text:
|Publication number
|Publication type
|Application number
|Publication date
|May 2, 2006
|Filing date
|Aug 6, 1998
|Priority date
|Oct 30, 1996
|Fee status
|Also published as
|Publication number
|H. Craig Dees, Eric A. Wachter
|Original Assignee
|Xantech Pharmaceuticals, Inc.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (48), Non-Patent Citations (45), Referenced by (15), Classifications (14), Legal Events (8)
|External Links: USPTO, USPTO Assignment, Espacenet
This is a continuation-in-part of U.S. patent application Ser. No. 08/739,801, filed on Oct. 30, 1996, now U.S. Pat. No. 5,829,448-Nov. 3, 1998 entitled "Method for Improved Selectivity In Photoactivation of Molecular Agents".
The present invention is directed to a method and apparatus for treating pigmented tissues by selective photoactivation of pigments in such tissues using optical energy and more specifically two-photon excitation. This selective photoactivation may be used to effect photobleaching of such pigments or to effect photochemical conversion of such pigments into phototoxic products. Photobleaching reduces or eliminates undesirable pigmentation, for example that caused by pigments present in moles, freckles, hair follicles and tattoos. Photochemical conversion produces phototoxic products that destroy pigmented tissues, such as those pigmented tissues in pigmented tumors. The present invention is also directed to selective thermal destruction of pigmented tissues using related optical means.
Photobleaching is the transient or permanent reduction of pigmentation in pigmented tissues upon optical illumination, typically occurring during intense illumination with visible or ultraviolet light. Photobleaching occurs when photoactive pigments are photochemically transformed from a highly colored state to a less highly colored state (de-pigmentation). For example, photobleaching may be used to reduce or eliminate undesirable pigmentation present in moles and hair follicles or to destroy dyes present in tattoos. It is desired that treated tissues will exhibit localized de-pigmentation without side effects, such as irritation or cell necrosis. However, previous methods for photobleaching tissues using visible or ultraviolet light have produced undesirable collateral effects, including irritation of surrounding tissues and possible scarring at the treatment site.
In contrast to photobleaching, photochemical conversion of pigments into phototoxic products involves stimulation of localized cell necrosis in treated tissues. This is also effected by optical illumination, typically occurring when intense visible or ultraviolet light is used to illuminated susceptible pigmented tissues. Such localized necrosis may be useful for selective destruction of diseased tissues, such as those present in tumors or benign skin lesions.
More specifically, an important subset of pigmented tissues are pigmented tumors, such as melanomas, which are life threatening and highly difficult to treat. While melanomas can be treated if detected early using standard surgical, radiation or chemotherapeutic methods, these methods still do not have acceptable levels of effectiveness and produce high levels of collateral damage to normal tissue. Hence, even if detected relatively early, the prognosis is usually poor.
Further, if a melanoma has metastasized beyond the primary tumor site, less than 20% of patients will survive beyond five years. For such melanomas, there are no effective therapies. Patients diagnosed with such a metastatic melanoma will survive on average only 3–6 months after the diagnosis even with therapeutic intervention.
Further exacerbating the difficulties in treating melanomas is the fact that the incidence of melanoma in Caucasians is increasing at a rate of 6% per year. This is currently the second fastest rate of increase in cancer occurrences—second only to tobacco related cancers of the lung in women. Currently, the lifetime risk of melanoma in the U.S. is 1 in 75. Accordingly, new effective therapeutic modalities are required to treat both primary and metastatic pigmented tumors such as melanomas.
One possible approach for treating pigmented tissues involves the use of melanins, their precursors, and other endogenous or exogenous pigments.
More specifically, there are several pigments in humans that are collectively known as melanins. The function of melanins are to protect tissues from the deleterious effects of electromagnetic radiation (e.g. light). However, melanins and their precursors can also be converted to phototoxic products. For example, a melanin precursor (5-SCD) has been shown to photobind to DNA after exposure to 300 nm (ultraviolet light) illumination. Further, 5-SCD has been shown to be chemically unstable in the presence of ultraviolet (UV) illumination and oxygen, thereby suggesting that phototoxic products of the (1) Type I variety (phototoxic) or the (2) Type II variety (photocatalytic) may be produced.
Additionally, many melanoma cells are amelanotic. These cells produce melanin precursors but only small quantities of melanin. Phototoxic damage (induction of single strand breaks) to DNA by at least two precursors to melanin (5-SCD and DIHCA) has been demonstrated upon exposure to UV light. Amelanotic cells will be killed by photodynamic therapy (PDT) performed on such precursors to melanin (e.g., 5-SCD, DIHEA). Thus, melanomas can be killed by delivering energy via light.
However, utilization of such phototoxic reactions by illumination of melanin, melanin precursors, or other endogenous pigments has not previously been possible. The UV/Near UV light required for photoactivation is unable to penetrate into normal or cancerous skin (i.e. beyond 2–3 mm.) More specifically, the poor penetration of such light has produced little effect on patients whose skin tumors are larger than or at a depth greater than 3 mm. As a result, only 40–50% of patients whose tumors exceed 3 mm will survive. Accordingly, the survival rate of melanoma patients with tumors whose depth is less than 1 mm is drastically better than those who have tumors which are either located at a depth of greater than 3 mm or extend to a depth greater than 3 mm.
Previous photodynamic methods using UV/Near UV light also produced undesirable collateral effects that not only prohibited the photoconversion of melanin and prevented it from killing pigmented tissues but also was potentially dangerous to the patient. For example, UV light can create thymidine dimers which damage genetic material. DNA damage is a major and possibly the sole cause of skin cancers like melanomas. Melanin's absorbance of UV light is designed to prevent this from happening. However, UV light, chemotherapy, and ionizing radiation have recently been shown to increase the virulence of tumor cells. As a result, tumor cells when treated with UV light will have a greater mutation and error rate because the UV light can inactivate mechanisms designed to identify and correct genetic errors (in addition to creating new errors). Therefore, prior techniques were not only unable to effectively kill pigmented tissues by accessing endogenous pigments but also created side effects that could be lethal.
In many instances, the effectiveness of various photodynamic processes have been found to be markedly increased by simultaneous photoactivation and localized heating (hyperthermia). Typically, by heating the treatment zone 2–10° C. above normal temperatures, the effectiveness of PDT is increased many fold. Such heating alone, however, has not been shown to produce a significant therapeutic effect. In contrast, the inventors of the present invention have conceived that more acute localized heating (i.e., >2–10° C. temperature rise) of tissues and tissue components within the treatment zone may produce a therapeutic effect by causing thermal overload in the treated tissues.
Therefore, it is an object of the present invention to provide a method for accessing endogenous pigments in pigmented tissues so as to be able to selectively photobleach said pigments.
It is another object of the present invention to provide a method for accessing endogenous pigments in pigmented tissues so as to be able to photochemically convert said pigments into phototoxic products.
It is another object of the present invention to provide a method that will access said endogenous pigments in pigmented tissues without accessing endogenous pigments in healthy tissues surrounding said pigmented tissues.
It is another object of the present invention to provide a method that will augment the effectiveness of said photochemical conversion of said endogenous pigments in said pigmented tissues through the localized application of hyperthermia in said pigmented tissues.
It is another object of the present invention to provide a method that will photothermally destroy pigmented tissues without harming healthy tissues surrounding said pigmented tissues.
The present invention is directed to a method and apparatus for treatment of a particular volume of tissue or material containing an endogenous pigment. In general, typically, the present invention uses the unique properties of simultaneous two-photon excitation with endogenous pigment in a particular volume of tissue, such as a tumor, to selectively photoactivate the pigment.
This photoactivated pigment may thereby be photobleached or photochemically converted into a phototoxic product. Such photoactivation results from the simultaneous two-photon excitation of the pigment. Preferably, the photons responsible for photoactivation are provided by a laser which produces a beam of light comprising a train of one or more ultrashort pulses. This beam of light can be a focused beam of light if the location and extent of the particular volume of tissue to be treated is precisely known. The focused beam of light can then be scanned throughout the volume of the tissue to treat the entirety of the pigmented tissue. Alternatively, where the location and extent of the pigmented tissue in a volume of tissue is not precisely known, a non-focused light beam can be used.
In an alternative embodiment, an exogenous photodynamic agent can be added to the particular volume of tissue. The exogenous agent can be photoactivated by the simultaneous two-photon excitation. Activation of the exogenous photodynamic agent augments the effectiveness of the endogenous pigment.
In a further alternate embodiment of the invention, the effectiveness of such photoactivation is augmented through the localized application of hyperthermia in the pigmented tissues.
In an additional further alternative embodiment of the invention, the particular volume of tissue is treated with light to promote thermal overload of the pigmented tissues. Thermal overload heats and kills the pigmented tissues.
In describing the preferred embodiments, reference is made to the accompanying drawings:
The present invention is directed to a method and apparatus for treating pigmented tissues using light. Such treatment includes the following photochemical outcomes of therapeutic value: (1) the elimination of undesirable pigmentation in pigmented tissues through photobleaching; and (2) the permanent destruction of pigmented tissues through photochemical conversion of pigments into phototoxic products. More specifically, simultaneous two-photon excitation is used to photochemically convert endogenous or exogenous pigments into desired photoactive products, resulting in the desired photobleaching or tissue destruction. Photobleaching is used to reduce or eliminate undesirable coloration of tissue, such as that in moles, freckles, hair follicles and tattoos. The production of phototoxic products may be used to preferentially kill pigmented tumor cells or other undesirable tissues while sparing normal cells. Significantly, the methods and apparatus in the present invention used for photobleaching and production of phototoxic products utilize equivalent photoactivation mechanisms, differing substantially only in the intended treatment target.
In the preferred embodiment, the present invention uses simultaneous two-photon excitation to photoactivate pigments in the pigmented tissues, yielding photobleached or phototoxic products.
In an alternate preferred embodiment, the present invention uses related optical means to selectively destroy pigmented tissues via photothermal means.
Simultaneous Two Photon Excitation
"Simultaneous two-photon excitation" is the non-linear optical excitation occurring as a result of the essentially simultaneous interaction of two photons originating from a single ultrashort laser pulse with one or more agents or pigments to produce one or more photoactivated agents or pigments. "Non-linear optical excitation" means those excitation processes involving the essentially simultaneous interaction of two photons with one or more agents or pigments. "Essentially simultaneous interaction" means those excitation processes occurring as a result of the interaction of one or more agents or pigments with photons provided by a single ultrashort laser pulse. Ultrashort means less than approximately 10 ns.
As shown in
Simultaneous two-photon excitation may thereby be used to excite processes that normally occur upon absorption of a single UV or visible photon through the simultaneous absorption of two near-infrared photons.
An example of the simultaneous two-photon excitation process is the promotion of melanin precursors from a ground electronic state to an excited electronic state through the simultaneous absorption of two photons at 600 nm, followed by binding of the excited melanin precursor to DNA (this is conventionally excited using a single photon at 300 nm). In this example, the probability of excitation is related to the product of the instantaneous or peak powers of the first of two photons 12 and the second of two photons 14. This can be conceptualized in the form of a photochemical reaction,
MoleculeGROUND STATE+2hν 600 nm→MoleculeEXCITED STATE (1)
which shows that a molecule in the ground state is promoted to an excited state following simultaneous absorption of two photons at 600 nm, hν600 nm. The reaction rate R, is given by R=k[MoleculeGROUND STATE] [hν600 nm]2, where k is a rate constant and where [MoleculeGROUND STATE] and [hν600 nm] symbolize concentrations of ground state molecules and excitation photons, respectively. Hence, due to the well known quadratic dependence on instantaneous photon irradiance, simultaneous two-photon excitation to an allowed energy level 10 is also referred to as a non-linear excitation process.
A more detailed explanation of simultaneous two-photon excitation and other non-linear and linear processes is described in U.S. patent application Ser. No. 08/739,801 filed Oct. 30, 1996 for "Method For Improved Selectivity In Photoactivation Of Molecular Agents" assigned to the same assignee of the present application and which is incorporated herein by reference.
Significance of Absorbance and Scattering Properties in Single-Photon and Simultaneous Two-Photon Processes:
While the cross-section for simultaneous two-photon excitation may be considerably lower than that observed with single-photon excitation, use of the simultaneous two-photon excitation in the present invention may be favorable over single-photon excitation under many conditions because of lower matrix absorption and optical scattering of longer wavelength optical radiation. For example,
These differences in optical properties have two important consequences. First, absorption of short-wavelength, higher-energy photons 32 by tissue can result in undesirable tissue damage upon exposure to UV or other high-energy light. In contrast, negligible effects may be experienced upon illumination with lower-energy photons 34, such as NIR light, even when the optical power of the NIR light is many-fold higher than that of the UV light. Secondly, the inherently high absorption and scatter of higher-energy photons 32 by tissue can result in very shallow tissue penetration depths, while lower-energy photons 34 generally have much greater penetration depths.
These important differences in absorption and penetration depth properties for higher-energy and lower-energy light are shown schematically in
In contrast, NIR light 58, for example at 800 nm, will not be appreciably absorbed or scattered by tissue 52 or its outermost layers 54. The overall depth of penetration will be much greater, and the extent of collateral damage to cells will be substantially lower. Hence, if long-wavelength excitation light is used to replace the higher-energy light used for conventional single-photon excitation, it is possible to photoactivate specific molecules or pigments using relatively non-damaging, high penetration depth, simultaneous two-photon excitation.
Furthermore, the properties of simultaneous two-photon excitation have additional implications when coupled with the inherent non-damaging nature and low absorption of NIR light. For example,
Single-photon excitation 60 produces a photoactivation zone 66 that extends substantially along the entire optical path and has no significant biospecificity. Hence, in addition to induction of the desired photoactivation in the tumor 64, collateral damage can occur throughout surrounding tissues, such as the dermis 68 and surrounding healthy tissue 70. If the single-photon excitation 60 is focussed, the photoactivation zone 66 will be slightly enhanced at the focus 72. This photoactivation zone 66, however, might not even extend into the tumor 64 if the UV or visible light is absorbed by the epidermis, dermis 68 or surrounding healthy tissue 70 prior to reaching the tumor 64. This can occur as a consequence of the inherently high absorptivity of tissue at short wavelengths.
In contrast, use of NIR light for simultaneous two-photon excitation 62 produces a sharply defined remote photoactivation zone 74 that is spatially localized at the focus 76 as a consequence of the non-linear properties of this excitation method. Such localization of activation in such a focal zone is a unique property of non-linear excitation processes, such as two-photon excitation. Furthermore, because tissue does not appreciably absorb NIR light, collateral damage to the surrounding dermis 68 and healthy tissue 70 is minimized.
Therapeutic Applications of Simultaneous Two-Photon Excitation:
The foregoing discussion suggests that the fundamental differences in the absorption of UV and NIR light by tissue and cellular constituents, coupled with the special non-linear properties of simultaneous two-photon excitation, have direct applicability for improvements in various medical treatments, specifically in the modification or elimination of pigmented tissues.
Such simultaneous two-photon excitation enables improved localization in the photoactivation of photoactive agents with significantly reduced potential for collateral tissue damage compared with that possible using conventional methods.
Where control of penetration is not critical, non-focussed NIR light may be used to stimulate simultaneous two-photon photoactivation of agents present in a relatively large illuminated area. In such a case, the extent of agent photoactivation is controlled by varying the location, intensity and duration of exposure of such agents to the NIR beam.
Where precise control of penetration depth or volume extent of therapeutic application is more critical, focussed NIR light may be used to stimulate the simultaneous two-photon photoactivation process. In such a case, beam irradiance, exposure duration, and degree of focussing are used to control the extent of agent photoactivation.
In both cases, high-irradiance NIR light may be used to achieve maximum efficacy. Furthermore, the high penetration depths achievable with NIR light combined with the inherent localization of photoactivation that is possible with focused simultaneous two-photon excitation provide a means for photoactivating agents in subsurface tissues without damaging overlying or underlying healthy tissues.
Simultaneous Two-Photon Treatment with Endogenous Pigments
The method of the present invention improves on the above-described advantages through the use of simultaneous two-photon excitation to produce a therapeutic outcome based on photoactivation of endogenous pigments in order to treat pigmented tissues. "Endogenous" means pre-existing in a patient or target. "Pigments" means naturally occurring agents that absorb optical energy. Examples of such pigments include melanin, melanin precursors, carotenes, porphyrins (such as hemoglobin), various tattoo dyes and other optically active species. "Therapeutic outcome" means photobleaching or photodynamic destruction of treated pigmented tissues resulting from the natural biological action of a photoactivated endogenous pigment. "Photobleaching" is the reduction or elimination of undesirable pigmentation, for example that caused by endogenous pigments present in moles, freckles, hair follicles and tattoos. "Photodynamic destruction" is localized tissue necrosis resulting from photochemical production of phototoxic products that destroy pigmented tissues, such as those pigmented tissues in pigmented tumors. Tissues suitable for treatment include pigmented tissues in which a specific therapeutic outcome is desired, such as moles, freckles, pigmented tumors, benign lesions, hair follicles and tattoos.
In a further embodiment of the present invention, a precursor to the endogenous pigments may be used. Examples of such precursors to pigments include 5-S-cysteinyldopa (5-SCD) and 5,6-dihydroxyindole (DHI), dopa, dopa semiquinone, leucodopachrome, dopachrome, eumalanins, pheomelanins, sepia melanins, and 5,6-dihydroxyindole-2-carboxylic acid. Such precursors have both photoprotective and phototoxic abilities. A metabolic precursor to melanin is a biochemical (e.g. 5-SCD, DHI) that is produced by the cell as part of the synthetic pathway that produces melanin. Melanin precursors, when activated by light, can generate photoxic products that damage cellular materials (e.g., DNA) killing the target cells. Melanin precursors can be activated by two-photon excitation, as explained supra.
As also explained supra, melanin, melanin precursors, and other endogenous pigments are naturally occurring in human tissue, including in tumors. Such melanins, melanin precursors, or other endogenous pigments can be converted to phototoxic products after exposure to light.
The present invention uses the above-described simultaneous two-photon excitation to specifically target melanin, melanin precursors, or other endogenous pigments in pigmented tissues (such as melanomas and other tumors). The pigment is converted to a phototoxic product by NIR light upon simultaneous two-photon excitation. The phototoxic product then causes damage to the pigmented tissues (by for example photobinding to cellular DNA or causing breaks in this DNA). This kills the cells in the pigmented tissues and, therefore, destroys it. Because simultaneous two-photon excitation is used to specifically target the melanin, melanin precursors, or other endogenous pigments only in the targeted tissue, any melanin, melanin precursors, or other endogenous pigments in the tissue surrounding the targeted tissue are not converted to phototoxic products.
More specifically, use of simultaneous two-photon excitation produces a sharply defined focal zone that is substantially localized in depth and cross-section. This focal zone can be localized to the targeted tissue (such as a tumor) to be killed or a small zone within or surrounding this tissue. As a result, photoactivation will only occur in the focal zone (i.e. in the tumor). Hence, any melanin, melanin precursors, or other endogenous pigment not in the targeted tissue, such as for example, in tissue surrounding a tumor, will not be photoactivated because it is outside the focal zone.
Additionally, as explained supra, the simultaneous two-photon excitation is able to penetrate deep into normal or cancerous tissue and photoactivate melanin or other endogenous pigments located deep within the tissue. As a result, tumors located deep within the body or large, deep tumors can be reached and destroyed. Destruction of these tumors can be done without activating melanin or other endogenous pigments along the path of the light or surrounding the tumor.
In addition to photodynamic destruction of pigmented tissues, such as those in pigmented tumors, the above-described unique features of simultaneous two-photon excitation may be used to achieve improved safety and specificity in the photobleaching of pigmented tissues, such as in moles, freckles, hair follicles and tattoos. The pigments present in such tissues can be activated by simultaneous two-photon activation, as explained supra, and upon activation may become photobleached. Thus, the present invention also uses simultaneous two-photon excitation to specifically target endogenous pigments in such pigmented tissues, thereby causing photobleaching and a desired reduction or elimination of apparent pigmentation.
It is a specific preferred embodiment of the present invention to employ the output of a NIR source, such as the mode-locked titanium:sapphire laser, to induce simultaneous two-photon photoactivation so as to photoactivate melanin, melanin precursors, or other endogenous pigments using light at a wavelength approximately twice that necessary for such conversion using conventional single-photon photoactivation. As explained supra, such NIR light exhibits improved penetration into tissue relative to that used for conventional single-photon photoactivation, and is less likely to produce collateral damage in tissues adjacent to the desired treatment target.
For the sake of simplicity and clarity, the following descriptions of preferred embodiments will focus on photodynamic destruction of pigmented tumor tissues, such as those in melanomas. However, it is important to note that the methods and apparatus described are equally applicable to the photobleaching of pigmented tissues, such as moles or tattoos, differing substantially only in the intended treatment target. In both classes of treatment, it is the photoactivation of the pigment that is fundamentally responsible for the desired therapeutic outcome.
Accordingly, a preferred embodiment is shown in
Simultaneous two-photon photoactivation of the melanin, melanin precursors, or other endogenous pigments will be substantially limited to the focal zone 90 of the focused light beam 86 due to the high instantaneous irradiance level that is only present at the focus. Furthermore, regardless of whether melanin, melanin precursors, or another endogenous pigment is present in surrounding healthy tissue 92 or skin 94, insignificant collateral photoactivation, photodamage or conversion into a phototoxic product will occur outside the focal zone 90. This is a consequence of the non-linear relationship between instantaneous optical power and simultaneous two-photon excitation, which limits significant excitation to the focal zone 90. Even if melanin, melanin precursors, or another endogenous pigment is present outside of the focal zone 90, excitation intensities are below that necessary to produce significant photoactivation.
The apparatus of the present invention can also include, for example, a focusing apparatus for focusing the light throughout a range of focal lengths extending from a surface of the tissue to a depth substantially beyond the surface. The source of light and focusing apparatus cooperate to promote simultaneous two-photon excitation of the pigment at controllable locations throughout the volume of tissue.
By scanning the location of the focus of the beam 86 throughout the volume of the tumor 88, complete photoactivation of the melanin, melanin precursors, or other endogenous pigments into a phototoxic product throughout the tumor 88 can be effected. This scanning action can be produced by changing the position of the focus 86 relative to the tumor 88, or by moving the tumor 88 relative to a stationary focus 86 location. The quality of the focal region 90 of the focused light beam 86 may be improved by pre-expanding the light beam 82, using a beam expander or other device, prior to focusing using standard optical means.
This scanning can be done, for example, by positioning a focus of a beam of light over a range of positions so that a focal plane of the light beam occurs at a site located between a surface of the tissue and a point substantially beyond the tissue surface. As a result, treating the particular volume of tissue may extend to penetrate deep within the tissue. This scanning can further include varying, while the beam of light is extant, the radial position of the focal plane within the tissue, thereby to photoactivate the endogenous pigment at a multiplicity of positions between the tissue surface and a position located substantially beyond the tissue surface.
The simultaneous two-photon photoactivation embodiment of the present invention has several variations for the treatment of topical tissues, as shown in
Focused simultaneous two-photon photoactivation of melanin or other endogenous pigments for topical therapy, as shown in
Non-focused simultaneous two-photon photoactivation of melanin, melanin precursors, or other endogenous pigments for topical therapy, as shown in
A final related variation of this preferred embodiment for simultaneous two-photon photoactivation is shown in
Preferably, the simultaneous two-photon excitation will be produced by an ultrashort pulsed NIR laser light having a wavelength of from approximately 450 nm to 1400 nm with a pulse width of from approximately 25 fs to 10 ns and a greater than approximately 1 kHz pulse repetition frequency. Such laser light can be produced by a mode-locked titanium:sapphire laser or related laser sources.
The extent and duration of excitation affected with such sources will be controlled by varying the location, irradiance and duration of application of the light.
The effectiveness of the therapeutic outcome may be markedly increased by simultaneous photoactivation and localized heating (hyperthermia) of the treatment site. Such heating occurs as a secondary effect of illumination with laser light, and may also be controlled by varying the location, irradiance and duration of application of the light, so as to yield heating in the treatment zone of 2–10° C. above normal temperatures. For example, application of light at intensities of 150–3000 mW/cm2 may be used to produce such desirable hyperthermia. Alternately, secondary thermal sources, such as infrared lamps or warm fluid baths, may be used to effect such desirable hyperthermia at the treatment site.
While the foregoing disclosure has primarily focused on example therapeutic applications using two-photon excitation of agents with ultrashort pulsed NIR light produced by mode-locked titanium:sapphire lasers, the present invention is not limited to such excitation nor to such narrowly defined optical sources. In fact, aspects of the present invention are applicable when optical excitation is effected using linear or other non-linear methods. For example, various other optical sources are applicable, alone or in combination, such as continuous wave and pulsed lamps, diode light sources, semiconductor lasers; other types of gas, dye, and solid-state continuous, pulsed, or mode-locked lasers, including: argon ion lasers; krypton ion lasers; helium-neon lasers; helium-cadmium lasers; ruby lasers; Nd:YAG, Nd:YLF, Nd:YAP, Nd:YVO4, Nd:Glass, and Nd:CrGsGG lasers; Cr:LiSF lasers; Er:YAG lasers; F-center lasers; Ho:YAG and Ho:YLF lasers; copper vapor lasers; nitrogen lasers; optical parametric oscillators, amplifiers and generators; regeneratively amplified lasers; chirped-pulse amplified lasers; and sunlight.
In an alternative embodiment, an exogenous photodynamic agent can be added to the patient to be activated in conjunction with the endogenous pigments. "Exogenous" agents are photoactive materials not pre-existent in a patient or other target which are for example administered for the purpose of increasing efficiency of conversion of optical energy into a therapeutic process. Examples of such exogenous agents include Rose Bengal, psoralen derivatives, indocyanine, Lutex, Sn(ET2) and various porphyrin derivatives, including porfimer sodium and benzoporphyrin derivative. Preferably, the targeted tissue is pretreated with the exogenous agent so that it retains a therapeutic concentration of the agent when the tissue is treated with light so as to promote simultaneous two-photon activation of the agent. Alternatively, the agent can be added at other times during the process. Upon administration and accumulation in targeted tissue, such agents can be used to efficiently interact with NIR light so as to kill tissue by Type I or Type II PDT mechanisms. Such killing can be used to augment or supplement killing of pigmented tissues using endogenous photoactive agents as described supra.
Another alternate embodiment of the present invention is directed to the thermal destruction of melanomas and other pigmented lesions.
Melanomas are usually dramatically darker than surrounding healthy tissue. The dark color associated with melanomas is caused by increased production of melanin by tumor cells. Melanin is a strong absorber of ultraviolet (UV) and visible light, and normally protects cells from the deleterious effects of solar UV radiation. For example,
Currently, laser illumination is used in cosmetic applications to remove unwanted hair. Laser hair removal is accomplished because there is more pigment in the hair follicles than in surrounding tissue. Therefore, when a laser illuminates the pigmented hair follicle, it absorbs much more of the light, causing localized heating. The localized hyperthermia thereby created in the bulb of the hair follicle kills the hair follicle while sparing surrounding tissue (which is not heated to a significant extent by the laser illumination).
The inventors of the present application have discovered a process to kill pigmented tumor cells by thermally overloading them whereas the relatively unpigmented cells in healthy tissues surrounding the tumor are spared.
For wavelengths between 450 and 800 nm, direct linear excitation of melanin is used to selectively promote thermal overload of pigmented tumor cells 98. Light in this band is preferred when pigmented tumor cells 98 are located at the surface of tissue or at depths of approximately 2 mm or less below the surface since such light is not capable of penetrating tissue to significantly greater depths. For such excitation, it is preferred that illumination be effected via application of one or more short pulses of light having a pulse duration of 10 ns (nanoseconds) or less, and more preferably of 10 ps (picoseconds) or less. Use of such short duration pulses reduces thermal loss to surrounding tissues, thereby improving efficiency in selective thermal overload of the pigmented tumor cells 98. It is further preferred that the wavelength of this light be between approximately 600 and 800 nm to afford improved specificity for excitation of melanin relative to hemoglobin. Moreover, it is further preferred that such light be produced by a light source such as a mode-locked titanium:sapphire laser, which is readily able to deliver such light pulses at such wavelengths. A focused light beam 86 is preferable where the location and extent of the lesion is precisely known, since improved control over the extent of the treatment zone is thereby possible. By scanning this focused light beam 86 throughout the volume of the tumor, it is possible to treat the entirety of the pigmented tumor cells 98. However, where the location and extent of the lesion is not precisely known, or where the lesion is exceptionally large, use of a non-focused light beam 96 is preferred to assure that treatment is effected in all of the pigmented tumor cells 98.
For wavelengths between 800 and 1400 nm, excitation of melanin via linear mechanisms and non-linear two-photon mechanisms is used to selectively promote thermal overload of pigmented tumor cells 98. Light in this band is preferred when pigmented tumor cells 98 are located below the surface of tissue at depths of approximately 2 mm or greater since such light is capable of penetrating tissue to such depths. For such excitation, it is preferred that illumination be effected via application of one or more short pulses of light having a pulse duration of 10 ps or less, and more preferably of 1 ps or less. Use of such short duration pulses increases the efficiency of non-linear excitation mechanisms while simultaneously reducing thermal loss to surrounding tissues, thereby improving efficiency in selective thermal overload of the pigmented tumor cells 98. A focused light beam 86 is preferable where the location and extent of the lesion is precisely known, since improved control over the extent of the treatment zone is thereby possible. Use of such a focused light beam 86 improves efficiency of non-linear excitation mechanisms, allowing relatively low energy light sources 80, such as mode-locked titanium:sapphire lasers, to be successfully used. By scanning this focused light beam 86 throughout the volume of the tumor it is possible to treat the entirety of the pigmented tumor cells 98. However, where the location and extent of the lesion is not precisely known, or where the lesion is exceptionally large, use of a non-focused light beam 96 is preferred to assure that treatment is effected in all of the pigmented tumor cells 98. Under such illumination conditions, amplified or other higher energy light sources 80, such as the regeneratively amplified mode-locked titanium:sapphire laser, are preferred so as to increase illumination intensities to levels sufficient to achieve efficient non-linear excitation.
It will be clear that the methods and apparatus described for this alternate embodiment will be equally applicable to the treatment of other pigmented blemishes, such as for example moles, port wine stains, freckles, scars, and tattoos, and for the reduction or elimination of pigments in hair.
While the present invention has been illustrated and described as embodied in general methods and apparatus for killing pigmented tumors by activation of endogenous pigments using optical radiation, it is not intended to be limited to the details shown, since it will be understood that various omissions, modifications, substitutions and changes in the forms and details of the method illustrated and in its operation can be made by those skilled in the art without departing in any way from the spirit of the present invention.
This description has been offered for illustrative purposes only and is not intended to limit the invention of this application, which is defined in the claims below.
What is claimed as new and desired to be protected by Letters Patent is set forth in the appended claims.
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text:
advice on next steps
hi all, I went to the doctors finally in October after 2 years of utter exhaustion, it was by then affecting my relationship etc as I had withdrawn from all socialising in the evenings etc. it took everything I had to do my full time job. at the time I did not link other symptoms which I now know to be linked ie pins and needles, stabbing pains in my fingers and chest, hair falling out. being psychologically so very low at times. I was lucky in that the doctor I happened to get an appointment with that day was knowledgeable in b12 and PA. he tested me and my b12 was around 150. I had loading injections every week for 5 weeks and now I am on every two months as the symptoms returned with vengeance after around 7 weeks. i tested negative for IF, this was done after all my loading doses. I haven't had any advice about next steps as I still dont know the route cause of my condition. can anyone advise whether I should press for this or just accept I am at least lucky to be receiving the treatment at the frequency I need it as I know many arnt from following this site.

subset: commoncrawl


text:
Homeowner Association (HOA) Management
Contact AMS | Association Management Services NW
(formerly TMG Northwest Association Management NW)
360-891-8060 Vancouver
503-598-0552 Portland
888-485-9676 Toll Free
888-846-5963 Emergency After Hours
HOA management is becoming increasingly more challenging and requires a fresh approach to meet the needs of today's homeowner associations and condominium associations.
Your association's management company is not simply a service provider, but is often the face of your community and the voice of its residents.
Our knowledgeable and dedicated staff bring together their collective experience to enhance and strengthen your community. If you are looking for full service, financial only, or consulting services, AMS has the tools, contacts and resources to help manage and care for your association.
|Full Service Homeowner
Association Management
|HOA Developer Services
Experienced and Dedicated HOA Management Professionals
You will have the full support of the AMS team. From our executive leadership team to our administrative and accounting teams, we are proud of our experience and expertise. AMS' staff love what they do, and it shows in their tenure with AMS and the pleasure with which they serve their communities and boards.
It's now more important than ever to entrust the management of your association with a firm that exceeds the industry standard. We are one of only a handful of HOA management companies in the Portland and Vancouver area that have attained the AMO accreditation from the Institute of Real Estate Management. AMS joins 537 AMO firms worldwide that hold this distinguished accreditation. Association Business Managers attend Community Association Institute (CAI) classes and events that are required to obtain their CMCA designation. Education for board members is also a priority at AMS. Our company presents monthly Board Education Classes, held in AMS' Oregon and Washington office locations. These well-attended, complimentary classes include guest speakers with specific expertise relevant to community associations and provide a venue for directors to meet and share experiences.
Most homeowner associations are incorporated and are subject to state statutes that govern non-profit corporations and homeowner associations. New bills affecting associations are frequently being introduced in state legislatures and may be in different states of consideration, approval, or enactment. Association Business Managers are expected to understand the fundamental Oregon and/or Washington laws, revised statutes and code, as well as monitor new legislation, tax rulings and other civil code requirements. Interpretation of these laws and statutes is often challenging, and therefore managers have access to legal counsel to assist them in interpretation.
Management Team
As the Managing Agent, AMS shall be responsible to perform the services described in the Management Agreement and provide counseling and advice to the Association's Board of Directors, officers and committees in accordance with generally accepted industry standards.
In order to provide top-level customer service and support, each association is assigned a Management Team, consisting of a Association Business Manager, Community Administrator and a Staff Accountant.
AMS prides itself on the level of service we provide to homeowners. In addition to the management team, homeowners will be able to contact AMS' Member Services Coordinator. The Member Services Coordinator is the initial point of contact for homeowners and can assist owners with logging onto the community website, making payments, retrieving documents needed for a sale or refinance, submitting an architectural request, requesting parking space assignments, and obtaining a clubhouse key or making a clubhouse reservation. These are just a few examples where the Member Services Coordinator can assist the homeowner and ensure personalized customer service.


text:
Brett takes aim at the newest addition to the Call Of Duty franchise, ADVANCED WARFARE. Thanks for watching folks, please Like and Subscribe to Glitch for more game reviews — http://bit.ly/1cwjFRS
Another year another Call Of Duty, this time around the popular long running franchise has been put in the creative hands of developer Sledgehammer Games.
In Call Of Duty: Advanced Warfare we have some great graphics and jaw dropping motion capture covering a game that continues the steady decline in quality of the Call Of Duty storytelling during gameplay as well as the gameplay itself.
Advanced Warfare is another near future outing from Activision that puts you into the role of Jack Mitchell, a private in the United States Marine Corp.
After a little mishap he finds himself discharged from the Marine Corps and instead working for the private military organisation ATLAS who's headed up by CEO Jonathan Irons, played by Kevin Spacey.
The story while entertaining enough, unless you're a new comer to the first person military shooter, is as predictable as they come.
It follows the same formula as many other Call Of Duty games and very rarely strays from it.
Even some of the characters feel like rehashed versions of previous Call Of Duty characters.
The storytelling during gameplay is pretty much made up of shooting enemy, maybe have a quick-time event, continue shooting, chuck in a vehicle section and then explosions, explosions everywhere.
While I get that this is an action game that takes place in the near future, earlier titles also had a pretty good sense of realism where Advanced Warfare is more of an over exubrant collection of set pieces that do nothing to add to a players connection to the characters.
Your character would have to be one of the luckiest people in the world with the amount of times he cheats death that it becomes boarderline laughable.
While the gunplay, as you would expect, is up to the Call Of Duty standard the AI is something that I found myself raising an eyebrow to, as it seemed to be bit broken at times and only posed a real threat on the harder difficulties.
Not necessarily because the AI improved in anyway, but because the AI was masked by the fact that it takes less hits to actually kill you.
Also let's not forget that you are rarely ever left on your own and your party members are pretty much invulnerable and do a pretty good job of taking out the enemy.
Advanced Warfare has some of the most amazing motion captured cut scenes that I have ever seen in a video game and with so much attention to detail and facial expressions, you would be forgiven for thinking you were watching an animated feature.
Of course Advanced Warfare's gameplay adds to that feeling, I have no doubt that this Call Of Duty game has given me the biggest feeling of being dragged along from point A to point B ever in the franchise.
The majority of the missions are made up of following someone and having them bark commands at you ad nauseam.
I'm fine with the fact that this game takes place in a world where there are very few car types that don't seem to care about explosions and bombs going off around them.
But too include it as some sort of gameplay that has no real sense of urgency or consequence makes it come off as something of an afterthought.
Much like hopping on what looks like a pretty nice hover bike only to at first have all control taken away from you and the second time have it once again be an instance where I can do nothing more than follow an npc like a good lapdog.
Even levels that give you a little bit of freedom, while standouts are nothing more than a tease of what the developers were maybe trying to do yet they themselves maybe couldn't explore further due to the formula of a Call Of Duty title.
The grappling stealth level is an example of this that is probably one of the most half-hearted attempts at stealth I've ever encountered, yet is one of the levels in Advanced Warfare where I actually stood up and took notice.
How the enemy couldn't see me zip line about a metre away from them is anyone's guess.
Linear doesn't even begin to describe the straight line corridor like level design which makes the addition of the exo-suit at times pointless.
The exo-suit itself is probably the biggest tease in the entire game. The idea behind it is definitely nothing new with crysis having done it much better. The suit itself becomes more of a gimmick, thats abilities can for the most part only be used when you're told to use it.
Want to use the grappling hook to take down an enemy outside the designated stealth section? Nope that aint gonna happen unless a prompt pops up.
Things such as this happened so much playing through Advanced Warfare that you could end up playing it just like a straight shooter with a few more grenade choices.
While that's perfectly okay I don't see the point in giving me the awesome exo-suit that's main use is nothing more than a double jump.
The exo-suits usage outside of prompts is rendered useless by taking away the freedom to use it.
With the single player clocking in at around 8 to ten hours including cutscences the game will most likely give you more excitement the multiplayer.
First let me say that I am in no way an expert in the world of cod multiplayer and have never professed to be and I will say that when I wasn't pitted against players who were many levels higher than me I really did start enjoy my multiplayer experience.
While it was a bit of a stripped down version it made it easier for a multiplayer novice like myself to get into it and will more than likely go back to it in the future.
It's also where I found myself using more of the exo-suits abilities, well more of the double jump anyway. The exo-suit might not bring cod up to anywhere near the pace of a game like titanfall it was fun to use the mini titan at times.
With an average single player experience that relies on a big name star to carry the story and gameplay which is nearly less engaging than a point and click adventure, Call Of Duty: Advanced Warfare is another entry that is lowering the Call Of Duty single player to the level of battlefield proportions.
If there is ever a series that needs a breather and a bit of a rethink when it comes to single player, Call Of Duty is it.
Thankfully the multiplayer picks it up a bit, which these days seems to be the only real reason for picking up a Call Of Duty title.
Activision could probable release a Call Of Duty that is nothing more than multiplayer and it would still sell millions, but for me, I'm still someone who remembers being totally engrossed with the first player campaigns of the earlier Call Of Duty titles.
This game is another notch that shows that the focus is on being a competitive shooter with money spent on big name actors to drum up interest for a single player campaign instead the gameplay and having the developers breathe a bit more life into this worn out series.
I'm giving Call Of Duty: Advanced Warfare a 5.5 out of 10.


text:
Janesville Parker baseball to rely on starting rotation
You can never have enough of it, especially at the high school level, where Mother Nature can often force teams to play four or five games in a week.
Janesville Parker coach Brian Martin has an influx of pitchers, including four starters who could give the Vikings with the deepest staff in the Big Eight Conference.
�I�d put our top four pitchers against anybody else in the league,� Martin said. �We don�t have that one big stud like Middleton has (Shane Adler), but one through four, I don�t know if there are too many teams better than us.
�If we can score three or four runs in a game, I feel like we should be in pretty good shape with our pitchers. But we�ll see.�
Martin�s starters include juniors Andy Kersten, Kyle Johnson and Trent Kobs, along with senior fireballer Tyler Teubert. Kersten, Kobs and Teubert are right-handers, while Johnson is a left-hander.
�All four bring a little something different to the mound,� Martin said. �Andy has made huge strides from a year ago, and Kyle has looked very strong.
�Teubert was throwing 85-plus (miles per hour) at a combine at Mankato State, and when Trent is on and throwing strikes, he�s tough to hit.�
Parker will need better run production if it hopes to improve upon last season�s 7-20 record. The outfield will have senior Matt Fiedler in right, Kobs in center and senior Josh Garcia in left. Juniors Taran Kobs and Chase Lee, along with junior Zach Harmel, also can play in the outfield.
Sophomore Jake Welch will start at third, with Teubert at shortstop, senior Tanner Moe at second, and Kersten or Johnson at first base. Junior Jeff Henke also is a candidate at first base.
�We bring back all four starters on the infield, so they all know what to expect,� said Martin, who is starting his 10th season as head coach. �They are all a year older and a little bit stronger, so we�re already ahead of where we were last year at this time.
�And with the weather being nice enough to practice outside, we�ve gotten a lot of things done.�
Martin also expects senior Marques Emerson, sophomore Hunter Marshall and junior Conner Long to fill in at times on the infield.
�Defensively, I think we�re going to be fine,� Martin said. �We moved Welch to third where I think he�s a little more comfortable, and Moe to second because he�s got a little more range.
�My main concern is putting the bat on the ball. We�re going to have to go back to playing the old-fashioned way. That means taking one base at a time, bunting guys over and being opportunistic on the base paths.�
Senior Aaron Polzin will start at catcher, with Taran Kobs also expected to play there, especially with three doubleheaders on the schedule.
Despite having four quality starters, Martin also expects Fiedler, Emerson and Garcia to contribute on the mound.
Parker�s schedule, with home games at Riverside Park:
(5 p.m. starting times, unless indicated)
APRIL: 6�Beloit Memorial; 8�Madison East; 13�At Madison West; 15�Portage (at Miller Park), 7 p.m.; 17�Verona (doubleheader), 11 a.m.; 20�Janesville Craig; 22�At Madison La Follette; 27�Madison Memorial; 29�At Middleton; 30�At Oconomowoc, 4:30 p.m.
MAY: 4�At Beloit Memorial; 8�At Sun Prairie (doubleheader), 11 a.m.; 11�At Madison East; 14�At Marshfield Tournament (River Falls), 7:30 p.m.; 15�At Marshfield Tournament (Holmen and Marshfield), 10 a.m. and 1 p.m.; 18�At Janesville Craig; 20�Madison La Follette; 21�Milton; 22�At Kenosha Tremper, noon; 25�At Madison Memorial; 27�Middleton.
Last updated: 1:43 pm Thursday, December 13, 2012