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Specialized perfusion protocol for whole-body hyperthermia
A method for extracorporeal blood heating to effect whole body hyperthermia, which utilizes a hemodialyzer with a sorbent suspension in the dialysate, a blood pump and a heat exchanger--in addition to various probes and catheters and heated anterior and posterior blankets for the patient--to effect extracorporeal treatment without adverse effect on blood physiology and without the need for general anesthesia. Blood returning to the body is heated to at least about 46.degree. C. Incorporation of hemodialysis into the blood heating treatment solves at once several problems which plagued prior art hyperthermia techniques: it rectifies any imbalances of sodium, potassium, magnesium, bicarbonate or phosphate, and may remove toxins incident to necrosis of tumors and virally infected cells. Hyperthermia protocols with sorbent--based dialysis of blood thus avoid the various serious side effects which complicated--even to the point of death--the hyperthermia treatments known from the past.
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The present invention relates to a specialized method for whole-body hyperthermia, including extracorporeal blood heating and dialysis, as an antiviral protocol.BACKGROUND OF THE INVENTION
Hyperthermia as a treatment of tumors has been carefully studied and applied since the 1960's. Prior to that period there were multiple reports of tumor regression coincident with episodes of fever. Biochemical analysis of the effects of hyperthermia has indicated that temperatures greater than 41.degree. C. generally are needed to induce tumor necrosis (tumor death). Although there are multiple methods of inducing hyperthermia including paraffin wax baths, a heat chamber and a water blanket, many physicians now favor an extracorporeal heat exchange (blood) circuit when whole body heating is the goal. Patients may be maintained at 41.5.degree. to 42.degree. C. (core body temperature) for three to four hours without severe compromise of cardiovascular function, although some physicians have reported elevation of serum transaminases and bilirubin in patients kept at these temperatures for greater than 10 to 40 minutes. Instances of neurologic damage have been reported in association with serum hypophosphatemia, although no significant problems occurred once phosphate levels were maintained. Deaths have also been reported in two patients receiving hyperthermia at 41.5.degree. to 42.degree. C. for 11/2 to 2 hours, presumably from massive tumor necrosis, particularly in the liver.
DeMoss, J. L. et al., "Hyperthermia in the Treatment of Cancer," The Journal of Extra-Corporeal Technology, Vol. 17, No. 1, pp. 37-43, 1985, explains how tumors are vulnerable to externally applied heat and that the goal of hyperthermic treatment therapy is to achieve cytotoxic temperatures in the tumor for a sufficient length of time without damaging the surrounding normal tissue. The rate at which blood flows through any given area of tissue determines the amount of heat that may be carried away and therefore is a major determinant of the temperature rise in that tissue. In normal tissue, heat causes vasodilation. In a tumor, the microvasculature is made up of an overabundance of capillary beds which are unable to dilate. Blood flow through the area is thus more sluggish and commensurately unable to dissipate heat applied to the area. The inability to respond to heat by dilation, as normal vasculature would, also subjects the tumor to hypoxia, anaerobic metabolism and local acidosis; these conditions in turn make the tumor tissue more vulnerable to thermal injury. Conversely, when extracorporeal heating is used to create hyperthermia, the inability of tumor vasculature to constrict results in higher temperature and more cellular damage.
Other literature addressing the utility of hyperthermia in the treatment of malignancy includes: Sanchez, R., "Overview of Whole Body Hyperthermia Experience at American International Hospital," Consensus on Hyperthermia for the1990's, Plenum Press, New York, pp. 203-208 (1990); Levin, R. D. et al., "Whole Body Hyperthermia Experience in Breast Cancer at American International Hospital, " Consensus on Hyperthermia for the 19905, Plenum Press, New York, pp. 387-391 (1990); Perez, C. A. et al., "Randomized Phase III Study Comparing Irradiation and Hyperthermia with Irradiation Alone in Superficial Measurable Tumors," Am. J. Clin. Oncol., Vol. 14, no. 2, pp. 133-141 (1991); and others.
Patents relating to methods for the extracorporeal treatment of blood for cancers, viruses and parasites include U.S. Pat. Nos. 2,886,771 to Vincent, 3,482,575 to Claff, 4,061,141 to Hyden, 4,191,182 to Popovich, 4,321,918 to Clark, 4,322,275 to Jain, 4,381,004 to Babb, 4,479,798 to Parks, 4,540,401 to Marten, 4,563,170 to Aigner, 4,576,143 to Clark and 4,692,138 to Troutner et al.
There were two reasons for exploring the use of hyperthermia as a treatment for viral-associated neoplasms when such work began a few years ago. First, hyperthermia was known to have caused tumor regression in both animal and in human sarcomas. Studies on the biochemical and physiologic effects of hyperthermia had shown that damage to microvasculature is important for tissue necrosis associated with heat. Second, the human lymphadenopathy associated virus was known to be heat-sensitive. McDougal et al. incubated lymphadenopathy associated virus at temperatures ranging from 37.degree. to 60.degree. C. and found the log kill followed first order kinetics. Thermal inactivation was decreased when the virus was in the lyophilized state compared to the liquid state (10 fold loss in LD50 121 seconds at 56.degree. C. for virus in media versus 32 minutes in lyophilized state). It was also found that lymphadenopathy virus was 40% inactivated after 30 minutes in a 42.degree. C. waterbath, and 100% inactivated after the same time period at 56.degree. C. Thus, hyperthermia can benefit patients suffering from viral infections in two ways. First, the hyperthermia kills malignant cells in the viral-associated neoplasms. Second, the hyperthermia directly inactivates the viruses themselves by denaturing them.
Studies have previously been completed in which whole body hyperthermia, achieved via extracorporeal heating of blood, was used to treat Kaposi's Sarcoma associated with human immunodeficiency virus infection. While evaluation of the therapeutic effects of such treatment on Kaposi's sarcoma was the primary purpose of these studies, the simultaneous effects on HIV disease were evaluated by studying immunologic and virologic parameters of HIV infection.
The use of hyperthermia in acquired immunodeficiency syndrome patients with Kaposi's Sarcoma has received considerable public and media attention. After treatment of the first two patients upon whom this procedure was performed, the treating physicians requested that the National Institute of Allergy and Infectious Diseases (NIAID) evaluate the study techniques, results and patients.
As reported in O'Malley, S., "Hyperthermia: Perfusion's Answer . . . ?", Perfusion Life, January 1991, pp 6-13, a patient named Carl Crawford experienced a dramatic recovery from head-to-toe skin cancers after being treated with extracorporeal blood heating. (This case study was published in Logan, W. D. et al., "Case Report: Total Body Hyperthermia in the Treatment of Kaposi's Sarcoma . . . ," Med. Oncol. & Tumor Pharmacother., vol. 8, no. 1, pp. 45-47 (1991).) Mr. Crawford had been diagnosed as having Kaposi's Sarcoma incident to human immunodeficiency virus infection, and had been told he had only two to four weeks left to live. Mr. Crawford was the first patient whose blood was heated to create a core temperature of 42.degree. degrees C. which, the doctors said, killed the cells infected with human immunodeficiency virus. Although NIAID discounted Mr. Crawford's recovery due to an alleged error in diagnosis--NIAID maintained that Mr. Crawford never had Kaposi's Sarcoma but had cat--scratch fever instead--several other doctors besides the treating physicians had diagnosed Mr. Crawford's skin lesions as Kaposi's Sarcoma. Growing numbers of physicians are convinced that hyperthermia provides a proven antiviral protocol. For example, Dr. Robert S. Jenkins, Medical Director of the Immuno Suppressed Unit at Hollywood Community Hospital, believes that the hyperthermia was responsible for curing Mr. Crawford's Kaposi's Sarcoma lesions.
In a completely separate effort, Dr. Shawn Hankins, a chiropractor in Port Angeles, Wash., has supported hyperthermia treatments since July, 1987 (as explained in the Acquired Immunodeficiency Syndrome Treatment News, Issue No. 104, Jun. 1, 1990, page 2). (He points out that human immunodeficiency virus is heat-sensitive and, in addition, hyperthermia can cause increased T-cell proliferation, phagocytosis, and increased production of antibodies and interferon. Observations of phenomenon such as the "honeymoon effect" that sometimes follows pneumocystitis (which causes a high fever) also support this conclusion.)
Other publications directed generally toward the treating of human immunodeficiency virus with heat include: Weatherburn, H., "Hyperthermia . . . ," The British Journal of Radiology, Vol. 61, no. 729, pp. 863-864 (1988); Yatvin, M. B.,"An Approach . . . Using Hyperthermia and Membrane Modification," Medical Hypotheses, Vol 27, pp. 163-165(1988); and U.S. Pat. No. 4,950,225 to Davidner et al., "Method for Extracorporeal Blood Shear Treatment."
The latter, Davidner et al., discusses the extracorporeal treatment of the blood of a human immunodeficiency virus patient with a) hyperthermia; b) mechanical shear and/or c) irradiation. When hyperthermia is used, the blood is heated to between 41.0.degree. and 42.5.degree. C. (or somewhat higher), and pH is adjusted by adding sodium bicarbonate intravenously when necessary. Blood is held under low flow or static conditions, extracorporeally, so that the blood treatment or treatments are (assertedly) maximally successful in ineffectuating the human immunodeficiency virus.
Among the known protocols for extracorporeal heating of blood, various difficulties persist, including (as outlined above) elevated serum transaminases and bilirubin, instances of neurologic damage associated with serum hypophosphatemia, risk due to abnormal pH or to abnormal sodium, sodium bicarbonate or potassium levels, and possible death from massive tumor necrosis. A need therefore remains for a more reliable, simpler and more comprehensive extracorporeal hyperthermia treatment method in which unwanted side effects are reduced or eliminated altogether.SUMMARY OF THE INVENTION
The present invention is a method for extracorporeal blood heating to effect whole body hyperthermia, which utilizes a hemodialyzer with sorbent suspension in dialysate, a blood pump and a heat exchanger--in addition to various probes and catheters and heated anterior and posterior blankets for the patient--to effect extracorporeal treatment without adverse effect on blood physiology and without the need for general anesthesia. Blood returning to the body is heated to about 46.degree. C. Incorporation of hemodialysis into the blood heating treatment solves at once several problems which plagued prior art hyperthermia protocols: it rectifies any imbalances of sodium, potassium, magnesium, bicarbonate, or phosphate, and may remove toxins incident to necrosis of tumors and virally infected cells. Hyperthermia protocols with sorbent-based dialysis of blood avoid the various serious side effects which complicated--sometimes even to the point of death--the hyperthermia treatments known from the past.BRIEF DESCRIPTION OF THE FIGURE
FIG. 1 is a schematic illustration of a combination of devices used to effect a preferred embodiment of the present hyperthermia technique.DETAILED DESCRIPTION OF THE INVENTION
The present invention is a method for extracorporeal blood treatment which utilizes a hemodialyzer, a blood pump, and a heat exchanger--in addition to various probes and catheters and heated anterior and posterior blankets for the patient--to effect extracorporeal treatment without adverse effect on blood physiology and without the need for general anesthesia. Incorporation of hemodialysis into the blood heating treatment rectifies any imbalances of sodium, potassium, bicarbonate, or phosphate, and removes any toxins incident to necrosis of any tumors or virally-infected cells.
The technique itself can be summarized as follows. After amnesiacs and analgesics or other sedation (typically not general anesthesia for the patient's sake) are given to the patient, an Impra double-lumen catheter (or smaller or larger arterial or venous catheters or equivalent structure(s)) is placed--by catheter placement techniques known in the art including local anesthesia--in the jugular, subclavian or femoral vein (whichever is most accessible for any given patient). Heparinization is effected only upon initial catheterization at a level of approximately 2.4 mg. per kilogram patient body weight. A heating-cooling mattress is positioned under the patient, and a heating-cooling blanket over the patient, to assist in effecting whole-body hyperthermia. A hemodialyzer is incorporated into the extracorporeal blood "Circuit"; the circuit also contains a blood pump, a heat exchanger and, most preferably, a primary blood heater, for rapid control of the patient's body temperature. When all these devices are used and when the blood returning to the patient is heated to at least about 46.degree. C., preferably about 48.degree. C., the desired core body temperature of about 42.degree. C. (41.degree.-42.5.degree. C., more preferably 41.5.degree.-42.degree. C.) is reached in about 40 to 50 minutes. This elevated body temperature is maintained for about 1 or 2 hours, and cooling is subsequently effected over a period of 20 to 40 minutes. During the procedure, the patient is monitored for pulmonary artery pressure, radial artery pressure and pulmonary artery and bladder temperature. After 1 or 2 hours, the patient is cooled to between 38.degree. and 39.degree. C. and extracorporeal blood circulation is ended.
According to one embodiment of the invention, after placement of the catheter, the blood flows through 1) a hemodialyzer; 2) a blood pump; 3) a tubular heat exchanger and 4) a stopcock for collecting and/or monitoring the extracorporeal blood, prior to return of circulation through the same catheter; and 5) associated other optional control structures including temperature and pressure sensors and air filters (which remove any air emboli which may be circulating in the system). The patient should rest on and be covered by heating/cooling mattresses/blankets to allow the practitioner to augment blood heating with direct body heating, to facilitate the raising of the core body temperature.
All of the above equipment is well-known in the art and only minor modifications are required prior to its use in the present process. The hemodialyzer should be modified to allow the temperature of the dialyzing fluid to be maintained at up to 48.degree. C., something hemodialyzers have previously not typically been designed to do. Notwithstanding this, however, modifying a hemodialyzer to provide controlled heat to the dialyzing fluid is a simple mechanical modification well within the ordinary skill of the art. The heat exchanger is included in the system to confer (or remove) additional heat beyond that provided by the heated dialyzing fluids. Heating/cooling blankets/mattresses and their associated equipment (an entire system of these devices is available, for instance, from Cincinnati Sub-Zero Products, Inc.) may be used minor modification permitting a higher upper temperature limit.
Because of the patient's natural depletion of carbohydrate and fat stores, these substances should be administered during and/or after treatment to assure that these precursors are adequately available to marginally competent metabolic pathways. Hemodialysis maintains levels of phosphate and calcium during treatment--which levels would otherwise fall as a result of the hyperthermia--especially when acid/bicarbonated water is used as the dialyzing solution. Maintenance of arterial oxygen tensions as high as possible during hyperthermia by use of 100% oxygen for ventilation should satisfy the need to maintain greater than normal blood and tissue oxygen tensions necessitated by hyperthermia-increased oxygen consumption.
Blood flew rates should be between about 300-750 ml per minute when human patients are treated with the present whole-body hyperthermia technique.
Prior to treatment, patients are screened for underlying heart disease; underlying lung disease (including pulmonary Kaposi's Sarcoma if one or more lesions is greater than a certain size); pregnancy; a Karnofsky score of less than 60%; a non-correctable hematocrit of less than 30 ml; hemoglobin less than 10%; active opportunistic infection; bleeding disorders; or Diabetes Mellitus. Any of the foregoing warrants careful consideration of the risks versus the benefits of hyperthermia treatment, since an important consideration in the practice of the present technique is whether the patient can tolerate it. The prehyperthermia evaluation requires a routine history and physical examination, routine laboratory studies, chest x-rays, urinalysis, electrocardiogram and pulmonary function studies. Special studies include P-24 antigen level assay; reverse transcriptase assay; human immunodeficiency virus cultures; lymphocyte quantitative analysis and thyroid profile.
The present improved hyperthermia technique has application in every indication for which hyperthermia was indicated in the past, namely, to combat neoplasms and viral infections. Human clinical studies have already shown that hyperthermia is effective to treat (not necessarily to cure) viral infections including the retroviral infections such as Hepatitis B and human immunodeficiency viruses. That hyperthermia is effective in all these applications has already been established; the present invention inheres in the improvements to the preexisting hyperthermia methods and the way in which the improvements avoid the side effects ubiquitous in the prior art.
Unlike previously known whole-body hyperthermia techniques, the present protocol is not conducted using general anesthesia per se but is instead conducted using sedation. The use of sedative amounts--as distinct from anesthetic amounts--of thiopental sodium is preferred. With the patient sedated, but not unresponsive, central nervous system activity can readily be monitored during hyperthermia treatment.
The use of hemodialyzers, as well as the underlying technology of their manufacture, is well-known and well established in the medical arts. The various acid- and bicarbonate-containing dialyzing solutions available are also well-known; typical commercially available dialyzing solutions are Centrisol (Cobe) or Renasol (Fresenius). Much of dialysis technology is itself well understood, and therefore is not being repeated here. For the purpose of the present invention, the incorporation of dialysis into the extracorporeal blood surface is intended to accomplish the same blood "clean-up" as ordinary dialysis of a renally compromised patient would remove toxins of kidney failure. The dialysis procedure during hyperthermia allows many important electrolytes to be regulated (sodium, potassium, phosphate, calcium, magnesium and pH are all kept at appropriate levels in the blood) and in addition any toxins incident to death of virally infected cells and Kaposi's Sarcoma cells are filtered out. One part of the present invention is in the realization that adding hemodialysis to extracorporeal hyperthermia could maintain more normal blood chemistries. The other part is the development of a sorbent suspension to automatically create the dialysate concentrations to counteract changes in blood chemistry.
Although hemodialysis generally encompasses all known methods of dialysing the blood, a particular type of hemodialysis is contemplated as most preferred: sorbent-based hemodialysis. This preferred form of hemodialysis is described further below and in the examples, particularly Example 2. U.S. Pat. No. 5,277,820 to Ash discloses a sorbent-based hemodialysis method and apparatus, and this patent is hereby incorporated herein by reference. This hemodialysis technology resides in the use of a specialized sorbent (a sorbent suspension) as the hemodialysing solution, and the use of all types of sorbent preparations as dialysates is contemplated as a part of the present invention.
The sorbent suspension generally includes powdered surface adsorptive agents, ion exchangers, physiologic electrolytes and macromolecular flow inducing agents. In general, these components are present in effective amounts to achieve the desired removal of substances from the electrolyte balance in the blood of the patient while maintaining the stability and fluidity of the sorbent suspension. The powdered surface adsorptive agent is usually activated charcoal, preferably with an average particle diameter not exceeding about 74 microns. Even more preferably, the average particle diameter does not exceed 50 microns. Macromolecular flow inducing agents such as glycol derivatives help to maintain the flow properties and stability of the particle suspensions.
The sorbent suspensions also may include ion-exchange substances to bind ions, such as ammonia, which may appear in the patient's blood. Many suitable ion exchangers including polystyrene sulfonate and zeolite are known in the art. The ion-exchanger is preferably a cation-exchange resin, which is desirably loaded with sodium, calcium, magnesium, and some hydrogen. For example, to date, sodium polystyrene sulfonate has been a preferred cation exchange resin.
The surface adsorptive agent, electrolytes, flow inducing agents and any other additives will usually comprise about 5% to 30% by weight of the sorbent suspension formulation as a whole, with the remainder being water. Typically, solid sorbents will comprise about 2% to 25% by weight of the suspension formulation, and electrolytes will comprise about 1% to 5% of the suspension formulation. Within these parameters, more preferred sorbent suspension formulations comprise about 2% to 20% powdered surface adsorptive agent, up to about 10% ion-exchanger, and up to about 1% flow agent such as a pluronic and/or polyvinylpyrrolidone (PVP).
There are many dialyzer membranes which are known for use in dialysing body fluids such as blood, and these membranes may be used with the sorbent suspension as though the sorbent suspension were a simple dialysis solution. One suitable membrane of this type is a cellulosic membrane composed of regenerated cuproammonium cellulose (Cuprophan.RTM.).
Sorbent suspensions as described above are advantageously used in a dialysis instrument including a parallel plate dialyzer, by moving the sorbent suspension formulation in a counter-current mode by the direct application of alternating negative pressure and positive pressure on the dialysate side. Back and forth movement of the membrane not only propels blood through the dialyzer but mixes sorbent suspension at the membrane surface.
The sorbent suspension works as follows. When blood opposes the sorbent suspension, separated only by the dialysis membrane, diffusion causes many chemicals to pass from the blood into the sorbent suspension on the other side of the membrane. Depending upon the binding characteristics of the sorbents, some chemicals remain at low concentration in the sorbent suspension (and are therefore efficiently removed from the blood) and others reach concentrations similar to the blood (and are therefore not removed from the blood). Inclusion of certain chemicals in the sorbent suspension composition can partially saturate sorbent binding sites or create precipitates which can return chemicals to the blood during treatment. Thus, the sorbent suspension may be tailored to remove very specific compounds from the blood, without removing others.
When the above-described sorbent suspensions are used in hyperthermia treatments, the following adaptations of the disclosure of U.S. Pat. No. 5,277,820 are typical. Although the same cation exchangers are used in sorbent-based hemodialysis without hyperthermia, the cation exchangers are generally heavily loaded with Ca, K and Mg ions at the start of hyperthermia (in an amount to be in equilibrium with the normal blood concentration of these cations). Also, for control of blood phosphate concentration during hyperthermic treatments, calcium phosphate is created on and around the charcoal in the sorbent suspension (the calcium and phosphorus concentrations in the blood are roughly equivalent to their levels when calcium phosphate is suspended in water and dissolves). Because of the calcium-phosphate solubility product, whenever blood phosphate levels fall, calcium phosphate dissolves and phosphate is released into the blood. Conversely, whenever blood calcium falls, the calcium phosphate dissolves and releases calcium, augmenting the return of calcium from the cation exchanger. Because changes in blood concentrations of calcium and phosphate are not likely to be quantitatively the same during hyperthermia, 10% calcium chloride solution is available, for infusion separately into blood returning to the patient as needed. The suspensions must be made carefully to assure that the calcium phosphate precipitate has maximal surface area for release or absorption of calcium or phosphate; forming the precipitate on the charcoal surfaces is one way to achieve this goal.
Also, when the above-described sorbent suspension dialyzer is used in conjunction with hyperthermia treatments, a blood pump must be added to the extracorporeal blood circuit in order to provide fast enough blood flow to effect the desired body heating in the time allotted. Fast blood flow is essential to the success of the hyperthermia treatment and its reversal. A blood pump is used to propel blood through a circuit containing a heat exchanger. In parallel to this circuit are inflow and outflow lines leading to the sorbent suspension dialysis system.
The membranes used for sorbent-based dialysis allow passage of all soluble chemicals under 5,000 molecular weight. The first function of hemodialysis with sorbent suspensions is to correct simple abnormalities in blood cationic electrolytes (known to vary during hyperthermic therapy) including sodium, potassium, calcium, magnesium and hydrogen (blood pH). This is achieved by loading the cation exchanger in the sorbent with sufficient cation amounts at equilibrium with the desired (normal) blood levels. If the blood concentration of a particular cation is lower than the equilibrium level, the cation will be released from the cation exchanger. If the blood concentration is above normal, the cation will be absorbed by the cation exchanger.
The cation exchanger of the sorbent suspension has some buffering effect to maintain normal blood pH. As a backup blood pH control, the pH of the sorbent suspension is monitored. If the sorbent pH becomes higher or lower than normal blood pH, an alarm sounds, and the user can direct the system to infuse acidic or basic solutions until the sorbent pH is the same as normal blood pH.
An exemplary sorbent suspension contains: 140 grams powdered activated charcoal; 22.1 grams Na.sub.2 HPO.sub.4 *7H.sub.2 O; and 3.0 grams CaCl.sub.2 *2H.sub.2 O (added together, to the charcoal suspension); 200 grams Amberlite IRP-69 cation exchange resin loaded with blood equilibrium levels of Na, Ca, Mg and K ions; 13.0 grams NaCl; 15.1 grams NaHCO.sub.3 ; and 1.5 grams of a glycol derivative and 1.5 grams of PVP to enhance stability and flow properties of the sorbent suspension. This is an example only, and is not intended to be limiting.
During hyperthermia, there may be other toxins which evolve, due to diminished kidney or liver function. The charcoal and cation exchangers in the sorbent suspension will remove many of these toxins, including: creatinine; aromatic amino acids; gamma-amino butyric acid; phenols; mercaptans; ammonium ion; nitric oxides; and various vasodilating hormones. Naturally, the sorbent suspension is not intended to remove proteins, intercellular messengers or cells, although to the degree that albumin-bound toxins can dissociate from albumin, these can also transfer across the membranes and be bound by the sorbents in the suspension.
Controlling plasma phosphate concentration is a little more complicated. In the body, calcium and phosphate concentrations are determined by their mathematical product. When the concentration of calcium in blood plasma goes up, calcium phosphate precipitates on bone and plasma phosphate level falls. Conversely, when plasma calcium concentration goes down, calcium phosphate is solubilized and plasma phosphate goes up. The present method invokes a system similar to the body's for phosphate concentration control, by creating a precipitate of calcium and phosphate on the large surface area of the charcoal (and in free suspension with the charcoal). When blood phosphate falls, the calcium phosphate dissolves to increase the free phosphate concentration in the sorbent suspension and transfer phosphate to the blood plasma. Conversely, if blood phosphate rises, phosphate can be removed from blood by precipitation of calcium phosphate in the sorbent suspension. The calcium-loaded cation exchanger moderates calcium concentration during these phosphate concentration changes. The sorbent suspension can be "tuned" to give more phosphate to all patients during treatment, by diminishing the amount of calcium added during the calcium phosphate precipitation step. Conversely, it can be "tuned" to give less phosphate to patients by adding more calcium in the calcium phosphate precipitation step.
When the subject matter of U.S. Pat. No. 5,277,820 is combined with the hyperthermia treatment described above, the main adaptations preferably include the addition of the blood pump discussed above and the use of various types of heating equipment to heat blankets over and underneath the patient, to heat the dialysate and directly to heat the blood through a heat exchanger. Most preferably, the sorbent suspension is maintained at 42.degree. C., not 48.degree. C., so that the blood tubing, dialyzer and sorbent suspension containers contact blood at modestly elevated temperature. The heat exchanger, final microfilter and the tubing returning blood to the patient will contact blood at a higher temperature (47.degree.-48.degree. C.), but these same components are used in open heart surgery to warm patients and safety of contact with blood of abnormal temperature has been thoroughly documented. It should be noted that this cautious approach was designed to expedite FDA approval, however, and that even when the sorbent suspension is heated to 48.degree. C., no toxic reactions have occurred anywhere in the hyperthermia system.
FIG. 1 illustrates all of the cooperating elements for achieving the sorbent-based hemodialysis contemplated as a part of the present invention. The patient 10 is positioned on or between hyperthermia sources 12, which may be a heated mattress, a heated mattress with heated air emitting blanket, or a similar heat-imparting patient chamber. A blood outflow catheter 14 connects the patient to extracorporeal blood circuit tubing 18. The tubing 18 transports blood from blood outflow catheter 14 to a pump/heater control 20, through a pressure gauge 26 and to tubing which leads both to and past a sorbent-based hemodialyzer 30. The pump/heater control 20 and the sorbent-based hemodialyzer 30 are connected by a heater power line 22 and a heater temperature feedback control line 24, whereas the pump/heater control 20 and the pressure gauge 26 are connected by a pressure gauge feedback line 27. A hemodialyzer bypass control valve 28 is provided on the tubing passing the inlet and outlet of the sorbent-based hemodialyzer 30 to normally allow some of the blood to bypass the hemodialyzer when open, or to pass all blood through the dialyzer when closed. After the blood has passed through or past the hemodialyzer, it enters a heat exchanger 34 where it is heated, by heated water generated from a hyperthermia unit 36 and carried through hyperthermia unit heater lines 38. The hyperthermia unit 36 also provides heat to the hyperthermia sources 12 via hyperthermia unit heater lines 38. After the blood is heated in heat exchanger 34, it passes through temperature gauge 32 and flows back to the patient 10 past a blood sample port 40. Air bubbles are removed from the blood in a drip chamber and micro bubble filter 42 located between sample port 40 and a blood return catheter 44. The blood outflow catheter 14 and blood return catheter 44 may be separate arterial and venous catheters or a single, double-lumen structure, both of which are well-known in the art. Regardless of how catheters 14 and 44 are configured, they are connected by a bypass control valve 16 to provide the option of immediate return of blood to the patient, should need arise, without the blood's travelling through the entire extracorporeal circuit. The pump/heater control 20 imparts some heat to the blood through heating the sorbent suspension but preferably does not raise the sorbent suspension temperatures above about 42.degree. C. In this way, heat loss from the blood is avoided when body core temperature increases to 42.degree. C.
Blood flow rates of 300-600 ml/minute are preferred, with a maximum blood flow rate of 800 ml/minute. "Roller pumps" or centrifugal pumps capable of achieving these blood flows are known in the art, and typically are the same pumps used for heart perfusion during so-called "open heart" surgery. Referring once again to FIG. 1, such a roller pump appears as the pump/heater control 20.
When the sorbent-based hemodialysis is used, the sorbents clear approximately 50% of the sedative from the bloodstream. Therefore, administration of approximately twice the dosage of sedative will give the same sedative effect as when standard dosage is used.
Besides the current ability to control a number of blood chemistry values, some modifications of the sorbent suspension could control other chemistries. If the sorbent suspension were loaded with a sedative such as thiopental sodium to be in equilibrium with a level causing sedation, then the blood level quickly rises to this concentration when the patient is placed on hyperthermia. Further sedation can be created by administering an injection of thiopental sodium to the blood; the pre-loaded sorbent suspension would not remove significant amounts of the drug. If any organic chemical were found to augment the effects of hyperthermia on HIV, it could be loaded into the sorbent suspension and delivered during treatment to maintain a reasonably constant blood concentration.
The invention may be further illustrated by means of the following examples.EXAMPLE 1 Animal Studies
A. Normal Calves
Tests were performed to determine the safety of WBHT. These animal experiments were performed with the apparatus depicted in FIG. 1, except that no heating blanket was employed. The sorbent temperature at 44.degree. C. during the treatments. Nine normal Holstein calves, average weight 70 kilograms, were sedated with Rompun to a level which caused a slow but regular respiratory rate. If respirations became slow and irregular, the animals were intubated and placed on mechanical ventilation (this was necessary in 3 animals). By dissection, 16 French cannulas were inserted in the carotid artery and vein, an intra-arterial temperature probe was placed through the carotid artery, and another temperature probe was placed in the esophagus. The treatment raised the core temperature to 42.degree. C. for 35.varies.55 minutes; the animals were then cooled to normal blood temperature. Blood chemical values and cellular counts were measured frequently during the treatment. After treatment, the catheters were removed, the incisions closed, and the animals allowed to awaken. The animals were observed for the next 30 days, and had blood tests drawn each week. No prophylactic antibiotics were administered to the animals.
All of the animals achieved 42.degree. C. core temperature, and all survived the hyperthermic procedure. None of these animals developed evidence of bleeding tendency or DIC. Slight increases in SGOT and SGPT occurred in all animals, and an increase in alkaline phosphatase occurred in six animals. Serum potassium increased slightly in a few animals, due to the fact that potassium was added to the calcium chloride in the replacement fluid. No calf died within 24 hours of the procedure. One died 14 days after the procedure, due to pneumonia (confirmed by autopsy). This complication might have been avoided if prophylactic antibiotics were administered. Another calf expired 28 hours after the treatment from pulmonary edema (confirmed by autopsy, with no other pathological changes noted in any organ). Each of these calves had been intubated and placed on a respirator during WBHT. Evaluation of the treatment of this calf led to the conclusion that if fluid replacement had been performed according to a protocol to maintain pulmonary wedge pressure or central venous pressure at normal levels, acidosis and hypotension would have been prevented, as well as the cardiac damage which eventually led to pulmonary edema.
These animal studies, performed with minimal cardiovascular monitoring, indicate that the treatment is generally safe, with all animals surviving the procedure and two late complications. Administering fluids according to the need, as indicated by Swan-Ganz catheter, careful antisepsis techniques during catheter placement, and administration of prophylactic antibiotics would have diminished the animal mortality of this study to zero.
An animal study was designed to closely monitor the chemical changes which occur during WBHT treatment. In this study a normal pig of 20 kg weight was treated in accordance with the general procedure in Example 1(A), with sorbent temperatures of 48.degree. C. to provide a more strenuous test for the equipment, blood and subjects. After sedation with Rompun, the pig was intubated and allowed to breathe naturally. Temperature monitors were placed in the esophagus, bladder, and rectum. By surgical cutdown, 8 French catheters were placed in femoral artery and femoral vein, and a Swan Ganz catheter placed in the pulmonary artery. The apparatus was attached to the femoral artery and vein catheters, blood flow was set at 450 ml/min, and within 30 minutes the core temperature of the animal reached 42.degree. C.
Blood sodium and potassium concentrations remained normal during the procedure. Blood calcium and magnesium concentrations remained normal during the procedure, while an abnormally elevated phosphorus level fell towards normal during the procedure. The results demonstrate that when the apparatus of the invention is used in WBHT, blood chemistries either remain normal or become more normal.
C. Simian Immunodeficiency Virus (SIV)-infected Rhesus Monkey
SIV is a retrovirus highly similar to HIV in its physical characteristics and in its effects on the body. To investigate the effect of WBHT on primates with this infection, an 8 kilogram Rhesus monkey infected with SIV was treated according to the general procedure of Example 1(A). The sorbent temperature was 48.degree. C.
The animal was anesthetized and intubated, and 8 French catheters were placed in the femoral artery and vein. A Swan-Ganz catheter was placed, and fluid management was according to the protocol for human treatments. The apparatus was attached to the femoral catheters, and blood treatment rate set at 200 ml/min (a high rate, considering the small size of the animal). Within one hour the core temperature of the monkey reached 42.degree. C. and this core temperature was maintained for one hour. Blood sodium and potassium concentrations remained normal during and after the treatment. Calcium and magnesium remained normal during and after the treatment, though phosphorous declined during the treatment (leveling out probably due to phosphate replacement from the sorbent). Blood pH was maintained at a normal value in spite of slightly falling pCO.sub.2 and HCO.sub.3 levels. Urine output remained relatively constant during the treatment, and increased after the treatment. There was an immediate drop in hematocrit at the start of the treatment (due to dilution of the blood volume by the extracorporeal circuit volume), but the hematocrit remained stable during the rest of the treatment.
Blood drawn before and after the treatment indicated no change in liver enzymes, creatinine, electrolytes or other laboratory values. There was a drop in albumin concentration and platelet count, partly accounted for by dilution of blood by the volume of the extracorporeal circuit, and by the huge surface area of the circuit relative to the animal's size.
The monkey survived the treatment and was returned to his cage shortly after the procedure, in good health. On the first day after treatment, the animal appeared in good health. On the second day after treatment, the animal was found in the cage without pulse or respiration, still warm. An autopsy was performed, which showed no macroscopic or microscopic pathology of any organ system, and no signs of significant internal bleeding (in spite of a drop in blood platelet concentration during the treatment). Dr. James Blanchard, director of the Tulane Primate Center, reviewed all data related to the case and stated in a letter that the death of the animal "was not related any side-effect of the treatment," even though it was not clear just what caused the death. Tissue samples were submitted for determination of viral load by the limiting dilution PCR test. Compared to titers determined on tissue just before the treatment, the viral load had diminished from a titer of 1:64 to 1:32. Though this change is not statistically significant, it is impressive, given the short time between treatment and measurement of the titer.EXAMPLE 2 Treatment of HIV-Infected Patients with KS
Two patients with HIV infection and Kaposi's Sarcoma were treated as follows. The treatments were performed in Santo Domingo, under approval of the Director of the Ministry of Health. Screening techniques were as follows. A pre-operative evaluation included: biopsy of any existing Kaposi's Sarcoma lesion; complete blood cell count; biochemical profile; electrolytes; antigen P24; reverse transcriptase assay; western blot; human immunodeficiency virus antibody; immunologlobin assay; lymphocyte fractions (including CD.sub.4); coagulation studies; spirometry; and echocardiogram. Patients were selected for treatment in this study if they were between the ages of 18 and 40, tested positive for the human immunodeficiency virus, had Kaposi's Sarcoma as a result of HIV, and had normal or at least 80% normal pulmonary, cardiac, renal and hepatic functions. (Patients were excluded from this study if they exhibited severe immunodepression, extensive Kaposi's lesions in vital organs, were at cardiac risk or had had radiation of the mediastinum or vital organs.)
The first patient was a 38 year old male having had known HIV infection for about four years. In 1989 he developed numerous nodular, red-violet colored lesions on both feet, the abdomen and the back. Biopsies in 1989 and 1993 confirmed the lesions to be Kaposi's Sarcoma. The leg lesions, which bothered the patient the most, had previously been irradiated many times, but had only partially responded. The largest lesion, on the dorsum of the right foot was quite painful and tender, and developed during 1993. Other symptoms of HIV included diarrhea and weight loss, though the patient's physical examination was normal and he appeared reasonably able to complete daily activities. He had not taken any medications for HIV infection, but had taken antibiotics intermittently.
Treatment was performed with the apparatus illustrated in FIG. 1, with a sorbent suspension temperature of 48.degree. C. Access was established using an ultrasound-guided needle under local anesthesia, and the following were positioned: a 7 French Swan-Ganz catheter through a femoral vein (and advanced into the pulmonary artery); an 18 gauge catheter in a femoral artery for arterial pressure monitoring; a 10 French catheter in a femoral artery; and a 10 French catheter in a femoral vein. Through a peripheral vein, 100 mg thiopental sodium was administered, and the procedure begun. The patient was given 4000 units of heparin at the start of the procedure, and 2 mg of dexamethasone, as planned. By blood clotting tests, the patient required one more injection of 2000 units of heparin during the treatment. Fluid replacement in the patient was effected according to the skill of the art, to keep the wedge pressure constant at its starting value; 3 liters of normal saline were administered total. A total of 700 mg thiopental sodium was administered during the procedure. Calcium chloride infusion to blood was made at the rate of 5 ml/hour.
Blood flow in the extracorporeal circuit was begun at a rate of 500 ml/minute, and was increased slowly to 600 ml/minute. The sorbent suspension contained 140 grams powdered activated charcoal; 22.1 rams Na.sub.2 HPO.sub.4 *7H.sub.2 O; 12.2 grams CaCl.sub.2 *2H.sub.2 O; 100 grams Amberlite IRP-69 cation exchange resin loaded with blood equilibrium levels of Na, Ca, Mg and K ions; 8.8 grams NaCl; 15.1 grams NaHCO.sub.3 ; and 3 grams of a glycol derivative to enhance stability and flow properties of the sorbent suspension, and its temperature remained stable at 48.degree. C. during the treatment (as did the water temperature), and the temperature of blood leaving the heat exchanger reached nearly 47.degree. C. When esophageal and rectal (core) temperature reached 42.degree. C., the water temperature was decreased from 48.degree. C., and the exiting blood temperature dropped to 45.degree. C. (while core temperature remained constant). It was pre-planned that the patient would be heated to a core temperature of 42.degree. C. for only a half hour's duration, so the cool-down period was begun at 90 minutes of treatment. The procedure ended 140 minutes after it had begun, and all catheters were removed (except the Foley catheter--left in place for post-procedure urine collection). Encyclopedic records of blood levels and organ functions were kept throughout the procedure.
The patient's antigen status by PCR changed 4 weeks post treatment, from positive to negative, indicating a decrease in viral load in body and blood. The morning after the procedure the patient stated he had no pain and was "filled with vigor" and felt great. Over the course of the first post-procedural week, the largest lesion, on the right foot, decreased 50% in size and by two weeks post treatment the lesion had only 25% of its original size and was much less tender and painful. It remained so at 8 weeks post procedure.
The second patient was a 28 year old patient who had become HIV positive about three years earlier. Beginning in December of 1992, he developed black to purplish lesions on his right arm, then on his left arm, then over his entire body including forearms, legs, chest, nose and face. Biopsy proved the lesions to be Kaposi's Sarcoma. Therapy in 1993 included radiation which only made the lesions look slightly less dark and did not change the size at all. Intra-lesion injections of cytotoxins made the lesions more solid. The patient had taken AZT but had quit, not perceiving any benefit. Though the patient exercised frequently and ate well, he had lost 25 pounds in the preceding year, dropping from 145 to 120 pounds.
Treatment was performed, again with a 48.degree. C. sorbent suspension temperature, according to the same protocol described for the first patient except with minor adjustments in dosages. Patient wellbeing improved according to the patient's comments post procedure, and the Kaposi's Sarcoma lesions faded. The patient gained 5 pounds and maintained this weight.
Although the invention has been described with particularity above, it is to be limited only insofar as is set forth in the accompanying claims.
1. A method for the extracorporeal heating of blood in a patient having veins and arteries for the flow of blood in which extracorporeal hyperthermia is indicated, comprising the steps of:
- creating an extracorporeal blood circuit;
- catheterizing one of said veins or said arteries;
- connecting said catheterizing vein or artery to said extracorporeal blood circuit, whereby blood flows from said vein or artery into said circuit;
- heating at least some of the blood in said extracorporeal blood circuit to a temperature of at least 46.degree. C. by a primary heating means;
- subjecting at least some of the blood in said extracorporeal blood circuit to hemodialysis; and returning said heated blood to the patient.
2. The method according to claim 1 wherein said heating step further comprises heating at least some of the blood in said extracorporeal blood circuit by elevating the temperature of a dialyzing solution used in the hemodialysis step.
3. The method according to claim 2 wherein said heating step further comprises heating at least some of the blood in said extracorporeal blood circuit by elevating the temperature of the blood directly with a heat exchanging means.
4. The method according to claim 1 wherein said heating step further comprises heating at least some of the blood in said extracorporeal blood circuit to raise the core temperature of the patient to approximately 41.5.degree.-42.degree. C.
5. The method according to claim 1 wherein said extracorporeal blood circuit includes a blood pump.
6. The method according to claim 5 wherein said blood pump is upstream of a means for effecting said hemodialysis, and including a supplemental heating means associated with said blood pump.
7. The method according to claim 6 wherein said hemodialysis is effected by means of a hemodialyzer containing at least one dialysis membrane and a sorbent suspension.
8. The method according to claim 7 wherein said heating step further includes heating the body of the patient with a heated mattress.
9. The method according to claim 8 wherein said heating step further includes heating the body of the patient with a heated blanket.
10. The method according to claim 9 wherein said extracorporeal blood circuit contains a heat exchanger downstream of said hemodialyzer.
11. A method for treating a neoplasm in a patient, comprising the steps of heating and dialyzing the blood of said patient, wherein the blood of the patient is heated for a period of time to at least 46.degree. C.
12. The method according to claim 11 wherein said heating effects whole body hyperthermia to a core body temperature of 41.5.degree.-42.degree. C.
13. The method according to claim 12 wherein said dialyzing is accomplished by means of sorbent suspension containing a water suspension of 140 grams powdered activated charcoal; 22.1 grams Na.sub.2 HPO.sub.4 *7H.sub.2 O; 12.2 grams CaCl.sub.2 *2H.sub.2 O; 100 grams cation exchange resin loaded with Na, Ca, Mg and K ions; 8.8 grams NaCl; 15.1 grams NaHCO.sub.3; and 3 grams of a glycol derivative.
14. A method for treating a viral infection in a patient, comprising the steps of heating and dialyzing the blood of said patient, wherein the blood of the patient is heated for a period of time to at least 46.degree. C.
15. The method according to claim 14 wherein said heating effects whole body hyperthermia to a core body temperature of 41.5.degree.-42.degree. C.
|3482575||December 1969||Claff et al.|
|4061141||December 6, 1977||Hyden et al.|
|4191182||March 4, 1980||Popovich et al.|
|4321918||March 30, 1982||Clark, II|
|4322275||March 30, 1982||Jain|
|4381004||April 26, 1983||Babb|
|4479798||October 30, 1984||Parks|
|4540401||September 10, 1985||Marten|
|4563170||January 7, 1986||Aigner|
|4576143||March 18, 1986||Clark, III|
|4692138||September 8, 1987||Troutner et al.|
|4787883||November 29, 1988||Kroyer|
|4808189||February 28, 1989||Wilson|
|4950225||August 21, 1990||Davidner et al.|
- DeMoss, J. L. et al., "Hyperthermia in the Treatment of Cancer", 1985, vol. 17, No. 1, pp. 37-43. Sanchez, R. et al., "Overview of Whole Body Hyperthermia Experience at American International Hospital", 1990, pp. 203-208. Levin, R. D. et al., "Whole Body Hyperthermia Experience in Breast Cancer at American International Hospital", 1990, pp. 387-391. Perez, C. A. et al., "Randomized Phase III Study Comparing Irradiation and Hyperthermia with Irradiation Alone in Superficial Measurable Tumors", Am J Clin Oncol (CCT) 14(2) 1991, pp. 133-141. O'Malley, S. "Hyperthermia: Perfusion's Answer to AIDS?", Jan. 1991, pp. 6-13. Logan, W. D. et al., "Case Report: Total Body Hyperthermia in the Treatment of Kaposi's Sarcoma in an HIV Positive Patient", 1990, pp. 45-47. James, J. S., "Hyperthermia Report: Only One Patient", AIDS Treatment News, Issue No. 104 Jun. 1, 1990, pp. 1-2. Yatvin, M. B., "An Approach to AIDS Therapy Using Hyperthermia and Membrane Modification", Medical Hypotheses (1988) 27, 1988, pp. 163-165.
Filed: Oct 4, 1994
Date of Patent: Dec 19, 1995
Assignee: IDT, Inc. (Pittsburgh, PA)
Inventors: Norman G. Keeling (McMurray, PA), Stephen R. Ash (Lafayette, IN), Robert B. Truitt (Lafayette, IN), Joseph A. Guzman (Atlanta, GA)
Primary Examiner: Sam Rimell
Law Firm: Webb Ziesenheim Bruening Logsdon Orkin & Hanson
Application Number: 8/318,132
International Classification: A61M 103;

domain: medical


Get your little one to stay cool and look trendy this summer, in the Coral Salad Button Down. Made with 100% chemical-free, organic cotton, he is goint to want to live in this shirt all summer long. The shirt features a Chinese collar with an interesting Miko Lolo twist. Don't forget to check out the hidden pocket at the waist!
- Printed on certified organic cotton
- Wooden buttons
- Made in India
- 2 yrs : Length 15" ; Chest 24.5”
- 3-4 yrs : Length 17" ; Chest 26.5”
- 5-6 yrs : Length 19" ; Chest 29”
- 7-8 yrs : Length 21" ; Chest 30.5”
The above measurements are those of the final garment with ease.
Color: Coral Print
Material: Organic Cotton Only
Wash Care: Hand wash gently, do not bleach, do not tumble, iron on medium, do not dry clean, handle with love


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- Warm your night stick in these Star studded long johns from Ginch Gonch's 'Be A Star' collection.
- When you're a rockin', they're a knockin'.
- Made with 4-way stretch cotton for extra comfort and perfect fit so you can be covered down below in style.
- 95% Cotton, 5% Lycra Spandex
- Slim fit long underwear
- Mid-rise waist
- 1.5'' logo waistband
- Semi-contoured fly pouch
- Black cotton body
95% Cotton, 5% Lycra® Spandex
Machine wash cold. Do not bleach.
- Individual brands may fit differently, so we recommend always reviewing the size chart before placing your final order!
Shipping & Returns:

domain: fashion


text:
Operation Valentine Movie Review and Rating
Movie Review: Operation Valentine
Director: Shakti Pratap Singh Hada
Producers: Sony Pictures International and Sandeep Mudda
Music Director: Mickey J Meyer
Starring: Varun Tej, Navdeep, Ruhani Sharma, Manushi Chhillar, Paresh Pahuja and others
Release Date: March 01, 2024
Operation Valentine Movie Review and Rating: Varun Tej, Navdeep, Ruhani Sharma, Manushi Chhillar, Paresh Pahuja and others starrer Operation Valentine helmed by Shakti Pratap Singh Hada, has hit the theaters on 1st March. Let’s see the story of Operation Valentine.
Story: Arjun Rudra (Varun Tej) is a Wing Commander in the Indian Air Force. Arjun works in the department that tests aircrafts that are ready for national defense. Rudra, who is fiery by nature, fails in ‘Operation Vajra’. Meanwhile, a terror attack occurs in Srinagar, and upon learning it’s the work of Pakistan, the IAF plans for a retaliation. What is the Indian Air Force’s fight in retaliation?, What is the plight of Wing Commander Arjun Rudra?, What is the role of another commander Aahna Gill (Manushi Chillar) who is Rudra’s wife in this whole war? To get these answers, one should watch Operation Valentine on the silver screen.
Aerial combat scenes
Weak Emotional Connect
Performance: Varun Tej acted very well in the role of Rudra. He tried to impress with his realistic acting in some space scenes. His performance is good especially in some emotional scenes in the first half. Manushi Chhillar who played the female lead in this movie also impressed with her performance. Mir Savar who played another key role was also impressive. Navdeep along with the rest of the lead actors did full justice to their roles.
Technical: Director Shakti Pratap Singh Hada made a good effort with his presentation but his narration is not completely engaging. He lags behind in writing a thrilling story. But, the scenes created by him in the background of space and the way he used VFX work are impressive. Mickey J Mayer’s music is good. Hari K. Vedantam’s cinematography is a special attraction of the movie. The production values by producers Sandeep Mudda and Sony Pictures are also very good. The cinematography by Hari K Vedantam is superb.
Analysis: Operation Valentine is a decent aerial action drama. The action scenes, emotional scenes and VFX work between the main point of the story and the flight are impressive in the movie. But the slow pace of the story and some key scenes without logic are the weak points of the movie.

domain: movie


Set-partitioned QAM Fast-OFDM with real-valued orthogonal circulant matrix transform pre-coding
No Thumbnail Available
Optical Society of America
We propose SP-QAM based Fast-OFDM with a novel real-valued OCT pre-coding scheme for IM/DD systems. For 19.76-Gbit/s 20-km transmission, the proposed scheme achieves 3.5-dB sensitivity improvement and higher filtering tolerance over conventional PAM Fast-OFDM.
Nonlinear optical fibers , Optical fibers , Orthogonal frequency division multiplexing , Quadrature amplitude modulation , Signal processing , Variable optical attenuators
Hu, Z., Zhao, J., Hong, Y., Gao, S., Chan, C.-K. and Chen, L.-K. (2018) ‘Set-partitioned QAM Fast-OFDM with real-valued orthogonal circulant matrix transform pre-coding’, Conference on Lasers and Electro-Optics (CLEO 2018), San Jose, California, United States, 13-18 May, JTu2A.41 (2pp). doi:10.1364/CLEO_AT.2018.JTu2A.41
© 2018, the Authors. Published by the Optical Society of America. All rights reserved.


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Rajinikanth’s cult film in December | Latest telugu cinema news
If there is any fashion-placing movie over the last many years, it is arguably superstar Rajinikanth starrer ‘Baasha’. This cult is being visible as a passport to Rajinikanth in reaching ‘celebrity’ photo. A tale of a don who turns ‘automobile driver’ remained as a conventional within the records books.
It’s miles now lower back inside the information! The film is presently getting remastered to have a re-release on celebrity’s upcoming birthday (66) i.e 12, December, 2016.
The Suresh Krishna directorial, which had a phenomenal run at box-office, is taken into consideration as a primary notion to among the scripts publish its launch. Having run for greater than a year in Tamil Nadu and Andhra Pradesh, ‘Baasha’ is a game changer for Thalaivar.
The remastered version will see the film getting greater and digitized in all elements such as sound and shade. Given Rajinikanth’s popularity throughout south India and country, no surprise if the film manages to keep the field-workplace numbers on a excessive.
News Rajinikanth’s cult film in December
After Kabali, the actor has worked on a sequel for his preceding blockbuster robot with Shankar. The unit lately finished the filming component and superstar nevertheless subsequent work below the manufacturer of son-in-law Dhanush.


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It's yet another birthday! Thank you Lord for giving me a Teacher, Father and mentor to teach me your word and lead me in the path which I must follow. Lord as I sorjoun in this earth, all I ask is the grace to grow and become more like Jesus everyday of my life.
I celebrate your labour of love, God bless you mightily. Happy birthday pastor sir

domain: christianity


text:
Basic Facts About Online Poker Tournaments
There is no doubt about the popularity of online poker games since it is played by thousands of people all over the world. The rules of online poker matches are similar to terrestrial poker games played in casinos. The main difference is that in online poker there is no personal interaction. To join online poker tournaments an individual must go to a casino website and enlist online for the game schedule. The buy-in price and the casino fee should first be settled prior to playing. The buy-in is incorporated to the prize while a small portion is kept by the casino.
The appropriate time and the kind of poker available for play can be checked at a specific time. All players get similar number of chips and play commences. The game goes several betting rounds controlled by the dealer. Some players consume their chips and steps out of the game. The person who lasts until the conclusion of the game becomes the winner and claims the prize. The splitting of the prize depends on the poker game played.
There are four divisions of tournaments namely sit-and -go, multi-table, free roll and satellite tournaments. Ten players can join in a sit-and-go tournament. Only one player wins and players battle each other at similar tables.
Nearly a thousand players enter multi-table tournaments. The winner in a certain table proceeds to the next table and the game goes on for many hours until only one winner emerges. Free-roll tournaments collect no-registration fees. They provide an opportunity for a person to win actual money free. Satellite tournaments are mini-tournaments wherein the winner qualifies for a place into any of World Series of Poker tournaments.
Re-buy tournaments allow players to buy additional chips before the commencement of the game. This may occur only up to a certain section in the tournament. A number of games have no restrictions on the cost of the wagers made, while pot-limit games restricts the highest bet from being higher than the pot money.
Online poker matches use buy-in which are higher than a few dollars, so everyone can enter.
Poker tournaments can have fixed betting or very flexible betting wherein the bet depends on the player. In fixed betting, the bet is restricted to the amount set by the casino. Likewise, the casino determines the winnings. Some tournaments only have one winner while in some winners split an equal amount of the pot money as determined by their hands.
It is convenient to join poker tournaments, but one must have a strategy in mind to emerge victorious. This is a probability when one picks a poker room where the games are quick. One should determine the budget so that there will be no overspending. Amateurs must play cautiously and practice deception while professionals can force the situation.
Poker tournaments provide all types of players an opportunity to earn enough cash and are worthwhile forms of fun and excitement for people for all ages. One needs to have patience and be wise enough to ponder on the moves of his opponent to remain in the game.

domain: gamble


text:
Roman remains of Arles
Caesar made Arles a Roman colony in 46 BC and it became the crossroads for trade between Italy, Spain and the Rhone, and consequently a ‘little Rome’. It grew quickly and was adorned with its own amphitheatre, a basilica, a circus, triumphal arches and temples. Its baths were as big as those in Rome. Over time much has been dismantled, but there still remains much to see today, and you can see everything for one price with a city pass - details are at the bottom of this page.
Most Roman buildings in Arles were dismantled for their stones, but the amphitheatre – Les Arènes – has largely survived. It would originally have been one arcade higher and marble-clad, and seated over 20,000 to enjoy the carnage of gladiator fights and other amusements. It is still very impressive with its 60 arches on each level, and today draws the crowds for (bull-friendly) bull-fighting from Easter to September.
The Théatre Antique, built in the reign of Augustus, was less fortunate and mostly dismantled in the 5th century – it would originally have been grander than the famous Roman theatre at Orange. Now only ghostly columns, some seats and the orchestra stand testimony to its former grandeur. Some statues and objects from the site are at the Musée Départementale Arles Antique (see below), but for the most famous piece, the Venus d’Arles, you would have to go to the Louvre in Paris.
The one aspect of Constantine’s palace in Arles that remains is the well-preserved baths (Thermes de Constantin or Constantine Baths). Only part of the baths are exposed but it is an interesting visit nonetheless and a World Heritage Site.
The Roman period takes pride of place at the Musée Départementale Arles Antique, with sculptures and mosaics, decorated sarcophagi, and some exceptional models showing how the city centre looked in Roman times.
The sarcophagi are from the Alyscamps, a burial site for prominent Romans superseded by medieval tombs. Just south of the centre of Arles, the Alyscamps is an atmospheric place with its tombs strewn about and at one end the St Honorat Priory, which is on the Santiago de Compostela pilgrimage route. Alyscamps is thought to be a corruption of Elisii campi, meaning Elysian Fields - in Roman mythology the last resting place of heroes.
Under the town hall (hotel de ville) is an unexpected treat from the Roman era - the cryptoportiques of Arles. If you are not into history or Rome, this will be just a long, rather dark, vaulted tunnel, offering welcome coolness on a hot day. But if you are intrigued by the past, this atmospheric and perfectly intact construction gives you the same experience a Roman would have had in the foundations of the main square. You can see the chisel marks in the stones. The cryptoportiques are accessed via the hotel de ville.
The best way to see the roman remains of Arles is with a city pass, available from the Arles tourism office, either in person or online.
There are two passes: Advantage Pass - gives you access to everything mentioned on this page plus the St Trophime cloister for 16 euros, a saving of 20.50 euros. Liberté Pass - access to 1 museum and 4 monuments of your choice, for 12 euros.

domain: history


text:
RB Leipzig, Timo Werner reunite once again
(MENAFN) RB Leipzig confirmed on Tuesday that German striker Timo Werner had made his come back to the Bundesliga team from English club Chelsea on a four-year deal.
Werner stated after the announcement ceremony that "I’m very happy to be able to play for RB Leipzig again. I had a great time here between 2016 and 2020, when we performed brilliantly as newcomers in the league."
"We want to achieve a lot and of course, I want to become the first Leipzig player to reach the 100-goal mark," he also expressed.
He contributed with Chelsea to achieve the 2020-21 UEFA Champions League title as well as the 2021-22 Super Cup title.
Werner, who is going to hold the No. 11 jersey, played games for RB Leipzig between 2016 and 2020 he got 95 goals under his name in 159 games, making him the Leipzig football club's record goal scorer.
The German who is 26 years old scored 24 goals in 53 games for the German national team as well.
MENAFN provides the information “as is” without warranty of any kind. We do not accept any responsibility or liability for the accuracy, content, images, videos, licenses, completeness, legality, or reliability of the information contained in this article. If you have any complaints or copyright issues related to this article, kindly contact the provider above.

domain: topicality


text:
Ryanair's Italian job would be game-changer
Ryanair boss Michael O'Leary often talked in the past about getting involved in long-haul travel.
But it was always with a couple of caveats: it would depend on buying long-haul jets at knock-down prices, and also that it would not be a business that would be directly operated by Ryanair.
Ryanair chairman David Bonderman flatly ruled out any chance that Ryanair would ever directly be involved in long-haul travel, because he insisted that the low-cost model perfected by Ryanair simply could not be effectively replicated when flying across the Atlantic. Aircraft utilisation wouldn't be high enough, he said, and no matter how cheap the fares, you couldn't typically stimulate someone to fly to New York for a weekend.
Norwegian has forged ahead with its low-cost long-haul model however, enabling no-frills travel across the Atlantic for a couple of hundred euro return if you catch the right deals.
But in its plans to buy Alitalia and keep its long-haul routes, Ryanair would indirectly take on the market. Conceivably, Ryanair jets could help funnel traffic to the Alitalia long-haul service - something Ryanair has been planning to do with other carriers including Norwegian and Aer Lingus.

domain: aerospace


Cotton twill jacket
Cotton twill shirt jacket. The shirt design and Sahariana jacket-inspired details, such as the accordion-style pockets, make this garment a summer must-have. The flowing garment can be worn with the tie fastening to accentuate the waist or without it for a straight fit. Unlined. Length: 68 cm.
97% cotton, 3% elastane.
Do not wash; do not bleach; do not tumble dry; cool iron; professionally dry clean perchloroethylene - mild process; do not wet clean. do not wash do not bleach do not tumble dry cool iron professionally dry clean perchloroethylene - mild process do not wet clean.
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Product code: 1041061206002 - RENON


text:
Elton John,not John Elton is an all-time music legend and has sold more than 300 million records in the course of his five-decade career.
He has also gained a lot of reputation as one of the world’s best live performers (Stop thinking of the King of Pop for a while here).
He constantly tours all over the world and plays in a multitude of concerts no wonder he has such a good reputation.
He has countless hit songs from “Daniel’ to “Am Still Standing”.
However, there is more to the man behind the piano than most people know.
Get ready for some shocking facts on this iconic singer.
1. He Changed His Name
His name is Reginald Dwight,but he changed the name to Elton John.
He chose this name to pay tribute to Long John Baldry a vocalist and Elton Dean,a saxophonist, and for the middle name, he chose Hercules.
2. The First Western Singer to Tour The Soviet Union
In 1979. Elton John toured the Soviet Union,and this was the first time a western pop artist visited Russia.
It was the first time that the Russians saw a rich westerner.
3. Gay and Doesn’t Give a Toss About it Either
He registered his civil partnership with David Furnish his long-term partner.
They later married in 2014 after the legalization of homosexual marriages in Wales earlier that year.
His wedding was attended by so many famous artists.
4. He Has Performed at a Free Concert Once
Not so many artists have what it takes to perform for free, but Elton is unique in his own way.
He was enthusiastic enough to perform a free concert on September 12, 1980, where he performed to more than 400,000 fans.
He performed on the Great Lawn in New York’s Central Park.
5. Outrageous Outfits
He has numerous outrageous stage outfits. He has dressed up as Donald Duck, Mozart, the Eiffel Tower, and the Statue of Liberty.
As if all this isn’t enough, he has also worn a baseball kit, a Watford FC kit and ostrich feathers.
The best ones are the $5000 glasses that spell out his name in the light.
6. Sexual Harassment and Battery
Elton was accused of sexual harassment and battery by his bodyguard Jeffrey Wenninger.
He was a cop for the LAPD and a Captain for that matter and worked for John during his off hours.
7. Drug Addict
Were it not for rehab; Sir Elton would have had the worst celebrity life ever.
He had to hit rock bottom to seek professional help in the 1990s. He would have an epileptic seizure and turn blue.
People found him on the ground and lay him on the bed,but forty minutes after waking up, he would be snorting another line.
8. Sir Elton John was Admitted to Rehab
Elton John had his struggles with drugs up until the time he thought he was really going to die and he decided to seek professional help.
He even had the rehab diary that he recently handed to movie bosses for an upcoming biopic.
9. Tiaras Preparation
While he spends most of his life on road tours, he likes being prepared.
He does this by bringing two tiaras to every road tour he goes to.
According to him, you never know when you might be invited for something formal, and you are out there with your costumes only.
10. Dropped Out of School
What is it with celebrities dropping out of school?
Anyway, Sir Elton John was awarded a scholarship at the age of 11 at the Royal Academy of Music.
He, however, quit before graduation to pursue a rock career. It seems like it paid off.
11. Sir Elton John is a Knight
The Knighthood of British Empire was awarded to John Elton in 1998 hence the title Sir John Elton.
It’s a highly recognized title given to individuals who show service to people and humanity or something like that.
It’s rarely granted and only given to influential people.
Elton was given for his contribution to the music industry and fundraising for AIDS charities.
12. His Glasses Weren’t Prescribed
Don’t know what I mean? Well here is a little explanation.
Elton John didn’t have any problem with eyesight or his eyes.
He started wearing glasses to copy one of his idols Buddy Holly.
After a short while, his eyes had adjusted to the lenses,and since then, he needed the glasses.
13. He Doesn’t Like Madonna
The two have quarreled over the years,but Elton started the feud in 2004 when accepting his award for best classic songwriter.
He said, Madonna is an artist who just lip syncs on stage and should be shot.
He continued to say he doesn’t give a toss what she thought about that.
14. Yamaha Devotee
Yamaha is one of the manufacturers in the music industry,and Elton was hooked to them.
All the pianos he plays live are made and supplied by Yamaha. These include his Million Dollar Piano and his famous Red Piano.
15. A Spare Hotel Room for His Spectacles
John Elton owns more than a thousand pairs of glasses.
In 2013, there were claims that he hired a separate hotel room to store his numerous spectacles.
16, Humiliated Sylvester Stallone After 29 Years
In his recent autobiography titled, Me, Elton John has vividly written about an incident that happened in 1991.
He threw a grand house party for select VIP guests, which included A list Hollywood celebrities like Sylvester Stallone, Richard Gere and the gorgeous Princess Diana.
It so happened that Richard Gere and Princess Diana, were instantly attracted to each other and slowly drifted away into a totally
Passionately chatting with each other by the fireplace, Sylvester Stallone was least impressed by the instant attraction of two strangers, who became close friends in less than an hour.
When Elton invited everyone to gather at the dinner table, two prominent guest were missing.
A worried Elton sent a waiter to lookout for them, who came back holding Richard Gere and Stallone in each of his hands.
The shocked waiter told Elton John that Gere and Stallone were getting ready for a fist fight and he managed to abort it, just in the nick of time.
A furious Stallone told Elton John, that he would not have been here if he knew Prince charming (Richard Gere) was also invited.
A smiling Elton showed Stallone the way out , who stormed out in a flash.
Before he left, Stallone also told Elton, that he could have Princess Diana anywhere, anytime he wanted.

domain: celebrity


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text:
Trehalose is a small molecule – nutritionally equivalent to glucose – that helps to prevent protein from aggregating (that is, clustering together in a bad way).
Parkinson’s disease is a neurodegenerative condition that is characterised by protein aggregating, or clustering together in a bad way.
Is anyone else thinking what I’m thinking?
In today’s post we will look at what trelahose is, review some of the research has been done in the context of Parkinson’s disease, and discuss how we should be thinking about assessing this molecule clinically.
Neuropathologists examining a section of brain tissue. Source: Imperial
When a neuropathologist makes an examination of the brain of a person who passed away with Parkinson’s, there are two characteristic hallmarks that they will be looking for in order to provide a definitively postmortem diagnosis of the condition:
1. The loss of dopamine producing neurons in a region of the brain called the substantia nigra.
The dark pigmented dopamine neurons in the substantia nigra are reduced in the Parkinson’s disease brain (right). Source:Memorangapp
2. The clustering (or ‘aggregation’) of a protein called alpha synuclein. Specifically, they will be looking for dense circular aggregates of the protein within cells, which are referred to as Lewy bodies.
A Lewy body inside of a neuron. Source: Neuropathology-web
A cartoon of a neuron, with the Lewy body indicated within the cell body. Source: Alzheimer’s news
In addition to Lewy bodies, the neuropathologist may also see alpha synuclein clustering in other parts of affected cells. For example, aggregated alpha synuclein can be seen in the branches of cells (these clusterings are called ‘Lewy neurites‘ – see the image below where alpha synuclein has been stained brown on a section of brain from a person with Parkinson’s disease.
Examples of Lewy neurites (indicated by arrows). Source: Wikimedia
Given these two distinctive features of the Parkinsonian brain (the loss of dopamine neurons and the aggregation of alpha synuclein), a great deal of research has focused on A.) neuroprotective agents to protect the remaining dopamine-producing neurons in the substantia nigra, and B.) compounds that stop the aggregation of alpha synuclein.
In today’s post, we will look at the research that has been conducted on one particular compounds that appears to stop the aggregation of alpha synuclein.
It is call Trehalose (pronounces ‘tray-hellos’).
What is Trehalose?
Trehalose (also known as alpha-D-glucopyranosyl-1,1-alpha-D-glucopyranoside) is a disaccharide.
What is a disaccharide?
A disaccharide is a molecule that is composed of two smaller glucose molecules linked together.
Trehalose – 2 molecules of glucose. Source: Nutrientsreview
If that simple definition of a disaccharide is too basic for you and you want something more thorough, try this:
(This guy – Andrey Kopot of AK Lectures – is amazing!)
Trehalose can be found (in small amounts) in mushrooms, honey, lobsters, shrimps, certain seaweeds, wine, beer (don’t get too excited!), and most foods produced using baker’s yeast. And it is generally considered safe nutritionally – the U.S. Food and Drug Administration lists trehalose as a compound under the category of GRAS (or ‘Generally Recognised as Safe’) (Source and Source).
Trehalose occurs naturally in a wide variety of organisms, ranging from bacteria to invertebrates, and it serves as an energy source or stress protectant. For an interesting OPEN ACCESS review of the biological functions of trehalose – Click here.
And trehalose stops alpha synuclein from aggregating?!?
Back in 2004, this research report was published:
Title: Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease.
Authors: Tanaka M, Machida Y, Niu S, Ikeda T, Jana NR, Doi H, Kurosawa M, Nekooki M, Nukina N.
Journal: Nat Med. 2004 Feb;10(2):148-54.
Huntington’s disease is another neurodegenerative condition that is characterised by the aggregation of protein.
In the case of Huntington’s, however, the protein is called huntingtin (not a typo, that is the protein’s name). The researchers who conducted this study wanted to identify compounds that could reduce the aggregation of huntingtin protein, so they conducted a large screening experiment (more than 200 compounds) on cells growing in culture. They found that disaccharides appear to share an ability to slow the aggregation of huntingtin protein. One disaccharide in particular displayed really significant results… take a wild guess which one!
When the researchers feed trehalose (2% in drinking water – that is 2 grams trehalose in 100ml water) to mice that have been genetically engineered to have aggregation of huntingtin protein, they found that trehalose not only decreased huntingtin aggregates in brain and liver, but it also improved motor function in these mice and extended their lifespan (beyond that of the huntingtin-producing mice that were not treated with trehalose). The researchers concluded that the “lack of toxicity and high solubility, coupled with efficacy upon oral administration, make trehalose promising as a therapeutic drug or lead compound for the treatment” for Huntington’s disease.
But what about alpha synuclein?
Well, this aggregate-inhibiting ability of trehalose got other researchers thinking, and a couple of years later this research report was published:
Title: Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein.
Authors: Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC.
Journal: J Biol Chem. 2007 Feb 23;282(8):5641-52.
PMID: 17182613 (This article is OPEN ACCESS if you would like to read it)
In this study, the researchers replicated the findings of the previous study, and they then turned their attention to the Parkinson’s associated protein alpha synuclein and they found that trehalose also inhibits aggregation of this protein as well. What was particularly interesting, however, was their discovery that trehalose as an autophagy activator.
And what is autophagy?
Autophagy is an absolutely essential function in a cell. Without autophagy, old proteins and mitochondria will pile up making the cell sick and eventually it dies. Through the process of autophagy, the cell can break down the old protein, clearing the way for fresh new proteins to do their job.
Think of autophagy as the waste disposal/recycling process of the cell.
The process of autophagy. Source: Wormbook
Waste material inside a cell is collected in membranes that form sacs (called vesicles). These vesicles then bind to another sac (called a lysosome) which contains enzymes that will breakdown and degrade the waste material. The degraded waste material can then be recycled or disposed of by spitting it out of the cell.
By inducing autophagy, the researchers of this study showed that trehalose also protects cells against toxic insults. And this result has since been replicated by several independent research groups (Click here, here, here and here to read more about this).
Trehalose has also been tested in animal models of Parkinson’s, such as this study:
Title: Trehalose ameliorates dopaminergic and tau pathology in parkin deleted/tau overexpressingmice through autophagy activation.
Authors:Rodríguez-Navarro JA, Rodríguez L, Casarejos MJ, Solano RM, Gómez A, Perucho J, Cuervo AM, García de Yébenes J, Mena MA.
Journal:Neurobiol Dis. 2010 Sep;39(3):423-38.
In this study, the researchers looked at the use of trehalose in a genetic mouse model of Parkinson’s disease. These mice produce a great deal of human Tau protein and have no Parkin protein.
What is Tau?
I will be addressing Tau in an upcoming post, but briefly, Tau is a microtubule-associated protein.
What does that mean?
Microtubules are basically the highways and byways inside a cell, and Tau functions by stabilising those highways and byways. Tau holds together the roads which allows stuff to be moved around the cell (usually in sacks called vesicles, by transporter proteins like kinesin).
Tau: a stabilising presence. Source: Hindawi
So why is TAU interesting?
Because it is associated with both Parkinson’s disease AND Alzheimer’s disease. In both conditions there is a build up of Tau protein which accumulates and aggregates in a similar fashion to alpha synuclein (Click here for a good review article on this topic). Thus, by engineering mice to over-produce Tau, the researchers can model aspects of Parkinson’s disease.
Ok, but what about Parkin? What is that?
About 10% of Parkinson’s cases are associated with particular genetic variations that render people vulnerable to developing the condition. Some of these mutations are in sections of DNA (called genes) that provide the instructions for proteins that are involved in the process of autophagy (which I mentioned above). Two genes, in particular, are the focus of a lot of Parkinson’s-related research – they are called Parkin and Pink1.
What do Parkin and Pink1 do?
Both proteins appear to have many different functions, but their roles in the process of autophagy are well understood.
Pink1 acts like a kind of handle on the surface of old proteins that need to be broken down and recycled. And if Pink1 a handle, then Parkin is a flag that likes to hold onto the Pink1 handle. While exposed on the surface of old proteins, Pink1 starts grabbing the Parkin protein. This pairing is a signal to the cell that this particular bit of old protein is rubbish and needs to be removed. In the absence of normal Pink1 or Parkin proteins, there is no handle-flag system and old proteins start to pile up. They are not disposed of appropriately and as a result the cell getting sick and ultimately dying.
People with particular mutations in the Pink1 or Parkin genes are vulnerable to developing an early onset form of Parkinson’s disease. It is believed that the dysfunctional autophagy process is part of the reason why these individuals develop the condition at such an early age.
So the investigators have engineered a mouse that produces lots of Tau, and has no Parkin to help remove the waste?
But when they treated those mice with trehalose (1% in fresh drinking water, twice a week for 2.5 months from infancy), the researchers found that they could reduce the dopamine cell loss that is seen in these animals and also decrease the amount of Tau aggregates in the brain. And this neuroprotective process was partly the result of increasing autophagy (there are different mechanisms of autophagy, some of them are independent of Parkin – click here to read more about this).
What is particularly interesting in this study, however, was that after the investigators observed this effect, they next delayed treating the animals until 14-months of age (mid-late age for mice who live 2-2.5 years). They treated these older mice for just 3 weeks with 1% trehalose and observed improvements in motor behaviour, levels of anxiety, and reductions in their levels of aggregated protein in the brain.
Another interesting finding in this study is that while short term use of trehalose resulted in positive effects, consistent longer term use (4 months) of the compound was not associated with improvements in the dopamine system and also had lower body weights than their placebo-treated controls. This long term aspect of using trehalose needs to be further investigated independently. If it is replicated, then sporadic treatment with trehalose will need to be looked at.
This first investigation of trehalose in a model of Parkinson’s disease has subsequently been followed up by other research groups, including this report:
Title: Neuroprotective effect of the chemical chaperone, trehalose in a chronic MPTP-inducedParkinson’s disease mouse model.
Authors: Sarkar S, Chigurupati S, Raymick J, Mann D, Bowyer JF, Schmitt T, Beger RD, Hanig JP, Schmued LC, Paule MG.
Journal: Neurotoxicology. 2014 Sep;44:250-62.
The researchers who conducted this study used a neurotoxin (MPTP) to model Parkinson’s in mice. They found that pre-treatment with trehalose (for 6 weeks, starting 3 days before the neurotoxin was injected) significantly reduced the loss of dopamine neurons. Interestingly, trehalose also reduced the levels of microglial activation in MPTP injected mice, indicating protection against neuroinflammation.
What are microglia? And what is neuroinflammation?
Microglia are cells in the brain that form the main part of active immune defence to injury or disease. When any kind of trouble kicks off in the brain, microglia become activated and start dealing with the source of the trouble as well as removing any damaged/dying cells. They communicate with other cells (particularly cells of the immune system, such a T-cells and macrophage) by releasing chemicals which is part of the process of inflammation.
Microglia become activated around sick cells and release pro-inflammatory compounds. Source: NCBI
By reducing activation of microglia and subsequent inflammation in the brain, trehalose appears to provide further protection to the dopamine neurons.
Another investigation of trehalose in an animal model of Parkinson’s addressed the issue of alpha synuclein:
Title: Treatment with Trehalose Prevents Behavioral and Neurochemical Deficits Produced in an AAV α-Synuclein Rat Model of Parkinson’s Disease.
Authors: He Q, Koprich JB, Wang Y, Yu WB, Xiao BG, Brotchie JM, Wang J.
Journal: Mol Neurobiol. 2016 May;53(4):2258-68.
In this study, the researchers tested the ability of trehalose to protect cells against a mutant version of the alpha synuclein protein in rats. The mutant version of alpha synuclein was inserted into dopamine neurons via a virus, and this transfer caused the cells to slowly die, resulting in behavioural motor problems for the animals. The investigators found that at concentrations of 2% and 5% in drinking water (for 6 weeks; started immediately after the alpha synuclein virus was injected), trehalose protected dopamine cells against the toxic effects of alpha synuclein. In addition, they found that trehalose did a great job of activating autophagy, which helped clear the excess alpha synuclein from the cells.
The investigators concluded that “this study supports the concept of using trehalose as a novel therapeutic strategy that might prevent/reverse alpha synuclein aggregation for the treatment of Parkinson’s disease“. They also suggested that “further investigation is needed to define clinical design strategies and clarify the relationship between autophagy and neuroprotective effect of trehalose“.
Has Trehalose been tested clinically in Parkinson’s disease?
No. Not yet. It does appear to be on the list of things to do though.
In addition, there is a biotech company that is looking to take a synthetic version of trehalose into clinical trials.
The company is called Junaxo.
Incorporated in 2013, Junaxo is a ‘virtual biotech’ based out of Toronto (Canada). In a future post we will be re-visiting this ‘virtual biotect’ model of drug development, but basically by outsourcing their research work, companies like Junaxo can reduce the capital required it to reach their scientific/clinical goals.
Junaxo has a candidate drug (JNX3001) that is based on trehalose.
In 2013, the company was awarded a Michael J Fox Foundation Therapeutic Pipeline Program grant to assess the “efficacy of trehalose in an alpha-synuclein-based non-human primate model of Parkinson’s (Click here to read more on this). We are still awaiting the publication of those results, but they would hopefully represent the final pre-clinical data before trehalose (or JNX3001) is proposed for clinical trials.
What does it all mean?
So, summing up: Trehalose is an interesting compound that demonstrates remarkable protein aggregation inhibiting properties, in addition to activating autophagy and reducing inflammation in the brain. So remarkable are these properties, in fact, that they almost seem to good to be true…
…and this is the part of this post where I perform my habitual ‘rain on the parade’ piece.
Here’s the thing: When consumed orally, trehalose can be rapidly broken down into two glucose molecules by the enzyme trehalase, which is present in cells along the lining of the gut and also in the liver. Conversion into glucose is necessary for the body, but it is not a good scenario for our needs related to Parkinson’s disease. A comparative study of the effects of trehalose and glucose has been conducted in the Huntington’s disease study mentioned in this post (Click here), and it appears to rule out the possibility that glucose administration is having the same effects.
Thus, there are serious questions regarding how much orally consumed trehalose could potentially reach the brain in humans (and I am yet to find any evidence that it can cross the human blood-brain-barrier – the protective membrane surrounding the brain). Oral trehalose is accessing the blood stream – a double blind clinical trial reported last year that oral trehalose improves arterial and microvascular function in elderly folks (Click here to read more about this study) – but this does not mean that enough is reaching the brain to have beneficial effects.
This company is attempting to take trehalose to the clinic for both oculopharyngeal muscular dystrophy (OPMD – a rare genetic muscle disorder with onset during adulthood) and spinocerebellar ataxia type 3 (SCA3 – a condition characterised by progressive problems with movement). Both of these conditions are associated with protein aggregation. But this company is proposing to treat the conditions by injecting trehalose directly into the blood (bypassing the gut completely). They have just finished a phase I clinical trial testing the safety of this intravenous approach, and we are waiting to here the results of that study. If successful, this could be an option with regards to using trehalose in Parkinson’s disease.
As always, I will report back here when new information comes to hand. A lot of people are looking at trehalose for various conditions, so there will certainly be a lot of new information in the near future.
EDITOR’S NOTE: The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.
The banner for today’s post was sourced from Wikipedia

domain: biology