Elements of a list are caused to scroll in a first display mode on a display device in response to a movement made on a touch interface along a determined scroll axis, and starting from the first mode, a display is triggered on the display device of the list in at least one second display mode in response to a movement made on the touch interface along a trigger axis that is different from the list scroll axis.

The present invention relates to the general field of multimedia applications.
More particularly it relates to using a touch interface to control the display of elements of a list by means of a display device. The elements of the list may in particular be multimedia contents such as video streams, images, applications, data files, etc., and the display device may be a screen, e.g. a computer screen or a TV screen.
The invention thus applies in preferred, but non-limiting manner, to displaying audiovisual content on a screen, e.g. in order to provide a channel-switching service amongst a plurality of channels broadcast by a digital TV operator, or to offer a service of navigating a video catalog.
Over the last few years, there has been considerable development in multimedia equipment fitted with touch interfaces, such as a touch screen or a touchpad.
A touchpad is conventionally used as means for replacing a mouse, in particular on laptop computers. It constitutes a high performance pointer device that enables a cursor to be moved easily on the screen of a computer.
Nevertheless, use thereof becomes more difficult when it is necessary to act on elements displayed on the computer screen.
To mitigate that problem, a touchpad is often associated with one or more buttons located above or below the touchpad and acting as selector buttons in the same manner as the buttons on a mouse, thus limiting the actions that can be performed using the touchpad on its own. Those buttons associated with the touchpad serve in particular to control the display of elements on the screen, where such control is not presently possible in easy and reliable manner using a touchpad.
There thus exists a need to have a method of controlling the display of elements on a display device by means of a touch interface that does not require recourse to additional peripheral equipment such as buttons, and that is equally applicable to utilization of a touch interface in the form of a touchpad or in the form of a touch screen.
Document EP 2 116 927 describes a mobile telephone with a touch screen suitable for displaying a list of messages. Using the touch screen, the user can cause the messages to scroll along a first axis. Furthermore, a movement along a second axis makes it possible, at the location of a selected message, to display some other message associated with the selected message. Nevertheless, it is not possible to increase the quantity of information displayed for a selected message.

Method and device for controlling the display of a plurality of elements of a list on a display device


Two spaced halyard restraining devices that are fixed to spreaders attached to a sailboat's mast. The two spaced spreaders are horizontally disposed from and fixed to opposite sides of an interposed vertically disposed mast. The halyard restraining devices are identical and each is shaped like a U-shaped bracket having one leg fixed to a spreader while another outer leg is a longer leg with a rounded free end. Each restraining device has a legs joining bight portion with the opened side facing generally either towards the boat's bow or stern. The halyard or the like are pulled into engagement with the device's bight portion to restrain their movement towards the mast by placing them under increased tension. To accommodate two different common cross sectional types of spreaders, round or wing shaped, the outer opposite side bearing surfaces of the inner leg may be shaped differently to complement these two types of spreader's shapes thus allowing for their dual-use with two different shaped spreaders.

On windy days it is common for suspended ropes on sailboats to slap against the mast and other exposed boat parts creating loud noises. One solution is to use rope or elastic cord to tie or retain the suspended noise causing rope away from the mast. Another solution to abate the noise is to have arms that extend horizontally from the vertical mast. Neither tubular shaped C members may extend from the arms or some kind of wing to engage the vertically suspended noise causing rope. With the present invention the horizontally disposed arms mounted to the mast have a hooked shaped members fixed to them that can retain the movement of the suspended noise causing rope to prevent the same from slapping against the vertical mast even under strong wind conditions all as will be described in detail hereafter.


An endoesophageal balloon and catheter for operation with a transesophageal echocardiography (TEE) probe includes an inflatable balloon body disposed over the ultrasound element of the TEE probe, a liquid inflow lumen in fluid communication with the balloon, and a liquid outflow lumen in fluid communication with the balloon. The balloon is inflated with an acoustically transmitting liquid.

This disclosure is generally directed to endocavitary imaging systems, and more particularly, to transesophageal echocardiography (TEE). One embodiment is directed to devices and methods to optimize TEE visualization of left atrial wall ablation for treatment of atrial fibrillation.
Various non-invasive, semi-invasive and invasive ultrasound imaging systems have been described to view tissue structures within a human body, such as the heart structures, the abdominal organs, the fetus, and the vascular system. A challenge for any ultrasound image system is to have a sufficient contact of the transducer head to the target tissue being scanned, as well as an ultrasound transmissible, or coupling, agent to avoid the disruption by intervening air. Air contact with the transducer surface represents a markedly lower sound speed than adjacent tissue, resulting in massive ultrasound reflection at the tissue interface with minimal penetration of ultrasound signals and therefore minimal signals returning from the tissue to the transducer to make an image. The most common coupling agent is accomplished by ultrasound gel. Therefore, imaging a body part usually requires direct contact with tissue and thereby limits accurate visualization of tissues within the near-field of the transducer.
Another challenge in ultrasound image systems is placing targets within the higher resolution focal zone of a transducer. Still another challenge is to increase the field of view in the near field including increasing the filed of view over longer segments for both curved and linear arrays.
Various patents have addressed some of the above shortcomings including U.S. Pat. No. 4,543,960 to Harui et al.; U.S. Pat. No. 4,841,977 to Griffith et al.; U.S. Pat. No. 8,118,743 to Park et al.; and U.S. Pat. No. 6,139,502 to Fredriksen. In the '502 Patent to Fredriksen, for example, a standoff from the tissues is described to improve the field of view.
Transesophageal echocardiography (TEE) also suffers from the above described challenges. Nearly all current TEE transducers produce a sector image which markedly limits the field of view (FOV), particularly in the near field. The near field is thus viewed as a point source with the imaging sector expanding from that point on the esophageal wall. Much of the operator-dependent "art" of TEE scanning thus requires a physician imager to be able to manipulate the articulated flexible tip of the transducer head into a position that maintains imaging contact, yet still places the anatomic target to be imaged within the sector FOV. Anatomically, this places severe limitations on imaging any extent of the left atrial wall since it generally immediately abuts the esophageal wall in the near field. Very little extent of the left atrial wall can thus be seen within the near field apex of the usual sector image, making visualization or monitoring of any procedure addressing the left atrial wall. Suboptimal, if not impractical.
TEE scanning during left atrial wall ablation for treatment of atrial fibrillation has additional challenges related to safety. TEE is generally considered a well-tolerated procedure that has minimal side effects related to the actual scanning of the heart and is considered safe for the esophageal wall. However, severe pressure or manipulation of the transducer head has been known to cause rare pressure damage or small tears in the esophageal lining. Moreover, even the minor pressure asserted to again good imaging contact further presses into the adjacent left atrial wall, such that minimal FOV and extent of the left atrial wall is presented to the imager. The numerous ablation foci required to terminate atrial fibrillation are thus poorly seen, especially when they need to extend to most, if not all, of the associated entrances of the pulmonary veins where the foci of abnormal electrical activity causing atrial fibrillation frequently arise. The minor scanning pressure of the TEE transducer head also limits the thin space of safety between the left atrial wall and the adjacent esophageal wall. Penetration into the esophageal wall of any ablation of the left atrial wall thus presents a potential life-threatening communication between the beating heart and the esophageal lumen. Patients have died from exsanguination when a left atrial wall ablation site breaks down and allows communication of the left atrium with the esophageal lumen. Therefore, nearly all monitoring of the ablation is required to stop left atrial fibrillation are generally performed by fluoroscopic imaging and/or sophisticated electrical sensing processes that target the origin of the fibrillation.
Improvements in TEE imaging the left atrial wall during ablation are thus needed to make visualization even practical, let alone safe.
There are several medical procedures where ultrasound imaging systems are not yet widely used. Currently, for example, interventional cardiologists use mainly fluoroscopic imaging for guidance and placement of devices in the vasculature or in the heart. These procedures are usually performed in a cardiac catheterization laboratory (Cathlab) or an electrophysiology laboratory (EPlab). During cardiac catheterization, a fluoroscope uses X-rays on a real-time frame rate to give the physician a transmission view of a chest region, where the heart resides. A bi-plane fluoroscope, which has two transmitter-receiver pairs, mounted at 90° to each other, provides real-time transmission images of the cardiac anatomy. These images assist the physician in positioning various catheters by providing him (or her) with a sense of the three-dimensional geometry of the heart.
While fluoroscopy is a useful technique, it does not provide high quality images with good contrast in soft tissues. Furthermore, the physician and the assisting medical staff need to cover themselves with a lead suit and need to reduce the fluoroscopic imaging time whenever possible to lower their exposure to X-rays. In addition, fluoroscopy may not be available for some patients, for example, pregnant women, due to the harmful effects of the X-rays. Recently, transthoracic and transesophageal ultrasound imaging have been very useful in the clinical and surgical environments, but have not been widely used in the Cathlab or EPlab for patients undergoing interventional techniques.
Therefore there is a need for transesophageal ultrasound systems, apparatuses and methods that can provide atraumatic, fast and computationally inexpensive real-time imaging. The images should enable accurate, large-field of view, and increased near field visualization of the internal anatomy that includes various structures and provide selected views of the tissue of interest.
There is a need for transesophageal ultrasound imaging systems, apparatuses and methods that can provide tissue contact with the esophageal wall over a greater extent, thereby allowing an improved imaging standoff to place the left atrial wall within the improved focal zone of the transducer, as well as providing the associated greater FOV of the entire heart.
There is a need for transesophageal ultrasound imaging systems, apparatuses and methods that can provide a mechanism by which the temperature of the esophageal wall can be regulated to prevent either hot or cold lethal temperatures from the left atrial wall extending into the esophageal lumen.

Endoesophageal balloon catheter, system, and related method


A system, method, and computer program product are provided for allowing a head to enter a reduced power mode. A first processor having a first head is provided. Additionally, a second processor having a second head is provided. Furthermore, a link is provided, coupled between the first head of the first processor and the second head of the second processor for communicating first data therebetween. In operation, at least the second head of the second processor is capable of entering a reduced power mode.

In multi-processor systems, multiple processors may be connected via one or more video bridges. During use, the bridge may be utilized for use of one or more additional processors for distributed processing. Currently, input/output resources of the one or more additional processors may be disabled when distributed processing is not being utilized. However, a head of such one or more additional processors remains enabled even when distributed processing is not being utilized, resulting in wasted power.
There is thus a need for addressing these and/or other issues associated with the prior art.

System, method, and computer program product for allowing a head to enter a reduced power mode


One or more events occurring within a client-side web application are logged at a remote server using a script-based invocation mechanism. The mechanism comprises a client-side script, and associated server-side code. Upon occurrence of an event to be logged, a script object is created on the client and used to pass logged data to the server, which then issues a response to destroy the script object. In this manner, the script object is created and persists in the client only as long as it is needed to log the event.

Technical Field
The disclosed subject matter relates generally to software and rich media monitoring, tracking, and return on investment (ROI) analysis.
Description of the Related Art
It is known in the prior art to provide methods and systems for centrally coordinating, collecting and storing error, trace, audit and other information in a computer network. A representative example is U.S. Pat. No. 6,470,388. In this patent, selected applications or processes running at various entities or hosts within the network instantiate one or more "debug" objects that collect given information. Each entity also includes at least one logging service layer that communicates with the application or process, and includes a communications resource and one or more state machine engines. In response to collecting error, trace, audit or other information, each debug object passes that data to the respective logging service layer, which decides whether to forward the data to a centralized logging facility disposed within the network. The forwarding of collected information depends on the state of the debug object. At the centralized logging facility, the information is time-stamped and appended to a log file along with the application's name and the name of the entity or host at which the application is running.
Another representative patent is U.S. Pat. No. 6,591,228. In this patent, a logging service logs to a centralized log diagnostic messages from applications executing in a computing environment in which a plurality of computers are coupled to data storage area. Each computer has one or more subsystems that execute applications. A logging service API writes diagnostic messages to the data storage and, depending on the type of problem, contacts an alert facility.

This patent is subject to a terminal disclaimer.


The present invention relates to a haemodialysis solution or concentrate thereof comprising creatine compound(s) and the use of creatine compound(s) for preparing a dialysis solution or concentrate thereof. Furthermore, the present invention is directed to a method for preparing creatine-containing dialysis solutions and concentrates. In addition, the present invention is directed to a method for treating patients with dialysis dependent renal failure with creatine compounds and to provide a variety of significant health benefits and improvement of life quality parameters for dialysis patients. This is achieve by supporting and improving the physiological functions of the patients organs and cells via creatine compounds delivery to the patients, and by protecting organs and cells (specifically including blood cells) of these patients from deleterious effects of a variety of endogenous or exogenous cellular stressors that are linked to the disease state or to the clinical treatment modalities. Furthermore in peritoneal dialysis solutions creatine can be used as an osmotic agent preventing side effects caused by high glucose supplementation.

The present invention is directed to the field of creatine supplementation and hemodialysis and/or peritoneal dialysis for patients with renal failure, who depend on dialysis treatment. Creatine is a natural body substance involved In numerous physiological functions and, hence, of particular relevance for the vertebrate organism, in particular the brain, skeletal and cardiac muscle, where most of the creatine is located in adult mammals (120 to 150 g for a human of about 75 kg weight). Creatine and phosphocreatine are the key substrates of the creatine/phosphocreatine-kinase system that supplies cells with energy. In cells creatine kinase reversibly converts phosphocreatine (PCr) and ADP into ATP and creatine. This reversible reaction plays a key role in the energy metabolism of skeletal and cardiac muscle, the brain, sensory cells, e.g. retina and inner ear, as well as sperm and other cells. The creatine/phoshocreatine-kinase system has a dual function. It represents an immediately available, high energy phosphate buffer system for regenerating ATP as well as an intracellular energy transport system or shuttle between either mitochondria or sites of glycolysis to those places where energy is needed, e.g. at sites of high ATPase activity (for cell locomotion, ion-pumping etc). More specifically, the creatine system sustains the local cellular ADP/ATP-ratio in the vicinity of ATPases and thereby ensures the effective functioning of these ATPases. The concentration of phospho-creatine/creatine is much higher than that of ADP/ATP, has a lesser influence on cell metabolic regulation and replenishes ATP upon demand. Furthermore, ATP and ADP have limited diffusion abilities whereas creatine and phospho-creatine are readily diffusing from either mitochondria or from regions of ATP production by glycolysis to those places where energy and ATP is needed. Nutritional or supplemented Creatine is actively transported into cells by a Creatine-Na/K-cotransporter (CrT).
In animal experiments it was demonstrated that creatine deficit leads to functional abnormalities and histopathological changes in muscle similar to those of patients with mitochondrial myopathies. Creatine kinase knock-out mice (in brain and muscle) demonstrated a significant loss of muscle power and problems relating to muscle relaxation, due to creatine's key role in providing the contractile apparatus and the calcium ion pumps with energy. Also, these transgenic mice show irregular behavioral phenotypes and histological abnormalities in muscle and brain. Patients with genetic deficits in the creatine metabolism present with severe neurological symptoms. For example, children with these genetic defects show development disorders, speech delay, autism and epilepsy. Depending on the type of genetic defect oral creatine supplementation can reverse these abnormalities.
Creatine supplementation has been shown to elicit significant cell protective, antioxidant and even anti-apoptotic effects, in particular for skeletal and cardiac muscle cells, as well as for nerve and skin cells. These effects of creatine are of benefit for healthy people as well as patients with diverse muscular, neuromuscular, neurological and neurodegenerative disorders. Endogenous creatine is mainly produced in the kidney and liver. Specifically, in the kidney guanidino-acetate is produced from arginine and glycine and subsequently methylated by activated methionine to methyl guanidino acetate, i.e. creatine, in the liver. The daily human demand for creatine is approximately 3 to 4 g, whereas the endogenous production is limited to about 1 to 2 g/day. Natural creatine is mainly available in fish and meat and to some extent also in milk.
Dietary Creatine, taken up with meat and fish consumption, or supplementation of Creatine in form of chemically pure substance (e.g. Creatine Monohydrate or Creatine salts) has a number of benefits and advantages for humans. Naturally, it helps for compensating the chronic creatine deficits of vegetarians. Also, it is an officially authorized diet supplement for athletes leading to an enhanced cellular energy status that results in prolonged muscle endurance, in a delay of muscle fatigue and in an accelerates muscle recuperation. Moreover, creatine supplementation has shown to be beneficial in a number of muscular, neuromuscular, neurological and neurodegenerative diseases, for example, congestive heart failure, cardiac insufficiency, cardiac arrhythmia, muscle disuse atrophy, gyrate atrophy, McArdle's disease, diabetic and toxic neuropathies, peripheral nervous system diseases, dysmyelination and demyelination diseases, motor neuron disease, traumatic nerve injury, multiple sclerosis, mitochondrial diseases, muscular dystrophy, amyotrophic lateral dystrophy (ALS), Morbus Huntington, Morbus Parkinson, Charcot Marie tooth syndrome, epilepsy, stroke, spine injuries, cranial cerebral injury, brain atrophy, cognitive dysfunction (see EO 03/101402 A2) osteoporosis, skin disorders (see WO 2008/073332, WO 01/00203 A1), dermatitis (see W02009/002913), eye disorders (see US 2009/0005450 A1), transmissible spongiform encephalopathies (see WO 01/00212), disorders of the glucose metabolism (see EP 0 854 712 B1).
The positive effects of creatine supplementation are directly or indirectly based on its effect on the energy status of cells, its ability to protect cells and its anti-apoptotic influence.
Clinical studies have demonstrated creatine to be safe up to extremely high doses, for example up to 20 g daily intake for adults. Up to date no serious side effects are known. Creatine in the form of creatine monohydrate is a white powder that can be stored at room temperature. In acidic aqueous solutions it displays some instability at temperatures over 60° C. At neutral pH and cooled, however, it can be stored for thirty days without losses. When administered orally, most of the creatine passes unchanged through the acidic stomach environment. Next to creatine monohydrate, which is only moderately soluble in water, a number of more soluble salts like creatine pyruvate and citrate are commercially available. For people with severely reduced body creatine levels, an initial loading phase with 4×5 g of creatine per day during a 7-10 days period, followed by a low dose daily intake of 3 to 6 g is generally recommended. It has been shown that the simultaneous administration of creatine and glucose is beneficial in order to compensate for energy losses due to creatine phosphorylation.
Hemodialysis is used for providing an artificial replacement for lost kidney function due to renal failure. Dialysis may be used for patients with sudden but temporary loss of kidney function (acute renal failure) or for patients permanently lacking kidney function (stage 5 chronic kidney disease). When healthy, the kidneys maintain the body's internal equilibrium of water and minerals and remove the daily metabolic load of waste products and toxins from the blood. As part of the endocrine system they produce erythropoletin and 1.25-dihydroxycholecalciferol (calcitriol). Dialysis is an imperfect treatment for replacing kidney function because it does not correct the endocrine functions of the kidney. It replaces the excretory function through diffusion (waste removal) and ultrafiltration (fluid removal) of solutes. But prolonged dialysis treatment also leads to a wash-out of valuable body substances (minerals, vitamins and other nutrient compounds, which are lost during the dialysis process, due to lack of resorption by the kidneys. Therefore, dialysis patients are creatine-depleted because endogenous creatine synthesis is hampered in the diseased kidney and ingested creatine is washed out during dialysis.
Hemodialysis works on the principles of (i) diffusion of solutes and (ii) ultrafiltration of fluid across a semi-permeable membrane. On one side of the semi-permeable membrane blood flows by and the dialysate flows by the opposite side. Small and medium-size solutes (typically up to 25 kDa) and fluid pass through the membrane. The counter-current flow of blood and dialysate maximizes the concentration gradient of solutes between the blood and dialysate, which helps to remove more urea and creatinine from the blood. The concentrations of solutes (for example potassium, phosphorus, and urea) are undesirably high in the blood, but low or absent in the dialysis solution and constant replacement of the dialysate ensures that the concentration of undesired solutes is kept low on this side of the membrane. The dialysis solution has levels of minerals similar to their natural concentration in healthy blood. For another solute, bicarbonate, dialysis solution level is regularly set at a slightly higher level than in normal blood, to encourage diffusion of bicarbonate into the blood, to act as a pH buffer to neutralize the metabolic acidosis that is often experienced in these patients. The levels of the dialysate components are typically prescribed by a nephrologist according to the needs of the individual patient.
In hemodialysis, the patient's blood is pumped through the blood compartment of a dialyzer exposing it through a semipermeable membrane to the compartment of the dialysis solution and Diffusion of salutes is possible. The cleansed blood is then returned via the circuit back to the body. Ultrafiltration occurs by increasing the hydrostatic pressure across the dialyzer membrane. This is usually done by applying a negative pressure to the dialysate compartment of the dialyzer. This pressure gradient causes water and dissolved solutes to move from blood to dialysate and allows the removal of several litres of excess fluid during a typical three to five hour treatment.
In peritoneal dialysis a sterile solution containing minerals and glucose is run through a tube into the peritoneal cavity, the abdominal body cavity encasing the intestines, where the peritoneal membrane acts as a semipermeable membrane. The dialysate is left there for a period of time to absorb waste products and then it is drained out through the tube and discarded. This cycle or "exchange" is normally repeated four to five times a day (CAPD: Continuous Ambulatory Peritoneal Dialysis), and sometimes overnight with an automated system (APD: Automated Peritoneal Dialysis). Ultrafiltration occurs via osmosis; the dialysis solution used contains a high concentration of glucose, and the resulting osmotic pressure causes fluid to move from the blood into the dialysate. The amount of ultrafiltration is directly dependent from the level of concentration of glucose or other osmotic active substances such as poly-sugars (eicodextrin) or amino acids. As a result, more fluid is drained than was instilled.
Hemofiltration is a treatment similar to hemodialysis, but it makes use of a different principle. The blood is pumped through a dialyzer or "hemofliter" as in dialysis, but no dialysate is used. A pressure gradient is applied; as a result water moves across the very permeable membrane rapidly, "dragging" along with it many dissolved substances, importantly ones with large molecular weights, which are cleared less well by hemodialysis. Salts and water lost from the blood during this process are replaced with a "substitution fluid" that is infused into the extracorporeal circuit during the treatment. Hemodiafiltration is a term used to describe several methods of combining hemodialysis and hemofiltration in one process.
Due to the loss of excretory function the blood volume and the metabolic toxic load that accumulates between dialysis treatments regularly reaches an unhealthy range leading to an increased number of disorders directly related to renal failure and dialysis treatment, e.g. hypotension, hypertension, muscle cramps, fatigue, nausea, vomiting. Furthermore, the high mechanical (shearing forces) and immunological stress (bioincompatibility of contact surfaces) regularly imposed on the blood and the blood cells in the dialyzer leads to further and often chronic disorders, e.g. hemolysis, amyloidosis, probably malnutrition and cardiovascular morbidity and mortality. Loss of physiologically functioning blood cells, e.g. erythrocytes and immune cells due to mechanical and chemical stress during dialysis treatment is a major problem for patients undergoing regular long-term dialysis treatment. The choice of materials for the dialyzer and an accompanying anticoagulant treatment, including the choice of optimally composed blocompatible dialysis fluids is often an important factor influencing patient mortality.
Cell and Organ Protection by Creatine
Modes of Action and Pleiotropic Functions of Creatine Compounds for Cell and Organ Protection
Anti-catabolic Effects of Creatine
It has been found out that creatine generally enhances muscle cell proliferation and muscle cell differentiation. For example, creatine has been shown to enhance the release of growth hormone (GH), insulin-like growth factors (IGF-I and IGF-1), as well as insulin itself. In addition, creatine promotes the expression of myogenic transcription factors and positively affects muscle cell signaling via the Akt/PKB signaling pathway. Finally, creatine promotes the recruitment and division of muscle satellite cells that are important for muscle build-up and repair. Since endogenous synthesis of creatine uses a significant proportion of the cells activated methionine in the form of S-adenosyl-methionine (SAM), external creatine supplementation spares labile methyl groups in the form of SAMS which then is available for protein synthesis, cell and tissue anabolism.
All these effects contribute to the anti-catabolic effects of creatine and lead to an improvement and/or maintenance of muscle cells and lean body mass, as well as muscle strength and better coordination of movement. This holds especially true in situations of muscle-disuse by which muscle atrophy is induced. Immobilization and muscle cell loss is indeed a general problem in dialysis patients. creatine has been shown to prevent such immobilization-induced muscle cell atrophy and to improve and speed-up rehabilitation. Therefore, by preventing catabolic events and loss of cells, creatine supplementation also helps dialysis patients to be able to maintain their muscle cell mass and to keep their physiological functions, which positively affects life quality and mobility, resulting In more independence and security for the patient. By doing so creatine supplementation with creatine compounds delays entrance into the disability zone, thus extending a plethora of positive life-quality parameters for such dialysis patients.
Improvement of Cellular Energy Status of Cells and Organs.
As a consequence of creatine supplementation, cells take up creatine that Is subsequently phosphorylated by intra-cellular creatine kinase to give high-energy-rich Phospho-Creatine (PCr). By elevation of intra-cellular Phospho-Creatine levels, creatine supplementation improves the cellular energy status, i.e. by increasing the PCr/ATP energy-charge ratio and intracellular energy trafficking via the PCr/Cr shuttle (Wallimann et al. 2007). Creatine stimulates mitochondrial respiration and thus improves energy production in mitochondria. Creatine also activates the AMP-stimulated protein kinase (AMPK) a general energy sensor and cell stress kinase that improves energy provision via enhancing glucose uptake and oxidation in cells. Such energy charging of cells by Creatine compounds leads to higher metabolic activity of cells and improved cell function.
Prevention of Mitochondrial Permeability Pore Opening, Membrane Damage and Cell Death (Apoptosis)
Creatine prevents mitochondrial swelling and induction of programmed cell death (apoptosis), thus rendering cells more resistant to metabolic and environmental stress. Creatine and even more so, Phospho-Creatine, as amphiphiles, are able by interaction with lipid bilayers to stabilize membranes and cells against mechanical and osmotic stress. Since these cells are able to take up external Creatine and express creatine kinase, some of the supplemented Creatine taken up is then converted into Phospho-Creatine, which can invoke membrane stabilization and protection from the intro-cellular side of the cell. These latter facts are especially relevant for protection by Creatine, Phospho-Creatine or other Creatine compounds of erythrocytes and of white blood cells during the dialysis process, when both metabolic and mechanical stress is imposed on these very cells during the dialysis process. Thus supplementation of dialysis fluid by a Creatine compound leads to significant cell protection and thus to a health benefit for dialysis patients.
Direct and Indirect Anti-oxidant Effects of Creatine, Reduction of Advanced Glycosylation End Products (AGE) And Anti-aging of Cells and Organs
Creatine has been shown to act either directly or indirectly as an anti-oxidant to cells in vitro and in vivo and thus exert protective effects on cells and tissues against oxidative stress and lipid peroxidation, including lowering of TBARS (thiobarbituric-acid reaction products); 2008). Thus, Creatine generally protects cells in the body from numerous stress factors. This protection is especially relevant again for dialysis patients whose erythrocytes and white blood cells are mechanically and oxidatively stressed during the process of dialysis. Therefore, Creatine compounds reduce anemia and weakening of the immune response that are commonly observed in dialysis patients. Creatine enhances the levels of camosin and anserin in muscle, compounds that are involved in reducing Advanced Protein Glycation (AGE) that is inflicted in faster cell aging. Thus, supplementation by Creatine compounds leads to cell protection and acts as anti-aging intervention also for dialysis patients.
Reduction of Homocysteine Levels by Creatine Supplementation
Creatine supplementation has been shown to reduce serum levels of homocystelne, in an animal model, a significant cardiovascular risk factor that is also generally elevated in haemodialysis patients. Another study showed a reduction of homocystein levels upon creatine supplementation in humans with approximately 5 g Cr/day. With a lower daily dosage of 2 g/day, in additionally vitamin B supplemented subjects, no such effects were seen. It Is likely, however, that dialysis patients take profit from supplementation of a Creatine compound at a dosage of 5 g or more per day, with or without additional supplementation by Vitamin B complex, by reducing homocysteine concentration in their blood and thus lower the risk of cardiovascular and endothelial damage, which is a serious problem in dialysis patients.
Addition of Osmotically Active Creatine Makes Possible to Reduce Glucose Concentration in Peritoneal Fluid.
Creatine is an osmotically active substance and thus the glucose concentration needed to obtain the osmolarity needed for peritoneal dialysis fluids can be reduced significantly, thus alleviating the bio-incompatibility of chronic high-glucose exposure of the peritoneum that eventually may lead to fibrosis of the peritoneum and Diabetes II with all its negative consequences for health.
Other Actions of Creatine On Cells and Organs.
It is obvious to the educated reader that Creatine acts as a pleiotropic nutritional supplement. Therefore, it is likely that there are many more positive effects of Creatine on cells and tissues that have not been described yet and that are still waiting to be discovered. It is thus self-understood that dialysis patients would eventually profit from those effects, as well. For a detailed review on creatine and its physiological impact on healthy and diseased humans see the article of Theo Wallimann, "Kreatin-warum, warm und für wen?", Schweizer Zeitschrift für Ernährungsmedizin, 5/08, p. 29-40, 2008, which is incorporated herewith by reference.
Cell Protection by Creatine Compounds Relevant for Dialysis Patients
Protection of Residual Kidney Cell Function by Creatine Compounds
Haemodialysis patients often still show some residual renal function and in this case creatine, due to its cell protective and anti-apoptotic effects, can protect renal cells and stop or delay further degeneration and cell death in the kidney.
Protection of Blood Cells: Erythrocytes and Immune Cells by Creatine Compounds:
During the dialysis process, blood cells are subjected to metabolic, mechanical, osmotic and oxidative and other stresses, which can lead to toss of cell function and cell death. Thus, in dialysis patients, creatine will energetically charge blood cells, protect the cell against metabolic and oxidative stress and protect its membranes against mechanical stress, thus counteracting the loss of red blood cells, and together with erythropoietin (EPO) act synergistically to prevent anemia, a problem commonly encountered in haemodialysis patients. Since EPO, however, is known to cause serious side effects, by the addition of Creatine, which protects erythrocytes from haemolysis, less EPO is needed for treating haemodialysis patients and thus the probability of EPO-related side effects is lowered in haemodialysis patients by Creatine supplementation.
In addition, white blood cells, that is, cells of the immune system will also be protected by creatine and Phospho-Creatine from energy loss due to creatine depletion and by stabilizing cell membranes will protect these cells against mechanical stress. Thus, Creatine will maintain proper cell function and strengthen the patient's immune system, which is of paramount importance also for haemodialysis patients.
Protection of Muscle and Muscle Cells by Creatine Compounds
Due to its anti-catabolic effects (by increased of secretion of growth hormone and muscle differentiation factors), supplementation by Creatine compounds improves muscle cell mass, muscle cell function, proliferation and differentiation and finally overall muscle cell performance (force generation), parameters that are all highly relevant quality of life parameters for haemodialysis patients, who generally loose body weight, muscle mass and muscle force.
Protection and Maintenance by Creatine Compounds of Brain and Brain Cells from Uremic Toxins
The neuro-protective effects of Creatine compounds are well documented (for review see Andres et al. 2008) and it is obvious that dialysis patients are also taking advantage from brain and nerve cell protection by creatine, resulting in tower fatigue levels, improved memory and learning function and general well-being.
In addition, uremic toxins are known to negatively influence brain function and morphology, and Creatine compounds are neuro-protective to a significant extent towards these toxins, some of them have been demonstrated to affect Creatine synthesis and Creatine transport in the brain, Creatine supplementation is exerting its neuroprotective effect towards such toxins and thus also improving brain function and life quality of dialysis patients.
Protection and maintenance of bone cells by Creatine compounds
Creatine enhances bone cell proliferation, differentiation and mineralization thus counteracting osteoporosis, osteomalacia and adynamic bone disease, problems often encountered in dialysis patients.
Anti-aging effects by Creatine Compounds on Cells and Organs
Supplementation by creatine compounds leads to protection of body cells and tissues, against oxidative stress, lipid peroxidation, advanced glycation end products (AGE's). These protective mechanisms of Creatine are true also and important for dialysis patients as well.
Creatine an Essential Supplement for Dialysis Patients
Dialysis Patients are generally catabolic and energy-depleted, as well as creatine-depleted in their skeletal muscles and in heart and other tissues and cells. The latter is due to a reduced endogenous synthesis in the kidney of guanidino acetate, the precursor of Creatine, as well as lower alimentary intake of Creatine by Dialysis patients compared to healthy meat-eaters. Creatine in this case turns out to be an essential nutrient for dialysis patients and externally added Creatine is absolutely necessary for normal physiological body and organ function in these patients.
Instead of forcing dialysis patients to consume 5-20 grams of Creatine powder daily by oral intake, Creatine is added directly to dialysis fluid from where it is taken up (unnoticed by the patient) into the blood and from there via the Creatine-Transporter into the target organs, such as muscle, brain and nervous tissue etc. By adding Creatine to the dialysis fluid only so much Creatine is taken up by the cells as is necessary to fill up the cellular Creatine pools and the rest of the Creatine remains in the dialysis fluid. The advantage of such treatment is that these patients are not burdened by an over-load of Creatine, which may be the case, if Creatine would be taken orally. Under the latter circumstances, excess of orally taken Creatine has to be eliminated and may represent a burden for the patients organism. If, however, Creatine is supplemented into the dialysis fluid, each patient, depending on his Creatine status, is taking up only as much Creatine as is needed to fill his cellular Creatine pools, and no elimination of creatine is necessary and no extra burden is inflicted on the patients system.
Addition of Osmotically Active Creatine Allows for Significant Reduction of the Glucose Concentration in Peritoneal Dialysis Fluid.
For peritoneal dialysis, the very high concentration of glucose or other osmolytes that potentially have negative effects, e.g. exposure to constantly high glucose concentration present the peritoneal fluid significantly increases in the dialysis patients the formation of Advanced Glycation Endproducts (AGE's), loss of transport function of the peritoneum and finally enhances the chances of weight increase and of acquiring Diabetes-II. Since Creatine is an osmotically active substance, the glucose concentration in the dialysis fluid can be significantly lowered if Creatine is added instead, in this case preferentially at the highest concentration possible, e.g. up to 24-25 g of Creatine per liter of dialysis fluid at a body temperature of 37° C. By this invention, deleterious side effects caused by high glucose exposure of the dialysis patient to this very fluid can be reduced. As an example Creatine concentrations near the respective solubility limit at the requested temperatures are added for this purpose to significantly reduce the glucose concentration but retain the require osmolarity for peritoneal dialysis. During a typical peritoneal dialysis set-up, the peritoneal dialysis fluid of 2-3 liters is replaced 4-5 times, that is, between 8-15 liters of peritoneal fluid are used per patient and treatment, such that the patient's peritoneum is exposed to a total of 8×25 to 15×25 g less of glucose, corresponding to 200 g to 375 g less glucose than with the regular peritoneal dialysis treatment. This reduction of glucose is highly significant.
Creatine may also be combined with other osmotically active compounds such as betaine, amino acids, mono- or poly-sugars of glucose or other sugar compounds, such that glucose can be even more reduced.
This strategy has two advantages in one, first creatine is used as osmolyte to substitute glucose and second, at the same time the creatine needed is transported through the peritoneum and taken up by the target organs of the patient. This combination is novel and it makes possible that chronic ambulatory peritoneal dialysis (CAPD) or automated peritoneal dialysis (APD), as a simpler and cheaper option of dialysis treatment as compared to hemodialyis, may be used for a much more prolonged period of time for the treatment of chronic renal failure patients, compared to conventional treatments.
Routes of Creatine Supplementation for Dialysis Patients
The routes of creatine delivery vary according to the specific needs of patients and modalities of the clinical setting. Creatine may be delivered via an oral, intra-peritoneal, intra-venous route or by the hemodialysis fluid.
1) For Oral Creatine Supplementation
The specific range of oral Creatine supplementation for dialysis patients would similar as used by athletes. The recommended range of daily Creatine intake would be at a dosage of 1-20 g Creatine per day (as Cr-monohydrate or other Cr-containing compounds, Cr-salts or Cr-analogs) taken orally in form of a powder, tablets, and aqueous solution or as a suspension. The preferred supplementation scheme would allow for 5-20 g of Creatine or Creatine analogs per day for a loading phase period of 7-14 days, followed by a maintenance phase of 2-5 g of Creatine per day during an unlimited time frame or as long as needed. Oral supplementation may also be combined with supplementation of creatine via dialysis fluid.
2) For Peritoneal And/Or Haemodialysis
a) Addition of Creatine Directly to the Final Dialysis Fluid for Peritoneal or Hemodlalysis
The novelty of the present invention and its preferred embodiment consists of the addition of Creatine (Mr 131.13 Daltons), Creatine-Monohydrate, Creatine-containing salts or Cr-analogs directly to the final dialysis solution. The specific, therapeutically effective range of Creatine concentrations for this application is from 0.05 m/l to 20 m/l final concentration of Creatine as Cr-monohydrate or other Cr-containing compounds Cr-salts or Cr-analogs added in its solid form (powder) to the final dialysis fluid, immediately before usage, to avoid the generation of unwanted creatinine during prolonged storage of Creatine in solution.
Creatine or Creatine-analogues are preferably to be added in solid state (as powder) immediately before the final dialysis solutions are made up. This has the advantage that Creatine, which is not very stable in solution at room temperature during, longer periods of time (weeks), is not converted to unwanted creatinine that otherwise would be generated by a spontaneous non-enzymatic chemical reaction during prolonged storage of Creatine in solution.
b) Addition of Creatine to the Dialysis Fluid Concentrate for Peritoneal or Hemodialysis
The novelty of the present invention and its preferred embodiment consists of the addition of Creatine (Mr 131.13 Dattons) Creatine-Monohydrate, Creatine-containing salts or Cr-analogs to the concentrated dialysis stock solution (concentrate). For peritoneal dialysis this Creatine-containing concentrate is directly diluted before usage. For haemodialysis, creatine present in the concentrate would be continuously diluted during the course of haemodialysis, such that the patient is constantly exposed to an entirely physiological concentration of Creatine during the entire dialysis treatment process. This concentration of Creatine (in the final dialysis liquid) is in the range of 0.05 to 20 mM and thus in the same range as reached in the serum of subjects supplemented with a singly portion of 5-20 g of Creatine. The Creatine concentration proposed herein together with Creatine uptake during a 3-4 hr dialysis is sufficient to provide those cell protection effects and health benefits for the patient that are claimed here.
Creatine or Creatine-analogues are preferably added in solid state (as powder) immediately before the dialysis concentrate solutions are made up. This has the advantage that Creatine, which is not very stable in solution at room temperature during longer periods of time (weeks), is not converted to unwanted creatinine that otherwise would be generated by a spontaneous non-enzymatic chemical reaction during prolonged storage of creatine in solution.
3) For Peritoneal Dialysis: Creatine Compounds as Osmolytes for Peritoneal Dialysis
The novelty of the present invention is that for peritoneal dialysis fluid, high concentrations of osmotically active Creatine or Creatine compounds are added to substitute or replace glucose or other osmolytes necessary for peritoneal dialysis.
By addition of high concentrations of osmotically active creatine in a peritoneal dialysis setting, 24-25 g of creatine, creatine salts, or creatine analogues per liter are added immediately to the final peritoneal dialysis solution at a temperature 37° C. These concentrations are near the saturation limit of creatine the solubility of which is highly sensitive to temperature. By this way, a maximum of osmotically active creatine compound can be dissolved and thus the glucose content in the peritoneal dialysis fluid can be reduced accordingly. In this set-up creatine compounds primarily act as osmolyte and only secondarily are taken up in a very small proportion of the total creatine compound added. Such a strategy, by significantly reducing glucose in the dialysis fluid, allows in the long-term to alleviate the potentially deleterious side effects of chronic exposure of the peritoneum and the dialysis patient to a high glucose load, e.g. fibrosis of the peritoneum and loss of function of peritoneal membranes and induction of diabetes in the patients.
For peritoneal dialysis, a high concentration of creatine is proposed herein, e.g. 24-25 g of creatine compound per liter of dialysis fluid 37° C. (up to approximately 190 mM/l) where creatine acts in the first place as an osmolyte to replace or reduce the high-glucose concentration. The crucial difference of peritoneal dialysis versus hemodialysis is that in the first case, the dialysis fluid is not in direct contact with the patient's blood system, since the peritoneal dialysis fluid is separated from the patients blood system by the peritoneum representing a biologically active filter equipped with transport systems and ion pumps. Whereas in hemodialysis the dialysis fluid is only separated by a metabolically inert and passive diffusion membrane. Therefore, for peritoneal dialysis, in contrast to hemodialysis where this should be avoided, creatine compounds can be added to the peritoneal dialysis liquid at high concentrations near saturation at body temperature. The uptake of creatine compound by the peritoneum then is a secondary but entirely wanted effect, as creatine transport through the peritoneum is not passive by simple diffusion, as in hemodialysis, but actively mediated via a specific sodium chloride-dependent creatine transporter (CRT). Thus only a very small fraction of the actual creatine compound, to which the peritoneum is exposed to, is taken up via CRT.
Most importantly this CRT-mediated uptake is governed by the actual physiological needs and requirements of the patient's body for creatine and thus no overloading by creatine compounds is possible by peritoneal dialysis, even though an excess of creatine may be offered in the fluid. This novel strategy to be able to reduce, by addition of high concentrations of creatine compounds, the exposure of the patients to very high glucose levels and at the same time allow for physiological uptake of creatine compound avoids the numerous unwanted potential side-effects eluded to below.
Chang et al., Nephrol. Dial. Transplant, 17: 1978-1981 (2002) teaches that creatine monohydrate treatment alleviates hemodialysis-associated muscle cramps (HAMC), which are assumed to be the result of disturbances in the muscle energy metabolism, intradialytic hypotension, excessive ultrafiltration and/or elevation of serum creatine kinase. For this purpose ten patients with frequent muscle cramps during hemodialysis were selected, five for the creatine supplementation group and five for the placebo group. To the creatine receiving group 12 g creatine monohydrate in 100 ml water were administered orally 5 minutes before starting hemodialysis. The authors claim that there was a 60% decrease in muscle cramps in the creatine receiving group and that serum creatinin increased from 10.7 to 12.4 mg/dl in the four week treatment period.
Next to the limited number of patients in each group (five each) it should be recognized that 12 g of creatine monohydrate are not easily solubilized at once and ingested creatine that has to be taken up by intestinal epithelial cells will take about two to four hours to reach maximal levels in the blood stream. Hence, the timing of the administration of creatine five minutes before starting dialysis is irrelevant for its alleged effect. The authors themselves admit that further long term, large-scale studies are mandatory to confirm the effects and safety of creatine monohydrate supplementation in HAMC because of the small number of patients and brief follow-up period.
US patent application 2003/0013767 A1 teaches a method of using a creatine compound to specifically treat weight loss associated with liver and kidney diseases and in this respect discloses a dialysis fluid for hemodialysis containing 1.5 g creatin/100 ml corresponding to a concentration of 114.4 mM/1. The disadvantage of such high concentrations of creatine for hemodialysis, however, are:    1) During hemodialysis, creatine may precipitate or crystallize in different parts of the hemodialysis machine.    2) Such high concentrations of creatine during hemodialysis are neither necessary nor desired because they are far from physiological and in fact are two orders of magnitudes higher than the concentrations of those serum creatine concentration that are reached post-prandial after a meal rich in fish or meat or after direct oral creatine supplementation with 5-20 g of chemically pure creatine.    3) A chronic overload with creatine is bound to down-regulate endogenous creatine bio-synthesis in the body (Guerrero and Wallimann 1998), whereas moderate creatine supplementation, even if given long-term as proposed herein, is not.    4) A chronic overload of a dialysis patient with creatine is a burden for the liver if its creatine storage is exhausted by excess creatine supply    5) A chronic overload with creatine leads to ATP-depletion, for cellular ATP will be used for phosphorylation of creatine taken up into the target organs to produce phospho-creatine (PCr)    6) Creatine overload has been shown to influence cell signaling, e.g. to activate the low-energy-sensor and cellular stress-responding AMP-activated protein kinase (AMPK), with potentially unknown side-effects, and    7) High oral dosage of creatine have been shown to influence inflammatory markers and hormone responses that may not be desired for dialysis patients
In view of the above it is the objective of the present invention to provide new means for alleviating or avoiding disorders and/or side effects directly or indirectly attributed to hemodialysis treatment. Furthermore, it is the objective to provide new medical indications and new medical compositions for creatine supplementation.
The present invention is predicated, at least in part, by the surprising and unexpected discovery that creatine supplementation at very tow concentrations to a hemodialysis solution can alleviate or avoid disorders and/or side effects directly or indirectly attributed to hemodialysis treatment, in particular mechanical, oxidative, pro-apoptotic, metabolic and immunological stress of the blood cells being dialyzed.
In view of this discovery and in a first aspect the present invention provides a new (haemo)dialysis solution comprising one or more creatine compound(s) in a concentration equivalent of 0.002 to 45 mM/l creatine, preferably of 0.05 to 40 mM/l ans most preferably of 0.05 to 20 mW creatine.
The term "concentration equivalent to 0.05 to 20 mM/l creatine" refers to a total concentration of 0.05 to 20 mM/l for all creatine compound(s) in the dialysis solution.
The term dialysis solution as used herein is any solution suitable for the safe treatment of renal failure by dialysis including hemodialysis, peritoneal dialysis, hemofiltration and hemodiafiltration. It is the solution Into which the blood solutes of small and moderate size (typically 15 to 50, preferably 20 to 35, more preferably about 25 kDa) diffuse during dialysis. It typically comprises mineral salts and buffer substance(s) In physiologically acceptable concentrations. Additionally, it may comprise nutrients, e.g. glucose and amino acids, anticoagulants such as heparin, antioxidants and other physiologically or medically relevant compounds. Naturally, its pH and osmolality is physiologically acceptable.
The creatine compound in the dialysis solution may be any physiologically acceptable creatine and/or phosphocreatine ((phospho)creatine) compound, derivative, analog and/or precursor thereof that will eventually raise the creatine and phosphocreatine level to normal physiologically healthy concentrations in the blood of the dialysis patient. For example, suitable creatine compounds and derivatives are (phospho)creatine, (phospho)cyclocreatine, homocyclocreatine, (phospho)creatine monohydrate, (phospho)creatine salts such as creatine -pyruvate, -lactate, -ascorbate, -acetate, -citrate, -hydroxycitrate, -aleurate, -phytate, -mandelate, -malate, -glycolate, -cinnamate, -salicylate, -hyluronate, -β-hydroxybutyrate, -gluconate, -choline, -camitine, -propionyl camitine, -coenzyme Q10, -adenosine, -fructose, -fructose-1,8-biphosphate, etc. Other examples are the ester of creatine-adenosine, the acid anhydride of creatine-glutamine and the acid anhydride of creatine pyruvate. Preferred creatine ascorbyl derivatives for practicing the present invention are those specifically mentioned in WO 2008/137137 A1 in claims 1 to 11, which are hereby incorporated in their entirety by reference. Further preferred creatine derivatives are those specifically mentioned in WO 2007/133731 A2 in claims 1 to 11, which are hereby incorporated in their entirety by reference, more preferably creatine-ligand compounds, wherein the ligand is selected from the group consisting of an aminoacid, a water-soluble vitamin, preferably vitamin C or a vitamin B complex vitamin, preferably, selected from the group consisting of thiamine, riboflavin, pyridoxine, niacin, vitamin B12, folic acid, pantothenic acid, biotin, resveratrol, omega-fatty acids, poly-unsaturated fatty acids, linoteic acid, S-adenosine-methionine (SAM), L-camitine, and betaine.
Preferred creatine precursors are guanidinoacetic acid, 3-guanidinopropionic acid, guanidino benzoic acid and the combination of the three basic building blocks of creatine glycine, arginine and methionine as well as their physiologically acceptable salts and derivatives. For precursors, it is noted that one or more precursors may be necessary to form one creatine compound. Hence, for precursors the term "in a concentration equivalent to 0.05 to 20 mW creatine" should be interpreted as the amount of precursors necessary for providing to 0.05 to 20 mM/l creatine.
Creatine analogs are compounds lacking creatine structure but mimicking its biological activity in vivo. Preferred creatine analogs are those specifically mentioned in EP 1 719 510 A1 in claim 2 and in claim 7 of US 2009/0005450 A1, which are hereby incorporated in their entirety by reference.
Typically, healthy humans have a fasting concentration of creatine compounds in the serum of about 20 to 40 μM/l. Upon consumption of creatine-containing food, like fish and meat, this concentration transiently increases to 1 to 2 mM/l. Erythrocytes (red blood cells) and immune cells in the blood are able to accumulate creatine inside the cell via the creatine-transporter (CRT) and due to the presence of creatine kinase (CK) in these cells, some of the creatine is converted to phospho-creatine, such that these cells contain approximately ⅔ of phospho-creatine and ⅓ of creatine. The concentration of total creatine (phospho-creatine plus creatine) in erythrocytes is approximately 0.5 to 1 mM/l, depending on the cell age, and in white blood cells approximately 0.75 to 1.25 mM/l.
Whereas creatine concentrations as high as feasible (solubility limitation) are good for muscle mass maintenance, as taught in the prior art, the concentration of creatine compound(s) of the hemodialysis solution of the invention may be much lower than the (phospho)creatine concentration in the blood of a healthy human and still be physiologically highly effective in protecting dialysed blood cells. This effect is due to the active uptake of creatine and most creatine compound(s) by blood cells. As mentioned before, under physiological conditions blood cells comprise (phospho)creatine in a concentration about 10-50 times higher than the concentration In the surrounding serum. Hence, creatine compounds in the dialysis solution of the present invention will be actively taken up by cells and thus accumulate in blood cells providing the desired cell protective and anti-apoptotic effects.
Therefore, in a preferred embodiment, the dialysis solution of the invention comprises one or more creatine compound(s) in a concentration equivalent to 0.05 to 20 mM/l creatine, 0.05 to 15 mM/l, 0.05 to 10 mM/l, preferably 0.1 to 10 mM/l, most preferably 0.1 to 5 mM/l, also preferably 0.1 to 2.0 or 0.1 to 1.0 mM/l creatine. Additionally, it is noted that the concentration range of creatine compounds in the dialysis solution of the present invention may have a lower value selected from 0.001, 0,002, 0.003, 0.004, 0.005, 0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5 mM/l and an upper value selected from 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 mM/l. All of the above lower and upper values may be combined to ranges for concentrations for creatine compounds suitable for a dialysis solution of the invention and all of the options resulting therefrom are considered as being specifically listed and fully disclosed.
Depending on the type and mode of dialysis, the extent of renal dysfunction and other physiologically parameters, a patient typically receives a volume of a dialysis solution in the range of 5 to 200 liters, regularly about 100 to 600 liters per treatment session, typically 120 to 170 l within a time period of about 3 to 8 hours. Depending on treatment duration and bloodflow (100 to 400 ml/min) 18 to 192 liters blood is regularly presented to the dialysis solution.
The skilled person is fully enabled and aware of how to prepare, adjust, sterilize, store and utilize common dialysis solutions. The principles of hemodialysis and the basic requirements for preparing dialysis solutions have been known since the late 1940s. For a more detailed discussion of hemodialysis and hemofiltration reference is again made to Kuhlmann, Walb, Luft, Nephrologie, 4th ed., chapter 15, 516, 2003 et seq. and to the sales brochure "Hämodialyse; Konzentrate and Lösungen für die Dialyse", Lieferprogramm, Fresenius Medical Care, 2008, both of which are hereby incorporated by reference.
A common dialysis solution typically comprises the mineral ions Na—, K—, Ca—, Mg—, Cl— and at least one buffering substance adjusting and buffering the pH to a physiologically acceptable value, most commonly in the range of 7 to 7.8, preferably to 7.1 to 7.5, more preferably to 7.2 to 7.4.
Because dialysis reduces the carbohydrate-based energy content of the dialyzed blood and thereby depletes the patient of energy, most dialysis solutions comprise glucose and/or some other carbohydrate source of energy. However, in the case of the dialysis solution of the present invention, the creatine compound(s), in particular the phosphorcreatine compound(s) can supplement for the lost energy. On the other hand, it is probably still beneficial to have some carbohydrate energy source in the dialysis solution of the present invention in order not to unbalance the glycolysis hemostasis in the cells. Moreover, creatine compounds have been shown to elicit pharmaceutically beneficial effects when given in combination with dextrose (glucose) (see e.g. WO 2007/133673 A2). Last but not least, carbohydrate energy sources like glucose In the dialysis solution of the present invention have the advantage that they enable blood cells to energize, i.e. phosphorylate the creatine compounds.
In a preferred embodiment the dialysis solution of the invention further comprises:                (i) Na—, K—, Ca—, Mg—, Cl-ions,        (ii) at least one physiologically acceptable buffering substance, preferably selected from bicarbonate, lactate and/or acetate, and        (iii) optionally but preferably a carbohydrate source, more preferably glucose, all of (i) to (iii) in physiologically acceptable concentrations.
In an additional preferred embodiment the dialysis solution of the present invention may also comprise any physiologically acceptable additive in physiologically acceptable concentrations, preferably additives selected from the group consisting of water-soluble vitamins, trace elements, nutrients, preferably amino acids.
As mentioned above creatine compounds suitable for use in this invention are any physiologically acceptable creatine and/or phosphocreatine compounds, derivatives, analogs and/or precursors that will eventually raise the creatine and phosphorcreatine level to normal physiologically healthy concentrations in the blood and body of the dialysis patient.
In a preferred embodiment the creatine compound(s) of the dialysis solution of the present invention is(are) selected from the group consisting of:    (i) (phospho)creatine compounds, preferably (phospho)creatine, (phospho)creatine monohydrate, (phospho)cyclocreatine, homocyclocreatine,    (II) (phospho)creatine derivatives, preferably (phospho)creatine salts, more preferably creatine -pyruvate, -lactate, -ascorbate, -acetate, -citrate, -hydroxycitrate, -aleurate, -phytate, -mandelate, -malate, -glycolate, -cinnamate, -salicylate, -hyaluronate, -β-hydroxybutyrate, -gluconate, -choline, -camitine, -propionylcarnitine, -coenzyme Q10, -adenosine, -fructose, -fructose-1,6-biphosphate, esters of creatine-adenosine, acid anhydrides of creatine-glutamine and creatine pyruvate,    (iii) creatine precursors, preferably guanidinoacetic acid, 3-guanidinopropionic acid, guanidino benzoic acid and the combination of glycine, arginine and methionine as well as their physiologically acceptable salts and derivatives, and    (iv) creatine analogs, preferably those disclosed above by specific reference.
In a more preferred embodiment, the creatine compound(s) of the dialysis solution of the present invention is(are) selected from the group consisting of (phospho)creatine compounds, preferably (phospho)creatine, (phospho)creatine monohydrate, and (phospho)creatine salts, preferably pyruvate, lactate, ascorbate, acetate, citrate and hydroxycitrate.
Most of the creatine compounds will contribute to the osmolality of the dialysis solution of the invention. It goes without saying that the osmolality of the dialysis solution of the invention must be adjusted to meet physiologically acceptable limits. Because the concentration of the creatine compounds in the dialysis solution of the present invention is very low, much lower than recommended for anti-catabolic effects, these creatine concentrations will not cause any osmolaltity problems.
In a specific non-limiting and preferred embodiment, the dialysis solution of the present invention, essentially consists of:    a) 0.05 to 20, preferably 0.1 to 10, more preferably 0.5 to 10, most preferably 0.1 to 5 mmol/l creatine compound(s),    b) 130 to 150, preferably 135 to 145, more preferably about 138 mmol/l Na ions,    c) 0 to 10, preferably 1 to 6, more preferably 1 to 4 mmol/K ions,    d) 0,5 to 3, preferably 1 to 2, more preferably 1 to 1.25 mmol/Ca ions,    e) 0 to 10, preferably 1 to 6, more preferably 1 to 4 mmol/Mg ions,    f) 0 to 10, preferably 1 to 6, more preferably 1 to 4 mmol/Cl ions, and preferably comprising    g) 0.2 to 3 g/l, preferably 0.5 to 2.5 g, more preferably 1 to 2 g/l glucose, as well as    h) 25 to 40, preferably 28 to 35, more preferably about 32 mmol/l bicarbonate ions, and    i) 1 to 5, preferably 2 to 4, more preferably 2 to 3 mmol/l acetate ions, as physiologically acceptable buffer substances, and    j) optionally further physiologically acceptable compounds in physiologally acceptable concentrationswherein the theoretical osmolality of the dialysis solution is 270 to 310, preferably 280 to 305, more preferably 285 to 300, most preferably 287 to 298 and the pH is in the range of 7.1 to 7.5, preferably 7.2 to 7.4.
Because large amounts of dialysis solutions are typically required for hospital dialyzers, it is common in the art to produce dry and aqueous concentrates for preparing dialysis solutions that are manually or automatically diluted, admixed (multiple component systems), sterilized and warmed to body temperature. In the case of less soluble components, in particular minerals such as magnesium and calcium, the about pH-neutral ready-to-use dialysis solutions are often produced and stored as acidic and/or basic solutions and/or concentrates. In particular bicarbonate-buffered dialysis solutions tend to precipitate carbonates at neutral to basic pH if stored over prolonged times. Therefore, the bicarbonate component is typically added to the dialysis solution of the dialyser only shortly before the administration of the dialysis solution to the patient. Standard commercial concentrates for dialysis solutions are multiple (mostly two) part systems, usually comprising (i) a dry or aqueous bicarbonate concentrate in a container such as a bag or cartridge and (ii) a dry or aqueous mineral concentrate in a container such as a canister optionally comprising further non-mineral components such as glucose.
The term "dialysis solution" as used herein is meant to indicate any ready-to-use dialysis solution or component of a dialysis solution that does not require further dilution before administering it to a patient in need thereof. The term "dialysis concentrate" as used herein is meant to indicate any dry or aqueous dialysis solution component that requires at least aqueous dilution and optionally addition of further components before becoming a ready-to-use dialysis solution suitable for administering to a patient in need thereof, According to the present invention the creatine compound(s) can be present in (i) a ready-to-use dialysis solution, but also in (ii) a dry or aqueous concentrate as a one component dialysis system or (iii) a dry or aqueous concentrate being part of a multi-component dialysis system for preparing a ready-to-use dialysis solution.
In another aspect the present invention is directed to a dry or aqueous dialysis concentrate comprising (i) at least one creatine compound and (II) physiologically acceptable ions and/or at least one buffering substance(s), wherein said concentrate results in a dialysis solution according to the invention upon aqueous dilution and optionally addition of further substances.
(Phospho)creatine and many of the creatine compounds for use in the present invention have a tendency to form creatinine at an acidic pH and higher temperatures by a spontaneous non-enzymatic reaction. Hence, it is of advantage to avoid creatinine formation by keeping creatine compounds in dialysis solutions and dry or aqueous concentrates of the invention at low temperatures and a neutral to basic pH. If kept as aqueous solution, it is preferably cooled to 2 to 5° C., because the chemical stability of creatine is enhanced and storage life of the solution is extended in the cold. However, even under neutral and alkaline conditions, e.g. pH 7.0 to pH 8.5, dialysis solutions and concentrates of the invention can comprise creatine compounds without significant creatinine formation for an acceptable time span that can be extended by storage in the cold.
Hence, in a preferred embodiment the present invention also relates to an acidic dialysis concentrate, comprising                (i) Na—, K—, Ca—, Mg— and Cl-ions,        (ii) at least one creatine compound,        (iii) optionally at least one physiologically acceptable buffering substance, preferably selected from bicarbonate, lactate and/or acetate        (iv) glucose,        in concentrations providing for physiologically acceptable concentrations and a pH in the range of 7.1 to 7.5 upon dilution and addition of at least one basic physiologically acceptable buffering substance, preferably selected from bicarbonate, lactate and/or acetate.
For example, acidic dialysis concentrates according to the invention can be prepared by adding creatine compound(s) in physiologically acceptable amounts to suitable concentrates.
The osmolality and pH of the acidic concentrate has to be adjusted depending on the type and amount of creatine compound(s) added.
Because of better stability a more preferred embodiment of the invention is directed to a basic dialysis concentrate comprising at least one creatine compound and at least one basic physiologically acceptable buffering substance, preferably selected from bicarbonate, lactate and/or acetate, preferably essentially free of magnesium and calcium. Most preferably, the basic dialysis concentrate of the invention is a bicarbonate concentrate. Dry concentrates have the advantage of avoiding the weight as well as the chemical and biological disadvantages attributed to water, e.g. instability of some components in aqueous environments, oxidation and microorganism growth.
In a most preferred embodiment the present invention relates to a dry dialysis concentrate of the invention, essentially free of water, preferably consisting of at least one creatine compound and at least one basic buffering substance, preferably selected from the group consisting of bicarbonate, lactate and/or acetate.
Preferably a dialysis concentrate of the invention is one for which water dilution by a factor of 25 to 60, preferably 30 to 50, more preferably 32 to 48, most preferably 35 to 45 by weight is required in order to produce a dialysis solution of the invention as described above.
In a further aspect the present invention is directed to the use of at least one creatine compound for preparing a dialysis solution or a dialysis concentrate of the invention. For said use creatine compound(s) as mentioned above are suitable, preferably creatine compound(s) selected from the group consisting of (phospho)creatine compounds, preferably (phospho)creatine, (phospho)creatine monohydrate, and (phospho)creatine salts, preferably pyruvate, lactate, ascorbate, acetate, citrate and hydroxycitrate.
In an additional aspect the present invention pertains to a method for preparing a dialysis solution or a dialysis concentrate of the invention, comprising the steps of admixing at least one (i) creatine compound and (lie) physiologically acceptable ions and/or (iib) at least one physiologically acceptable buffering substance.
Preferably, the invention relates to the above method resulting in (i) a concentrate useful for preparing a dialysis solution or (ii) a dialysis solution, said dialysis solution essentially consisting of:    a) 0.05 to 20, preferably 0.1 to 10, more preferably 0.5 to 10, most preferably 0.1 to 5 mmol/l creatine compound(s)    b) 130 to 150, preferably 135 to 145, more preferably about 138 mmol/l Na ions,    c) 0 to 10, preferably 1 to 6, more preferably 1 to 4 mmol/K ions,    d) 0.5 to 3, preferably 1 to 2, more preferably 1 to 1.25 mmol/Ca ions,    e) 0 to 10, preferably 1 to 6, more preferably 1 to 4 mmol/Mg ions,    f) 0 to 10, preferably 1 to 6, more preferably 1 to 4 mmol/Cl ions, and preferably comprising    g) 0.2 to 3 g/l, preferably 0.5 to 2.5 g, more preferably 1 to 2 g/l glucose, as well as    h) 25 to 40, preferably 28 to 35, more preferably about 32 mmol/l bicarbonate ions, and    i) 1 to 5, preferably 2 to 4, more preferably 2 to 3 mmol/l acetate ions, as physiologically acceptable buffer substances, and    j) optionally further physiologically acceptable compounds in physiologically acceptable concentrations,wherein the theoretical osmolality of the dialysis solution is 270 to 310, preferably 280 to 305, more preferably 285 to 300, most preferably 287 to 298 and the pH is in the range of 7.1 to 7.5, preferably 7.2 to 7.4.
In a special embodiment a dialysis solution comprising one or more creatine compound(s) in a concentration equivalent to 0.002 mM/l to 45 mM/l, preferably to 0.05 mM/l to 40 mM/l at 37° C. is used for hemodialysis.
Other embodiments a dialysis solution comprising one or more creatine compound(s) in a concentration equivalent to 40 mM/l to 200 mM/l 37° C. is directed to the use for peritoneal dialysis, wherein the creatine compounds are acting as osmolyte. Preferably the the concentration is equivalent to 115 mM/l to 200 mM/l at 37° C., most preferably to 120 mM/l to 200 mM/l at 37° C.
A further embodiment is directed to the use of an unsaturated dialysis solution comprising one or more creatine compound(s) for peritoneal dialysis, wherein the creatine compounds are acting as osmolyte. Said dialysis solution can further comprise one or more organic osmolytes from the following three classes of compounds:                A) polyols, preferably inositol, myo-inositol or sorbitol;        B) methylamines, preferably choline, betaine, camitine (L-, D- and DL forms), n-acetyl-camitine, L-camitine derivatives, phosphorylcholine, lyso-phosphorylcholine or glycerophosphorylcholine; and        C) amino acids.
A further embodiment is directed to a dialysis solution comprising one or more creatine compound(s) in a concentration equivalent to 40 to 200 mM/l creatine and an amount of glucose inferior to 106 g/l, preferably inferior to 62.6 g/l and most preferably inferior to 37.5 g/l.
Last but not least, one more aspect of the present invention is directed to a method of treatment comprising the step of administering a dialysis solution according to the Invention in a physiologically effective volume to a patient in need thereof, e.g. for blood detoxification. A further aspect of this invention is directed to a method for treating a patient with renal dysfunction, said method comprising                a) in a first step the oral administration of a creatine compound; and        b) in a second step the dialysis with a creatine compound.
By "treating" is meant the slowing, interrupting, arresting or stopping of the progression as well as the preventing of the onset of a disease or condition associated with renal dysfunction and/or dialysis treatment and treating does not necessarily require the complete elimination of all disease symptoms and signs. "Preventing" is intended to include the prophylaxis of a disease or condition, wherein "prophylaxis" is understood to be any degree of inhibition of the time of onset or severity of signs or symptoms of the disease or condition, including, but not limited to, the complete prevention of the disease or condition.
This and other objects of the present invention as well as additional inventive features, will be apparent from the detailed description provided herein.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.
Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention. The following example serves to illustrate further the present invention and is not intended to limits its scope in any way.

Hemodialysis and peritoneal dialysis solutions comprising one or more creatine compounds


A decorative headband is provided including an elastic and flexible band having a top edge, a bottom edge, an outer surface, and an inner surface. The band may be fitted about a forehead of a user. Next provided is a coupling mechanism mounted on the elastic and flexible band. Also included is a plurality of decorative attachments each removably attached to the coupling mechanism.

1. Field of the Invention
The present invention relates to headbands and more particularly pertains to a new interchangeable headband for adorning a small child.
2. Description of the Prior Art
The use of headbands is known in the prior art. More specifically, headbands heretofore devised and utilized are known to consist basically of familiar, expected and obvious structural configurations, notwithstanding the myriad of designs encompassed by the crowded prior art which have been developed for the fulfillment of countless objectives and requirements.
Known prior art headbands include U.S. Pat. No. 5,427,123; U.S. Pat. No. 5,377,360; U.S. Pat. No. 5,423,091; U.S. Pat. No. 5,426,788; U.S. Pat. No. Des. 343,282; and U.S. Pat. No. Des. 338,551.
In these respects, the interchangeable headband according to the present invention substantially departs from the conventional concepts and designs of the prior art, and in so doing provides an apparatus primarily developed for the purpose of adorning a small child.


An SRAM memory cell (40) uses GCMOS transistors (42, 44, 56, and 58) for improving discharge of complementary bit lines (60 and 62). The GCMOS transistors (42, 44, 56, and 58) have a graded-channel region on only the source side of the transistors. Configuring the pass-transistors (56 and 58) having the drain terminals connected to the complementary bit lines (60 and 62) and the cross-coupled transistors (42 and 44) having drain terminals connected to the memory cell outputs improves timing for a read operation of the memory cell (40).

The present invention relates, in general, to integrated circuits and, more particularly, to field effect transistor memories.
Static memory cells typically have cross-coupled transistors combined with load devices to provide data storage. The memory cell includes pass-transistors controlled by a word line for either writing data to the memory cell for storage or reading the stored data for transfer to complementary bit lines.
The length of the complementary bit lines depends on the configuration of the memory array. Long complementary bit lines have large parasitic capacitance which slows the read operation from the memory cell. Because the transistors of the memory cells are small, they are unable to charge and discharge the parasitic capacitance of the complementary bit lines in a timely fashion.
Accordingly, a need exists for improving the speed of reading data stored in a memory cell. Further, it would be advantageous to improve the speed of the read operation without increasing the size of the memory cell.

Static random access memory cell having graded channel metal oxide semiconductor transistors and method of operation


An imaging apparatus comprises an imaging device which images an image, an exterior member which contains the imaging device, an interior member which is arranged inside of the exterior member and contains the imaging device, a heat insulator arranged between the exterior member and the interior member, for thermally insulating between the exterior member and the interior member, and a cooling unit configured to cool the imaging device and the interior member respectively and radiating heat that is absorbed from the imaging device and the interior member to the exterior member independently.

1. Field of the Invention
The present invention relates to an imaging apparatus including a cooling function and a dew condensation prevention function of an imaging device.
2. Description of the Related Art
Conventionally, according to an imaging apparatus for imaging by using a solid-state imaging device, it has been known that an image is deteriorated as a temperature of the solid-state imaging device becomes higher.
Therefore, in the case of using such a solid-state imaging device, an imaging device is entirely cooled in order to prevent the temperature of the solid-state imaging device from being increased. As cooling means for this purpose, for example, a Peltier element has been known.
FIG. 1 shows a conventional imaging apparatus including a cooling structure using a Peltier element.
In FIG. 1, a solid-state imaging device 41 for imaging an image has a Peltier element 42. The Peltier element 42 serves as an element for cooling the solid-state imaging device 41, and its COOL surface is closely attached to the solid-state imaging device 41 and its HOT surface is closely attached to a surface of a base 43a of an exterior unit 43, respectively.
The exterior unit 43 has the base 43a and an exterior cover 43b. The exterior cover 43b is provided so as to cover the periphery of the solid-state imaging device 41. The exterior cover 43b has a window unit 43e with opposed to the imaging surface of the solid-state imaging device 41. The exterior cover 43b is attached on the base 43a in airtight by a screw 43c with a packing 43d interposed therebetween. A cover glass 44 is disposed at the window unit 43e of the exterior cover 43b. The cover glass 44 adheres to the window unit 43e in airtight by means of an adhesive agent or the like. The lead wires 45 and 46 are connected to the solid-state imaging device 41 and the Peltier element 42, respectively. The lead wires 45 and 46 are guided to the outside penetrating through the base 43a of the exterior unit 43, and are connected to a power source (not shown) or the like. The base 43a through which the lead wires 45 and 46 penetrate are sealed by injecting a silicon resin or the like therein so as to prevent air from moving in and out. A silica gel 47 dries a space that is sealed by the exterior cover 43b including the solid-state imaging device 41.
According to the imaging apparatus configured as described above, the solid-state imaging device 41, of which temperature rises upon imaging, is cooled by the Peltier element 42. The Peltier element 42 radiates heat that is absorbed from the solid-state imaging device 41 to the exterior unit 43, and further, the exterior unit 43 radiates the heat to air.
However, the exterior unit 43 radiates the heat to air and simultaneously, also radiates the heat to an inner space of the exterior cover 43b including the solid-state imaging device 41. Therefore, the inside of the exterior cover 43b also rises in temperature, and as a result, an internal circulation of heat is generated to increase a temperature of the solid-state imaging device 41.
Cooling of the solid-state imaging device 41 is simply represented by the following expression.
Amount of cooling of solid-state imaging device (W)=amount of heat radiation to air−amount of internal circulation of heat
As being obvious from this expression, for example, as shown in FIG. 2, Peltier output by the Peltier element 42 is increased, and as shown in FIG. 2A, a cooling temperature of the solid-state imaging device 41 is increased. As a result, the temperature of the exterior unit 43 is increased, and as shown in FIG. 2B, an amount of heat radiation to air is increased. However, as shown in FIG. 2C, an amount of internal circulation of heat within the exterior cover 43b is also increased, so that a cooling efficiency is deteriorated. If the Peltier output is further increased from this state, a difference ΔW between the amount of heat radiation to air and the amount of internal circulation of heat is saturated, and the cooling temperature of the solid-state imaging device 41 is also saturated.
Therefore, for example, technologies disclosed in Jpn. Pat. Appln. KOKAI Publication No. 7-211823 and Jpn. UM Appln. KOKOKU Publication No. 5-46381, respectively, are known.
FIG. 3 is a diagram showing a schematic configuration of an imaging apparatus disclosed in Jpn. Pat. Appln. KOKAI Publication No. 7-211823. In FIG. 3, the same parts as FIG. 1 are given the same reference numerals.
As shown in FIG. 3, a COOL surface of a second Peltier element 51 is closely attached to the outside surface of the base 43a of the exterior unit 43. On a HOT surface of the second Peltier element 51, a cooling wheel 52 is closely attached. Between the cooling wheel 52 and the outside surface of the base 43a, a heat insulator 53 is arranged so as to surround the second Peltier element 51. The base 43a, the heat insulator 53, and the cooling wheel 52 are fixed in one portion by a fixing screw 54. A lead wire 55 is connected to the second Peltier element 51.
According to such a configuration, it is possible to further radiate a portion of the heat radiation from the solid-state imaging device 41 to the exterior unit 43 via the Peltier element 42 to the cooling wheel 52.
Movement of heat in this case can be represented by the following expression.
Amount of cooling of solid-state imaging device (W)=amount of heat radiation to outside by cooling wheel+amount of heat radiation to outside by exterior unit−internal circulation of heat
Thereby, as the solid-state imaging device 41 is intensively cooled (output to the Peltier element 42 is increased), increasing amount of heat radiation to the cooling wheel 52 by the second Peltier element 51 and making the heat radiation by the exterior unit 43 even, the internal circulation of the heat is decreased. Thereby, a cooling efficiency of the solid-state imaging device 41 is improved so as to increase a cooling temperature.
On the other hand, FIG. 4 is a block schematic view of an imaging apparatus disclosed in Jpn. UM Appln. KOKOKU Publication No. 5-46381. In FIG. 4, the same parts as FIG. 1 are given the same reference numerals.
As shown in FIG. 4, a heat insulator 61 is disposed on the inside surface of the base 43a of the exterior unit 43 and the inside surface of the exterior cover 43b of the exterior unit 43.
According to such a configuration, due to a heat insulation effectiveness of the added heat insulator 61, a heat radiation amount to the inside of the exterior unit 43 can be decreased, and thereby, the internal circulation of the heat can be decreased. As a result, improving the cooling efficiency of the imaging device 41, the cooling temperature can be also increased.


A drum type image scanner includes a transparent cylinder 2, and a cylinder drive motor 16, which are concentrically and rigidly fixed with a bracket 18. The bracket 18 is fixed to a base 12 by connecting a key way 24 of the bracket 18 and another key way 42 of the base 12 with a key 46. An optical unit 10 is movable along a track rail 34 on the base 12. When the cylinder unit 4 and the optical unit 10 are attached to the base 12, the track rail 34 runs parallel to the axis of the cylinder 2 owing to the connection of the key ways 24 and 42. The structure eliminates troublesome adjustment for parallelism between the axis of the cylinder 2 and the track rail 34 and the concentricity of the cylinder 2 with the cylinder drive motor 16, thus simplifying attachment of the cylinder 2 to the drum type image scanner 1.

1. Field of the Invention
The present invention relates to a drum type image scanner, and especially to a drum type image scanner having an optical unit movable along a straight track rail.
2. Description of the Related Art
A drum type image scanner generally includes a freely rotatable cylinder, or a drum, on which a sheet of an original is mounted. FIG. 1 is a schematic view illustrating a transparent cylinder 100 applied to a drum type image scanner.
The cylinder 100 is provided with a fixture disc 102 on one end thereof. The fixture disc 102 has a cylinder support shaft 104 projecting at its opposite side to the cylinder 100, and a tapered shaft 106 at the end of the support shaft 104. The cylinder 100 and the fixture disc 102 are integrally manufactured so that the axis of the cylinder 100 and those of the cylinder support shaft 104 and the tapered shaft 106 coincide with each other.
The tapered shaft 106 is inserted into a chuck 110 connected to a cylinder drive motor and fixed with a clamp ring 112 of the chuck 110. The cylinder 100 is thus rotatably held on the drum type image scanner.
The drum type image scanner further includes a straight track rail, a track table movable along the track rail, and an optical unit fixed on the track table. The optical unit includes a light source and an optical sensor.
The drum type image scanner functions in the following manner. An original held on the circumference of the cylinder 100 is irradiated with light emitted from the light source while the cylinder 100 is rotated and the optical unit is moving along the track rail in a direction parallel to the axis of the cylinder 100 (that is, in the subscanning direction). The photosensor receives light transmitted through or reflected from the original.
In such a conventional image scanner, however, the distance between the surface of the cylinder 100 and the photosensor is not always constant throughout scanning, which causes an out-of-focus or distorted image and poor resolution. The distance change is attributable to lack of parallelism of the axis of the cylinder 100 to the straight track rail, or to mismatch between the physical central axis of the cylinder 100 and its rotational axis. The distance change is seen as circumferential deviation of the cylinder 100.
The circumferential deviation of the cylinder 100 can be ascribed to mismatch between the central axis of the cylinder 100 and the rotational axis of the cylinder drive motor. The mismatch sometimes results from foreign matters such as dust between the tapered shaft 106 and the chuck 110.
Special care is thus required to check the outer face of the tapered shaft 106 and the inner face of the chuck 110 for foreign matters when the cylinder 100 is attached to the shaft of the cylinder drive motor. After the cylinder is attached, the circumferential deviation of the cylinder 100 is checked at regular intervals during test operation so as to ensure that the distance between the surface of the cylinder 100 and the photosensor is kept constant during scanning. When undesirable deviation of the cylinder 100 is detected, the cylinder 100 is reattached to the track rail and adjusted to make the circumferential deviation within an allowable range, thereby ensuring that the axis of the cylinder 100 is parallel to the track rail. These adjustments requires time, labor, and skills.


Devices and methods for transplanting tissue for the purpose of regeneration, for treating a patient having injured myocardial tissue, and/or for improving cardiac function through cell regrowth. More specifically, the devices and methods obviate the need for cellular alteration. The devices comprise a hollow tube with a sharp distal end, a stylet that is disposed and movable within the hollow tube, and a stopping device that constrains movement of the stylet. The methods comprise removing intact tissue from a first region of a mammalian organ and implanting the tissue in a second region of the same organ.

Myocardial infarction and ischemic heart disease in adult humans can result in dysfunction and irreversible cardiomyocyte loss, which damage and weaken the heart muscle. Cardiomyocyte loss and heart damage, if untreated, can lead to congestive heart failure, a leading cause of mortality, within a few years of the myocardial infarction or ischemia.
Myocardial functionality, especially among aging adult humans, typically, cannot be restored using a body's inherent healing mechanisms. Myocardial regeneration of cardiomyocytes in adult humans is also very limited. Furthermore, myocardial transplantation is restricted by a shortage of organ donors. Accordingly, means and methods of myogenesis and/or myocardial regeneration to supplement the adult human body's natural healing capability have become the subject of intensive research and investigation.
Cell transplantation, e.g., cellular cardiomyoplasty, is a method of replacing cardiomyocytes lost due to myocardial infarction or ischemia. Succinctly, autologous cells from other parts of the body or exogenous cells can be transplanted or engrafted in the myocardium. The transplanted or engrafted cells differentiate and, for reasons that are not fully known at this time, provide functional improvement of the myocardium.
A myriad of different cell types have been used for such cellular, or cell-based, therapies. For example, cell-based therapies have included, without limitation, adult cultured cardiac and skeletal muscle myocytes or myoblasts, progenitor cells from autologous bone marrow and/or peripheral blood, cultured mesenchymal and/or embryonic stem cells.
To enhance cell-growth, extracted cells regardless of their source of origin can be artificially cultured. Cell culturing involves harvesting autologous muscle cells or tissue, blood cells, stem cells, culturing the cells or tissue in vitro or in vivo to provide a higher cell density and introducing the cultured cells in the damaged portion of the myocardium. Historic problems with cell culturing include the expense, the potentially hazardous nature of the harvesting process, the time needed to culture the cells, and the equipment needed to harvest and implant the cells.
Methods for improving myocardial functionality include retrieving myocyte micro-granules from a donor area placing the myocyte micro-granules in a fluid container and implanting the myocyte micro-granule fluid.
There is a continuing need for improvement in systems and methods for cellular regeneration of tissue.

Devices and methods for tissue transplant and regeneration