis. Ox-N infusions stabilized the injured cells as 60% of all neurones were protected from lysis.
Control 34 ± 2 (SD)
Injury 2 ± 1.73*
Injury + Ox--N circulation
21 ± 5.12**
Table II Number of anterior horn cells containing acid phosphatase reaction product within well defined cytoplasmic borders, (*statistical difference from control P = <0.001, **Difference from injury alone P = <0.001).
Biochemical ATP tissue determinations were undertaken to determine the metabolic oxidative state of injured spinal tissues. This metabolite was selected for study since it reflects the progress of normal oxidative metabolism. ATP levels fall very rapidly under sufficient hypoxic-ischemic conditions. Untreated injured cords have a 200% ATP decline in one minute. In the current experiments ATP levels would be expected to reflect (1) the cellular oxidative capability and (2) functional cellular viability. The latter aspect is especially important in terms of cellular integrity which was discussed in the preceeding section.
From Table III it can be seen that 2 hour injury causes a four and three fold drop in grey matter and white matter ATP respectively. This information amply supports other observations about the degree of regional cord tissue ischemia after impaction. ATP was found in significantly higher concentration in the Ox-N experiments than noted after saline circulation alone. The high energy compound suffered only a 30% fall from normal in the oxygenated perfusion group which contrasts vividly with the 300-400% loss found with the saline treatments.
|ATP LEVELS (u mol/gm) (2 hours post injury) Injury & Saline Injury & Ox--N Control
Grey Matter
0.46 1.24* 1.88
White Matter
0.40 0.87* 1.23
Table III ATP tissue levels in control, saline and Ox--N injured cords. The difference between saline and Ox--N is significant *(P = <0.05). Although not shown in the Table, the Ox--N treatments also statistically increase ATP in spinal cord regions directly above (P = <0.05) and below (P = <0.001) the injury site.
Initial studies have been conducted to determine the efficiency of Ox-N emulsions in protecting the brain against profound ischemia. We employed the cat brain and utilized right hemispheric regional vascular interruption so that the left cerebral hemisphere might serve as an internal control. The middle cerebral artery of cat is accessible through the bony orbit. It lies immediately above the optic nerve after the canal has been opened and can be identified with certainty in that position. Preliminary experiments determined that an inconstant cerebral field was devascularized by occluding the middle cerebral artery. It became apparent that collateral blood flow via the anterior and posterior cerebral arteries supplied some retrograde filling into the experimental region. This phenomenon could be largely prevented by concommittantly reducing the mean systemic blood pressure to 70 mmHg by external bleeding. Hemorrhagic hypotension plus middle cerebral artery occlusion yielded a reasonably constant ischemic cerebral lesion from animal to animal.
In that model either saline or Ox-N were circulated from the right cerebral ventricle to the cisterna magna at a rate of 3 ml/min. Cerebral tissues were harvested one hour after vascular occlusion by immediate immersion in liquid Feron. The tissues were sectioned in the frozen state and reacted with luciferin upon photographic film. A combination of high energy cellular metabolites plus luciferin react to emit visible light, which is recorded upon the film. Tissues removed from saline treated ischemic cerebral regions were uniquely devoid of phospholuminescence, while the opposite hemispheric demonstrated this reaction to a degree similar to that found in normal animals. Middle cerebral ischemic tissue samples from Ox-N treated animals contained sufficient high energy materials to demonstrate a positive histochemical high energy reaction one hour after vascular arrest.
The combined evidence from spinal cord injury and middle cerebral artery occlusion models demonstrate that the preferred oxygenated nutrient emulsion can be circulated to maintain cellular integrity and aerobic metabolism under the stress of profound regional ischemia. A third model was utilized to determine if vascular deprived neurones perfused via cerebrospinal fluid pathways with oxygenated-nutrient would continue to perform a physiologic function. A transthoracic aortic ligation just distal to the left subclavian effectively devascularizes the cervical, thoracic and lumbar cat spinal cord. In some examples the lower brain stem was also found ischemic by regional flow studies. The mid and lower thoracic cord are universally and profoundly blood deprived by this vascular interruption. Animals under light Ketamine anethesia were treated by circulating from the lumbar subarachnoid space to the cisterna magna with either saline or Ox-N solutions. Respiratory movements were evaluated in these experiments. The lungs were ventilated by positive presence respiration, but the mechanical movements are easily distinguished from neuromuscular respiratory contractions. This is especially so since for the most part the respiration and neuromuscular drive occur at separate times and are largely asynchronous. Following the aorta ligation all physiologic neuromuscular respiratory movements progressively diminished to total cessation after 5-10 minutes in the saline treated cats. The arrest obtains for intercostal muscles as well as diaphragmatic contractions. The Ox-N treated animals, on the other hand, continue to respire in an essentially normal neuromuscular sequence. The respiration, under those conditions, were often of irregular rate, diminished in amplitude, and showed some individual magnitude variations. The singular difference between saline and Ox-N circulations is the universal persistence of respiration in the latter group. It is also true that Ox-N sustained sufficient chest bellow movements so that if the chest were closed the respirations were clinically adequate to support life.
As seen from the above examples, and the foregoing description, circulation of the preferred embodiment nutrient liquid is capable of sustaining cellular integrity, aerobic metabolism and ongoing neuronal function. Even for neurons deep within the spinal cord (grey matter) the process has been successful in nurturing the ischemic neurons. The ability to sustain the central nervous system in a lethally ischemic field which persists for longer than a few minutes has never been accomplished before. The extra vascular pathway has not been employed as a global nutrient route prior to the present invention, nor has the combined use of oxygen rich emulsion which also contains other disclosed, novel components been known to the art.
As seen from the above experiments, the methods, compositions and system of the present invention are capable of providing substantial amounts of oxygen to neurologic tissues to be treated, while at the same time, removing the by-products of oxidated metabolism, including carbon dioxide, which have been found to exist in substantially higher concentrations in the exit, diagnostic fluid. Similarly, as discussed above, rapid, normally lethal, lyses of anterior horn cells is readily preventable through the treatment of the present invention, protecting at least 60% of the cells through this modality. Similarly, high energy phosphate metabolism utilizing both oxygen and glucose is maintained at substantial levels. Accordingly, the methodology of the present invention represents a substantial advance in the treatment of central nervous system tissue. Prior to this invention there was no available method to sustain central nervous system tissues after a few minutes of profound ischemic insult. This invention should revolutionize the therapeutic capabilities by providing therapeutic approaches for stroke, brain injury, vasospasm, senility, tumors, coma, spinal cord injury, ischemia, vasospasm, and central nervous system poisoning.


text:
Filed Under (KTM) by admin on 12-11-2010
Repair manual KTM 250 / 300 / 380 Art No 3206004 -E 2-2C main jet jet needle jet needle air control screw idle adjusting screw idle jet throttle valve Idling range A Operation with closed throttle valve. This range is influenced by the position of the air control screw 1 and the idle adjusting screw 2 . Only make adjustments when the engine is hot. To this end, slightly increase the idling speed of the engine by means of the idle adjusting screw. Turning it clockwise produces a higher idling speed and turning the screw counterclockwise produces a lower idling speed. Create a round and stable engine speed using the air control screw (basic position of the air control screw = open by 1.5 turns). Then adjust to the normal idling speed by means of the idle adjusting screw. Opening up B Engine behavior when the throttle opens. The idle jet and the shape of the throttle valve influences this range. If, despite good idling-speed and part-throttle setting, the engine sputters and smokes when the throttle is fully opened and develops its full power not smoothly but suddenly at high engine speeds, the mixture to the carburetor will be too rich, the fuel level too high or the float needle is leaking. Part-throttle range C Operation with partly open throttle valve. This range is only influenced by the jet needle (shape and position). The optimum part-throttle setting is controlled by the idling setting in the lower range and by the main jet in the upper range. If the engine runs on a four-stroke cycle or with reduced power when it is accelerated with the throttle partly open, the jet needle must be lowered by one notch. If then the engine pings, especially when accelerating under full power at maximum engine revs, the jet needle should be raised. If these faults should occur at the lower end of the part throttle range at a four-stroke running, make the idling range leaner; if the engine pings, adjust the idling range richer. Full throttle range D Operation with the throttle fully open (flat out). This range is influenced by the main jet and the jet needle. If the porcelain of the new spark plug is found to have a very bright or white coating or if the engine rings, after a short distance of riding flat out, a larger main jet is required. If the porcelain is dark brown or black with soot the main jet must be replaced by a smaller one. mixture too rich: too much fuel in proportion to air mixture too lean: not enough fuel in proportion to air 1 2 OPERATING RANGES OF THE CARBURETOR 2-3C Carburetor adjustment Basic information on the original carburetor setting The original carburetor setting was adapted for an altitude of approx. 500 meters (1600 ft.) above sea level, and the ambient temperature of approx. 20°C (68°F), mainly for off-road use and central European premium-grade fuel (ROZ 95 MOZ). Mixing ratio 2-stroke motor oil : super fuel 1:40 – 1:60. Basic information on a change of the carburetor setting Always start out from the original carburetor setting. Essential requirements are a clean air filter system, air-tight exhaust system and an intact carburetor. Experience has shown that adjusting the main jet, the idling jet and the jet needle is sufficient and that changes of other parts of the carburetor will not greatly affect engine performance. RULE OF THUMB:

subset: commoncrawl


text:
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It took an angel investor of sorts to bring back to life the digital avatars of a slew of celebrities who sacrificed their online selves for a fundraising effort.
Stewart Rahr, the owner of Kinray, the largest privately owned pharmaceutical distributor in the world, donated $500,000 to help restore the Facebook, Twitter and blog accounts of Lady Gaga, Justin Timberlake, Kim and Khloe Kardashian and Ryan Seacrest, among others, who participated in Alicia Keys' Keep a Child Alive's "Digital Death" campaign, reports the New York Post.
The celebrities "killed" themselves on social media outlets (meaning no posting or tweeting) until $1 million dollars was raised for the charity, which funds HIV/AIDS relief efforts in Africa and India. The effort was accompanied by a high-profile press campaign that featured posters showing several of the celebs laying in coffins with wording saying, for example, "Kim Kardashian is Dead," with details of how to bring them back to life via donations also explained on the literature.
U.S. & World
But according to the Post report, many of the stars became frustrated by the slow pace of donations, so Rahr stepped in with his big money.
A source close to the fundraising effort told the Post that this was "the worst mismanagement of star power I've ever seen in my life."
Selected Reading: NY Post, TMZ, Hollywood Gossip


text:
Virgo 2009 Horoscope - Based on your Moon Sign
VIRGO (Aug. 22 - Sept. 21)
You will stay to be clever and generate your own innovative ways for doing things. You might change your occupation. An auspicious ceremony is guaranteed in your surroundings which will bring great happiness to you and your family.
Your financial state as well as your social contacts will increase and this will be beneficial to you every way. You will be able to face adversity with confidence and tact. Your career flight will be unusual this year. You love to be your own boss and there are chances that you can take such initiative for life.
Leo 2009 Horoscope - Based on your Moon Sign
LEO (July 22 - Aug. 21)
Leos love to travel far and wide. You tend to be unstable and emotional being. You have high imagination but are highly self centered.
Money will come to you easily but your spending will be high. You love artistic things but are not much creative yourself. You spread love and warmth wherever you go. You are a lover of music. You like to be a leader in workplace and cannot accept anything less than that. You will become very famous in the trade you work in.
Cancer 2009 Horoscope - Based on your Moon Sign
CANCER (June 22 - July 21)
You will work hard to achieve your goals but will face several short comings which will hamper your progress and slow your pace. These pitfalls may eventually reduce your capacity to work. Your parents may have ill health which might be a cause of worry to you. Drive safe this year as you are prone to accidents.
Your charm and magnetism are always high and which will be difficult for people to resist. You like to punish your lover by getting involved in various activities and keep them aloof and isolated in cases of jealousy. You love to court a lot and believe that love lies in the air. You are always devoted to your love of life and are tactful enough to play tricks in love.


text: Singleton Broadcaster in Angular2 05 January 2017 naspinski A simple way to subscribe and/or broadcast from anywhere in an app to anywhere else. Basically, I needed a simple way to send out global messages not knowing what components would be loaded and didn't want to deal with injecting this anywhere in older components. With a little messing around with some online guides (sorry I don't remember which ones) I came up with the following: broadcast.service.ts import { Injectable } from "@angular/core"; import { Subject } from "rxjs/Subject"; @Injectable() export class BroadcastService { static instance: BroadcastService; static isCreating: Boolean = false; private broadcastMessageSource = new Subject<string>(); broadcastMessage$ = this.broadcastMessageSource.asObservable(); constructor() { if (!BroadcastService.isCreating) { throw new Error("You can't call new in Singleton instances"); } } static getInstance() { if (BroadcastService.instance == null) { BroadcastService.isCreating = true; BroadcastService.instance = new BroadcastService(); BroadcastService.isCreating = false; } return BroadcastService.instance; } broadcastMessage(modal: string) { this.broadcastMessageSource.next(modal); } } Then simply make sure to import it where you need it, and send out a broadcast: BroadcastService.getInstance().broadcastMessage('message-i-care-about'); Where you need to, subscribe in the constructor (or ngOnInit): BroadcastService.getInstance().broadcastMessage$.subscribe(this.receiveBroadcastMessage.bind(this)); And deal with the broadcast however you will: receiveBroadcastMessage(broadcast: string): void { console.log('broadcast received: ' + broadcast); // I generally run it through a switch to see if its something this component cares about switch (broadcast) { case 'message-i-care-about': doSomething(); break; } // or just ignore it } There you go, just sent and received a global broadcast message.


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The Secret
Jason Shawn Alexander is a painter and draftsman from Tennessee. He lives and works in Los Angeles, California. He makes horror paintings, and has also done comic book art. He has produced illustrations and comics for Dark Horse Comics ('Abe Sapien', 'The Escapists', 'Damnation'), Warner Brothers, DC Comics ('Gotham Central'), Hasbro, White Wolf Inc, Dynamite Entertainment ('Dead Irons') and Dalmatian Press.
Abe Sapien
His creator-owned 'Empty Zone' was published by Sirius Entertainment. He also contributed to Sirius's 'Poison Elves: Lusiphur and Linlith'.


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John 18:12-27 New International Version (NIV)
12 Then the detachment of soldiers with its commander and the Jewish officials arrested Jesus. They bound him 13 and brought him first to Annas, who was the father-in-law of Caiaphas, the high priest that year. 14 Caiaphas was the one who had advised the Jewish leaders that it would be good if one man died for the people.
Peter's First Denial
15 Simon Peter and another disciple were following Jesus. Because this disciple was known to the high priest, he went with Jesus into the high priest's courtyard, 16 but Peter had to wait outside at the door. The other disciple, who was known to the high priest, came back, spoke to the servant girl on duty there and brought Peter in.
17 "You aren't one of this man's disciples too, are you?" she asked Peter.
He replied, "I am not."
18 It was cold, and the servants and officials stood around a fire they had made to keep warm. Peter also was standing with them, warming himself.
The High Priest Questions Jesus
19 Meanwhile, the high priest questioned Jesus about his disciples and his teaching.
20 "I have spoken openly to the world," Jesus replied. "I always taught in synagogues or at the temple, where all the Jews come together. I said nothing in secret. 21 Why question me? Ask those who heard me. Surely they know what I said."
22 When Jesus said this, one of the officials nearby slapped him in the face. "Is this the way you answer the high priest?" he demanded.
23 "If I said something wrong," Jesus replied, "testify as to what is wrong. But if I spoke the truth, why did you strike me?" 24 Then Annas sent him bound to Caiaphas the high priest.
Peter's Second and Third Denials
25 Meanwhile, Simon Peter was still standing there warming himself. So they asked him, "You aren't one of his disciples too, are you?"
He denied it, saying, "I am not."
26 One of the high priest's servants, a relative of the man whose ear Peter had cut off, challenged him, "Didn't I see you with him in the garden?" 27 Again Peter denied it, and at that moment a rooster began to crow.
Cross references:
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I Love innovative design, graphics, art & crafts and I'm a novelist who likes to create story telling graphics.
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How to Become a Firefighter
What does it take to be a City of Lake Oswego Firefighter/Paramedic?
Check here for current job openings.
The City of Lake Oswego recruits highly trained and motivated people with exceptional customer service skills who are interested in becoming Firefighter/Paramedics. The Firefighter/Paramedic position is responsible for the protection of life and property through the suppression and prevention of fires, and response to medical and other emergency calls.
Candidates must meet several requirements to apply for a position within the fire department. At minimum, candidates must be 18 years old, EMT Paramedic with firefighting experience and have a valid state driver's license. In addition to the minimum requirements the most desirable candidates would have the following abilities:
• Ability to learn firefighting tactics and EMS techniques
• Ability to operate and maintain firefighting equipment
• Ability to deal with injured patients, including fatalities
• Ability to understand and follow oral & written communications
• Ability to communicate effectively with co-workers, supervisors, citizens and other customers
• Ability to read, write and use a computer for basic functions
• Ability to make public presentations
• Ability to keep records & make reports
• Ability to recognize fire code violations
• Ability to do strenuous physical activity for extended periods of time
• Ability to act calmly & effectively in emergency situations
• Ability to maintain harmonious relationships with others in a group-living environment
Applicants who meet the minimum qualifications are invited to take a written test. This test may cover basic firefighting knowledge, reading, writing, math, and communication skills.
Top scoring candidates will move on to the Physical Agility, Skills Evaluation, and Oral Interview portion of the testing process.
• Physical Agility test is an obstacle course that is conducted while applicants wear firefighting turnouts and an SCBA. The course consists of a tower climb carrying a hose bundle, hand over hand hoist of a hose roll to the 4th floor, use a 11.5 lb sledge hammer to drive a weighted sled 6 feet, pull a charged 1 ¾" hose line 100 ft, then drag a 140lb dummy 100'. This is a pass fail evaluation. The evolution must be done safely within 6 minutes to pass.
• Skills evaluation is a scored component of the test process. Candidates will be asked to perform a variety of fire ground skills utilizing provided equipment. This is an opportunity for candidates to display their fire ground skills. Tasks may include deploying hose lines, raising ladders, taking hydrants, and utilizing tools carried on a fire engine.
• Oral Interview is a scored component of the test process. Candidates will sit before a panel of 3 to 6 evaluators. They are asked questions that will allow evaluators to score them based on their past experiences, presentation skills, ability to work with others, ability to work under stressful situations, and ability to communicate.
The top scoring candidates will move on to a Chiefs interview. This is where the Fire Chief will make a hiring decision after personally interviewing each top scoring candidate.
The job offer is contingent upon successful completion of a background investigation and medical evaluations which will include drug and psychological testing.
The City is an Equal Opportunity and Affirmative Action Employer. Minorities, women and qualified individuals with disabilities are strongly encouraged to apply. If you wish modification of the selection process in order to accommodate a disability, please make your request in writing and submit it with your required application materials before the application deadline.


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|New Castle, Del.
|High School:
|William Penn
2012 Outdoor: Led off for the America East champion 4x100m relay team... Also led off for the 4x100 and 4x200 relays teams which broke the respective school records... Placed fifth in the 100m dash and eight in the 200m dash at the America East Outdoor Championships... Finished 14th in the long jump at the conference meet at Maine.
2011-12 Indoor: Helped the 4x200m relay team break the school record with a time of 1:41.38... Finished fifth in the 60m dash and eighth in the 200m dash at the America East Indoor Championships... Also placed eighth in the long jump at the conference meet... Ran a season-best 60m dash time of 7.74 at the Lafayette/Rider Winter Games.
Background: Competed in track and field at William Penn High School... Part of the 4x100m relay team that won the state championship.
Personal: Daughter of Trina and Ronald Jones, Jr. ... Has one brother, Ronald... Majoring in Biochemistry... Born Nov. 1, 1992.


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Exclusive Ferrari store in Singapore's Marina Bay Sands Resort
Singapore, September 23rd – The Ferrari Store of Singapore celebrates today its grand opening with a ceremony attended by Mr. Enrico Galliera, Ferrari Commercial & Marketing Director, Mr. Massimiliano Ferrari, Licensing and Retail Director, Mr. Edwin Fenech Ferrari APAC, Middle East and Africa CEO, and Mr. Teo Hock Seng, Managing Director of Ital Auto Pte who welcomed the guests together with the Scuderia Ferrari driver Felipe Massa.
The 170 square meters space is situated on one level in the spectacular 'triple towers' of the Marina Bay Sands Resort. Visitors will discover a wide range of lifestyle and luxury Ferrari products, together with a selection of items dedicated to Ferrari enthusiasts, children and collectors. These include miniatures and models of cars from past and present, a display case showcasing a crankshaft, valves and a piston, and the Cavallino collection of leather accessories and sportswear.
The design of the Ferrari Store Singapore reflects the Ferrari Atelier ambience of the main Ferrari showroom in Leng Kee Road, with furnishings of the highest quality and the combination of soft leather and sleek brushed lacquer. The display concept clearly evokes the dynamic lines of Ferrari's legendary cars and characterises the story, tradition and spirit of Ferrari not only through the products on display, but also through finishes and materials that typify the two souls of luxury and racing.
The Singapore Ferrari Store will be managed by ItalAuto, which is also the official importer for the Prancing Horse in Singapore. This is the 38th store to open worldwide and it joins prestige Ferrari retail locations around the world, including those in Milan, Rome and Venice (Italy), London (UK), Barcelona (Spain), Athens (Greece), New York (USA), and Dubai (UAE), to name a few. The Ferrari Store development programme includes plans to reach the objective of 60 locations worldwide over the next two years in Europe, America, and the Middle and Far East.


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Collection Description
The Detainee Allies Letter Collection (previously Otay Mesa Detention Center Detainee Letters) documents the hidden stories of hundreds of refugees from human rights hot spots around the world--including Honduras, El Salvador, Venezuela, Brazil, Cameroon, Eritrea and China. The letters are from detainees held at various detention centers under the authority of the U.S. Immigration and Customs Enforcement Agency (ICE). These letters provide insight into the lives of asylum seekers and migrants both before and during detention. Identifying information has been redacted to protect the privacy and safety of the writers. Letters date from July 2018 to present.
If you would like to help the effort please fill out our Volunteer form.


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Home -> Browse Galleries -> Industrial
Spectra Energy Fort Nelson North Processing Facility
View as slideshow Gear notes Guestbook Gallery map
68 photos found in the category 'All' . sorting: 'publish order/descending order'. This gallery has 68 photos in total. Gallery was launched 2012-05-22. Combined page views in this gallery is 1137762. Easy link to this gallery is http://www.dlpgraphics.ca/gallery_ee2/list.php?exhibition=125. Photo gallery code generated by Exhibit Engine 2.04. All rights reserved. All unauthorized usage forbidden.


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WS-Messenger (WSMG)
IU WS-Notification & WS-Eventing Implementation
WS-Messenger is an implementation of latest WS-Notification and WS-Eventing. It is developed by Extreme Lab at Indiana University. It is based on the latest version of WS-Notification specification (3/5/2004) and WSRF specification (1/20/2004) and WS-Eventing specification (8/2004). The Web service interfaces are developed using XSUL toolkit developed at Indiana University.
WS-Messenger supports both WS-Notification and WS-Eventing. The message format can be automatically converted between the two specifications. The subscription request type (Ws-Notification or WS-Eventing) for a listener determines the message format that the notification consumer will receive. If WS-Notification subscription request is received by the broker, it will send WS-Notification messages to the listener. Similarly, if WS-Eventing subscription is received by the broker, the broker will produce WS-Eventing messages for that listener. The publisher can publish messages in any format. It makes no difference to the notification consumers.
The Web service interfaces have been tested in "WS-ResourceFramework and WS-Notification Interop Workshop" in April 2004 and the result shows that they can interop with other providers successfully.
WS-Messenger provides basic Publish/Subscribe functions specified by WS-Notification and WS-Eventing. More features are under development.
The implementation is open source with Extreme Lab license. It can be downloaded at here. (Version 1.76.2, 5/7/2007)
Earlier versions are available here.
Maven repository is here.
User Guide is available at here.
API Guide is available here.
WS-Messenger also provides some GUI tools to help you monitoring the broker, debugging and manage the subscription.
WS-Eventing Listener GUI is useful for monitoring the event traffic and debugging in the distributed systems. This GUI can listen to the events sent by the broker.
You can download the executable jar file from here. Then double click it to run it. You can also run it using this command:
java -jar WseViewer.jar
The notification listener GUI is a notification consumer. It waits for notifications to arrive at the port specified by the "port" you set in the GUI. When you click the "Start" button, it subscribes to the broker and starts the listener. When you click the "Stop" button, it will stop the listener and unsubscribe. You can click "Clear Messages" button to clear the messages in the text area.
If you are behind a firewall, you can select "MsgBox URL"
to specify a message box location. The message viewer will periodically "pull"
messages from a message box. The default value "rainier.extreme.indiana.edu:13333/MsgBox"
is a message box running at our Extreme lab (It may not be running all the time.
Let me know if you need it). You can create your own message box using our WS-MsgBox.
It needs to be running in a server that is outside of the firewall or can open
a listening port that can receive messages from the notification server.
Brief Messages View
Whole message view (click for larger view)
You can manage your subscription through the Administration web page (http://rainier.extreme.indiana.edu:16666/nmi/wsnt/subscriptionmanager). You can view all subscriptions and delete subscriptions. You just need to enter your broker URL and click "Check Subscription" button.
Document for LEAD project is available here. It has information specific to LEAD project.
Y. Huang, A. Slominski, C. Herath, and D. Gannon, " WS-Messenger: A Web Services based Messaging System for Service-Oriented Grid Computing ," 6th IEEE International Symposium on Cluster Computing and the Grid (CCGrid06).
Y. Huang and D. Gannon, "A Comparative Study of Web Services-based Event Notification Specifications," Proc. of Workshop on Web Services-based Grid Applications (WSGA), 2006.
Y. Huang and D. Gannon, "A Flexible and Efficient Approach to Reconcile Different Web Services-based Event Notification Specifications," International Conference on Web Services (ICWS), 2006
B. Plale, D. Gannon, Y. Huang, G. Kandaswamy, S. L. Pallickara, and A. Slominski, "Cooperating Services for Data-Driven Computational Experimentation " Computing in Science & Engineering, vol. 7, 2005.
D. Gannon, B. Plale, M. Christie, L. Fang, Y. Huang, S. Jensen, G. Kandaswamy, S. Marru, S. L. Pallickara, S. Shirasuna, Y. Simmhan, A. Slominski, and Y. Sun, "Service Oriented Architectures for Science Gateways on Grid Systems," International Conference on Service Oriented Computing (ICSOC 2005), 2005.
G. Kandaswamy, L. Fang, Y. Huang, S. Shirasuna, S. Marru, and D. Gannon, "Building web services for scientific grid applications," IBM Journal of Research and Development, vol. 50, 2006.
Please contact Yi Huang (yihuan AT cs.indiana.edu), Aleksander Slominski (aslom AT cs.indiana.edu) and Chathura Herath (cherath AT cs.indiana.edu) for any problems or questions.
Created: 5/4/2004
Updated: 10/12/04
Updated: 1/15/2005, 1/18/2005,4/14/2005, 9/20/2005,10/11/2005, 3/3/2006, 10/27/2006


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Homemade with Love Card
Learn how to make this card using these free instructions. Handmade cards are the perfect way to show you care, and with these card-making steps, creating this design is easy.
SUPPLIES: Cardstock: (white) Hobby Lobby Patterned paper: (Princess Pintuck from Lost & Found Two collection) My Mind's Eye; (Travel Skirt from On Holiday collection) The Girls' Paperie Digital element: (mom circle from Mom's Kitchen kit Amanda McGee/happytocreate.com Fibers: (blue twill) Hobby Lobby Tool: (decorative-edge scissors) Fiskars Other: (measuring spoon) Finished size: 5" square
1 Make card from cardstock.
2 Adhere patterned paper square to card.
3 Trim cardstock rectangle with decorative-edge scissors.
4 Adhere panel behind patterned paper rectangle and adhere to card.
5 Print mom circle on cardstock, trim with decorative-edge scissors, and adhere to card with foam tape.
6 Tie twill to measuring spoon and adhere.
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