A colloidal system for detection of a variety of analytes involves techniques which permit reconstitution of a desiccated substance such as for surface enhanced Raman spectroscopic analysis and multiple sensors at once, each having different spectra through the use of markers or the like. Competitive assay techniques and a variety of substances are explained to permit a practical an versatile system which can also be used for immunological assays and can include antibodies tagged to provide spectroscopic indicia.

Generally, this invention relates to a method of determining the concentration of an analyte in a mixture using a spectrographic method of analysis and unique methods of spectral analysis. Specifically, the invention covers the use of Raman spectroscopy, desiccated metal particles, molecular specific coatings, sample containers, and multivariate analysis to determine the concentration of an analyte.
One of the first examples of the importance of chemical analysis in the chemical industry comes from Pliny the Elder (AD 23-79). Pliny the Elder was concerned about contamination of copper sulfate with iron sulfate. Copper sulfate was the principle ore for making copper and bronze. The purity of the copper ore ultimately determined the purity of the copper or bronze. Pliny the Elder found that the extract of gallnuts turned black in the presence of iron sulfate. This simple visual test was the first example of what today is known as Analytical Chemistry.
Since this early work in metallurgical process control the field of analytical chemistry has expanded greatly. The methods of analysis encompass 4 categories. The oldest, represented by Pliny the Elder""s work, is wet chemistry. This method involves mixing chemicals together to observe a quantitative change. The other three categories are more modern and represent an improvement in sensitivity, measurement time, and selectivity over wet chemical methods. These methods are: spectroscopy, chromatography, and electrochemistry.
This invention relates to a spectroscopic analysis known as Raman spectroscopy. Raman scattering involves the inelastic scattering of light by vibrational modes within a molecule. This can be very advantageous as no two molecules exhibit exactly the same Raman spectrum. This makes it possible to distinguish between similar components in a mixture.
This advantage in specificity associated with Raman spectroscopy is overshadowed by an inherent lack of sensitivity. Typically about one in a million photons of light incident on a sample will take the form of Raman scattering. In practical terms Raman is limited to about one part in a thousand detection levels when the analyte is in a matrix.
The Discovery of Surface Enhanced Raman Scattering
Surface enhanced Raman scattering (SERS) like many scientific discoveries, evolved out of serendipitous events. In the early 1970""s electrochemists began using optical methods to study electrode surfaces. Flieschmann and Hendra decided to experiment with Raman spectroscopy as a method of analyzing electrode surfaces. Due to the low sensitivity of Raman spectroscopy they chose silver as the electrode material since it is easily roughened by oxidation-reduction cycles in the presence of chloride. The growth of silver chloride crystals and reduction back to silver leads to a roughened surface with many times the surface area of a smooth polished electrode. This will increase the Raman signal as there are more molecules in the laser beam. They chose pyridine as the probe molecule as it should adsorb through the pyridine nitrogen and it is an inherently strong Raman scatterer. Their experiment was a success. They did not know it but this was the first experiment using SERS. It was not until four years later that this experiment was correctly interpreted. In 1977 Van Duyne at Northwestern University was also trying to study electrodes with Raman spectroscopy. His approach was to use resonantly enhanced molecular probes to overcome the sensitivity problem. He had performed calculations to determine the amount of resonance enhancement needed to observe a monolayer on an electrode. This number was at least 1000 for a strong scatterer like pyridine. This made Flieschmann and Hendra""s results look anomalous. To test if the enhancement was due to increased surface roughness Van Duyne""s student David Jeanmaire tried a milder oxidation-reduction cycle and achieved even stronger signals. This lead to the first announcement of an anomalous phenomena at silver surfaces.
It is now known that the SERS effect arises through an electromagnetic resonance that can occur strongly in noble metal particles and to a lesser extent in some other metals. The resonance occurs because the electrons in the particle are affected by the excitation light to produce a polarization in the particle that makes it more likely to become more polarized. This phenomenon will produce very large electric fields near the particle surface and thus amplify optical events near the surface that are dependent on the electromagnetic field. Raman scattering is just one class of such events. Others might include fluorescence and absorbance. Further, each may be enhanced through a surface phenomenon as in the case of surface enhanced Raman spectroscopy.
While SERS was discovered on electrode surfaces, it is not limited to these. Today SERS is being performed on evaporated metal surfaces, etched metal foils, microlithographically produced surfaces, carefully assembled particle arrays, colloidal suspensions, and with other methods that are capable of producing small submicron sized particles. An excellent discussion regarding aspects and uses of Raman Spectroscopy in a detection context is contained in the document xe2x80x9cMethod and Apparatus for Detection of a Controlled Substancexe2x80x9d, International Application Published Under The Patent Cooperation Treaty (PCT), WO 98/59234, United States National Stage Application No. 09/446,168.
Several problems have plagued the development of SERS into a practical analytical tool. One such problem is the delicate nature of the SERS substrate. The SERS phenomenon is associated with particles or roughness features that are about {fraction (1/10 )} the size of the wavelength of the light used for excitation. Typically this means 40 to 100 nanometers (a nanometer is one billion of a meter). Particles this size are very susceptible to chemical damage, aggregation, and photo damage.
A survey of the different SERS substrates produces one type that stands out with respect to practical analytical chemistry. These are colloidal suspensions. Two significant advantages are found with colloidal suspensions. First, a large volume of colloidal particles can be made at one time. Within this batch of colloids every sample will be identical. This overcomes the irreproducibility of non free floating particulate surfaces. The second advantage is that the colloidal particles are suspended in a solution and therefore tend to be much less susceptible to thermal damage. They also are subject to Brownian motion which tends to continually refresh the particles in the excitation beam, thus eliminating problems with photodegradation of the sample.
In addition to problems with SERS substrate stability and reproducibility an additional factor needs to be included in the analysis. The SERS substrates are typically noble metal particles. The noble metals are aptly named for their ability to resist the aggressions of other materials. In a practical sense this is good for stability of the surfaces, but is impractical in terms of attracting an analyte to the surface. In order for the SERS substrate to act as a tool for detecting an analyte, it must attract the analyte to the surface or in some way be specifically affected by the analyte to show a spectroscopic response.
Initially SERS was seen as advantageous because of its strong enhancement. This invention realizes a different aspect of SERS. The localization of the SERS enhancement near the surface very effectively separates the signal from the analyte that is in close proximity with the surface from analyte or other material in the sample matrix. The locality of the analyte can be used to a strong advantage with respect to the ease of analysis. SERS allows one to measure an analyte in the presence of species that would strongly interfere and cripple other methods of analysis that do not have a localized area of detection.
The problem of inertness with noble metal SERS active surfaces can be overcome with a coating material that attracts or is affected by the analyte. Basically, this combines the strong advantages of an enhanced sensitivity from the SERS substrate with the reactivity or affinity of a molecular specific coating.
Four classes of coatings can be described for a SERS surface. These are passive coatings that can attract the analyte into close proximity of the surface through a chemical affinity for the analyte, the presence of which is detected by its SERS spectrum. Active coatings bind the analyte reversibly and indicate the presence of the analyte through a spectroscopically observable change in their chemical structure. Reactive coatings actually react with the analyte through a covalent bond and create a new species on the surface; this new species is related to the analyte and produces an analyte distinct spectrum for identification and quantitation. The fourth class of coatings are sandwich coatings that bind the analyte and with the addition of a reporter molecule produce a quantifiable signal for the analyte. The latter often consist of immunological coatings with an inherent specificity built into the coating by an organism""s immune response.
A problem that exists when these coatings are combined with a SERS active surface is that the surface becomes less stable. This is particularly true with colloidal suspensions. Colloidal suspensions are stable because the colloidal particles maintain a strong electrical charge through adsorbed ions. In most SERS active systems the colloids are stabilized by the adsorption of citrate ion. This creates a strong net negative charge on the particles and makes them repel each other in solution. Without this net charge the particles would rapidly coalesce into a SERS inactive aggregate of colloidal material.
When coatings are applied to the active colloids it is often impossible to displace the citrate or if the citrate is displaced the colloids begin to aggregate and fall out of suspension in a short time. In some instances it is necessary to add stabilizers of some type to increase the lifetime of the colloids; however, over long periods of time the effectiveness of these stabilizers may be insufficient. It would be commercially desirable to produce a colloidal SERS active system that contains a coating specific for an analyte which had long term stability. Such an invention would have tremendous advantage as a quick and easy to use method for chemical analysis.
The present invention includes a variety of aspects which may be selected in different combinations based upon the particular application or needs to be addressed. In one basic form, the invention discloses the use of Raman spectroscopy to analyze colloidal particles that have been specially prepared to have long term stability and to be sensitive to a specific analyte or group of analytes. A specific advantage of this approach is that the SERS phenomenon exhibits a signal from material localized near the particle surface. This precludes the need for removing excess analyte, impurity, or reagent that indicates the presence of an analyte from the sample mixture. This aspect combined with the aspect of a coated particle with long term stability leads to the invention of a commercially important one-step assay.
This invention includes aspects of colloidal preparations that can be stored for long periods of time and reconstituted to a SERS active suspension. A particularly important aspect of this is the amount of colloid is determined very accurately though a volumetric delivery of known concentration or delivery of a known mass of colloidal suspension. The mass delivery is enabling to an assay since a large mass of diluted colloid can be used to accurately deliver a small amount of colloid into a sample chamber.
The preparation of the colloidal assay potentially includes pretreatment of the sample chamber to prevent the colloidal particles from binding to the surface or each other. This aspect may also include the use of a sample container that naturally possesses the ability to contain the colloids without affecting their ability to be reconstituted.
The configuration of the test materials in the sample container is an important aspect of this invention. Many of the assays covered under this invention will use reagents that should be added in a sequential fashion. This could be carried out with a one-step addition of sample if the different reagents are placed in matrices that control their rate of release, though in many cases controlled release may not be necessary.
The invention also includes aspects of the colloid particle nature that allow a coating to easily displace a prior coating on the colloid formed during preparation that is present for stability.
In keeping with our goal of designing an assay system that has long term stability such that a pretreated assay could be produced for the customer for later use, the invention includes a sample container design that incorporates these features. Assays are typically performed both individually or multiply. Multiple assays have an advantage that many of the steps involved in the assay can be performed in parallel thus decreasing the time of assay. This invention describes a sample chamber that can be easily fabricated in a multisample format. Additionally, as our assay takes special advantage of the SERS effect to produce a one-step assay the sample containers can be sealed to prevent contamination of the sample or, more importantly, prevent potential spread of the sample which may be hazardous to the testing personnel or facility.
Naturally, further objects of the invention are disclosed throughout other areas of the specifications.

Practical method and apparatus for analyte detection with colloidal particles


An image containing data relating to the tissue-state and the tissue-form of a target area is displayed. A fluorescent-light image having two different wavelength bands of fluorescent-light is obtained, based on the strength of the fluorescent light emitted from a target area irradiated by stimulating-light. A reflected-light image is obtained based on the strength of the light reflected from a target area irradiated by white-light as reference-light. A hue is assigned to a computed-image based on a division value of each pixel value of aforementioned fluorescent-light image to form a tissue-state image reflecting mainly the tissue-state, and a brightness is assigned to the reflected-light image to form a tissue-form image reflecting mainly the tissue-form. The tissue-state image and the tissue-form image are combined to form a composite-image, and the composite-image is displayed.

1. Field of the Invention
The present invention relates generally to a fluorescent-light image display method and apparatus therefor, and more particularly to a method of and apparatus for detecting the fluorescent-light emitted from a living-tissue subject upon irradiation thereof by a stimulating-light and displaying the detected fluorescent light as an image representing the data relating to the living-tissue subject.
2. Description of the Related Art
It has been known in the field of radiology that when a living-tissue subject is irradiated by a stimulating wavelength having a predetermined wavelength, the strength of the fluorescent light emitted from the normal tissue and the strength of the fluorescent light emitted from the diseased tissue differ. Technologies have been proposed, wherein, by making use of this difference, a living-tissue subject is irradiated by a stimulating-light of a predetermined wavelength and by receiving the fluorescent-light image emitted from the living-tissue subject, the location and range of infiltration of a diseased tissue is displayed as a fluorescent-light image.
Normally, upon irradiation by stimulating-light, as shown in FIG. 21, because a strong fluorescent-light is emitted from normal tissue and a weak fluorescent-light is emitted from diseased tissue, by measuring the strength of the fluorescent light, the state of the disease can be determined.
Basically, this type of fluorescent-light image display apparatus comprises a stimulating-light emitting means for projecting the stimulating-light onto a living-tissue subject, a fluorescent-light image obtaining means for obtaining a fluorescent-light image of the fluorescent light emitted from the living-tissue subject, and a display means for receiving the output of the fluorescent-light image obtaining means and displaying aforementioned fluorescent-light image. In many cases, this apparatus is incorporated into an endoscope for insertion into a body cavity of a patient, a colposcope, or a surgical-use microscope.
However, when using a fluorescent-light image display apparatuses such as that described above, because there is unevenness on a the surface of a portion of the living-tissue subject, the distance between the stimulating-light emitting system and the living-tissue subject is not uniform, and the intensity of the stimulating-light irradiating a living-tissue subject is generally not uniform at all positions of the living-tissue subject. The strength of the fluorescent light emitted from the living-tissue subject is substantially proportionate to the degree of the stimulating-light irradiation received by the living-tissue subject, and the degree of stimulating-light irradiation received by the living-tissue subject is in inverse proportion to the square of the distance. Therefore, there are cases in which a diseased tissue located closer to the stimulating-light emitting system emits a stronger fluorescent light than a normal tissue located at a position further removed from the stimulating-light emitting system, and if an operator makes a determination as to the state of the disease based solely on the strength of the fluorescent light, an erroneous diagnosis result is obtained.
In order to reduce the uncertainty and itinerant precariousness in diagnosis due to the circumstances described above, the applicants of the present application propose a fluorescent-light image display apparatus for displaying a pseudo color image, wherein a narrow-band fluorescent-light image near the 480 nm wavelength range is obtained of the normal tissue, and a wide-band fluorescent-light image of the fluorescent light in the visible spectrum is obtained of the diseased tissue, a division value is obtained of the light strength of the wide-band image fluorescent-light image, and based on this division value, aforementioned pseudo color image is displayed.
That is to say, the term representing the strength of the fluorescent light, which is dependent on the distance between the stimulating-light source and the living-tissue subject, is cancelled by aforementioned division process, and an image displaying only the difference in the spectra of the fluorescent light is obtained.
Further, on the other hand, the applicants of the present application propose a method of facilitating discernment of the state of a living-tissue subject by obtaining the ratio of the strength of the stimulating-light received by the irradiated living-tissue subject and the fluorescent light emitted therefrom, that is, the value reflecting the fluorescent light emission output, which is a value that is not affected by the distance or angle from which the stimulating-light has been projected onto the living-tissue subject.
When obtaining the value reflecting aforementioned fluorescent light emission output, because the stimulating-light is not absorbed the same by the various types of tissue, even if the distribution of the light strength of the irradiated stimulating-light is measured, the distribution of the light strength of the stimulating-light received by the living-tissue subject is not correctly measured.
Here, one strategy for obtaining the fluorescent light uptake rate is to irradiate a living-tissue subject with a near-infrared light, which is absorbed uniformly by various types of tissue, as a reference light and to photograph a reflected-light image of the reflected reference-light reflected from the living-tissue subject; the light strength of this reflected-light image is used in place of the light strength of the stimulating-light received by the living-tissue subject and a division value of the fluorescent-light image and the light strength of the reflected-light image is obtained, and based on this division value, a pseudo color image is displayed.
That is to say, by aforementioned division process, the term representing the light strength of the fluorescent-light, which is dependent on the distance between the stimulating-light source and the living-tissue subject is cancelled, and an image reflecting only the difference in the fluorescent light emission output is obtained.
However, as described above, by performing aforementioned division process between fluorescent-light images or between a fluorescent-light image and a reflected-light image, although the pseudo color image in which the distance data has been cancelled contains the data relating to the fluorescent light emitted from the living-tissue subject, after being used as a diagnostic tool for determining the state of a disease, it becomes a composite-image in which the valuable data relating to the form of the living-tissue subject has been omitted. And once again, to the operator, the composite-image gives the impression of flatness devoid of any unevenness whatsoever, and becomes considered as a dubious image.

This patent is subject to a terminal disclaimer.

Fluorescent-light image display method and apparatus therefor


A method of treatment or prevention of breast and endometrial cancer, osteoporosis and endometriosis in susceptible warm-blooded animals comprising administering a low dose of a progestin or other steroid derivative having androgenic activity and low masculinizing activity. Pharmaceutical compositions useful for such treatment and pharmaceutical kits containing such compositions are disclosed. An in vitro assay permitting specific measurements of androgenic activity of potentially useful compounds is also disclosed.

This invention relates to a method for treating or preventing breast and endometrial cancer, bone loss, and for treating endometriosis in susceptible warm-blooded animals including humans involving administration of a compound possessing androgenic activity, and to kits containing active ingredients to be used in the therapy.
Various investigators have been studying hormonal therapy for breast and endometrial cancer as well as for the prevention and treatment of bone loss and for treatment of endometriosis. The main approaches for the treatment of already developed breast cancer are related to the inhibition of estrogen action and/or formation. The role of estrogens in promoting the growth of estrogensensitive breast cancer is well recognized (Lippman, Semin. Oncol. 10 (suppl. 4): 11-19, 1983; Sledge and McGuire, Cancer Res. 38: 61-75, 1984; Wittliff, Cancer 53: 630-643, 1984; Poulin and Labrie, Cancer Res. 46: 4933-4937, 1986).
Estrogens are also known to promote the proliferation of normal endometrium. Chronic exposure to estrogens unopposed by progesterone can lead to the development of endometrial hyperplasia which predisposes to endometrial carcinoma (Lucas, Obstet. Gynecol. Surv. 29: 507-528, 1974). The incidence of endometrial cancer increases after menopause, especially in women receiving estrogen therapy without simultaneous treatment with progestins (Smith et al., N. Engl. J. Med. 293: 1164-1167, 1975; Mack et al., N. Engl. J. Med. 294: 1262-1267, 1976).
Various investigators have been studying hormone-dependent breast and endometrial cancer. A known form of endocrine therapy in premenopausal women is castration most commonly performed by surgery or irradiation, two procedures giving irreversible castration. Recently, a reversible form of castration has been achieved by utilizing Luteinizing Hormone-Releasing Hormone Agonists (LHRH agonists) which, following inhibition of secretion of bioactive Luteinizing Hormone (LH) by the pituitary gland, decrease serum estrogens to castrated levels (Nicholson et al., Brit. J. Cancer 39: 268-273, 1979).
Several studies show that treatment of premenopausal breast cancer patients with LHRH agonists induces responses comparable to those achieved with other forms of castration (Klijn et al., J. Steroid Biochem. 20: 1381, 1984; Manni et al., Endocr. Rev. 7: 89=94, 1986). Beneficial effects of treatment with LHRH agonists have also been observed in postmenopausal women (Nicholson et al., J. Steroid Biochem. 23: 843-848, 1985).
U.S. Pat. No. 4,071,622 relates to the use of certain LHRH agonists against DMBA-induced mammary carcinoma in rats.
U.S. Pat. No. 4,775,660 relates to the treatment of female breast cancer by use of a combination therapy comprising administering an antiandrogen and an antiestrogen to a female after the hormone output of her ovaries has been blocked by chemical or surgical means.
U.S. Pat. No. 4,775,661 relates to the treatment of female breast cancer by use of a therapy comprising administering to a female, after the hormone output of her ovaries has been blocked by chemical or surgical means, an antiandrogen and optionally certain inhibitors of sex steroid biosynthesis.
U.S. Pat. No. 4,760,053 describes a treatment of selected sex steroid dependent cancers which includes various specified combinations of compounds selected from LHRH agonists, antiandrogens, antiestrogens and certain inhibitors of sex steroid biosynthesis.
In U.S. Pat. No. 4,472,382 relates to treatment of prostatic adenocarcinoma, benign prostatic hypertrophy and hormone-dependent mammary tumors with specified pharmaceuticals or combinations. Various LHRH agonists and antiandrogens are discussed.
International Patent Application PCT/W086/01105, discloses a method of treating sex steroid dependent cancers in warm-blooded animals which comprises administering specific pharmaceuticals and combinations. Antiandrogens, antiestrogens, certain inhibitors of sex steroid biosynthesis and blocking of hormonal output are discussed.
The inventor's co-pending U.S. patent application Ser. No. 07/321926 filed Mar. 10, 1989, relates to a method of treatment of breast and endometrial cancer in susceptible warm-blooded animals which may include inhibition of ovarian hormonal secretion by surgical means (ovariectomy) or chemical means (use of an LHRH agonist, e.g. [D-Trp.sup.6, des-Gly-NH.sub.2.sup.10 ]LHRH ethylamide, or antagonists) as part of a combination therapy. Antiestrogens, androgens, progestins, inhibitors of sex steroid formation (especially of 17.beta.-hydroxysteroid dehydrogenase- or aromatase-catalyzed production of sex steroids), inhibitors of prolactin secretion and of growth hormone secretion and ACTH secretion are discussed.
Androgen receptors have been shown to be present in normal (Witliff, In: Bush, H. (Ed.), Methods in Cancer Res., Vol. 11, Acad. Press, New York, 1975, pp. 298-304; Allegra et al., Cancer Res. 39: 1447-1454, 1979) and neoplastic (Allegra et al., Cancer Res. 39: 1147-1454, 1979; Engelsman et al., Brit. J. Cancer 30: 177-181, 1975; Moss et al., J. Ster. Biochem. 6: 743-749, 1975; Miller et al., Eur. J. Cancer Clin. Oncol. 2: 539-542, 1985; Lippman et al., Cancer 38: 868-874, 1976; Allegra et al., Cancer Res. 39: 1447-1454, 1979; Miller et al., Eur. J. Clin. Oncol. 21: 539-542, 1985; Lea et al., Cancer Res. 49: 7162-7167, 1989) as well as in several established breast cancer cell lines (Lippman et al., Cancer Res. 36: 4610-4618, 1976; Horwitz et al., Cancer Res. 38: 2434-2439, 1978; Poulin et al., Breast Cancer Res. Treatm. 12: 213-225, 1988). Androgen receptors are also present in dimethylbenz(a)anthracene (DMBA)-induced mammary tumors in the rat (Asselin et al., Cancer Res. 40: 1612-1622, 1980).
Androgen receptors have also been described in human endometrium (MacLaughlin and Richardson, J. Steroid Biochem. 10: 371-377, 1979; Muechler and Kohler, Gynecol. Invest. 8: 104, 1988). The growth inhibitory effects of the androgen methyltrienolone (R1881), on endometrial carcinoma in vitro have been described (Centola, Cancer Res. 45: 6264-6267, 1985).
Recent reports have indicated that androgen receptors may add to the selective power of estrogen receptors or even supplant estrogen receptors as best predicting response to endocrine therapy (Teulings et al., Cancer Res. 40: 2557-2561, 1980; Bryan et al., Cancer 54: 2436-2440, 1984).
The first androgen successfully used in the treatment of advanced breast cancer is testosterone propionate (Nathanson, Rec. Prog. Horm. Res. 1: 261-291, 1947). Many studies subsequently confirmed the beneficial effect of androgens on breast cancer (Alan and Herrman, Ann. Surg. 123: 1023-1035; Adair, Surg. Gynecol. Obstet. 84: 719-722, 1947; Adair et al., JAMA 140: 1193-2000, 1949). These initial results stimulated cooperative studies on the effect of testosterone propionate and DES which were both found to be effective in producing objective remissions. (Subcommittee on Steroid and Cancer of the Committee on Research of the Council on Pharmacy and Chemistry of the Am. Med. Association followed by the Cooperative Breast Cancer Group under the Cancer Chemotherapy National Service Center of the NCI who found that testosterone propionate improved remission rate and duration, quality of life and survival (Cooperative Breast Cancer Group, JAMA 188, 1069-1072, 1964)).
A response rate of 48% (13 of 27 patients) was observed in postmenopausal women who received the long-acting androgen methonolone enanthate (Kennedy et al., Cancer 21: 197-201, 1967). The median duration of survival was four times longer in the responders as compared to the non-responder group (27 versus 7.5 months). A large number of studies have demonstrated that androgens induce remission in 20 to 40% of women with metastatic breast cancer (Kennedy, Hormone Therapy in Cancer. Geriatrics 25: 106-112, 1970; Goldenberg et al., JAMA 223: 1267-1268, 1973).
A response rate of 39% with an average duration of 11 months has recently been observed in a group of 33 postmenopausal women who previously failed or did not respond to Tamoxifen (Manni et al., Cancer 48: 2507-2509, 1981) upon treatment with Fluoxymesterone (Halostatin) (10 mg, b.i.d.). Of these women, 17 had also undergone hypophysectomy. There was no difference in the response rate to Fluoxymesterone in patients who had previously responded to Tamoxifen and in those who had failed. Of the 17 patients who had failed to both Tamoxifen and hypophysectomy, 7 responded to Fluoxymesterone for an average duration of 10 months. Among these, two had not responded to either Tamoxifen or hypophysectomy.
The combination Fluoxymesterone and Tamoxifen has been shown to be superior to Tamoxifen alone. In fact, complete responses (CR) were seen only in the combination arm while 32% showed partial response (PR) in the combination arm versus only 15% in the monotherapy arm. In addition, there were only 25% of non-responders in the combination therapy arm versus 50% in the patients who received TAM alone (Tormey et al., Ann. Int. Med. 98: 139-144, 1983). Moreover, the median time from onset of therapy to treatment failure was longer with Fluoxymesterone+Tamoxifen (180 days) compared to the Tamoxifen arm alone (64 days). There was a tendency for improved survival in the combination therapy arm (380 versus 330 days).
The independent beneficial effect of an androgen combined with an antiestrogen is suggested by the report that patients who did not respond to Tamoxifen could respond to Fluoxymesterone and vice versa. Moreover, patients treated with Tamoxifen and crossing over to Fluoxymesterone survived longer that those treated with the reverse regimen (Tormey et al., Ann. Int. Med. 98: 139-144, 1983).
Since testosterone propionate had beneficial effects in both pre- and postmenopausal women (Adair et al., J. Am. Med. Ass. 15: 1193-1200, 1949), it indicates that in addition to inhibiting gonadotropin secretion, the androgen exerts a direct inhibitory effect on cancer growth.
Recent in vitro studies describe the relative antiproliferative activities of an androgen on the growth of the estrogen-sensitive human mammary carcinoma cell line ZR-75-1 (Poulin et al. "Androgens inhibit basal and estrogen-induced cell proliferation in the ZR-75-1 human breast cancer cell line", Breast Cancer Res. Treatm. 12: 213-225, 1989). As mentioned above, Poulin et al. (Breast Cancer Res. Treatm. 12: 213-225, 1989) have found that the growth of ZR-75-1 human breast carcinoma cells is inhibited by androgens, the inhibitory effect of androgens being additive to that of an antiestrogen. The inhibitory effect of androgens on the growth of human breast carcinoma cells ZR-75-1 has also been observed in vivo in nude mice (Dauvois and Labrie, unpublished data).
As a possible mechanism of androgen action in breast cancer, it has recently been shown that androgens strongly suppress estrogen (ER) and progesterone (PgR) receptor contents in ZR-75-1 human breast cancer cells as measured by radioligand binding and anti-ER monoclonal antibodies. Similar inhibitory effects were observed on the levels of ER mRNA measured by ribonuclease protection assay. The androgenic effect is measured at subnanomolar concentrations of the non-aromatizable androgen 5.alpha.-adihydrotestosterone, regardless of the presence of estrogens, and is competitively reversed by the antiandrogen hydroxyflutamide (Poulin et al., Endocrinology 125: 392-399, 1989). Such data on estrogen receptor expression provide an explanation for at least part of the antiestrogenic effects of androgens on breast cancer cell growth and moreover suggest that the specific inhibitory effects of androgen therapy could be additive to the standard treatment limited to blockade of estrogens by antiestrogens.
Dauvois et al. (Breast Cancer Res. Treatm. 14: 299-306, 1989) have shown that constant release of the androgen 5.alpha.-dihydrotestosterone (DHT) in ovariectomized rats bearing DMBA-induced mammary carcinoma caused a marked inhibition of tumor growth induced by 17.beta.-estradiol (E.sub.2). That DHT acts through interaction with the androgen receptor is supported by the finding that simultaneous treatment with the antiandrogen Flutamide completely prevented DHT action. Particularly illustrative of the potent inhibitory effect of the androgen DHT on tumor growth are the decrease by DHT of the number of progressing tumors from 69.2% to 29.2% in E.sub.2 -treated animals and the increase by the androgen of the number of complete responses (disappearance of palpable tumors) from 11.5% to 33.3% in the same groups of animals. The number of new tumors appearing during the 28-day observation period in E.sub.2 -treated animals decreased from 1.5.+-.0.3 to 0.7.+-.0.2 per rat during treatment with the androgen DHT, an effect which was also reversed by the antiandrogen Flutamide. Such data demonstrate, for the first time, that androgens are potent inhibitors of DMBA-induced mammary carcinoma growth by an action independent from inhibition of gonadotropin secretion and suggest an action exerted directly at the tumor level, thus further supporting the in vitro data obtained with human ZR-75-1 breast cancer cells (Poulin et al., Breast Cancer Res. Treatm. 12: 213-225, 1988).
The natural androgens testosterone (TESTO) and dihydrotestosterone (DHT) are formed from conversion of androstenedione into TESTO by 17.beta.-hydroxysteroid dehydrogenase and then TESTO into DHT by the action of the enzyme 5.alpha.-reductase. The adrenal precursor 5-androst-5-ene-3 .beta.,17.beta.-diol can also be converted into TESTO by action of the enzyme 3.beta.-hydroxysteroid dehydrogenase/.DELTA..sup.5 .DELTA..sup.4 isomerase (3.beta.-HSD).
Since the natural androgens TESTO and DHT have strong masculinizing effects, numerous derivatives of TESTO as well as progesterone have been synthesized in order to obtain useful compounds having fewer undesirable masculinizing side effects (body hair growth, loss of scalp hair, acne, seborrhea and loud voice).
Medroxyprogesterone acetate (MPA) is one of the most widely used compounds in the endocrine therapy of advanced breast cancer in women (Mattsson, Breast Cancer Res. Treatm. 3: 231-235, 1983; Blumenschein, Semin. Oncol. 10: 7-10, 1983; Hortobagyi et al., Breast Cancer Res. Treatm. 5: 321-326, 1985; Haller and Glick, Semin. Oncol. 13: 2-8, 1986; Horwitz, J. Steroid Biochem. 27: 447-457, 1987). The overall clinical response rate of high doses of this synthetic progestin averages 40% in unselected breast cancer patients (Horwitz, J. Steroid Biochem. 27: 447-457, 1987), an efficacy comparable to that of the nonsteroidal antiestrogen tamoxifen (Lippman, Semin. Oncol. 10 (Suppl.): 11-19, 1983). Its more general use, however, is for breast cancer relapsing after other endocrine therapeutic modalities. The maximal inhibitory action of medroxyprogesterone acetate (MPA) on human breast cancer cell growth in vitro may be achieved at concentration as low as 1 nM while an approximately 1000-fold higher dose is often required for glucocorticoid action (Poulin et al., Breast Cancer Res. Treatm. 13: 161-172, 1989).
Until recently, the mechanisms underlying the antitumor activity of MPA were poorly understood and have been attributed to interaction with the progesterone receptor. This steroid, however, presents a high affinity for progesterone (PgR) as well as for androgen (AR) and glucocorticoid receptors (GR) in various animal tissues (Perez-Palacios et al., J. Steroid Biochem. 19: 1729-1735, 1983; Janne and Bardin, Pharmacol. Rev. 36: 35S-42S, 1984; Pridjian et al., J. Steroid Biochem. 26: 313-319, 1987; Ojasso et al., J. Steroid Biochem. 27: 255-269, 1987) as well as in human mammary tumors (Young et al., Am. J. Obstet. Gynecol. 137: 284-292, 1980), a property shared with other synthetic progesterone derivatives (Bullock et al., Endocrinology 103: 1768-1782, 1978; Janne and Bardin, Pharmacol. Rev. 36: 35S-42S, 1984; Ojasso et al., J. Steroid Biochem. 27: 255-269, 1987). It is known that in addition to progesterone receptors (PgR), most synthetic progestational agents bind with significant affinity to androgen (AR) as well as glucocorticoid (GR) receptors, and induce biological actions specifically determined by these individual receptor systems (Labrie et al., Fertil. Steril. 28: 1104-1112, 1977; Engel et al., Cancer Res. 38: 3352-3364, 1978; Raynaud et al., In: Mechanisms of Steroid Action (G. P. Lewis, M. Grisburg, eds), MacMiland Press, London, pp. 145-158, 1981; Rochefort and Chalbos, Mol. Cell. Endocrinol. 36: 3-10, 1984; Janne and Bardin, Pharmacol. Rev. 36: 35S-42S, 1984; Poyet and Labrie, Mol. Cell. Endocrinol. 42: 283-288, 1985; Poulin et al., Breast Cancer Res. Treatm. 13: 161-172, 1989). Accordingly, several side effects other than progestational have been noted in patients treated with MPA.
The most easily explained adverse side effects of MPA are related to its glucocorticoid-like action with Cushingoid syndrome, euphoria and subjective pain relief (Mattsson, Breast Cancer Res. Treatm. 3: 231-235, 1983; Blossey et al., Cancer 54: 1208-1215, 1984; Hortobagyi et al., Breast Cancer Res. Treatm. 5: 321-326, 1985; Van Veelen et al., Cancer Chemother. Pharmacol. 15: 167-170, 1985). Suppression of adrenal function by MPA is believed to be caused both by an inhibitory action on ACTH secretion at the pituitary level and by direct inhibition of steroidogenesis at the adrenal level (Blossey et al., Cancer 54: 1208-1215, 1984; Van Veelen et al., Cancer Chemother. Pharmacol. 15: 167-170, 1985; Van Veelen et al., Cancer Treat. Rep. 69: 977-983, 1985).
Despite its high affinity for AR, MPA seldom causes significant virilizing symptoms (acne, hirsutism, etc.) (Haller and Glick, Semin. Oncol. 13: 2-8, 1986). Moreover, its inhibitory effect on gonadotropin secretion is clearly exerted through its direct interaction with pituitary AR in the rat (Labrie et al., Fertil. Steril. 28: 1104-1112, 1977; Perez-Palacios et al., J. Steroid Biochem. 19: 1729-1735, 1983) and human (Perez-Palacios et al., J. Steroid Biochem. 15: 125-130, 1981). In addition, MPA exhibits androgenic activity in the mouse kidney (Janne and Bardin, Pharmacol. Rev. 36: 35S-42S, 1980) and in the rat ventral prostate (Labrie, C. et al., J. Steroid Biochem. 28: 379-384, 1987; Labrie C. et al., Mol. Cell. Endocrinol. 68: 169-179, 1990).
Poulin et al. "Androgen and glucocorticoid receptor-mediated inhibition of cell proliferation by medroxyprogesterone acetate in ZR-75-1 human breast cancer cells", Breast Cancer Res. Treatm. 13: 161-172, 1989) have recently found that the inhibitory effect of medroxyprogesterone acetate (MPA) on the growth of the human ZR-75-1 breast cancer cells is mainly due to the androgenic properties of the compound. The androgenic properties of MPA have been demonstrated in other systems (Labrie C. et al., J. Steroid Biochem. 28: 379-384, 1987; Luthy et al., J. Steroid Biochem. 31: 845-852, 1988; Plante et al., J. Steroid Biochem. 31: 61-64, 1988; Labrie C. et al., Mol. Cell. Endocrinol. 58: 169-179, 1990). Other synthetic progestins have also been shown to possess, in addition to their progesterone-like activity, various degrees of androgenic activity (Labrie et al., Fertil. Steril. 31: 29-34, 1979; Poyet and Labrie, The Prostate 9: 237-246, 1986; Labrie C. et al., J. Steroid Biochem. 28: 379-384, 1987; Luthy et al., J. Steroid Biochem. 31: 845-852, 1988; Plante et al., J. Steroid Biochem. 31: 61-64, 1989).
High dose MPA as first treatment of breast cancer has shown similar effects as Tamoxifen (Van Veelen et al., Cancer 58: 7-13, 1986). High dose progestins, especially medroxyprogesterone acetate and megestrol acetate have also been successfully used for the treatment of endometrial cancer (Tatman et al., Eur. J. Cancer Clin. Oncol. 25: 1619-1621, 1989; Podratz et al., Obstet. Gynecol. 66: 106-110, 1985; Ehrlich et al., Am. J. Obstet. Gynecol. 158: 797-807, 1988). High dose MPA is being used with a success similar to that of Tamoxifen for the treatment of endometrial carcinoma (Rendina et al., Europ. J. Obstet. Gynecol. Reprod. Biol. 17: 285-291, 1984).
In a randomized clinical trial, high dose MPA administered for 6 months has been shown to induce resolution of the disease in 50% of the patients and a partial resolution in 13% of subjects compared to 12% and 6%, respectively, in patients who received placebo (Telimaa et al., Gynecol. Endocrinol. 1: 13, 1987).
The androgen methyltestosterone has been shown to relieve the symptoms of endometriosis (Hamblen, South Med. J. 50: 743, 1987; Preston, Obstet, Gynecol. 2: 152, 1965). Androgenic and masculinizing side effects (sometimes irreversible) are however important with potent androgenic compounds such as testosterone.
In analogy with the androgen-induced decrease in estrogen receptors in human breast cancer ZR-75-1 cells (Poulin et al., Endocrinology 125: 392-399, 1989), oral administration of MPA to women during the follicular phase caused a decrease in the level of estrogen binding in the endometrium (Tseng and Gurpide, J. Clin. Endocrinol. Metab. 41, 402-404, 1975).
Studies in animals have shown that androgen deficiency leads to osteopenia while testosterone administration increases the overall quantity of bone (Silberberg and Silberberg, 1971; see Finkelstein et al., Ann. Int. Med. 106: 354-361, 1987). Orchiectomy in rats can cause osteoporosis detectable within 2 months (Winks and Felts, Calcif. Tissue Res. 32: 77-82, 1980; Verhas et al., California Tissue Res. 39: 74-77, 1986).
While hirsute oligomenorrheic and amenorrheic women having low circulating E.sub.2 levels would be expected to have reduced bone mass, these women with high androgen (but low estrogen) levels are at reduced risk of developing osteoporosis (Dixon et al., Clinical Endocrinology 30: 271-277, 1989).
Adrenal androgen levels have been found to be reduced in osteoporosis (Nordin et al., J. Clin. Endocr. Metab. 60: 651, 1985). Moreover, elevated androgens in postmenopausal women have been shown to protect against accelerated bone loss (Deutsch et al., Int. J. Gynecol. Obstet. 25: 217-222, 1987; Aloia et al., Arch. Int. Med. 143: 1700-1704, 1983). In agreement with such a role of androgens, urinary levels of androgen metabolites are lower in postmenopausal symptomatic menopausis than in matched controls and a significant decrease in conjugated dehydroepiandrosterone (DHEA) was found in the plasma of osteoporotic patients (Hollo and Feher, Acta Med. Hung. 20: 133, 1964; Urist and Vincent, J. Clin. Orthop. 18: 199, 1961; Hollo et al., Acta Med. Hung. 27: 155, 1970). It has even been suggested that postmenopausal osteoporosis results from both hypoestrogenism and hypoandrogenism (Hollo et al., Lancet 1357, 1976).
As a mechanism for the above-suggested role of both estrogens and androgens in osteoporosis, the presence of estrogen (Komm et al., Science 241: 81-84, 1988; Eriksen et al., Science 241: 84-86, 1988) as well as androgen (Colvard et al., Proc. Natl. Acad. Sci. 86: 854-857, 1989) receptors in osteoblasts could explain increased bone resorption observed after estrogen and androgen depletion.
In boys, during normal puberty, an increase in serum testosterone levels procedes an increase in alkaline phosphate activity (marker of osteoblastic activity) which itself precedes increased bone density (Krabbe et al., Arch. Dis. Child. 54: 950-953, 1979; Krabbe et al., Arch. Pediat. Scand. 73: 750-755, 1984; Riis et al., California Tissue Res. 37: 213-217, 1985).
While, in women, there is a rapid bone loss starting at menopause, bone loss in males can be recognized at about 65 years of age (Riggs et al., J. Clin. Invest. 67: 328-335, 1987). A significant bone loss is seen in men at about 80 years of age, with the accompanying occurrence of hip, spine and wrist fractures. Several studies indicate that osteoporosis is a clinical manifestation of androgen deficiency in men (Baran et al., Calcif. Tissue Res. 26: 103-106, 1978; Odell and Swerdloff, West. J. Med. 124: 446-475, 1976; Smith and Walker, California Tissue Res. 22 (Suppl.): 225-228, 1976).
Although less frequent than in women osteoporosis can cause significant morbidity in men (Seeman et al., Am. J. Med. 75: 977-983, 1983). In fact, androgen deficiency is a major risk for spinal compression in men (Seeman et al., Am. J. Med. 75: 977-983, 1983). Decreased radial and spinal bone density accompanies hypogonadism associated with hyperprolactinemia (Greespan et al., Ann. Int. Med. 104: 777-782, 1986) or anaorexia nervosa (Rigotti et al., JAMA 256: 385-288, 1986). However, in these cases, the role of hyperprolactinemia and loss in body weight is uncertain.
Hypogonadism in the male is a well-recognized cause of osteoporotic fracture (Albright and Reinfenstein, 1948; Saville, Clin. End. Metab. 2: 177-185, 1973). Bone density is in fact reduced in both primary and secondary hypogonadism (Velentzas and Karras. Nouv. Presse Medicale 10: 2520, 1981).
Severe osteopenia as revealed by decreased cortical and trabecular bone density was reported in 23 hypogonadotropic hypogonadal men (Finkelstein et al., Ann. Int. Med. 106: 354-361, 1987; Foresta et al., Horm. Metab. Res. 15: 56-57, 1983). Osteopenia has also been reported in men with Klinefelter's syndrome (Foresta et al., Horm. Metab. Res. 15: 206-207, 1983; Foresta et al., Horm. Metab. Res. 15: 56-57, 1983; Smith and Walker, California Tissue Res. 22: 225-228, 1977).
Androgenic-reversible decreased sensitivity to calcitonin has been described in rats after castration (Ogata et al., Endocrinology 87: 421, 1970; Hollo et al., Lancet 1: 1205, 1971; Hollo et al., Lancet 1: 1357, 1976). In addition, serum calcitonin has been found to be reduced in hypogonadal men (Foresta et al., Horm. Metab. Res. 15: 206-207, 1983) and testosterone therapy in castrated rats increases the hypocalcemic effect of calcitonin (McDermatt and Kidd, End. Rev. 8: 377-390, 1987).
Albright and Ruferstein (1948) originally suggested that androgens increase the synthesis of bone matrix. Androgens have also been shown to increase osteoid synthesis and mineralization in chicken (Puche and Rosmano, California Tissue Res. 4: 39-47, 1969). Androgen therapy in hypogonadal men increases skeletal growth and maturation (Webster and Hogkins, Proc. Soc. Exp. Biol. Med. 45: 72-75, 1940). In addition, testosterone therapy in man has been shown to cause positive nitrogen, calcium and phosphate balance (Albright, F., Reifeinstein, E. C. In: The parathyroid glands and metabolic bone disease. Williams and Williams Co.: Baltimore, pp. 145-204, 1948). As studied by bone histomorphometry, testosterone therapy in hypogonadal males resulted in increases in relative osteoid volume, total osteoid surface, linear extend of bone formation and bone mineralization (Barau et al., Calcif. Tissue Res. 26: 103-106, 1978).
Treatment with testosterone has been shown to increase osteoid surfaces and beam width with unchanged or reduced oppositional rates, thus indicating and increase in total bone mineralization rate (Peacock et al., Bone 7: 261-268, 1986). There was also a decrease in plasma phosphate probably due to an effect on renal tubular reabsorption of phosphates (Selby et al., Clin. Sci. 69: 265-271, 1985).
Cortical bone density increases in hyperprolactinemic men with hypogonadism when testicular function is normalized (Greenspan et al., Ann. Int. Med. 104: 777-782, 1986; Greenspan et al., Ann. Int. Med. 110: 526-531, 1989). Testosterone therapy increases bone formation in men with primary hypogonadism (Baron et al., Calcif. Tissue Res. 26: 103-106, 1978; Frands et al., Bone 7: 261-268, 1986).
In 21 hypogonadal men with isolated GnRH deficiency, normalization of serum testosterone for more than 12 months increased bone density (Kinkelstein et al., J. Clin. Endocr. Metab. 69: 776-783, 1989). In men with already fused epiphyses, however, there was a significant increase in cortical bone density while no significant change was observed on trabecular bone density, thus supporting previous suggestions of variable sensitivity of cortical and trabecular bone to steroid therapy.
Previous studies with anabolic steroids in small numbers of patients have suggested positive effects on bone (Lafferty et al., Ann. J. Med. 36: 514-528, 1964; Riggs et al., J. Clin. Invest. 51: 2659-2663, 1972; Harrison et al., Metabolism 20: 1107-1118, 1971). More recently, using total body calcium measurements by neutron activation as parameter, the anabolic steroid methandrostenolone has shown positive and relatively long-term (24-26 months) effects in a doubleblind study in postmenopausal osteoporosis (Chessnut et al., Metabolism 26: 267-277, 1977; Aloia et al., Metabolism 30: 1076-1079, 1981).
The anabolic steroid nandrolone decanoate reduced bone resorption in osteoporotic women (Dequeker ancl Geusens, Acta Endocrinol. 271 (Suppl.): 45-52, 1985) in agreement with the results observed during estrogen therapy (Dequeker and Ferin, 1976, see Dequeker and Geusens). Such data confirm experimental data in rabbits and dogs when nandrolone decanoate reduced bone resorption (Ohem et al., Curr. Med. Res. Opin. 6: 606-613, 1980). Moreover, in osteoporotic women (Dequeker and Geusens, Acta Endocrinol. (Suppl.) 271: 45-52, 1985) the anabolic steroid not only reduced bone loss but also increased bone mass. Vitamin D treatment, on the other hand, only reduced bone resorption.
Therapy of postmenopausal women with nandrolone increased cortical bone mineral content (Clin. Orthop. 225: 273-277). Androgenic side effects, however, were recorded in 50% of patients. Such data are of interest since while most therapies are limited to an arrest of bone loss, an increased in bone mass was found with the use of the anabolic steroid nandrolone. A similar stimulation of bone formation by androgens has been suggested in a hypogonadal male (Baran et al., Calcif. Tissue Res. 26: 103, 1978). The problem with regimens which inhibit bone resorption with calcium, calcitriol or hormones is that they almost certainly lead to suppression of bone formation (Need et al., Mineral. Electrolyte Metabolism 11: 35, 1985). Although, Albright and Reiferestein (1948) (See Need, Clin. Orthop. 225: 273, 1987) suggested that osteoporosis is related to decreased bone formation and will respond to testosterone therapy, the virilizing effects of androgens have made them unsuitable for the treatment of postmenopausal women. Anabolic steroids, compounds having fewer virilizing effects, were subsequently developed. Although, minimal effects have been reported by some (WiIson and Griffin, Metabolism 28: 1278, 1980) more positive results have been reported (Chessnut et al., Metabolism 32: 571-580, 1983; Chessnut et al., Metabolism 26: 267, 1988; Dequeker and Geusens, Acta Endocrinol. (Suppl. 110) 271: 452, 1985). A randomized study in postmenopausal women has been shown an increase in total bone mass during treatment with the anabolic steroid stanazolol although side effects were recorded in the majority of patients (Chessnut et al., Metabolism 32: 571-580, 1983).
As mentioned above, the doses of "progestins" (for example medroxyprogesterone acetate) used for the standard therapy of breast cancer are accompanied by undesirable important side effects (especially those related to interaction of the steroid with the glucocorticoid receptor, especially Cushingoid syndrome, euphoria) (Mattsson, Breast Cancer Res. Treatm. 3: 231-235, 1983; Blossey et al., Cancer 54: 1208-1215, 1984; Hortobagyi et al., Breast Cancer Res. Treatm. 5: 321-326, 1985; Von Veelen et al., Cancer Chemother. Pharmacol. 15: 167-170, 1985).
The term "progestin" refers to derivatives of progesterone and testosterone. Such progestins have, at times, been synthesized with the aim of developing compounds acting as analogs of progesterone on the progesterone receptors, especially for the control of fertility. With the availability of new and more precise tests, however, it became evident that such compounds, originally made to interact exclusively with the progesterone receptor, do also interact, frequently with high affinity, with the androgen receptor (Labrie et al., Fertil. Steril. 28: 1104-1112, 1977; Labrie et al., Fertil. Steril. 31: 29-34, 1979; Labrie, C. et al., J. Steroid Biochem. 28: 379-384, 1987; Labrie C. et al., Mol. Cell. Endocrinol. 68: 169-179, 1990). Sometimes, the androgenic activity of these compounds, especially at low concentrations, becomes more important than the true progestin activity. This is the case, for example, for medroxyprogesterone acetate (Poulin et al., Breast Cancer Res. Treatm. 13: 161-172, 1989).
A problem with prior-art treatments of breast and endometrial cancer with synthetic progestins is the side effects observed with such treatments. The blockade of estrogens, another common treatment for breast cancer, would have undesirable deleterious effects on bone mass in women. Similarly, blockade of estrogens, a common treatment for endometriosis, has similar undesirable deleterious effects on bone mass in women.

Methods of treating or preventing breast or endometrial cancer with low dose non-masculinizing androgenic compounds


A cooling fan module for a heat exchanger or the like, has a motor, a fan driven by the motor and a speed controller connected between the motor and a power supply. The speed controller is configured to operate the motor in a high speed mode and a low speed mode. The speed controller includes a high speed branch and a low speed branch connected in parallel. The low speed branch includes a pulse width modulation circuit configured to reduce an average voltage by a fixed duty ratio to achieve a low speed operation of the motor. By eliminating the conventional voltage dropping resistor, the speed controller reduces the power consumption, thus increasing the efficiency of the module, in the low speed mode of operation.

A cooling fan module comprises a fan driven by an electric motor. Cooling fan modules are used, for example in vehicles to cool the radiator of the engine of a conventional vehicle or the battery of an electric vehicle.
The motor drive circuit of a conventional two speed cooling fan module has a high-speed branch and a low-speed branch which are connected in parallel. When the high-speed branch is turned on, the motor runs at a high speed. When the low-speed branch is turned on and the high-speed branch is turned off, the motor runs at a low speed. Generally, power is directly connected to an input terminal (for example, a positive electrode) of the motor through the high-speed branch, and the low-speed branch outputs power to the motor terminal at a reduced voltage via a voltage dropping resistor. In this case, if the motor is running at a low speed, the voltage dropping resistor generates a lot of heat, which causes a great loss.
As known to those skilled in the art, a Pulse Width Modulation (PWM) circuit has an adjustable duty ratio, and the average value of an output voltage may be changed by adjusting the duty ratio of the PWM circuit. An improved variable speed cooling fan module is provided, in which the PWM circuit with an adjustable duty ratio is used to replace the conventional high-speed branch and low-speed branch.
In a vehicle radiator cooling system, the PWM circuit is connected to an Engine Control Unit (ECU) of the vehicle through a control terminal, and the duty ratio changes in response to instructions from the ECU in a real-time manner, thus the output voltage is adjusted and the motor is provided with various voltages to operate at different speeds in a low speed range. For example, where the duty ratio is 100%, the PWM circuit is equivalent to the conventional high-speed branch, the motor runs at a high speed; or where the duty ratio is smaller than 100%, the motor runs at a lower speed.
The loss of the PWM circuit described above is smaller than that of the convention circuit with the voltage dropping resistor. However, the overall cost is greatly increased because an additional control circuit (for example, a circuit for adjusting the duty ratio) is included in the PWM circuit. Besides, the conventional high-speed branch and low-speed branch connected in parallel are replaced by a power supply branch in the PWM circuit and the PWM circuit has an additional control terminal, which means that the interface of the cooling fan module adopting the PWM circuit is incompatible with the conventional interface. In the vehicle industry, different components are provided by different providers, hence, the incompatibility of the interface has a serious impact on sales of the cooling fan module adopting the PWM circuit and applications of the cooling fan module.
Therefore, an improved technical solution is desired.


A perfusion-type dilatation catheter with perfusion ports in the wall of the catheter shaft wherein the proximal edges of the perfusion ports have depressions extending into a guidewire receiving inner lumen which passes through the catheter shaft. The depressed proximal edges prevent excursions of guidewires through the perfusion ports as the guidewire is passed through the guidewire receiving inner lumen. The perfusion ports may be conveniently made by forming holes into the wall of the catheter shaft, inserting shaping pins into the holes, heating the wall of the catheter shaft to make it readily deformable and then rotating the shaping pins proximally along the longitudinal axis of the catheter shaft so that the rotated shaping pins form depressions along the proximal edges of the perfusion ports which extend into the guidewire receiving inner lumen within the catheter shaft.

This invention generally relates to perfusion-type balloon dilatation catheters used in percutaneous transluminal coronary angioplasty (PTCA).
PTCA is a widely used procedure for the treatment of coronary heart disease. In this procedure, a balloon dilatation catheter is advanced into the patient's coronary artery and the balloon on the catheter is inflated within the stenotic region of the patient's artery to open up the arterial passageway and increase the flow of blood through the artery. To facilitate the advancement of the dilatation catheter into the patient's coronary artery, a guiding catheter having a preshaped distal tip is first percutaneously introduced into the cardiovascular system of a patient by the Seldinger technique through the brachial or femoral arteries. The catheter is advanced until the preshaped distal tip of the guiding catheter is disposed within the aorta adjacent the ostium of the desired coronary artery. The guiding catheter is twisted or torqued from the proximal end, which extends out of the patient, to guide the distal tip of the guiding catheter into the ostium. A balloon dilatation catheter may then be advanced through the guiding catheter into the patient's coronary artery until the balloon on the catheter is disposed within the stenotic region of the patient's artery where it is inflated to open up the arterial passageway.
The perfusion-type dilatation catheter for angioplasty was introduced into the marketplace by Advanced Cardiovascular Systems, Inc.(ACS). This catheter, which can take the form of an over-the-wire, a fixed-wire or a rapid exchange type catheter, has one or more perfusion ports proximal and one or more perfusion ports distal to the dilatation balloon which are in fluid communication with a guidewire receiving inner lumen extending to the distal end of the catheter. When the balloon is inflated to dilate a stenosis, oxygenated blood in the artery or the aorta, or both, depending upon the location of the dilatation catheter within the coronary anatomy, is forced to pass through the proximal perfusion ports, through the inner lumen of the catheter and out the distal perfusion ports. The catheter provides oxygenated blood downstream from the inflated balloon which in turn prevents or minimizes ischemic conditions in tissue distal to the catheter. The perfusion of blood distal to the inflated balloon allows for long term dilatations, e.g. 30 minutes or even several hours or more. Commercially available perfusion-type dilatation catheters, which have been highly praised by the medical profession and which have met with much commercial success, include the STACK PERFUSION.RTM. Dilatation Catheter which is sold by ACS.
When using an over-the-wire version of a perfusion-type dilatation catheter, a guidewire is usually inserted into an inner lumen of the dilatation catheter before it is introduced into the patient's vascular system and then both are introduced into and advanced through the guiding catheter to its distal tip seated within the ostium of the desired coronary artery. The guidewire is first advanced out of the seated distal tip of the guiding catheter into the desired coronary artery until the distal end of the guidewire extends beyond the lesion which is to be dilatated. The dilatation catheter is then advanced out of the distal tip of the guiding catheter into the patient's coronary artery, over the previously advanced guidewire, until the balloon on the distal extremity of the dilatation catheter is properly positioned across the lesion to be dilatated. Once properly positioned across the stenosis, the balloon is inflated to a predetermined size with radiopaque liquid at relatively high pressures (e.g., generally 4-12 atmospheres), usually for extended periods, to dilate the stenosed region of a diseased artery. After the inflation, the balloon is finally deflated so that the dilatation catheter can be removed from the dilated stenosis to resume blood flow.
The rapid exchange version of the perfusion-type dilatation catheter has a short guidewire receiving sleeve or inner lumen extending through a distal portion of the catheter. The sleeve or inner lumen extends proximally from a first guidewire port in the distal end of the catheter to a second guidewire port in the catheter spaced proximally from the inflatable member of the catheter. Perfusion ports are provided proximal and distal to the inflatable member or balloon which are in fluid communication with the short guidewire receiving sleeve or inner lumen. A slit may be provided in the wall of the catheter body which extends distally from the second guidewire port, preferably to a location proximal to the location of the balloon. The structure of the catheter allows for the rapid exchange of the catheter without the need for an exchange wire or adding a guidewire extension to the proximal end of the guidewire.
The rapid exchange type perfusion catheter was introduced by ACS under the trademark the ACS RX PERFUSION.RTM. Coronary Dilatation Catheter. This catheter has likewise been widely praised by the medical profession and it has met with much success in the marketplace because of the advantages of its unique design. The rapid exchange features of this catheter are described and claimed in U.S. Pat. No. 5,040,548 (Yock), U.S. Pat. No. 5,061,273 (Yock) and U.S. Pat. No. 4,748,982 (Horzewski et al.) which are incorporated herein by reference.
One of the problems encountered with perfusion-type catheters is that when a guidewire is advanced within the guidewire lumen of the catheter, the guidewire may occasionally pass through a perfusion-port in the catheter shaft. This has become more common as the guidewire diameters have become smaller. Such guidewire excursions through the perfusion ports are not desireable because they interfere with the angioplasty procedure. In such a case the guidewire has to be withdrawn proximally to disengage the guidewire from the perfusion port and then advanced through the catheter lumen. If the guidewire excursion deformed the distal tip of the guidewire, the guidewire may have to be completely withdrawn from the patient so that the distal tip can be reshaped and then readvanced through the catheter shaft. When a guidewire passes out one of the perfusion ports, it may traumatically engage the blood vessel wall. Additionally, as catheter profiles are reduced, the more difficult it is to provided adequate blood flow distal to the balloon to avoid ischemic conditions. What has been needed and previously unavailable is an easily manufactured perfusion-type catheter which will reduce the incidence of a guidewire passing through a perfusion port when the guidewire is advanced through the guidewire lumen and provide effective blood flow through the perfusion ports to ensure adequate blood flow distal to the balloon when the balloon is inflated. The present invention satisfies these and other needs.

Perfusion type dilatation catheter having perfusion ports with depressed proximal edges


An opto-electronic module may be provided with an internal thermoelectric cooler. Components to be cooled may be positioned over the thermoelectric cooler. Other components may be positioned aside the cooled components but raised, using a riser, to position them away from the cooled components.

This invention relates generally to packages for optical modules and, particularly, to packages that receive an optical fiber and provide electrical connections thereto.
Standard techniques to carry an electrical signal across the wall of a package for optical modules include multi-layer ceramic inserts. Standard ceramic packages for optical modules, commonly called butterfly packages, may include a base, a fiber feed-through, a can body, and a ring frame made of metal, as well as one or more multi-layer ceramic inserts that receive electrical connectors. A lid is typically used to hermetically close the package by welding or soldering to the ring frame.
Commonly one or more opto-electronic components in the packages need to be cooled down or maintained at a given temperature. This is usually done using thermoelectric coolers based on the Peltier effect.
The power needed by the thermoelectric cooler to maintain the package at the preset temperature is usually much greater than the original thermal load to dissipate. It is therefore important to reduce or minimize the thermal load on the thermoelectric cooler if it is desirable to minimize or reduce the power dissipated by the opto-electronic package.
In some cases not all of the opto-electronic components in the package need to be cooled down. But, generally, for performance reasons, the cooled and uncooled components need to be located very close to one another.
Thus, there is a need for better ways to cool packages for optical modules.


This is mainly a one-cylinder environmental friendly two stroke engine with a lubrication and a gas control mechanism similar to a four stroke engine. An additional rotation inside of a cylinder of a piston making a stroke motion is utilized for a better gas control mechanism. Control edges on the rotating piston open and close ports in the cylinder in the right sequence, most importantly the exhaust port will be closed prior to the opening of the transfer port. The piston with the rigidly connected L-shaped piston rod rotate around the axis of symmetry of the piston by a rotating spherical bearing rigidly, but eccentrically connected to a rotating shaft. A certain angle between the shaft and the axis of rotation of the piston creates also a stroke motion. An oil-ring around the piston rod works in the same way as by a four stroke engine.

Today's small two stroke engines need oil in the gasoline. A second disadvantage is that the exhaust port and transfer port are open to the same time.
This invention will remove both disadvantages making the two stroke engine environmental friendly as the four stroke engine. A simple steam engine or air engine without extra valves are also in the scope of this invention.

Environmental friendly two stroke engine


An oil separator device for removing a substantial portion of the oil contained in the crankcase fumes of an internal combustion engine. The device is designed to be mounted on the inside of a rocker arm cover of the engine as a part of the crankcase ventilation system. Internal baffles direct a laminar flow of crankcase fumes through the separator canister along a folded path from an inlet in the bottom of the canister to an outlet in the top. Partially isolated channels extend along opposite edges of the flow path. Oil in the fumes attaches itself to the internal surfaces of the separator and flows down these surfaces, which are inclined, to a sump in the bottom. A tubular assembly connected to the bottom of the separator provides combined fume inlet and oil return passageways. The distal end of this tubular assembly has a special configuration which tends to prevent the upward flow of fumes through the oil return passageway, enhance the downward return flow of separated oil therein and prevent the reintroduction of returning oil into the fume stream inlet.

With the growing concern over air pollution, it has become imperative that crankcase fumes, generated during the normal operation of an internal combustion engine, not be vented into the atmosphere. Numerous crankcase ventilation systems have been developed which recirculate such fumes into the fuel-air intake of an engine. However, with the the high efficiency engines of today a serious problem is created when the recirculated fumes contain an excessive quantity of oil vapors or mist. The delicate fuel-air balance can be upset and improper combustion can occur with all of its attendent problems. Prior art oil separators for crankcase fumes have been used with only limited success. The problem appears to reside in achieving an acceptable balance between a separator's capability of separating oil vapors and mist from the crankcase fumes and its capability to return the separated oil to the engine from the separator. Accordingly, it is a general object of this invention to produce an oil separator which effectively separates an acceptable amount of oil from the crankcase fumes and has an enhanced capability of effectively making the collected oil available to the engine crankcase.


Systems and methods are provided for converting Sequential Function Chart (SFC) logic to function block logic for execution by a programmable controller. In one embodiment, a method includes receiving Sequential Function Chart (SFC) logic comprising Steps and Transition on a physical computing device, converting the Steps and Transitions of the Sequential Function Chart logic to function block logic on the physical computing device, and uploading the function block logic from the physical computing device to a controller.

The subject matter disclosed herein relates to control systems, and, more specifically, to designing and executing logic on programmable controllers.
Control systems for processes, plants, and equipment, may include a wide variety of logic to configure how the control system monitors and controls the processes, plants and equipment. A control system may include one or more programmable controllers. To enable design of the logic for a controller and to provide easier configuration, the control system logic may be displayed in various forms on a graphical user interface (GUI).
The graphical user interface (GUI) may be accessible to a user, and the user may design the logic and configure the controller from the GUI. The GUI may present design of the control logic by presenting the logic in a standard format and/or programming language. Sequential Function Charts (SFC) is a programming language defined according to the International Electrotechnical Commission (IEC) 61131-3 standard. Such SFC control logic may not be executable or understood by certain programmable control systems of a controller.

Method for executing sequential function charts as function blocks in a control system


There is disclosed herein a method for assessing the drilling performance of a drill bit configuration used to drill at least a portion of a wellbore in a formation, comprising: determining a value of at least one drill bit performance parameter at points along the wellbore, at least including at multiple points along an interval constituting at least part of the portion drilled using the drill bit configuration; determining rock characteristics for the interval; determining the drilling performance for said drill bit configuration in the interval based on the values for the drill bit performance parameter; and assessing the effectiveness of the drill bit configuration for drilling the interval based on the determined drilling performance and the determined rock characteristics. Also disclosed are related methods for comparing the performance of at least two different drill bit configurations; of designing a drill bit configuration for drilling at least part of a wellbore; for selecting a drill bit design for drilling at least part of a wellbore; and of well planning for drilling wells in a well field.

In the oil well drilling industry, it is important to reduce the economic cost of drilling a wellbore in order to extract oil and gas from underground reservoirs. With underground resources becoming accessible at even greater depths, it becomes evermore important to identify the most efficient and effective drilling configuration to be used in order to drill through the intervening rock formation and access the underground reservoir.
In order to plan any well drilling operation, it is common to conduct a preliminary study of the intervening rock formation between the surface and the underground reservoir, and to select and design a series of drill bits and drill bit configurations to be used in drilling a wellbore through the formation to the reservoir.
In any formation, there will often be a number of different types of rock, as well as one or more intervals, along the determined path of the wellbore, which provide a particular resistance to being drilled. Where such intervals can be identified, the drilling operation can be planned in advance so that drill bits capable of a high rate of penetration can be used in non-problematic sections of the wellbore, whilst specialized drill bit configurations which are more resistant to wear and have a greater cutting capacity can be used to drill through the more problematic intervals.
Nevertheless, the geological properties within any such interval will never be constant, and even in the same rock formation, the same apparent type of problematic rock interval can have markedly different constitution as between one interval and the next, both in terms of the geological composition throughout the interval, such as different proportions of different rock types within the formation, or simply a variation in the drillability of the rock, for example due to variations in the rock strength.
These natural variations in the geological properties of the formation make the prediction of drilling performance and the planning of well drilling operations difficult, and limit the accuracy with which any drilling performance can be predicted.
In order to calibrate the predictive models used to plan well drilling operations, accuracy can be improved by utilizing the results of actual drilling measurements obtained in order to compare the expected performance of a drill bit configuration against the actual performance of the drill bit configuration in use. The actual drilling results can be used to refine and improve the predictive drilling model.
Nevertheless, a drilling operator may feel more comfortable proceeding with the design and selection of drill bit configurations based on actual drilling results which have been obtained by using one or more particular drilling configurations in the field. In such situations, the drilling operator will often seek to compare the like-for-like real life performance of several different drill bit configurations, and will wish to base his selection and design of future drill bit configurations on those drill bit configurations which have proven most successful in actual drilling operations in the field.
In this situation, however, there is an inherent risk that the respective in-field performance results may be misleading as to which drill bit configuration actually provides the best performance. This problem arises due to the inherent natural variations in the geological properties of the formation, meaning that the drilling results from any two real-life drilling intervals can be difficult to compare in a simple side-by-side comparison.
Put in simple terms, if two different drill bit configurations are each used to drill a 100 m interval in a rock formation, for example in parallel wellbores, one cannot simply afterwards assess the measured rate of penetration or the actual time taken to drill through the 100 m interval in order to determine which drill bit configuration performed the best, or directly compare the extent of wear on the two bits to see which was most resistant to bit wear, as one of the two drilled intervals may have had a significantly higher proportion of a rock type which is resistant to being drilled or which produces a significantly higher degree of bit wear. Even where the constitution of the rock types in each interval is similar, one of the intervals may exhibit a significantly larger proportion of rock with high rock strength than the other interval.
It would therefore be advantageous to provide a method for assessing the performance of a drill bit for drilling an interval which takes account of the actual drilling conditions encountered, and which permits a meaningful comparison between the performances of different drill bit configurations used for drilling different intervals of the same or different wellbores.

Method for assessing the performance of a drill bit configuration, and for comparing the performance of different drill bit configurations for drilling similar rock formations


Embodiments of the present disclosure relate to a data transmission method, user equipment, and a control plane node. User equipment (UE) determines a security attribute of a session of the UE; the UE sends a session establishment request message to a control plane node when the security attribute of the session of the UE does not meet a security requirement of an application. The session establishment request message is used to request to establish a session corresponding to the security requirement of the application. Embodiments of the disclosed method reduce an unnecessary signaling exchange caused by establishment of a new session in a data transmission process to facilitate meeting requirements of different services.

End to end (E2E) security protection can implement security protection in a user data transmission process. A base station between a terminal device (such as user equipment) and a network device (such as the base station) is in a low-security area and is vulnerable to attacks, causing leakage of user privacy. An E2E protection link may be deployed at a gateway between the terminal device and the base station to improve security of user data. Moreover, the E2E security protection can meet differentiated security requirements of different applications and implement security isolation between different slices or services.
However, during the E2E security protection, the following phenomenon may exist: Different services may correspond to different security requirements. For example, user equipment (UE) has a plurality of sessions. When the UE initiates a new service, the UE cannot determine whether to reuse an existing session of the UE or to initiate a new session establishment process. In addition, different security requirements may correspond to different user plane protocol stacks. However, in the prior art, a problem of how the UE selects a suitable user plane protocol stack for data transmission is not resolved.

Data transmission method, user equipment, and control plane node


A panel for fingerprint identification and a control method thereof, and an apparatus for fingerprint identification. The panel for fingerprint identification includes: a display unit, a control unit, a unit for adjusting light transmittance and a unit for fingerprint identification which are disposed on a backlight side of the display unit, wherein an operating state of the panel for fingerprint identification includes: a display stage and a fingerprint identification stage. At the display stage, the display unit is configured to emit first light to display an image to be displayed, the unit for adjusting light transmittance is configured to transmit light transmitted through the display unit, and the control unit is connected with the unit for adjusting light transmittance and is configured to control the light transmittance of the unit for adjusting light transmittance.

Fingerprint identification refers to that identification of persons is performed by comparing detailed feature points of different fingerprints. Because everyone's fingerprints are different, identification of persons may be performed by fingerprints. Thanks to the breaking of a production capacity barrier of an organic light-emitting diode (OLED), technological maturity and foreseeable cost reduction, an optical fingerprint identification technology has become one of important means for realizing of fingerprint identification.
In the optical fingerprint identification technology, an optical fingerprint identification device is usually arranged on a side of a whole OLED display substrate. Light emitted from the OLED display substrate is reflected by a fingerprint and then transmitted through the whole OLED display substrate to reach the optical fingerprint identification device, and the optical fingerprint identification device forms a fingerprint image according to received light to identify the fingerprint.

Panel for fingerprint identification, and control method thereof, and apparatus for fingerprint identification

Beijing BOE Technology Development Co., Ltd.


An apparatus, including a server computer, located remote from a premises. The server computer receives a first message, transmitted from a user device located remote from the premises, and generates a second message containing information regarding an individual identified as being present inside or using the premises. If the premises is occupied or in use, the second message contains information identifying the individual. The server computer transmits a control signal or monitoring signal to a computer or processor located at the premises. The computer or processor performs a control operation or a monitoring operation regarding the premises, or the system, equipment, or device, of the premises in response to the control signal or monitoring signal.

A number of control, monitoring, and/or security, systems, products, and services, are available in the marketplace today which allows individuals, businesses, or other entities, to control, monitor, and/or to secure, their homes, businesses, premises, and/or vehicles. Many of these systems, products, and services, also allow or facilitate the use of same via the Internet and/or the World Wide Web. While these systems, products, and services, can prove to be valuable and convenient in accomplishing their intended goals, there are number of problems associated with same.
For example, a home control, monitoring, and/or security, system, which operates over a communication network, the Internet, or the World Wide Web, or any other network, and which allows an individual to control or monitor one or more home systems, equipment, devices, or cameras or video recording devices in his or her home, can be illegally accessed by, or infiltrated by, an unauthorized third party or any unscrupulous individual, or by a hacker, from anywhere in the World who could then, for example, exercise unauthorized control over a camera or video recording device in the home and use same in an unauthorized manner or fashion to record or to invade the privacy, or to spy on, an individual who is present in the home without that individual's knowledge or consent. In fact, news stories have been reported of individuals being photographed or recorded in a video recording, or otherwise spied on, in their own home, dorm room, or other place where it is typical to expect personal privacy, by an unauthorized individual who was able to gain access to a webcam associated with a computer located in the home.
In a similar manner, any Internet or web-based home, business, premises, vehicle, or article, control, monitoring and/or security system, and/or any system, equipment, or device, associated with or controlled by same, can also be accessed by or can be infiltrated by any unauthorized and/or unscrupulous individual who can then perform countless unauthorized actions in order to interfere with, or even sabotage, a home, business, premises, vehicle, or article, or any system, equipment, or device, or the operation of same, to invade an individual's privacy or spy on an individual, or in order to perform countless numbers of unauthorized activities or actions. The same can also hold true for any type or kind of control, monitoring, and/or security, systems, for or used in connection with any kind or type of premises, for any kind or type of vehicles, and/or for any kind or type of devices, and/or for any systems, equipment, or devices associated with same. Numerous other complications, and/or causes for concern, can arise when access to these control, monitoring, and/or security, systems are operated or accessible over a communication network of any kind or are Internet-based or web-based.
In short, there are numerous problems and shortfalls associated with present day control, monitoring, and/or security, systems for homes, business, premises, and vehicles. The present invention overcomes many of these problems and shortfalls.

Control, monitoring, and/or security, apparatus and method for premises, vehicles, and/or articles


An LED current control circuit including a current adjusting unit, a detecting unit, and a current control unit is provided. The current adjusting unit has a current control end coupled to an LED string for determining an amount of current flowing through the LED string according to a current control signal. The detecting unit detects the current control end and determines whether to generate a protecting signal according to a protecting voltage value. The current control unit generates the current control signal to control the amount of current flowing through the LED string of and determines whether to stop the current flowing through the LED string according to the protecting signal.

1. Field of the Invention
The invention generally relates to a light emitting diode (LED) current control circuit, a current balancer and a driving apparatus, and more particularly, to an LED current control circuit, a current balancer and a driving apparatus capable of adjusting the LED driving voltage to enhance the efficiency thereof.
2. Description of Related Art
The LED driving method can be classified into two types. One is providing a stable driving current to the LED in a current feedback control method; and another is providing a stable driving voltage to the LED in a voltage feedback control method. The latter provides a stable current flowing through the LED by a current control circuit. The advantages of the constant current driving method are high efficiency and stable light emitting. However, for driving a plurality of LED strings, an additional current balance circuit is required, so that the efficiency is lower. The advantage of the constant voltage driving method is that the control circuit is simply, and it is suitable for driving a plurality of LED strings.
FIG. 1 is a schematic circuit diagram of a conventional LED current driving apparatus in which the LED is driven by a constant driving voltage. Referring to FIG. 1, the LED driving apparatus includes an LED current control circuit 10, an LED module 60, and a power supply 70. The power supply 70 provides a stable output voltage VOUT through a voltage feedback signal VFB generated by a voltage feedback circuit. The LED module 60 includes a plurality of LED strings which are parallel between the power supply 70 and the LED current control circuit 10. The LED current control circuit 10 includes a current setting resistor 11 and a current mirror comprising a plurality of transistors 12 and 20. One end of the current setting resistor 11 is coupled to a voltage VCC, and the other end is coupled to the transistor 12, so that a setting current flows through the transistor 12. The transistors 20 are electrically connected to the corresponding LED strings in the LED module 60 one by one, and the current mirror mirrors the setting currents to the LED strings. Accordingly, the currents flowing through each LED string in the LED module 60 are substantially identical, so that the brightness of the LED strings is uniform.
Because the threshold voltages of the LEDs are much different, even if the currents are substantially identical, the required driving voltages are still different. For example, each LED string in the LED module 60 has 20 LEDs coupled in series, and the driving voltage for driving a single LED with 20 mA is about 3.4V-3.8V. Accordingly, the driving voltage range of the LED strings is about 68V-76V. the differences of the driving voltages of the LED strings are undertaken by the corresponding transistor 20. Moreover, for mirroring the current, the transistor 20 must operate in the saturation region. Accordingly, in order to ensure that the currents flowing through each LED string are substantially identical, the output voltage VOUT, provided by the power supply 70, must be higher than the maximum driving voltage among the LED strings to ensure that the transistors 20 operate in the saturation region.
However, it is hard to check the driving voltages of the LED strings one by one. The maximum driving voltages of the LED strings in the LED module 60 may be not 76V, the highest driving voltage among 68V-76V. However, for ensuring the output voltage VOUT being higher than the maximum driving voltage, the output voltage VOUT could be 80V. Accordingly, providing 80V driving voltage results in lower efficiency. Furthermore, in order to prevent any LED in the LED string from being damaged to cause the LED string not emitting light, some LED may be connected in parallel with the Zener diode. Hence, even if the damaged LED is open, the current can still flow through the corresponding Zener diode. The breakdown voltage of the Zener diode is set as a voltage, such as, being 2V higher than the threshold voltage of the LED to prevent the Zener diode from mis-operating. In this case, if there are two LEDs damaged in the LED string, the driving voltage of the LED string is raised up by 4V. Accordingly, it may cause that the current flowing through the LED string dramatically falls down, and even the LED string can not emit light any more. However, if the power supply 70 increases the output voltage VOUT to avoid any LED string not emitting light due to some damaged LED, the efficiency becomes much lower.

LED current control circuit, current balancer and driving apparatus


An audio signal amplifying device and method for reducing a size and corresponding power consumption of demodulation filters in the signal amplifying device. In the device and method, carrier waves having phase shifts are generated from a received audio signal. The shifted carrier waves are compared to the audio signal to generate modulation signals, which are amplified based on a power supply voltage. The amplified modulation signals or a power supply signal are output based on a comparison between the carrier waves and the audio signal. The output signals are synthesized to produce a synthesized signal having a lower average voltage and current value, thus reducing power consumption of the signal amplifying device.

1. Field
The present disclosure relates to a device for amplifying an audio signal and a method thereof.
2. Description of the Related Art
Conventional audio signal amplifying devices modulate an audio signal using a carrier wave. Conventionally, the modulated signal, which is generated by using the carrier wave, is amplified. Then, a demodulation operation is performed on the amplified modulated signal, using a demodulation filter, so that the carrier wave element included in the amplified modulated signal is eliminated. At this time, as the intensity of voltage and current of the amplified modulated signal is increased, the demodulation filter becomes larger. Accordingly, the size and power consumption of the audio signal amplifying device are increased.

Method and apparatus for amplifying audio signal


In certain implementations, a method consistent with certain embodiments involves associating a first headset with a first viewer profile; associating the first headset with a first audio channel within an audio channel multiplex and with a first set of display refresh time slots; selecting a first advertisement based on criteria contained in the first viewer profile; displaying a video portion of the first advertisement on a video display during the first set of refresh time slots associated with the first headset; transmitting a synchronization signal that is synchronized to a video frame refresh clock to establish the video time slots; and transmitting an audio portion of the first advertisement on the first audio channel associated with the headset. This abstract is not to be considered limiting, since other embodiments may deviate from the features described in this abstract.

Modern 3D (three dimensional, i.e., stereoscopic) televisions are, at this writing, emerging on the television (TV) market. In most cases, these devices utilize display panels that are refreshed at a high rate of speed—generally 240 Hz or more, with speed being expected to increase further with newer generations of television sets. In most implementations, left eye and right eye data are presented in alternating frames, sometimes with a blank or black frame separating the alternating frames to minimize crosstalk. Receipt of the left eye and right eye video frames are then alternated by use of synchronized shutter glasses which alternately open and close the left and right eye shutters in synchronization with the TV in order to create a three dimensional stereoscopic viewing experience.

Simultaneous viewing of multiple viewer-specific programming on a single display


A retaining device (1) adapted for retaining an electrical connector (2) on a peripheral electronic apparatus, includes a retaining member (10) and a locking member (13). The retaining member includes a board-shaped base section and a retention section (11) bending from an edge of the base section. The base section includes a retaining portion engaging with the connector, and the retention section includes a through-hole (110) thereon to engage with the locking member.

1. Field of the invention
The present invention relates to a retaining device, and more particularly to a retaining device for steadily retaining an electrical connector on a peripheral electronic apparatus.
2. Description of Related Arts
Referring to FIG. 1, a conventional electrical connector 4 usually used as an input/output is connected on a printed circuit board (PCB, not shown) by its soldering pads 41 and legs 42. And then the electrical connector 4 on the PCB is assembled to an electronic apparatus such as personal digital assistant (PDA). However, the electrical connector 4 will be loose from the PCB since the connector continually being connected or disconnected with a complementary connector.
Therefore, an improved invention is desired to overcome the disadvantages of the prior arts.

Retaining device for retaining electrical connector on peripheral electronic apparatus