text:
|Número de publicación
|Tipo de publicación
|Número de solicitud
|Fecha de publicación
|16 Mar 2010
|Fecha de presentación
|14 Sep 2007
|Fecha de prioridad
|14 Sep 2006
|También publicado como
|Número de publicación
|Larry Azure
|Cesionario original
|Lazure Technologies, Llc
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|BiBTeX, EndNote, RefMan
|Citas de patentes (91), Otras citas (30), Citada por (33), Clasificaciones (14), Eventos legales (4)
|Enlaces externos: USPTO, Cesión de USPTO, Espacenet
This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 60/825,660, filed Sep. 14, 2006, and U.S. Provisional Patent Application No. 60/863,484, filed Oct. 30, 2006, the full disclosures of which are incorporated herein by reference.
This application is related to U.S. application Ser. No. 11,855,956, entitled "Device and Method for Destruction of Cancer Cells," filed on Sep. 14, 2007, and U.S. application Ser. No. 11/855,940, entitled "Ablation Probe With Deployable Electrodes," filed on Sep. 14, 2007, both of which are being filed concurrently herewith, the full disclosures of which are incorporated herein by reference.
The present invention relates generally to electric field delivery to tissue regions. More specifically, the present invention relates to electric field delivery and non-thermal ablation of target tissue regions, including selective ablation of cancerous cells and solid tumors.
Current tissue ablation techniques rely on a high-frequency, hyper-thermia inducing electric current to the tissue of a patient (e.g., human, animal, etc.) as a means to remove unwanted tissue or lesions, staunch bleeding, or cut tissue. There has been increased interest and activity is the area of hyper-thermal ablation as a tool to treat cancer by heat-induced killing and/or removal of tumor tissue.
In hyper-thermal tumor ablation techniques, high-frequency RF (e.g., "RF thermal ablation") or microwave sources are used to heat tissue resulting in histological damage to the target tissue. In RF thermal ablation techniques, for example, high frequencies, including about 500 kHz and greater, are used to cause ionic agitation and frictional (e.g., resistive) heating to tissue surrounding a positioned electrode. Lethal damage to tissue (e.g., denaturation of tissue proteins) occurs at temperatures in excess of about 47 degrees C., though heat generated near electrodes in RF thermal ablation can reach temperatures up to or exceeding about 100 degrees C.
A number of different cancer ablation methods and devices relying on hyper-thermal ablation or heat-induced tumor tissue destruction have been proposed. One such example includes U.S. Pat. No. 5,827,276, which teaches an apparatus for volumetric tissue ablation. The apparatus includes a probe having a plurality of wires journaled through a catheter with a proximal end connected to the active terminal of a generator and a distal end projecting from a distal end of the catheter. Teachings include a method and probe deployable in a percutaneous procedure that will produce a large volume of thermally ablated tissue with a single deployment.
U.S. Pat. No. 5,935,123 teaches an RF treatment apparatus including a catheter with a catheter lumen. A removable needle electrode is positioned in the catheter lumen in a fixed relationship to the catheter. The treatment apparatuses are taught as being used to ablate a selected tissue mass, including but not limited to a tumor, or treat the mass by hyperthermia. Tumor sites are treated through hyperthermia or ablation, selectively through the controlled delivery of RF energy.
Numerous other methods and devices are taught using hyper-thermal or heat-induced cancer tissue destruction. However, a significant limitation of RF induced, hyper-thermal ablation is the difficulty of localizing the heat-induced damage to targeted cancerous tissue while limiting histological damage and destruction to surrounding healthy, non-target tissue.
Thus, there is a need for minimally invasive ablation techniques that selectively destroy cancerous cells while minimizing damage to healthy tissue.
The present invention provides systems, devices and related methods for applying electric fields for cancerous cell destruction and tissue ablation, e.g., non-thermal tissue ablation. Devices of the present invention will generally be designed to advance an electrode or plurality of electrodes to a target tissue region and apply an electric field to the target tissue region. The electrode or plurality thereof can be positioned such that the applied electric field radiates throughout the target tissue region, including, for example, where the electric field radiates outwardly and in a plurality of directions radially through the target tissue. Additionally, the energy applied to the target tissue region can be selected such that electrically generated heat is minimized and elevations in tissue temperature can be avoided. In particular embodiments, the applied electric field is generally a low-intensity (e.g., less than about 50 V/cm) and intermediate frequency (e.g., between about 50 kHz and 300 kHz) alternating current field sufficient to provide low-power or non-thermal ablation of target cells. The electrode positioning and application of the electric field (e.g., low-power/non-thermal ablative electric field) of the present invention has demonstrated to be surprisingly effective in ablating cancerous cells can occur without a thermal effect being a factor in the ablation process. Moreover, the ablative process according to one embodiment of the present invention primarily occurs among abnormally proliferating cells or cells exhibiting unregulated growth (e.g., cancerous cells). Thus, the present invention provides the additional advantage of providing minimally invasive, selective ablation or destruction of cancerous cells, while leaving normal cells or tissue substantially intact.
In one aspect, the present invention includes methods of destroying cancerous cells of a tissue. Such a method includes applying an alternating current to a target tissue and removing liquefied tissue from the target tissue region. Methods of delivering an electric field to a tissue and destroying cancerous cells are also provided. Such a method includes positioning an electrode within a target tissue region comprising cancerous cells and applying an alternating electrical current to the target tissue so as to non-thermally ablate cancerous cells of the target tissue, and removing ablated tissue from the target tissue region. In another embodiment, a method includes advancing a probe comprising a plurality of electrodes to a target tissue region comprising cancerous cells, and deploying the plurality of electrodes to at least partially define an ablation volume. The method can additionally include applying an alternating current to the ablation volume to destroy cancerous cells within the volume, and removing liquefied tissue from the target tissue region.
The present invention further includes devices, including those for delivering an electric field to a tissue to destroy cancerous cells therein. In one embodiment, a device includes a probe having one or a plurality of electrodes positionable at a target tissue region; and a tissue removal member for removing ablated tissue from the target tissue region. Systems for destroying cancerous cells of a tissue are also provided. A system can include a probe having electrode(s) positionable at a target tissue region, an energy source coupled to the prove to provide electrical current to ablate cancerous cells of the target tissue, and a removal unit configured for removing tissue from the target tissue.
For a fuller understanding of the nature and advantages of the present invention, reference should be made to the ensuing detailed description and accompanying drawings. Other aspects, objects and advantages of the invention will be apparent from the drawings and detailed description that follows.
The present invention provides systems and devices, and related methods for low-power or non-thermal tissue ablation. According to the present invention, an electrode or plurality of electrodes can be introduced into a target tissue region and an electric field applied to the target tissue region. The energy applied to the target tissue region can be selected such that electrically generated heat is minimized and rises in tissue temperature can be avoided, thereby providing low-power or non-thermal ablation of target cells. Devices and methods of the present invention have been demonstrated to be effective in ablating cancerous cells without a thermal effect being a factor in the ablation process, with ablation occurring primarily among abnormally proliferating cells or cells exhibiting unregulated growth (e.g., cancerous cells). Thus, the present invention is advantageous in providing minimally invasive, selective ablation or destruction of cancerous cells, while leaving normal cells or tissue substantially intact.
In one embodiment, the target tissue region includes a mass or solid portion of tissue. Typically, the target tissue region includes cancerous cells including, for example, a target tissue region including a solid tumor. The volume of the tissue to be subject to the inventive methods can vary, and will depend at least partially based on the size of the mass of cancerous cells. Peripheral dimensions of the target tissue region can be regular (e.g., spherical, oval, etc.), or can be irregular. The target tissue region can be identified and/or characterized using conventional imaging methods, and various imaging systems can be used for locating and/or positioning of a device or electrodes of the invention within a patient's tissue or at or within a target tissue region.
Electrodes can be positioned as described and an alternating electric field applied. Ablation techniques according to the present invention can be accomplished in some embodiments without an increase in local tissue temperature and without thermal effects of energy application being a primary means by which tissue ablation occurs. The applied electric field can include a low-intensity, intermediate frequency alternating current. In some embodiments, electrode configuration and field application can take advantage of tumor physiology, including, e.g., orientation of dividing/proliferating cells within a target tissue region, and ensure that the electric field provided is substantially aligned with a division axis of a dividing cancerous cell.
Referring to
The present invention can include a variety of electrode compositions, configurations, geometries, etc. In certain embodiments, electrodes can include tissue-penetrating electrodes including, for example, small diameter metal wires having tissue-piercing or sharpened distal ends that can penetrate tissue as they are advanced within the target tissue region. Electrodes can be non-insulated or can include an insulated portion. In one embodiment, a non-insulated portion of the electrode provides an electric field delivery surface for delivery of electrical current to the surrounding tissue. Electrodes can be substantially rigid, e.g., so as to be more easily advanced through tissue, including hardened or more dense tissue, or can be more flexible, depending upon the desired use. In one embodiment, an electrode includes a needle or needle-like electrode or electrode having a substantially linear portion. In another embodiment, electrodes can be curved, having a curved portion or portion with a radius of curvature. Electrode composition can vary and in certain embodiments can include a memory metal (e.g., commercially available memory metals, Nitinol™, etc.) or sprung steel. Suitable electrode materials can include, e.g., stainless steel, platinum, gold, silver, copper and other electrically conductive materials, metals, polymers, etc. In certain embodiments, electrodes can be positioned in and deployable from a lumen of a catheter and/or microcatheter or other member for introducing the electrode into a tissue.
In another embodiment, the present invention can make use of one or more sensor mechanisms to provide feedback and/or control the ablation process. Sensor mechanisms can include sensors or detectors that detect and measure parameters such as temperature, current, voltage, impedance, pH and the like. Certain embodiments of the present invention can include modifying the applied electric current at least partially based on a detected characteristic or a change in a detected characteristic. In one embodiment, for example, modification of the applied electric current can occur in response to a measured temperature, impedance, and the like. Modification can include, for example, modifying the voltage, frequency, etc. of the applied current and/or discontinuing application of the electric current, for example, where the ablation process or a stage thereof is determined to be completed.
A target tissue region can be located anywhere in the body where the tissue ablation methods of the present invention would be desired or beneficial. Target tissue is not limited to any particular type and non-limiting examples can include, e.g., breast tissue, prostate tissue, liver, lung, brain tissue, muscle, lymphatic, pancreatic tissue, colon, rectum, bronchus, and the like. The target tissue region will typically include a mass or solid portion of tissue. Typically, the target tissue region includes cancerous cells including, for example, a target tissue region including a solid tumor. The term "cancerous cell", as used herein, generally refers to any cells that exhibit, or are predisposed to exhibiting, unregulated growth, including, for example, a neoplastic cell such as a premalignant cell or a cancer cell (e.g., carcinoma cell or sarcoma cell), and are amenable to the ablation methods described herein. The volume of the tissue to be subject to the inventive methods can vary depending, for example, on the size and/or shape of the mass of cancerous cells, as well as other factors. Peripheral dimensions of the target tissue region can be regular (e.g., spherical, oval, etc.), or can be irregular.
Imaging systems and devices can be included in the methods and systems of the present invention. For example, the target tissue region can be identified and/or characterized using conventional imaging methods such as ultrasound, computed tomography (CT) scanning, X-ray imaging, nuclear imaging, magnetic resonance imaging (MRI), electromagnetic imaging, and the like. In some embodiments, characteristics of the tumor, including those identified using imaging methods, can also be used in selecting ablation parameters, such as energy application as well as the shape and/or geometry of the electrodes. Additionally, these or other known imaging systems can be used for positioning and placement of the devices and/or electrodes in a patient's tissues.
As set forth above, the electrode is positioned within the target tissue region and the applied electric field is sufficient to provide low-power or non-thermal ablation of target cells. The term "non-thermal ablation" as used herein generally refers to techniques of the present invention including the removal of or destruction of the function of tissue or cells of a tissue by application of an electric field, and where the energy application/delivery process occurs without a substantial increase in local tissue temperature and without thermal effects of energy application being a significant or primary means by which tissue ablation occurs. In many embodiments, an increase in local tissue temperature can be avoided altogether, with no resulting increase in temperature being detectable in the target tissue region. In some embodiments, however, small changes/elevations in temperature in the target tissue region may occur, but will typically be no more than a few degrees C. above body temperature (e.g., less than about 10 degrees C., but typically no more than about 2 degrees above body temperature), and without the thermal effects being the primary means by which tissue ablation occurs (e.g., no significant thermally-mediated, lethal protein denaturation). Typically, the applied electric field includes a low-intensity, intermediate frequency alternating current. The intermediate frequency employed according to the present invention, for example, will be less than that typically required for frictional/resistance heating to tissue surrounding the electrode (e.g., less than about 400 kHz, preferably about 300 kHz or less). In one embodiment, for example, the electric current provides a voltage field less than about 50 V/cm. In another embodiment, the electrical current includes a frequency between about 50 kHz and about 300 kHz.
The voltage field and/or the frequency and/or the magnitude of the applied current can be held constant during energy application or varied. One or more treatment phases can be applied, with each phase having selected treatment parameters (e.g., energy parameters, duration, etc.). In some embodiments, providing a non-constant or varying voltage and/or frequency and/or current by "scanning" across a given range may be desired, for example, to ensure that the optimal ablative voltage/frequency/current is applied to the target tissue region. In another embodiment, a particular voltage and/or frequency and/or current can be selected prior to energy application. Furthermore, the electrode(s) can be positioned within the target tissue region such that electrical current application occurs from within the target tissue, and the target tissue is ablated from the inside out. In one embodiment, electrode(s) are positioned within the target tissue region (e.g., tumor) and the applied electrical current provides an electric field extending radially outward from the electrode. In certain embodiments, such positioning can take advantage of tumor physiology, including, e.g., orientation of dividing/proliferating cells within a target tissue region, and ensure that the electric field provided by the electrode is substantially aligned with a division axis of a dividing cancerous cell.
In some embodiments, devices and/or systems of the present invention include electrically floating systems or systems designed to operate without an earth grounding. In some instances, it was observed that electrode configurations that were electrically floating in this manner allowed more accurate or controllable field application and/or delivery. The low-power requirements of systems according to certain embodiments allow more design options (e.g., battery operation) in configuring devices and systems that are electrically floating, as described, compared, for example, to known techniques such as thermal RF or microwave ablation, or high-voltage irreversible electroporation that require much higher powered energy delivery and corresponding power sources.
Another embodiment of a device of the invention is described with reference to
Electrodes of a device according to another embodiment of the present invention are described with reference to
A device can include a plurality of electrodes, each deployable or retractable in and out of a microcatheter, with each microcatheter/electrode assembly optionally positioned within a central lumen of a larger delivery member, as illustrated in
In use, as shown in
The present invention can include various means of accessing or addressing a target tissue and positioning electrodes/probes for delivery of the described ablative treatment. Typically, positioning of a device of the invention will include a minimally invasive access and positioning techniques, including, e.g., access techniques commonly used with other types of tissue ablation (e.g., thermal RF ablation, microwave ablation, high-voltage electroporation, and the like). For example, devices of the invention can be introduced percutaneously through the skin and advanced through tissue and positioned at a target tissue. Though, addressing a target tissue and positioning of a device can occur in conjunction with more conventional surgical techniques or laparoscopic techniques.
As set forth above, certain embodiments of the present invention include positioning of an electrode within the target tissue region and applying an alternating electrical current, with the applied electrical current providing an electrical field that radiates outwardly from the positioned electrode. Electric field application in this manner was found to be highly effective in disrupting and destroying cancerous cells via low-power ablation and in the absence of a thermal ablative effect. In certain embodiments, disruption of cancerous cells and resulting ablation according to the present invention even more effectively occurred where the electrical field provided by an electrode of an inventive device was substantially aligned with a division axis of a dividing cancerous cell or plurality of cells.
Furthermore, the electric field application as described was observed to be particularly effective in selectively disrupting and destroying the dividing cancerous cells, while having little or no effect on normal cells that were not exhibiting unregulated growth and proliferation. Without being bound by any particular theory, electric field application as described may specifically disrupt the cell division process (e.g., mitosis) or progression through the cell cycle, or a stage or process thereof (e.g., mitotic spindle formation, microtubule polymerization, cytoplasmatic organelle function or arrangement, cytokinesis, cellular osmotic balance or the like) and, therefore, more particularly effects cells exhibiting unregulated growth (e.g., cancerous cells) and progressing more rapidly through the cell cycle.
According to the present invention, a target tissue region can be ablated in whole or in part. It will be recognized that while it is generally desirable to ablate as much of the target region or tumor as possible, in some embodiments, methods can include ablation of a portion or less than the entirety of the target region. In some instances, partial tumor ablation can be sufficient to ultimately destroy or kill an entire tumor or cancerous tissue region.
Use of a device according to an embodiment of the invention (e.g., the device of
Another embodiment of a device of the present invention is illustrated in
As the ablation process is initiated, the field intensity is highest at the inner or central electrode and within tissue around and in close proximity to the inner or central electrode. As the ablation process progresses, cancerous cells near the inner electrode are observed to be destroyed or ablated first. The ablated cells effectively "liquefy" or assume properties of a low impedance, liquid-like material. The term "liquefy" is used herein for convenience and illustrative purposes, and does not necessarily imply any particular mechanism of ablation or cell death, which may include cell blebbing, apoptosis, lysis, or some other cellular process, and/or some combination thereof. Another possible cause of cell destruction may include disruption of cellular membrane integrity, e.g., including dielectric breakdown of one or more cellular membranes (see, e.g., below). The liquid-like material surrounds the central electrode and effectively enlarges the higher field intensity ablative area, with the highest field intensity ablative area being at the outer perimeter of the liquid-like material. Thus, the liquid-like material is said to become a "virtual electrode". As the ablation process progresses, the outer perimeter of the liquid-like material or "virtual electrode" expands, essentially ablating the target tissue region from the inside out. In some embodiments, target tissue regions were observed to be more pliable and soft or mushy following the ablation process. The ablated, liquid-like tumor tissue was eventually removed from the treatment site and/or absorbed by the surrounding tissue, and no longer detectible.
The virtual electrode effect is illustrated with reference to
The ablation process, including the progress thereof, can be monitored by detecting the associated change in impedance in the ablated tissue. Once the outer perimeter of the ablated, liquid-like tissue reaches the outer electrodes defining the ablation volume, the impedance stabilizes or levels out. Thus, the progress of the ablation process can be monitored by measuring change in impedance, and electric field application discontinued once a change in impedance is no longer observed.
Feedback measurements can also be used to ensure that the ablation of the target cancerous cells occurs by non-thermal ablation. In certain embodiments it may be desirable to generate as much field intensity at the inner electrode as possible without causing a hyper-thermal effect or thermal ablation. Certain hyper-thermal effects would be observable and distinguishable from the desired non-thermal ablation of the present invention, since thermal ablation would cause destruction of the surrounding cells without the "liquefying" effect described above. For example, if cell destruction is caused by a thermal ablation process, the impedance of the treated tissue may not decrease since the impedance of cells that are charred or become necrotic due to thermal effects typically increases. In one embodiment, non-thermal ablation according to the present invention can include placement of a sensor, such as a thermocouple, within the target tissue region (e.g., proximate to the inner electrode), and selection of an applied field intensity as below the intensity that would cause thermal effects on the target cells.
As stated above, in some instances, it may be desirable to increase the field intensity emanating from the position of the inner electrode within the target tissue region. In one embodiment of the present invention, field intensity can be increased by increasing the surface area of the inner electrode that is placed within the target tissue region. Various embodiments of increased surface area electrodes are illustrated in
Another embodiment of a device of the present invention is shown in
Another embodiment of a device of the invention is described with reference to
A system according to an embodiment of the present invention is described with reference to
A control unit can include a, e.g., a computer or a wide variety of proprietary or commercially available computers or systems having one or more processing structures, a personal computer, and the like, with such systems often comprising data processing hardware and/or software configured to implement any one (or combination of) the method steps described herein. Any software will typically include machine readable code of programming instructions embodied in a tangible media such as a memory, a digital or optical recovering media, optical, electrical, or wireless telemetry signals, or the like, and one or more of these structures may also be used to transmit data and information between components of the system in any wide variety of distributed or centralized signal processing architectures.
Components of the system, including the controller, can be used to control the amount of power or electrical energy delivered to the target tissue. Energy may be delivered in a programmed or pre-determined amount or may begin as an initial setting with modifications to the electric field being made during the energy delivery and ablation process. In one embodiment, for example, the system can deliver energy in a "scanning mode", where electric field parameters, such as applied voltage and frequency, include delivery across a predetermined range. Feedback mechanisms can be used to monitor the electric field delivery in scanning mode and select from the delivery range parameters optimal for ablation of the tissue being targeted.
Methods and techniques of the present invention may employ a single device or a plurality of devices. In one embodiment, for example, a device of the present invention (e.g., device as illustrated in
Systems and devices of the present invention can, though not necessarily, be used in conjunction with other systems, ablation systems, cancer treatment systems, such as drug delivery, local or systemic delivery, radiology or nuclear medicine systems, and the like. Similarly, devices can be modified to incorporate components and/or aspects of other systems, such as drug delivery systems, including drug delivery needles, electrodes, etc.
While some embodiments of the present invention can include positioning of an electrode directly within the target tissue region, in some instances it may be desirable to apply an electric field as described above, through the target tissue region (e.g., radially), in the absence of an electrode positioned within the defined ablation volume. Referring to
While embodiments of the present invention are discussed in terms of use for non-thermal ablation and destruction of cancerous cells as described above, in some instances systems and probes can be configured for delivering energy sufficient for other types of tissue ablation, such as thermal RF ablation, microwave ablation, irreversible electroporation via high-voltage direct current, and the like. For example, a system of the invention can include a power unit configured for delivery of energy suitable for any one or more types of tissue ablations. In fact, certain probe configurations have designs (e.g., electrode arrangements) that can provide improved delivery of a various types of tissue ablation, including, e.g., improved delivery of thermal RF ablation, and the like. And treatment according to methods of the present invention can include delivery of one or more types of tissue ablations for a given treatment. In some instances, for example, treatment may include one or more ablation delivery modes, such as one mode where non-thermal tissue ablation is delivered, which can precede or follow another ablation mode, such as thermal RF tissue ablation. For example, in one embodiment, treatment can include delivery of non-thermal tissue ablation followed by a shorter application or pulse of energy to produce a thermal mediated effect, e.g., to help "sterilize" one or more components of the probe for withdrawal from the target tissue through the entry track and reduced risk of tracking any potentially viable cancer cells through tissue during probe withdrawal.
In some embodiments, systems of the present invention can further include certain components and aspects for positioning and/or stabilizing probes and other components during the energy delivery process. For example, in instances where a phase of treatment, such as energy application, is expected to exceed more than a few minutes, it may be desirable to include a positioning or stabilizing structure to maintain a probe in a desired position/location without specifically requiring a user (e.g., surgeon) to hand-hold the probe. Thus a system can include a harness, belt, clamp, or other structure to maintain probe positioning. Systems can be designed for ambulatory use so as to allow for movement of the patient (e.g., shifting, walking, etc.) during treatment. In fact, the low-power requirements and corresponding design options (e.g., battery powered system) may make the current systems particularly well suited for use as an ambulatory system.
In some instances, it may be desirable to remove ablated tissue from the target tissue region at a stage of the ablation process described herein. For example, it has been observed that, in some instances, removal of ablated tissue can improve treatment and/or recovery of the subject, and possibly reduce stress and/or toxicity (e.g., local tissue toxicity, systemic toxicity, etc.) associated with the ablation process of the present invention.
Various devices and methodologies can be utilized for removing the ablated tissue. In some instances, as described above, the ablated tissue can effectively "liquefy" or assume properties of a liquid-like material. The liquid ablated tissue can then be drained or removed from the target tissue region. In one embodiment, removal of the ablated tissue can be as simple as allowing ablated tissue to leak or ooze out of target tissue region (e.g., with or without application of a force or pressure to the target tissue region or tissue proximate thereto), for example, by leaking out holes or piercings in the tissue, including, e.g., entry holes through which the device/electrodes are introduced into the target tissue region. In other embodiments, removal of ablated tissue can be more deliberate or controlled. The removal can be accomplished using a device or apparatus separate from the ablation device, such as a syringe or other liquid removing device, or the removal can be accomplished using the ablation device further configured for the tissue removal. A device configured for removal of ablated tissue can include a tissue removal member, which can be deployable from a delivery catheter. In one embodiment, the removal member includes a catheter-like member having a lumen for carrying liquid. The removal member can be separate from or combined with other components of the device, such as an electrode (e.g., central electrode), delivery member, and the like. Various configurations of removal members capable of removing ablated tissue from the target tissue region will be envisioned and certain exemplary embodiments are described herein. It will also be recognized that while removal members are discussed with respect to use in removing ablated tissue from the target tissue region, in some instances, removal members may have additional or multipurpose functionality and, for example, may be additionally used to deliver an agent or material (e.g., drug, chemotherapeutic agent, flushing buffer, etc.) to the target tissue region.
Referring to
As described above, various configurations and embodiments of a removal member are envisioned according to the present invention. Removal members according to exemplary embodiments of the invention are described with reference to
Another embodiment of a device of the invention is described with reference to
In another embodiment of the present invention, removal of liquid and/or ablated tissue can include application of a pressure or force at or proximate to the target tissue region. As illustrated in
Referring to
The following examples are intended to illustrate but not limit the invention.
One series of testing included treatment of breast cancer tumor models. In one example, testing was done on Female Fisher-344 rats (Charles River), with body weight 230-250 grams. Rat breast cancer cells (MTLn-3) were initially grown in culture and subcutaneous tumors were produced by implanting cells from cultures into the abdomen of the animal. When the tumors grew to approximately 1 cm or greater in diameter, the ablation treatment was administered. 18 solid breast tumors in rats were treated.
Ablation treatment included insertion of an ablation probe including a stainless steel needle electrode array percutaneously, through the skin and directly into the tumor, and then applying tumor treating electric fields. The needle array included a central needle surrounded with three parallel outer needles of approximate equal spacing. Probe design, including needle length and arrangement, were selected to traverse the approximate diameter of tumors being treated and needles were about 1 cm in length. The outer needles were spaced about 0.5 cm from the central needle. The central needle was activated with the tumor treating voltage, and the surrounding needles provided the return path for the current. No earth ground was provided (e.g., electrically "floating" system) where probes were operated in "bi-polar mode" as described, and the device included a battery powered source.
Using the above described probe and configuration of needles, the treating field was contained within a cylinder approximately 1 cm in diameter and 1 cm long, the volume of which was substantially occupied the tumor. The applied AC voltage was about 10-12 volts peak, at about 20-30 mA (starting current). The frequency was about 98 Khz.
A feedback circuit was included to measure the total current into the tumor during treatment. One hypothesis from preliminary experimentation was that when tumors cells began destruction from the applied field (e.g., lyse, disintegrate, spill cytoplasm, etc.), the current would actually increase due, for example, to increased conductance within the tumor area due to contents of the destroyed cells (e.g., cytoplasm, etc.) being more conductive than cells substantially in tact. Results indicated that the circuit worked as hypothesized. The current began to increase after the start of treatment in each case, indicating that treatment was effectively taking place. Observed current increase also provided indication of when the process reached a stage of substantial completion. For example, an observation of no further increase in current indicated that treatment could be discontinued. This plateau in current was observed to occur at approximately 40 mA, and typically within approximately 90 minutes into the treatment.
Tumors began to show cell destruction almost immediately after power was applied. Significant destruction occurred within 30 minutes into the treatment. In some instances, treatment was terminated after 30 minutes and the tumors were almost undetectable. In other treatment groups, treatment was completed at about 90 minutes, or within 3 hours. In all cases the treated tumor was virtually undetectable. Controls were included to confirm that tumor destruction was a result of the applied field. In one group, needles were inserted with no power applied as a control. Continued tumor growth was observed in controls.
A group of rats that were treated were selected for long term viability study and were not sacrificed following treatment. Survival was confirmed at one point at greater than 12 months from the date of treatment, which was >17 times the expected survival in the animal model when not having any treatment (e.g., about 3 weeks). These rats currently remain alive. Survival observations and histological analysis (e.g., see below) indicated destruction of a vast majority, if not substantially all, of the cancer cells within target tissue subject to treatment as described.
As noted above, treatment typically resulted in a sort of liquification of cancerous cells/tissue. Following treatment, a clear to pinkish fluid was observed present in the target tissue region subject to treatment, which could leak from needle entry locations and further excreted upon compression or application of pressure to the treated region. Histological analysis was performed on the fluid and the tumor area after treatment. The histology showed that the fluid primarily consisted of destroyed cancer cells, with destroyed cells appearing substantially necrotic and non-viable. Testing of pH indicated that the removed fluid was more highly alkaline (e.g., pH of about 7.8 or greater) than typical physiological fluids. Observed treatment areas were about 80-90% necrotic or non-viable cancer cells. The treated area which was not necrotic (e.g., typically about 10-20% of target tissue) appeared to be the part of the area which was healthy, non cancerous tissue. Thus, the results indicated a selective destruction of cancerous cells, while leaving healthy cells substantially unharmed or viable.
The observed treatment appeared to have no significant side effects. Surviving subjects not sacrificed for further analysis have exhibited no debilitation or any noticeable signs of negative side effects (viability, behavior, or otherwise) after treatment. No significant distress or discomfort, or irritation of the treatment region, due to application of energy was observed in the subjects. During treatment the rats appear comfortable, i.e., eating, drinking, and sleeping even though they are not anesthetized during treatment.
The only observation of a potential side effect appeared to be a result of non-removal of the fluid or ablated tissue following treatment. When fluid was not removed from the treatment region following treatment, subjects appeared lethargic for several hours and recovery time was increased compared to rats subject to fluid removal following ablation treatment.
As noted above, treatment as described was observed to be selective in destroying cancerous cells within a defined target tissue region. Without being bound by any particular theory, one or more reasons could explain the selective nature of the described treatment. One reason for the observed selectivity appeared to be design of the ablation probe—treatment was substantially confined to a treatment volume as defined by the positioning of the electrodes. Only the tissue is within the probe's outer electrodes appeared to receive the delivered energy and that is the area the electric field almost exclusively covers. The field does not appear to extend outside of the volume defined by the outer electrodes.
Second, selectivity may be inherent to the mechanism of cell destruction. The cell ablation is distinguished from a primarily thermal-mediated ablation as performed in known high-frequency RF thermal ablation, or microwave ablation techniques, nor is the effect due to high voltage irreversible electroporation by application high voltage direct current as has been previously described elsewhere. All of these previously taught methods, by design, destroy normal tissue as well as cancer. Techniques of the present invention make use of voltage, power and frequency ranges that are not within the range of thermal or high voltage ablation.
Furthermore, without being bound to any particular theory, additional cellular-level effects of the current techniques may cause selective destruction of cancerous cells compared to non-cancerous cells. The energy application as described herein appears to mediate breakdown of the cell membrane integrity. One potential reason for the breakdown of the cell membrane and/or destruction of cancer cells may include disruption of cell cycle progression and cell mitosis by the applied electric field, with the disruption triggering cell destruction (e.g., necrosis, apoptosis, disintegration) as has been observed herein. Since cancer cells in a tumor are actively dividing and proliferating and, therefore actively progressing through the cell cycle/mitosis at a much higher rate compared to orders of magnitude slower rates of non-cancerous or healthy cells, this energy application as described can be selective to cancer cells.
Another possible cause of cell destruction may include dielectric breakdown of the cellular membrane. Cell membranes are known to have a dielectric breakdown threshold, above which the cell is destroyed. A normal cell typically has a higher threshold than a cancer cell. Thus, it is possible to selectively breakdown a cancer cell membrane without harming a normal cell where the applied energy is above the dielectric breakdown threshold for cancerous cells but below that of normal/healthy cells. Breakdown in membrane integrity resulting from treatment as described herein may occur in both extracellular membranes as well as intracellular membranes, for example, causing rupture of lysosomes containing components (e.g., degradative enzymes, etc.) that further lead to cell destruction. Rupturing of cells and spilling of cellular contents can negatively effect nearby cells, resulting in a sort of cascade of cellular destruction. Treatment may also stimulate an immune response that can "clean up" the treatment region and may further destroy any residual/viable cancer cells not destroyed or removed. Other disruptions and/or mechanisms of action may also occur. Regardless of any particular mechanism of action, where cellular disruption occurs as described, the resulting fluid appears to further act in some instances as a sort of virtual electrode, making the electrode larger and larger in diameter, and finally substantially covering the entire target tissue region.
It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are included within the spirit and purview of this application and scope of the appended claims. Numerous different combinations are possible, and such combinations are considered part of the present invention.
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|Clasificación de EE.UU.
|607/115, 606/41, 607/116
|Clasificación internacional
|Clasificación cooperativa
|Clasificación europea
|15 Nov 2007
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text:
Has anyone had any experience with these pedals? Pro's? Cons? I've found a new cheap set and are considering replace my stock no-name brand ones. Just by looking at them I can tell that these pedals are for freeriding, dirt jumping and possibly downhill riding.
I'm not too sure about using these for XC, but I have heard they grip really well. The pedals I have now just don't suit me. Do most pedals fit on most crankarms? I really wouldn't mind having these pedals, they do look great, but would you recommend for XC?

subset: commoncrawl


text:
Don't worry about it.
Mod Review on Apr 7th, 2012
No review provided
Mod Review on Jan 6th, 2012 - 2 people agree
Those 1 out of 10 reviews are pretty much jokes. Unfortunately, They bring down the score by a decimal or two.
I am reviewing the current content here. So far, so amazing. This is professional grade stuff, and I can't wait to see what's in store for heroes and space. =)
Game Review on Jan 31st, 2011
Mod Review on Dec 11th, 2010
No review provided


text: Comments (1) + Add comment Comments (1) Featured Dragun619 + 1901d ago Looks like models for PS3 are looking pretty close to the CGI models. Glad there gonna upscale the game to HD. Always wanted to get this game last gen but never got around to picking it up. Gonna get this on PSN soon as it releases. #1 Agree(1) | Disagree(0) | Report | Reply Add comment You need to be registered to add comments. Register here or login Username Password Remember Rules & guidelines Login


text:
I'm not sure why any successful photographer would feel the need to be arrogant on a forum made up of mostly hobbyists, but often, those concerned with technique and science don't get on with the artists.
The person who commented about wanting to 'emulate' a photographer may not understand that this person could have spent his whole life developing his style, technique and art. His rudeness may have been a reaction to somebody trying to find out his secrets. In the same way, those concerned with photography as an exact science may be rude to very talented photographic artists with great eyes, natural ability with a camera, but lacklustre technique. The 'scientists' might be miffed that all their time spent learning the science hasn't paid off so much in terms of compelling photography.
This is without a doubt the best resource for the craft, with lots of very knowledgeable people always willing to share, but the artists tend to get what they need from APUG and carry on with their voyage into expressive photography.


text:
| The touchy subject of
|Key concepts
|Racism and racists
The term race refers to the scientifically-obsolete idea that it is possible to divide humanity into clear, well-defined groups based on a haphazard variety of traits, most commonly in terms of physical characteristics having to do with skin color. Besides physical characteristics, ideas about racial identity may be based on things like a hypothesized common ancestry, language and self-identification.
While people have and continue to ascribe assumptions about mental aptitude and moral characteristics onto individuals based on their racialized identity, the main biological difference between darker-skinned humans and lighter-skinned humans is that the latter will be more prone to sunburn but will be able to more quickly produce usable vitamin D from sunlight.
Well into the twentieth century, it was common to think of "the French race" or "the German race." Nowadays, these identities are more likely to be thought of as manifestations of ethnicity or ethnic group. This isn't just the same concept disguised with political correctness. The idea of ethnicity takes into account cultural identification, language, and religious beliefs — you can, in principle, belong to multiple ethnic groups — whereas an individual's race is thought to be essential based on physical difference.[1] Ethnicity is still as arbitrary and useless as a system of classification as "race," but used in context it doesn't really pretend not to be.
"Race" — in the sense of ancestry — is still used when assessing suitability for bone marrow transplants and other medical purposes.[2]
[edit] Identification of "races"
The races as we know them are products of relatively recent history. When the intellectual center of Europe was located in Greece and the eastern Mediterranean, it was generally perceived that skin colors formed a continuum. The ancient Egyptians placed themselves between Nubians and Greeks in skin color, and noted that they had features that did not appear in either. Aristotle observed that "(t)he nations inhabiting the cold places and those of Europe are full of spirit but somewhat deficient in intelligence and skill, so that they continue comparatively free, but lacking in political organization and capacity to rule their neighbors."[3] Pliny the Elder tells of an African, the boxer Nicaeus, who married a white Greek woman; their children appeared white, but darker skins appeared in the second generation.[4] Race as we know it is a post-classical and western European phenomenon. It owes its existence in part to the fact that a vast, sparsely inhabited desert fills inland western Africa, and that during the rise of Western Europe as a global power, the western African coast was populated by hostile Muslims. The dark Africans of the equatorial regions of west Africa were seen as vastly different.
As Western Europeans began to exert power around the globe, they directly encountered people of a variety of different appearances. At that time, geographical origins were a more likely way for Europeans to classify people than was "race." As European colonization and the trans-Atlantic slave trade began to define global relationships in the modern world, Europeans began to rely on the idea of "biologically distinct races," including such constructions as "Negroids," "Caucasoid," and "Mongoloids," a classification system which was developed by Blumenbach based on his studies of skull morphology.
This simple classification system failed in one significant area, however. Darker-skinned Europeans from southern Italy and southern Spain, Indians, and significantly Dravidic Indians clearly were not "Caucasian" but they were also not "Negroid." To the "American," these peoples, who increasingly emigrated to the United States in the early 20th century, were clearly "not like us," but were also "more like us than primitive blacks." Depending on the needs of the day, they would be tossed in with the "Negroid," or tossed in with "Caucasian." Jews, Arabs and Indians (from India, not Native Americans - they were just "savages"... unless they happened to be Algonquin, in which case they were "white" because the most powerful families from Plymouth had intermarried with the natives) fell into this strange place of not belonging to any "race." The US Supreme Court even ruled in U.S. v. Bhagat Singh Thind (1923) that Caucasian Indians were not "white" within the meaning immigration law, as, despite anthropologists classifying them with "white" Europeans, they were not considered that in the view of the "common man" which is apparently what counted. Seriously.
This not only led to Caucasian Indians now being ineligible for naturalized citizenship, but denaturalization of some immigrants already made citizens. Congress did not lift this restriction until 1946, when India was on the verge of becoming an independent country.[5]
[edit] "Race" vs. species
As there is only one extant human species, each human is genetically and physically capable of breeding with a fellow human (of the opposite sex and barring infertility obviously). Therefore it is difficult to see, from an objective taxonomical view, how humanity can be conclusively and objectively sub-divided into "races" based on the varying definitions that different societies have applied over time. Even if "race" is taken to mean subspecies, no modern subspecies of humans have been reliably identified.[6] Even if humans might have been divided into subspecies in the past, this is not the case today; with very few exceptions human populations are not isolated from one another, and no matter how upset some people might get at the idea, this means human populations are not genetically isolated either. A hundred generations from now, virtually all humans will have ancestors from virtually all "races". More recent (2009) studies from HUGO have determined significant shared ancestry patterns between Indians and Europeans (Caucasians) and East Asians.[7] Essentially, the term "race" is no more than a social invention, one which changes depending on the society and over time. Most people in the west will recognize "Chinese" as a "race," but in China you will find Hui, Han, Miao, Zhuang, and almost countless other "races" which are — to the Chinese — just as distinguishable as black and white is in America and Europe.
Typically, "race" is only used by more powerful groups in an attempt to provide some legitimacy for denigrating, controlling or exploiting others. It would be more difficult to start an effective slave trade, for example, if there wasn't a way of distinguishing people (however arbitrarily) in a way to legitimise it.
[edit] Racists
Racists exist and thrive in nearly every, if not every, country in the world. Along with religious affiliation/discrimination and nationalism, racism is among the most popular forms of tribalism in the world. Since "race" is arbitrary, any group of people that seek to identify "otherness" in another group of people can use racism to their own ends, by labeling the group they don't like as belonging to a certain "race."
The concept of "reverse racism" is an exceptionally silly one, implying that there is one correct or even one predominant way in which racism flows (usually assumed in the Western world to be whites discriminating against non-whites, especially blacks). If you take the definition that racism involves purely holding views of the superiority or inferiority of certain "races", no one group of people have a monopoly on racism. This gets more complicated, however, when bringing in the concept of privilege and social power- essentially, some sociologists, usually members of various social justice movements, define racism as "prejudice plus power", meaning that members of underprivileged ethnic groups who are racially prejudiced against the dominant ethnic group are not defined as racists.
[edit] Racist works
Apart from the various awful screeds such as Mein Kampf and the The Protocols of the Learned Elders of Zion, there have been several scientific attempts to link "race" and IQ (even though both are extremely imprecise measures). The Bell Curve, a book by Richard J. Herrnstein and Charles Murray, is a recent attempt at this flawed concept.
[edit] "Race-based medicine" and geographic ancestry
A topic that has been controversial (for both social and scientific reasons) is so-called "race-based medicine." Currently, some doctors may use racial profiling as a proxy for determining the geographic origins of the patient's lineage to diagnose and treat certain diseases.[8] However, this is not the same thing as "race." The researchers at the Human Genome Project sum it up:
""DNA studies do not indicate that separate classifiable subspecies (races) exist within modern humans. While different genes for physical traits such as skin and hair color can be identified between individuals, no consistent patterns of genes across the human genome exist to distinguish one race from another. There also is no genetic basis for divisions of human ethnicity. People who have lived in the same geographic region for many generations may have some alleles in common, but no allele will be found in all members of one population and in no members of any other.[6]
The word cline[wp] is sometimes used to describe this. To put it more succinctly, as the leader of the Human Genome Project, Francis Collins does:
""'Race' and 'ethnicity' are poorly defined terms that serve as flawed surrogates for multiple environmental and genetic factors in disease causation, including ancestral geographic origins, socioeconomic status, education and access to health care.[9]
Sickle-cell anemia is a famous example of how "race" can mislead. It was originally classified as a "negro disease" due to its high incidence in blacks. However, it was later found that sickle-cell anemia, being an adaptation to the risk of malaria, was also more common in central and western Africans (but not southern Africans) as well as Mediterraneans (Turks, Greeks, etc.) and Indians. Thus, the disease was not an indication of "race," but of geographic ancestry (in this case, areas where malaria was more common).[10]
It should be noted that all human classifications used in medicine are considered probabilistic heuristics and not perfectly deterministic. While research has shown that many people are extremely effective at classifying themselves based on ethnic origin[11] and so researchers may find "race" to be a convenient label, it fails as a source of attribution: "[R]ace as a social construct may result in differences in treatment that affect health outcomes, but such descriptive use does not imply that "race" can be used as a proxy for biological difference."[12]
"Race" will continue to exist as a cultural phenomenon; while great care should be taken in using this construct in medicine, it would be counter-productive to discard potentially useful information, such as the way in which racial identity shapes social, legal and economic outcomes. Unfortunately, the knotty history of "race" makes even the language used into a potential source of error - "race realists" often point to a news headline or study that uses "race" sloppily and declare it to be "evidence" of the truth of "race," mastering sufficient jargon to talk about the reality of "genetic clines" and missing the fundamental mismatch between "race" as culture and "race" as genetic destiny.
[edit] See also
[edit] External links
- American Anthropological Association's statement on "race"
- Is Race "Real"? a forum by the Social Science Research Council
- What Can DNA Really Tell Us About Race? Troy Duster, UCtelevision
- Anthropology and Race, Anthropology Report
- Race, the human spectrum
- Biological Anthropology: Human Nature, Race, Evolution
- Is race a social invention? A video discussion by a PhD biological anthropologist going into the problems with attempting to define race biologically.
- Lynn B. Jorde and Stephen P. Wooding. Genetic variation, classification and 'race'. Nature Genetics 36, S28 - S33 (2004)
- Kenneth M. Weiss and Stephanie M. Fullerton. Racing Around, Getting Nowhere. Evolutionary Anthropology 14:165–169 (2005)
[edit] Footnotes
- ↑ Which is why people of mixed racial background are so unsettling to the system.
- ↑ Bone Marrow Transplants: When Race Is an Issue
- ↑ Aristotle, Politics, book 7.
- ↑ Pliny the Elder, Natural History, book VII.
- ↑ Not All Caucasians Are White: The Supreme Court Rejects Citizenship for Asian Indians
- ↑ 6.0 6.1 Human Genome Project Information: Minorities, Race, and Genomics at the Wayback Machine (archived April 30, 2013)
- ↑ Mapping Human Genetic Diversity in Asia, The HUGO Pan-Asian SNP Consortium, 2009
- ↑ Race-Based Medicine: A Recipe for Controversy, Scientific American
- ↑ Francis S. Collins. What We Do and Don't Know About 'Race', 'Ethnicity', Genetics, and Health at the Dawn of the Genome Era. Nature Genetics Supplement, vol. 36, no. 11, Nov. 2004
- ↑ Race and Gene Studies: What Difference Makes a Difference? by Larry Adelman
- ↑ "Genetic Structure, Self-Identified Race/Ethnicity, and Confounding in Case-Control Association Studies", American Journal of Human Genetics. Hua Tang, Tom Quertermous, et al. 2005.
- ↑ "Defining Human Differences in Biomedicine", PLoS Medicine. Brown M. 2007. 4 (9): e228.


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Whether it's the result of poor editing or an outright oversight, hundreds of movies contain glaring plot holes, which baffle viewers and leave audiences with lingering questions. While many tiny holes and logical inconsistencies tend to go unnoticed, the largest ones are often debated over and over again among film buffs.
How did we get from this scene to the next? Don't they have weapons they can use? Isn't she contradicting what she said earlier in the movie?
Many minor plot holes stem from issues with continuity between scenes; watch the deleted scenes later, and there's the answer to your lingering question. Then, there are some that just can't be explained.
Check out which plot holes annoy us the most in the gallery below, and tell us in the comments which movie plot holes bother you the most. Did we miss any?
This film is chock full of questionable scenes, from policemen charging into hand-to-hand combat against tanks to Bruce's on-again, off-again limp. But the biggest plot hole may be the overall passage of time. How did Bain transport Bruce to the underground prison halfway across the world and return to Gotham so quickly? And how did Bruce have time to return to Gotham and do everything he needed to do? Read six other lingering questions HuffPost Entertainment's Mike Ryan had about "The Dark Knight Rises."
We know the machines chose 1999 so humans do not reject the dreamworld, but why didn't they chose a time when humans were less computer-savvy, i.e. capable of overthrowing the system?
Okay, Eddie; we get that you're now using 100 percent of your brain, making you one of the smartest people on Earth. So why didn't you stop to consider another way of accumulating $100,000 to bolster your stock investments rather than borrowing it from a Russian mobster?
So what happened to Uncle Ben's killer? We never find out after Peter abandons the quest to save New York City from Dr. Curt Connors who turns himself into a giant lizard. And don't even get us started on Peter's "choice" of search engine in the film. Though it may not be a plot hole, it's pretty questionable. Read five other lingering questions HuffPost Entertainment's Mike Ryan had about "The Amazing Spider-Man."
Go on, pick a time travel movie -- "Looper," "Back to the Future," "Men In Black 3." Pick. Any. Movie. You will find a plot hole. It is just nearly impossible to construct a completely plausible time travel movie without holes.
The entire movie is a plot hole. But specifically, when the "future cavemen" find 1,000-year-old jet fighters that they then fly in battle against an alien super power -- and win. How did they know what the jets were? How did they know how to fly them? How could the fighters even work after 1,000 years of neglect? How could they defeat alien technology?
A computer virus destroys an entire alien ship ... really? And where did David connect the device that uploaded the virus. We doubt they sell alien ports at Best Buy.
The scene where the boat arrives with an all dead crew and unloads a T. rex to wreak havoc? How exactly was the crew killed if the T. rex was initially locked up? You'll have to watch the deleted scenes to find out ...
The sequel's storyline creates a number of plot holes in the first film. Where's Rick's tattoo in the first film (hint: not on his forearm)? If Evelyn is the reincarnation of the Egyptian princess, why didn't Imhotep recognize her in the first film? The list goes on, and on ...
If paper is such a rare commodity, why are the 'Smokers' smoking what seems like an endless amount of cigarettes?
The entire movie is based on Kane's famous last word, "rosebud." However, Kane died alone. So who was there to pass on what he said?
As Mel Gibson's character discovers later in the film, the aliens invading Earth are harmed by water. Did they not realize this weakness before invading a planet that is covered in water? What happens if it rains -- wouldn't their entire invasion be thwarted? While there are several theories floating around the Internet that attempt to explain this plot hole -- maybe the aliens were peaceful -- another running theory counters that there was no invasion and the film is actually an allegory.
In the remake, Nicole Kidman's character comes face-to-face with her robot, but in the end, the wives return to normal once their microchips are fried. So which is it? Are they brainwashed by implanted microchips are replaced entirely by robots?
Feeding the Mogwai after midnight -- isn't it always after midnight somewhere in the world? Technically, if they're on Asian standard time, then feeding them after 12 a.m. EST actually means they were fed at ... oh never mind. There's just too many things wrong with this scenario.
If he can't store new memories how does he know he has anterograde amnesia?
The ending tried to disguise the fact the film had no plot. "It was all a dream!" A deus ex machina "twist" to mask the fact an entire movie was built on one big plot hole.
Like many time travel films, movies surrounding future timelines and predictions tend to be ripe with plot holes. "Minority Report" is no different, with the precogs predicting a future -- or at least future intentions -- that never comes to pass.
"The Dark Knight Rises" is not the only movie in Christopher Nolan's Batman trilogy that contains major plot holes. In the second film, when the Joker shows up at the fundraiser looking for Harvey Dent, he threatens Rachel, ultimately dropping her out of a window. Batman jumps after her, catching her in time to break her fall. But what happens to all those people still at the fundraiser? Did the Joker and his goons just shrug and leave?
While there are certainly other plot holes in the "Alien" series to point out, one of the biggest one occurs at the beginning of the third film. The movie shows one alien egg hanging on the wall in the sleep chamber. But how did it get there from the last film when the Queen never had the opportunity to leave an egg to in her wake?


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FIRST AID, CPR, AND PERSONAL SAFETY - Sheridan College PPT
Presentation Summary : Title: FIRST AID, CPR, AND PERSONAL SAFETY Author: Gary Wolfe Last modified by: Gary Wolfe Created Date: 9/20/1998 3:04:41 AM Document presentation format
Source : http://www.sheridan.edu/site/assetlibrary/nwccd/offices/msha/First%20Aid.ppt
CPR/First Aid - Career and Technical Education PPT
Presentation Summary : Community First Aid & Safety Consider this: The most important step you can take in an emergency: Bystander's Part in the Chain of Survival Did you know . . . ?
Source : http://cte.unt.edu/content/files/_HS/curriculum/CPR_First_Aid.ppt
CPR/AED/First Aid Training - Site Under Maintenance PPT
Presentation Summary : CPR/AED/First Aid Training by Rob Sundquist, MS ATC LAT Director of Sports Medicine/Head Athletic Trainer Creekview High School Chain of Survival The chain of ...
Source : http://cfbportal.schoolwires.net/cms/lib04/TX01001392/Centricity/Domain/2549/CPR_powerpoint.ppt
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Presentation Summary : Title: First Aid and CPR Subject: Health Care Science Technology: Career Foundations Author: Kathryn Booth Last modified by: LPS Lincoln Public Schools
Source : http://isite.lps.org/twiese/web/documents/Chapter04FirstAidandCPR.ppt
First Aid Awareness – April (ppt) - University of ... PPT
Presentation Summary : First Aid Awareness First Aid Safety Meeting Topic Use of UCOP first aid kits General awareness on what to do if: You have minor injuries; Co-workers or family ...
Source : http://www.ucop.edu/risk-services/_files/bsas/safetymeetings/firstaid_awareness.ppt
CPR and First Aid Guidelines PPT PPT
Presentation Summary : CPR and First Aid Guidelines . Emergencies happen all too often, and early intervention can save a life.
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Presentation Summary : CPR Introduction Mr. K ASU basketball game Student: You saved my child's life Introduce Annie CPR Training Precautions Do not practice on a person Clean faces ...
Source : http://www.clt.astate.edu/hadams/First%20Aid/CPR-3.PPT
Integration of EMS into School Coordinated School Health PPT
Presentation Summary : CPR. Emergency Procedures. Health Issues in Community. Education of Kids. First Aid. CPR "Hands Only CPR ...
Source : http://www.rhat.org/getattachment/98c5373a-727f-465e-b98d-e44c8a1d8ea5/Integration_of_EMS_into_School_Coordinated_School_Health.pptx.aspx
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Source : http://www.nsc.org/Chapters%20Site%20Document%20Library/Orientation-10-8-13.ppt
First Aid + CPR - OSHA Training PPT
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Basic First Aid - Middle Georgia State College PPT
Presentation Summary : Basic First Aid for Medical Emergencies Slide Show Notes When a serious injury occurs, you have to think and act quickly. Medical assistance may be only minutes away ...
Source : http://www.mga.edu/risk-management/docs/safety-powerpoints/Basic_First_Aid.ppt
First aid and CPR - United States Mine Rescue Association ... PPT
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FIRST AID AND HEALTH - United States Navy PPT
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I'm huge into camping I love going out into the woods and having fun with friends, or having people over in the backyard with a few drinks or a fire going, but I also love spending time indoors relaxing watching a movie especially with someone. I'm a major coffee drinker, I love coffee pretty much any time of the day. I enjoy going out and hunting as well. I like going out for a walk with my dog, he is amazing and I've had him since he was a little puppy. I enjoy the theater (like plays not just movies) I enjoy traveling but only because the couch is so far from the fridge.
If you want to know more about me just ask I would love to answer. Feel free to message me I'll always try to reply.


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Chronicle of the Gatekeepers Sidetrek: Speaking the Same Language (PFRPG) PDF
Bite Me! The Gaming Guide to Lycanthropes (PFRPG) PDF
Eidolons (13th Age) PDF
Zephyrus Base Class (PFRPG) PDF
Andrew Boucher 88
2300 AD RPG: Ranger
Megan Robertson
619 posts. Alias of eakratz.
F +6; R +6 (+7 traps); W +1 (+3 fear)
AC 20 (22 CE); TAC 14; FFAC 15; CMD 20 (22 vs dirty trick)
hp 37/37 | Temp 0 | NL 0
Half-orc Fighter-Rogue 2/3
(lore-warden-scout archetypes)
CG med humanoid
Int +2 Senses Darkvision 60 ft; Perception +7 (+12 sight)
AC 19 (21 CE)(+5 Armor +2 Dex +1 amulet +1 ring) (19 vs traps), flat-footed 15, touch 13
hp: 37 (f.c. lvls 1,4,5)
Fort +6 Reflex +6 (+7 traps) Will +3 (+5 fear)
Defensive abilities ferocity
Speed 30 ft
Melee Tempest +8 (+6 CE) (2d4+5+1d6 cold/18-20)
Ranged +6
Special Attacks Sneak Attack 2d6
Str 15 Dex 14 Con 12 Int 13 Wis 8 Cha 14
BAB +4 CMB +8(+10 Dirty Trick) CMD 20 (22 dirty trick)
Feats Catch Off-Guard, Improved Feint, Improved Dirty Trick, Combat Expertise, Dodge, Mobility, Spring Attack
Rogue abilities Trapfinding +1, Evasion
Rogue Talents Combat Trick (mobility)
Traits Brute, Nightstall Urchin
Skills (9/3 rog lvl +3/1 ftr lvl + 4 l.w.= 37)
3 Acrobatics +8 (+13 to jump)
5 Bluff +10
2 Climb +7
2 Diplomacy +7
5 Disable Device +11 (+13)
4 Intimidate +13
2 Knowledge (local) +6
2 Knowledge (dungeoneering) +6
5 Perception +7 (+12 sight)
2 Sense Motive: +4
1 Sleight of Hand +6
4 Stealth +9
1 Swim +6
Languages Common, Orc, Kelish, Gnoll
+1 Frost Falchion Attack +7 Dmg 2d4+4+1d6cold crit 18/x2
Dmg 1d6+2+2d6 (add +1 if used two-handed)
-- Masterwork Dagger--
Dmg 1d4+2 crit 19/x2 range 10 ft
Attack +6
Dmg 1d4+2 crit 20/x2
Range 50 ft
Traits: Brute +2 Intimidate; Night Stall Urchin - You gain a +2 trait bonus on saves against fear effects, and when you do make a successful save against a fear effect, the resulting rush of bravado grants you a +1 trait bonus on attack rolls and all skill checks for the next minute.
1228.61 gp
Hat of Disguise
Ring of Featherfalling
Chain shirt +1
Potions of CLW x5
Potion of CMWx3
Wand of CLW
Cloak of Resistance
potion of Cloak of Shade - reduces heat exposure by one level
Masterwork Backpack
Masterwork Thieves tools (+2 DD)
Trail Rations x5
Thieves tools
Belt pouch
Hot Weather Outfit (sandals, dark linen slacks, light linen shirt, brown leather vest, red silk sash, white turban)
Glass Bottle
Chain of office with Kelmarene emblem
50 ft of silk rope
2 sacks
Eyebrow rings of Eagle Sight
Ring of Jumping
Ring of Protection +1
Amulet of Natural Armor +1
P. of Invisibility
2 smokesticks
P. of Spider climb
MW cold iron flail
Lt wooden shield
P of True Strike
P of Expeditious Retreat
One day his expoits caught up to him. He was knocked unconscious and when he woke, he was being dragged along by gnolls to be tossed into a cage
Map of Kelmarane
son: Aab-i-Hayat
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