The present invention provides a new method for detecting, diagnosing, monitoring, staging, and prognosticating breast cancer.

This invention relates, in part, to newly developed assays for detecting, diagnosing, monitoring, staging, prognosticating, imaging and treating cancers, particularly breast cancer.
One of every nine American women will develop breast cancer sometime during her life based on a lifespan of 85 years. Annually, over 180,000 women in the United States will be diagnosed with breast cancer and approximately 46,000 will die of the disease.
Every woman is at risk for breast cancer. A woman""s chances of developing breast cancer increase as she grows older; 80 percent of all cancers are found in women over the age of 50. There are also several risk factors that can increase a woman""s chances of developing cancer. A woman may be at increased risk if she has a family history of the disease, if she had her first child after the age of 30 or has no children, or if she began menstruating early.
However, more than 70 percent of women who develop breast cancer have no known risk factors. Less than 10 percent of breast cancer cases are thought to be related to the BRCA1 gene discovered in 1994. Researchers are now investigating the role other factors such as nutrition, alcohol, exercise, smoking, and oral contraceptives may play in cancer prevention.
As with many other cancers, the best chance for successful treatment occurs when breast cancer is found early. Mammograms, special x-rays of the breast, can detect more than 90 percent of all breast cancers. If breast cancer is found early, the chance of cure is greater than 90 percent. Treatment options include surgery, chemotherapy, and radiation therapy depending on the stage of the cancer.
Procedures used for detecting, diagnosing, monitoring, staging, prognosticating and imaging breast cancer are of critical importance to the outcome of the patient. Patients diagnosed with early breast cancer generally have a much greater five-year survival rate as compared to the survival rate for patients diagnosed with distant metastasized breast cancer. New diagnostic methods which are more sensitive and specific for detecting early breast cancer are clearly needed.
Breast cancer patients are closely monitored following initial therapy and during adjuvant therapy to determine response to therapy and to detect persistent or recurrent disease of metastasis. There is clearly a need for a breast cancer marker which is more sensitive and specific in detecting breast cancer and its recurrence and progression.
Another important step in managing breast cancer is to determine the stage of the patient""s disease. Stage determination has potential prognostic value and provides criteria for designing optimal therapy. Generally, pathological staging of breast cancer is preferable over clinical staging because the former gives a more accurate prognosis. However, clinical staging would be preferred were it at least as accurate as pathological staging because it does not depend on an invasive procedure to obtain tissue for pathological evaluation. Staging of breast cancer would be improved by detecting new markers in cells, tissues, or bodily fluids which could differentiate between different stages of invasion.
In the present invention methods are provided for detecting, diagnosing, monitoring, staging, prognosticating, imaging and treating breast cancer via breast specific genes referred to herein as BSGs. For purposes of the present invention, BSG refers, among other things, to native proteins expressed by the gene comprising the polynucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 or 9. An exemplary BSG protein sequence is depicted in SEQ ID NO:10. By xe2x80x9cBSGxe2x80x9d it is also meant herein polynucleotides which, due to degeneracy in genetic coding, comprise variations in nucleotide sequence as compared to SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 or 9, but which still encode the same protein. In the alternative, what is meant by BSG as used herein, means the native mRNA encoded by the gene comprising the polynucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 or 9, levels of the gene comprising the polynucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 or 9, or levels of a polynucleotide which is capable of hybridizing under stringent conditions to the antisense sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 or 9.
Other objects, features, advantages and aspects of the present invention will become apparent to those of skill in the art from the following description. It should be understood, however, that the following description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following description and from reading the other parts of the present disclosure.
Toward these ends, and others, it is an object of the present invention to provide a method for diagnosing the presence of breast cancer by analyzing for changes in levels of BSG in cells, tissues or bodily fluids compared with levels of BSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein a change in levels of BSG in the patient versus the normal human control is associated with breast cancer.
Further provided is a method of diagnosing metastatic breast cancer in a patient having such cancer which is not known to have metastasized by identifying a human patient suspected of having breast cancer that has metastasized; analyzing a sample of cells, tissues, or bodily fluid from such patient for BSG; comparing the BSG levels in such cells, tissues, or bodily fluid with levels of BSG in preferably the same cells, tissues, or bodily fluid type of a normal human control, wherein a change in BSG levels in the patient versus the normal human control is associated with a cancer which has metastasized.
Also provided by the invention is a method of staging breast cancer in a human which has such cancer by identifying a human patient having such cancer; analyzing a sample of cells, tissues, or bodily fluid from such patient for BSG; comparing BSG levels in such cells, tissues, or bodily fluid with levels of BSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein a change in BSG levels in the patient versus the normal human control is associated with a cancer which is progressing or regressing or in remission.
Further provided is a method of monitoring breast cancer in a human having such cancer for the onset of metastasis. The method comprises identifying a human patient having such cancer that is not known to have metastasized; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for BSG; comparing the BSG levels in such cells, tissue, or bodily fluid with levels of BSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein a change in BSG levels in the patient versus the normal human control is associated with a cancer which has metastasized.
Further provided is a method of monitoring the change in stage of breast cancer in a human having such cancer by looking at levels of BSG in a human having such cancer. The method comprises identifying a human patient having such cancer; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for BSG; comparing the BSG levels in such cells, tissue, or bodily fluid with levels of BSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein a change in BSG levels in the patient versus the normal human control is associated with a cancer which is progressing or regressing or in remission.
Further provided are methods of designing new therapeutic agents targeted to a BSG for use in imaging and treating breast cancer. For example, in one embodiment, therapeutic agents such as antibodies targeted against BSG or fragments of such antibodies can be used to treat, detect or image localization of BSG in a patient for the purpose of detecting or diagnosing a disease or condition. In this embodiment, a difference in the amount of labeled antibody detected as compared to normal tissue would be indicative of tumor metastases or growth. Such antibodies can be polyclonal, monoclonal, or omniclonal or prepared by molecular biology techniques. The term xe2x80x9cantibodyxe2x80x9d, as used herein and throughout the instant specification is also meant to include aptamers and single-stranded oligonucleotides such as those derived from an in vitro evolution protocol referred to as SELEX and well known to those skilled in the art. Antibodies can be labeled with a variety of detectable and therapeutic labels including, but not limited to, radioisotopes and paramagnetic metals. Therapeutic agents such as small molecules and antibodies which modulate the concentration and/or activity of BSG can also be used in the treatment of diseases characterized by altered expression of BSG. Such agents can be readily identified in accordance with teachings herein.
Other objects, features, advantages and aspects of the present invention will become apparent to those of skill in the art from the following description. It should be understood, however, that the following description and the specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only. Various changes and modifications within the spirit and scope of the disclosed invention will become readily apparent to those skilled in the art from reading the following description and from reading the other parts of the present disclosure.
The present invention relates to diagnostic assays and methods, both quantitative and qualitative for detecting, diagnosing, monitoring, staging, prognosticating and imaging cancers by comparing levels of BSG with those of BSG in a normal human control. For purposes of the present invention, BSG refers, among other things, to native proteins expressed by the gene comprising the polynucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 or 9. An exemplary BSG protein sequence is depicted in SEQ ID NO:10. By xe2x80x9cBSGxe2x80x9d it is also meant herein polynucleotides which, due to degeneracy in genetic coding, comprise variations in nucleotide sequence as compared to SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 or 9, but which still encode the same protein. In the alternative, what is meant by BSG as used herein, means the native MRNA encoded by the gene comprising the polynucleotide sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 or 9, levels of the gene comprising the polynucleotide sequence of SEQ ID NO:. 1, 2, 3, 4, 5, 6, 7, 8 or 9, or levels of a polynucleotide which is capable of hybridizing under stringent conditions to the antisense sequence of SEQ ID NO: 1, 2, 3, 4, 5, 6, 7, 8 or 9. Such levels are preferably measured in at least one of, cells, tissues and/or bodily fluids, including determination of normal and abnormal levels. Thus, for instance, a diagnostic assay in accordance with the invention for measuring changes in levels of any one of the BSG proteins compared to normal control bodily fluids, cells, or tissue samples may be used to diagnose the presence of cancers, including breast cancer. By xe2x80x9cchangexe2x80x9d it is meant either an increase or decrease in levels of the BSG. For example, for BSGs such as Mam001 (SEQ ID NO:2), Mam004 (SEQ ID NO:4/SEQ ID NO:10) and Mam005 (SEQ ID NO:3), an increase in levels as compared to normal human controls is associated with breast cancer, metastasis and progression of the cancer, while a decrease in levels is association with regression and/or remission. For the BSG Mam002 (SEQ ID NO:1), a decrease in levels as compared to normal human controls is associated with breast cancer, metastasis and progression while an increase is associated with regression and/or remission. Any of the 9 BSGs may be measured alone in the methods of the invention, or all together or any combination of the nine.
All the methods of the present invention may optionally include measuring the levels of other cancer markers as well as BSG. Other cancer markers, in addition to BSG, such as BRCA1 are known to those of skill in the art.
The present invention provides methods for diagnosing the presence of breast cancer by analyzing for changes in levels of BSG in cells, tissues or bodily fluids compared with levels of BSG in cells, tissues or bodily fluids of preferably the same type from a normal human control. As demonstrated herein an increase in levels of BSGs such as Mam001 (SEQ ID NO:2), Mam004 (SEQ ID NO:4/SEQ ID NO:10) or Mam005 (SEQ ID NO:3) in the patient versus the normal human control is associated with the presence of breast cancer, while a decrease in levels of BSGs such as Mam002 (SEQ ID NO:1) in the patient versus the normal human control is associated with the presence of breast cancer.
Without limiting the instant invention, typically, for a quantitative diagnostic assay a positive result indicating the patient being tested has cancer is one in which cells, tissues, or bodily fluid levels of the cancer marker, such as BSG, are at least two times higher or lower, and most preferably are at least five times higher or lower, than in preferably the same cells, tissues, or bodily fluid of a normal human control.
The present invention also provides a method of diagnosing metastatic breast cancer in a patient having breast cancer which has not yet metastasized for the onset of metastasis. In the method of the present invention, a human cancer patient suspected of having breast cancer which may have metastasized (but which was not previously known to have metastasized) is identified. This is accomplished by a variety of means known to those of skill in the art. For example, in the case of breast cancer, patients are typically diagnosed with breast cancer following traditional detection methods.
In the present invention, determining the presence of BSG level in cells, tissues, or bodily fluid, is particularly useful for discriminating between breast cancer which has not metastasized and breast cancer which has metastasized. Existing techniques have difficulty discriminating between breast cancer which has metastasized and breast cancer which has not metastasized and proper treatment selection is often dependent upon such knowledge.
In the present invention, the cancer marker levels measured in such cells, tissues, or bodily fluid is BSG, and are compared with levels of BSG in preferably the same cells, tissue, or bodily fluid type of a normal human control. That is, if the cancer marker being observed is just BSG in serum, this level is preferably compared with the level of BSG in serum of a normal human patient. An increase in BSGs such as Mam001 (SEQ ID NO:2), Mam004 (SEQ ID NO:4/SEQ ID NO:10) or Mam005 (SEQ ID NO:3) in the patient versus the normal human control is associated with breast cancer which has metastasized while a decrease in BSGs such as Mam002 (SEQ ID NO:1) in the patient versus the normal human control is associated with breast cancer which has metastasized.
Without limiting the instant invention, typically, for a quantitative diagnostic assay a positive result indicating the cancer in the patient being tested or monitored has metastasized is one in which cells, tissues, or bodily fluid levels of the cancer marker, such as BSG, are at least two times higher or lower, and most preferably are at least five times higher or lower, than in preferably the same cells, tissues, or bodily fluid of a normal patient.
Normal human control as used herein includes a human patient without cancer and/or non cancerous samples from the patient; in the methods for diagnosing or monitoring for metastasis, normal human control preferably comprises samples from a human patient that is determined by reliable methods to have breast cancer which has not metastasized.
The invention also provides a method of staging breast cancer in a human patient. The method comprises identifying a human patient having such cancer; analyzing a sample of cells, tissues, or bodily fluid from such patient for BSG. Then, the method compares BSG levels in such cells, tissues, or bodily fluid with levels of BSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in levels of BSGs such as Mam001 (SEQ ID NO:2), Mam004 (SEQ ID NO:4/SEQ ID NO:10) or Mam005 (SEQ ID NO:3) or a decrease in levels of BSGs such as Mam002 (SEQ ID NO:1) in the patient versus the normal human control is associated with a cancer which is progressing and a decrease in levels of BSGs such as Mam001 (SEQ ID NO:2) Mam004 (SEQ ID NO:4/SEQ ID NO:10) or Mam005 (SEQ ID NO:3)(but generally still increased over true normal levels) or an increase in levels of BSGs such as Mam002 (SEQ ID NO:1) (but generally still decreased as compared to normal levels) is associated with a cancer which is regressing or in remission.
Further provided is a method of monitoring breast cancer in a human having such cancer for the onset of metastasis. The method comprises identifying a human patient having such cancer that is not known to have metastasized; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for BSG; comparing the BSG levels in such cells, tissue, or bodily fluid with levels of BSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in levels of BSGs such as Mam001 (SEQ ID NO:2), Mam004 (SEQ ID NO:4/SEQ ID NO:10) or Mam005 (SEQ ID NO:3) or a decrease in levels of BSGs such as Mam002 (SEQ ID NO:1) in the patient versus the normal human control is associated with a cancer which has metastasized. In this method, normal human control samples may also include prior patient samples.
Further provided by this invention is a method of monitoring the change in stage of breast cancer in a human having such cancer. The method comprises identifying a human patient having such cancer; periodically analyzing a sample of cells, tissues, or bodily fluid from such patient for BSG; comparing the BSG levels in such cells, tissue, or bodily fluid with levels of BSG in preferably the same cells, tissues, or bodily fluid type of a normal human control sample, wherein an increase in levels of BSGs such as Mam001 (SEQ ID NO:2), Mam004 (SEQ ID NO:4/SEQ ID NO:10) or Mam005 (SEQ ID NO:3) or a decrease in levels of BSGs such as Mam002 (SEQ ID NO:1) in the patient versus the normal human control is associated with a cancer which is progressing in stage and a decrease in the levels of BSGs such as Mam001 (SEQ ID NO:2), Mam004 (SEQ ID NO:4/SEQ ID NO:10) or Mam005 (SEQ ID NO:3) or an increase in levels of BSGs such as Mam002 (SEQ ID NO:1) is associated with a cancer which is regressing in stage or in remission.
Monitoring such patient for onset of metastasis is periodic and preferably done on a quarterly basis. However, this may be more or less frequent depending on the cancer, the particular patient, and the stage of the cancer.
The methods described herein can further be utilized as prognostic assays to identify subjects having or at risk of developing a disease or disorder associated with altered levels of BSG. The present invention provides a method in which a test sample is obtained from a human patient and BSG is detected. The presence of higher levels of Mam001 (SEQ ID NO:2), Mam004 (SEQ ID NO:4/SEQ ID NO:10) or Mam005 (SEQ ID NO:3) or lower levels of Mam002 (SEQ ID NO:1) as compared to normal human controls is diagnostic for the human patient being at risk for developing cancer, particularly breast cancer.
The effectiveness of therapeutic agents to alter expression or activity of the BSGs of the invention can also be monitored by analyzing levels of expression of the BSGs in a human patient in clinical trials or in in vitro screening assays such as in human cells. In this way, the gene expression pattern can serve as a marker, indicative of the physiological response of the human patient, or cells as the case may be, to the agent being tested.
The methods of the present invention can also be used to detect genetic lesions or mutations in BSG, thereby determining if a human with the genetic lesion is at risk for breast cancer or has breast cancer. Genetic lesions can be detected, for example, by ascertaining the existence of a deletion and/or addition and/or substitution of one or more nucleotides from the BSGs of this invention, a chromosomal rearrangement of BSG, aberrant modification of BSG (such as of the methylation pattern of the genomic DNA), the presence of a non-wild type splicing pattern of a mRNA transcript of BSG, allelic loss of BSG, and/or inappropriate post-translational modification of BSG protein. Methods to detect such lesions in a BSG of this invention are known to those of skill in the art.
Assay techniques that can be used to determine levels of gene expression, such as BSG of the present invention, in a sample derived from a host are well-known to those of skill in the art. Such assay methods include, without limitation, radioimmunoassays, reverse transcriptase PCR (RT-PCR) assays, immunohistochemistry assays, in situ hybridization assays, competitive-binding assays, Western Blot analyses, ELISA assays and proteomic approaches, two-dimensional gel electrophoresis (2D electrophoresis) and non-gel based approaches such as mass spectrometry or protein interaction profiling. Among these, ELISAs are frequently preferred to diagnose a gene""s expressed protein in biological fluids.
An ELISA assay initially comprises preparing an antibody, if not readily available from a commercial source, specific to BSG, preferably a monoclonal antibody. In addition a reporter antibody generally is prepared which binds specifically to BSG. The reporter antibody is attached to a detectable reagent such as radioactive, fluorescent or enzymatic reagent, for example horseradish peroxidase enzyme or alkaline phosphatase.
To carry out the ELISA, antibody specific to BSG is incubated on a solid support, e.g. a polystyrene dish, that binds the antibody. Any free protein binding sites on the dish are then covered by incubating with a non-specific protein such as bovine serum albumin. Next, the sample to be analyzed is incubated in the dish, during which time BSG binds to the specific antibody attached to the polystyrene dish. Unbound sample is washed out with buffer. A reporter antibody specifically directed to BSG and linked to horseradish peroxidase is placed in the dish resulting in binding of the reporter antibody to any monoclonal antibody bound to BSG. Unattached reporter antibody is then washed out. Reagents for peroxidase activity, including a calorimetric substrate are then added to the dish. Immobilized peroxidase, linked to BSG antibodies, produces a colored reaction product. The amount of color developed in a given time period is proportional to the amount of BSG protein present in the sample. Quantitative results typically are obtained by reference to a standard curve.
A competition assay may be employed wherein antibodies specific to BSG attached to a solid support and labeled BSG and a sample derived from the host are passed over the solid support and the amount of label detected attached to the solid support can be correlated to a quantity of BSG in the sample.
Using all or a portion of a nucleic acid sequence of BSG of the present invention as a hybridization probe, nucleic acid methods can also be used to detect levels of BSG mRNA as a marker for breast cancer. Polymerase chain reaction (PCR) and other nucleic acid methods, such as ligase chain reaction (LCR) and nucleic acid sequence based amplification (NASBA), can be used to detect cells for diagnosis and monitoring of various malignancies. For example, reverse-transcriptase PCR (RT-PCR) is a powerful technique which can be used to detect the presence of a specific MRNA population in a complex mixture of thousands of other mRNA species. In RT-PCR, an MRNA species is first reverse transcribed to complementary DNA (cDNA) with use of the enzyme reverse transcriptase; the cDNA is then amplified as in a standard PCR reaction. RT-PCR can thus reveal by amplification the presence of a single species of mRNA. Accordingly, if the MRNA is highly specific for the cell that produces it, RT-PCR can be used to identify the presence and/or absence of a specific type of cell.
Hybridization to clones or oligonucleotides arrayed on a solid support (i.e. gridding) can be used to both detect the expression of and quantitate the level of expression of that gene. In this approach, all or a portion of a cDNA encoding the BSG is fixed to a substrate. The substrate may be of any suitable type including, but not limited to, glass, nitrocellulose, nylon or plastic. At least a portion of the DNA encoding the BSG is attached to the substrate and then incubated with the analyte, which may be RNA or a complementary DNA (cDNA) copy of the RNA, isolated from the tissue of interest. Hybridization between the substrate bound DNA and the analyte can be detected and quantitated by several means including, but not limited to, radioactive labeling or fluorescence labeling of the analyte or a secondary molecule designed to detect the hybrid. Quantitation of the level of gene expression can be done by comparison of the intensity of the signal from the analyte compared with that determined from known standards. The standards can be obtained by in vitro transcription of the target gene, quantitating the yield, and then using that material to generate a standard curve.
Of the proteomic approaches, 2D electrophoresis is a technique well known to those skilled in the art. Isolation of individual proteins from a sample such as serum is accomplished using sequential separation of proteins by different characteristics usually on polyacrylamide gels. First, proteins are separated by size using an electric current. The current acts uniformly on all proteins, so smaller proteins move farther on the gel than larger proteins. The second dimension applies a current perpendicular to the first and separates proteins not on the basis of size but on the specific electric charge carried by each protein. Since no two proteins with different sequences are identical on the basis of both size and charge, the result of a 2D separation is a square gel in which each protein occupies a unique spot. Analysis of the spots with chemical or antibody probes, or subsequent protein microsequencing can reveal the relative abundance of a given protein and the identity of the proteins in the sample.
The above tests can be carried out on samples derived from a variety of cells, bodily fluids and/or tissue extracts such as homogenates or solubilized tissue obtained from a patient. Tissue extracts are obtained routinely from tissue biopsy and autopsy material. Bodily fluids useful in the present invention include blood, urine, saliva or any other bodily secretion or derivative thereof. By blood it is meant to include whole blood, plasma, serum or any derivative of blood.
Identification of BSGs is also useful in the rational design of new therapeutics for imaging and treating cancers, and in particular breast cancer. For example, in one embodiment, antibodies which specifically bind to BSG can be raised and used in vivo in patients suspected of suffering from breast cancer. Antibodies which specifically bind BSG can be injected into a patient suspected of having breast cancer for diagnostic and/or therapeutic purposes. Thus, another aspect of the present invention provides for a method for preventing the onset and treatment of breast cancer in a human patient in need of such treatment by administering to the patient an effective amount of antibody. By xe2x80x9ceffective amountxe2x80x9d it is meant the amount or concentration of antibody needed to bind to the target antigens expressed on the tumor to cause tumor shrinkage for surgical removal, or disappearance of the tumor. The binding of the antibody to an overexpressed BSG is believed to cause the death of the cancer cell expressing such BSG. The preparation and use of antibodies for in vivo diagnosis and treatment is well known in the art. For example, antibody-chelators labeled with Indium-111 have been described for use in the radioimmunoscintographic imaging of carcinoembryonic antigen expressing tumors (Sumerdon et al. Nucl. Med. Biol. 1990 17:247-254). In particular, these antibody-chelators have been used in detecting tumors in patients suspected of having recurrent colorectal cancer (Griffin et al. J. Clin. Onc. 1991 9:631-640). Antibodies with paramagnetic ions as labels for use in magnetic resonance imaging have also been described (Lauffer, R. B. Magnetic Resonance in Medicine 1991 22:339-342). Antibodies directed against a BSG can be used in a similar manner. Labeled antibodies which specifically bind BSGs can be injected into patients suspected of having breast cancer for the purpose of diagnosing or staging of the disease status of the patient. The label used will be selected in accordance with the imaging modality to be used. For example, radioactive labels such as Indium-111, Technetium-99m or Iodine-131 can be used for planar scans or single photon emission computed tomography (SPECT). Positron emitting labels such as Fluorine-19 can be used in positron emission tomography. Paramagnetic ions such as Gadlinium (III) or Manganese (II) can be used in magnetic resonance imaging (MRI). Presence of the label, as compared to imaging of normal tissue, permits determination of the spread of the cancer. The amount of label within an organ or tissue also allows determination of the presence or absence of cancer in that organ or tissue.
Antibodies which can be used in in vivo methods include polyclonal, monoclonal and omniclonal antibodies and antibodies prepared via molecular biology techniques. Antibody fragments and aptamers and single-stranded oligonucleotides such as those derived from an in vitro evolution protocol referred to as SELEX and well known to those skilled in the art can also be used.
The present invention also provides methods for identifying modulators which bind to BSG protein or have a modulatory effect on the expression or activity of BSG protein. Modulators which decrease the expression or activity of BSG proteins such as Mam001 (SEQ ID NO:2), Mam004 (SEQ ID NO:4/SEQ ID NO:10) and Mam005 (SEQ ID NO:3) or increase the expression or activity of the BSG Mam002 (SEQ ID NO:1) are believed to be useful in treating breast cancer. Such screening assays are known to those of skill in the art and include, without limitation, cell-based assays and cell free assays.
Small molecules predicted via computer imaging to specifically bind to regions of BSG can also be designed, synthesized and tested for use in the imaging and treatment of breast cancer. Further, libraries of molecules can be screened for potential anticancer agents by assessing the ability of the molecule to bind to the BSGs identified herein. Molecules identified in the library as being capable of binding to BSG are key candidates for further evaluation for use in the treatment of breast cancer. In a preferred embodiment, these molecules will downregulate expression and/or activity of BSGs such as Mam001 (SEQ ID NO:2), Mam004 (SEQ ID NO:4/SEQ ID NO:10) and Mam005 (SEQ ID NO:3) and/or upregulate expression and/or activity of the BSG Mam002 (SEQ ID NO:1) in cells.
Adoptive immunotherapy of cancer refers to a therapeutic approach in which immune cells with an antitumor reactivity are administered to a tumor-bearing host, with the aim that the cells mediate either directly or indirectly, the regression of an established tumor. Transfusion of lymphocytes, particularly T lymphocytes, falls into this category and investigators at the National Cancer Institute (NCI) have used autologous reinfusion of peripheral blood lymphocytes or tumor-infiltrating lymphocytes (TIL), T cell cultures from biopsies of subcutaneous lymph nodules, to treat several human cancers (Rosenberg, S. A., U.S. Pat. No. 4,690,914, issued Sep. 1, 1987; Rosenberg, S. A., et al., 1988, N. England J. Med. 319:1676-1680).
The present invention relates to compositions and methods of adoptive immunotherapy for the prevention and/or treatment of primary and metastatic breast cancer in humans using macrophages sensitized to the antigenic BSG molecules, with or without non-covalent complexes of heat shock protein (hsp). Antigenicity or immunogenicity of the BSG is readily confirmed by the ability of the BSG protein or a fragment thereof to raise antibodies or educate naive effector cells, which in turn lyse target cells expressing the antigen (or epitope).
Cancer cells are, by definition, abnormal and contain proteins which should be recognized by the immune system as foreign since they are not present in normal tissues. However, the immune system often seems to ignore this abnormality and fails to attack tumors. The foreign BSG proteins that are produced by the cancer cells can be used to reveal their presence. The BSG is broken into short fragments, called tumor antigens, which are displayed on the surface of the cell. These tumor antigens are held or presented on the cell surface by molecules called MHC, of which there are two types: class I and II. Tumor antigens in association with MHC class I molecules are recognized by cytotoxic T cells while antigen-MHC class II complexes are recognized by a second subset of T cells called helper cells. These cells secrete cytokines which slow or stop tumor growth and help another type of white blood cell, B cells, to make antibodies against the tumor cells.
In adoptive immunotherapy, T cells or other antigen presenting cells (APCS) are stimulated outside the body (ex vivo), using the tumor specific BSG antigen. The stimulated cells are then reinfused into the patient where they attack the cancerous cells. Research has shown that using both cytotoxic and helper T cells is far more effective than using either subset alone. Additionally, the BSG antigen may be complexed with heat shock proteins to stimulate the APCs as described in U.S. Pat. No. 5,985,270.
The APCs can be selected from among those antigen presenting cells known in the art including, but not limited to, macrophages, dendritic cells, B lymphocytes, and a combination thereof, and are preferably macrophages. In a preferred use, wherein cells are autologous to the individual, autologous immune cells such as lymphocytes, macrophages or other APCs are used to circumvent the issue of whom to select as the donor of the immune cells for adoptive transfer. Another problem circumvented by use of autologous immune cells is graft versus host disease which can be fatal if unsuccessfully treated.
In adoptive immunotherapy with gene therapy, DNA of the BSG can be introduced into effector cells similarly as in conventional gene therapy. This can enhance the cytotoxicity of the effector cells to tumor cells as they have been manipulated to produce the antigenic protein resulting in improvement of the adoptive immunotherapy.
BSG antigens of this invention are also useful as components of breast cancer vaccines. The vaccine comprises an immunogenically stimulatory amount of a BSG antigen. Immunogenically stimulatory amount refers to that amount of antigen that is able to invoke the desired immune response in the recipient for the amelioration, or treatment of breast cancer. Effective amounts may be determined empirically by standard procedures well known to those skilled in the art.
The BSG antigen may be provided in any one of a number of vaccine formulations which are designed to induce the desired type of immune response, e.g., antibody and/or cell mediated. Such formulations are known in the art and include, but are not limited to, formulations such as those described in U.S. Pat. No. 5,585,103. Vaccine formulations of the present invention used to stimulate immune responses can also include pharmaceutically acceptable adjuvants.

Method of diagnosing, monitoring and staging breast cancer


A system and method for facilitating automatic detection of a type of wireless network is provided. In accordance with an aspect of the present invention, wireless network client(s) can automatically detect the “type” of a network (e.g., method of authentication and encryption) without requiring input from the user. For example, unencrypted network, WEP encrypted network requiring a WEP key, WPA encrypted network requiring a pre-shared key, an IEEE 802.1x enabled network supporting WPA and/or an IEEE 802.1x enabled network not supporting WPA. In accordance with an aspect of the present invention, a wireless network detection system having a connection component and a detection component is provided. The connection component facilitates connection of a client system to at least one of a plurality of wireless networks. The detection component identities a type of an available wireless network. Identification can be based, for example, upon information received in an information element and/or iterative probing of the wireless network beacon.

Computer device(s) performing network communications over wireless links are becoming increasingly popular. Conventionally, when a user comes within range of a wireless network, the client device (e.g., computer system) is able to discern two pieces of information about that network, without connecting to it (e.g., from the wireless network beacon): (1) the service set identifier (SSID) of the network (e.g., essentially its name); and, (2) whether or not the network encrypts data. If the network employs encryption, an encryption key is required. The encryption key can be manually entered by the user and/or sent in accordance with the 802.1x protocol.
With the information that the client device can retrieve from the wireless network beacon, the client device can generally determine whether the network is of type unencrypted, encrypted or, with the addition of a Wi-Fi Protected Access (WPA) information element, encrypted using WPA-pre-shared key or encrypted using WPA. If it is unencrypted, then a user needs only to acknowledge that the network is insecure, and that they wish to use it in spite of that information. However, if it is encrypted and does not use WPA, then it either requires the user to enter a WEP key or it is an 802.1x-enabled network which distributes the WEP key automatically (requiring the client computer to enable 802.1x authentication to complete the connection).
Since the client computer cannot tell whether the non-WPA encrypted network requires the user to enter a WEP key or is an 802.1x-enabled network which does not support WPA, it typically requests input from the user. In the vast majority of cases, the user is in no position, from a technical knowledge perspective, to answer such a request.

Automatic detection of wireless network type


An automatic call distribution system (12) for interconnecting units (16) of an external telephonic network (18) with telephonic consoles (10) capable of multiple functions, a console personality control apparatus having a personality reset card (40) carrying information identifying a personality reset function, a card connector socket module (26) for releasable connection with the personality reset card (40), a memory (32) for storing a plurality of console function personalities and a microprocessor (20) for reading the personality reset card identifying information when the personality reset card is connected with the console (10) to reset the console function personality.

1. Field of the Invention
This invention relates generally to the field of telephonic consoles and, more particularly, to telephonic consoles used in an automatic call distribution system having multiple modes of operation.
2. Description of the Related Art Including Information Disclosed Under 37 C.F.R. .sctn.1.97-1.99
Telephonic console units having multiple function personalities are known. Each different personality is defined by a unique set of preselected functional characteristics such as the meaning of different indicators, the response to different key strokes and functional capabilities. Each different personality is programmed into the console to make the console function in a correspondingly different manner. In a call distribution system, the programmed personalities typically correspond to different types of users, such as customer service agents, supervisors, billing representatives, etc. In addition to each programmed personality, a default personality is also set at the manufacturing facilities to provide original program mode parameters for the various functions of the console in the absence of selection of one of the programmed personalities. Since the consoles contain multiple personalities, each console functions as an agent unit, a supervisory unit, a billing representative unit or any other personality type depending on the personality setting of the console.
However, in the known multipersonality consoles, the change from one console personality to another (i.e. from agent to supervisor) requires disassembly by a technician. Once the console housing is taken apart, the technician has to short two locations on the console printed circuit board subassembly and then power up the console to change the personality. Then the console is reassembled. Since this is a complicated and sophisticated process, many service representatives are not equipped to do this necessary change over work on site. Accordingly, the consoles are returned to the manufacturing or other central technical facility to reset the personality. The need for technically skilled individuals and the sending of consoles from a customer site to a manufacturing facility contributes to substantial maintenance costs for changing the personality of a console.

Telephonic console with multipersonality control apparatus and method


A flexible protector including a protector housing, clearance space defined by the housing the clearance being dimensioned and positioned to preserve flexibility of the housing while isolating a placed device from bending therein upon flexing of the housing. Also disclosed is a resource recovery system including a spoolable conductor, a device disposed in line with the conductor, and a spoolable protector disposed about the device. A method for protecting a device inline in a spoolable conductor including contacting the device with a buttress of a first half protector, securing conductors in the half protector, and interconnecting a second half protector with the first half protector. A method for instrumenting a target environment.

Where long lengths of conduit are employed for various power, communications, monitoring, etc. duties are employed they are normally spooled to manage the conduit and pay it out in an organized manner. In some cases, other devices are disposed in line on the conduit to be spooled out therewith. These include plugs for example that are spaced to be useful to whatever the end utility of the conductor has been planned. In resource recovery industries, there may also be a sheave through which the spooled conduit must be run. This presents even more difficulty as sheaves are often of an even smaller radius than spools and hence require conduits to bend even more to move therethrough.
The concept of spooling devices could be expounded upon except for the radii of the spools, and sheaves in some instances, versus the intolerance to spooling of devices that might be otherwise of interest. The art would welcome advancements that allow other devices to be spooled.


A chemical type CO.sub.2 gas generator for a carbonated drink dispenser, which while embodied in several different implementations, commonly includes a first and a second liquid reagent container with the second reagent container including a reaction chamber for generating a carbonating gas when the two reagents are mixed. The containers are coupled so that the first reagent transfers from the first container to the reaction chamber of the second container when the pressure of the generated gas falls below a predetermined value.

This invention relates generally to gas generator apparatus and more particularly to a CO.sub.2 gas generator module which generates the gas by a chemical reaction.
A beverage dispenser which uses syrup and carbonated water to produce a carbonated beverage typically uses a pressurized cylinder containing CO.sub.2 as part of the apparatus. Such systems, moreover, require complex controls to not only ensure the correct degree of carbonation, but also to provide a constant water pressure while dispensing. The latter is essential for providing proper control of the water-syrup dispensing ratio in a constant carbonation level while water is being drawn from either an on-board or external supply. Conventional CO.sub.2 cylinders comprise heavy, high pressure containers which are necessarily returnable, refillable packages and which are not only cumbersome and inconvenient in use, but also require external control of pressure and safety devices for safe operation.
With the trend toward mini-sized and home type dispensers of carbonated soft drinks, there is a present need for a non-pressurized or low pressure CO.sub.2 package inasmuch as it simplifies distribution through normal retail channels and provides greater convenience for the average user. Home dispensers are essentially relatively simple devices, with few controls, and in some instances, inserted in refrigerators, eliminating the need for separate cooling.
This in turn implies a need for a simple, disposable, yet durable CO.sub.2 generator module where generation of the CO.sub.2 gas occurs automatically with little or no user manipulation. Otherwise, the advantages of simplicity and cost effectiveness are counterbalanced by the lack of essential convenience.

Gas generator for a carbonated drink dispenser


A pressing device for a printing press or varnishing machine includes a pressing roller for rolling a cylinder packing or dressing onto a circumferential surface of a cylinder, and a finger protection device including a first flap and a second flap connected to the first flap via a swivel joint. The first flap is formed as a pressing element for pressing the cylinder packing on the cylinder. The first flap, in a protective position thereof, covers an inlet wedge or pocket jointly formed by the pressing roller and the cylinder. A printing press or varnishing machine having the pressing device is also provided.

The invention relates to a pressing device for a printing press or varnishing machine, which has a pressing roller for rolling a cylinder packing or dressing onto a circumferential surface of a cylinder, and has a finger protection device including a first flap and a second flap connected to the first flap via a swivel joint. The first flap, in a protective position, covers an inlet wedge or pocket jointly formed by the pressing roller and the cylinder.
German Published, Non-prosecuted Patent Application DE 100 18 923 A1 describes such a pressing device. However, in that device, it remains for the operator to bend the cylinder packing manually and without technical assistance into a cylinder gap formed in the cylinder and, in that regard, to force a trailing edge of the cylinder packing towards a clamping device disposed in the cylinder gap.
A pressing device described in German Published, Non-prosecuted Patent Application 2 156 044 has a similarly inconvenient type of operation.
It is accordingly an object of the invention to provide a pressing device for a printing press or varnishing machine, which overcomes the hereinafore-mentioned disadvantages of the heretofore-known devices of this general type and which permits more comfortable tight clamping of the trailing edge of the cylinder packing.
With the foregoing and other objects in view, there is provided, in accordance with the invention, a pressing device for a printing press or varnishing machine. The pressing device comprises a pressing roller for rolling a cylinder packing or dressing onto a circumferential surface of a cylinder, and a finger protection device including a first flap and a second flap connected to the first flap via a swivel joint. The first flap is formed as a pressing element for pressing the cylinder packing on the cylinder, and the first flap, in a protective position thereof, covers an inlet wedge or pocket jointly formed by the pressing roller and the cylinder.
In accordance with another feature of the invention, the first flap is mounted so as to be displaceable into a pressing position thereof wherein the first flap bears on the cylinder packing.
In accordance with a further feature of the invention, the first flap, in the pressing position thereof, is received in a cylinder gap formed in the cylinder.
In accordance with an added feature of the invention, the first flap, in the pressing position thereof, holds the cylinder packing on a clamping pad of a clamping device of the cylinder.
In accordance with an additional feature of the invention, the first flap, in the pressing position thereof, holds the cylinder packing bent into a cylinder gap formed in the cylinder.
In accordance with yet another feature of the invention, in a protective position of the first flap, a rolling element or a sliding element is disposed on the first flap. A spring holds the element in contact with a guide track.
In accordance with yet a further feature of the invention, the first flap is mounted so as to be swivelable about the swivel joint from the protective position into a switching position wherein the element is lifted off the guide track by overcoming the force of the spring.
In accordance with yet an added feature of the invention, in the protective position, the element is seated in a latching recess formed in the guide track.
In accordance with yet an additional feature of the invention, the guide track is a curved cam track of a cam, and the element is a cam follower element.
With the objects of the invention in view, there is also provided a printing press or a varnishing machine, comprising a pressing device. The pressing device includes a pressing roller for rolling a cylinder packing or dressing onto a circumferential surface of a cylinder, and a finger protection device including a first flap and a second flap connected to the first flap via a swivel joint. The first flap is formed as a pressing element for pressing the cylinder packing on the cylinder. The first flap, in a protective position thereof, covers an inlet wedge or pocket jointly formed by the pressing roller and the cylinder.
In the pressing device according to the invention, the first flap is multifunctional. The first flap serves, for one, for protecting the operator against injury and, for another, for making the work of the operator easier when a trailing edge of the cylinder packing is being clamped. A particularly compact construction of the pressing device is provided due to the multifunctionality. Only relatively little installation space is required within the printing press or varnishing machine for the integration of the pressing device. This compactness would not be provided in the case of a pressing device constructed differently from the pressing device according to the invention, which includes a pressing roller, a finger protection device and, in addition, a pressing element. In the case of the pressing device according to the invention, it is also advantageous that the pressing roller is available for rolling the cylinder packing on the cylinder, and the pressing element formed by the first flap is available for bending the cylinder packing into a cylinder gap of the cylinder and for pressing a trailing edge of the cylinder packing towards a clamping device disposed in the cylinder gap. Each of the two parts used to press the cylinder packing on the cylinder, i.e., the pressing roller and the pressing element, is optimally constructed with respect to the specific task thereof. The pressing roller is specifically constructed for rolling the cylinder packing onto the circumferential surface of the cylinder. The pressing element formed by the finger protection device is specifically constructed for bending the cylinder packing near the trailing edge thereof. In a pressing device wherein a pressing roller and a pressing element, differing from those of the invention, were not two different parts but one and the same part, construction compromises would have to be made and, therefore, functional deficiencies with respect to each of the individual functions, the rolling and the bending, would have to be accepted.
The pressing roller of the pressing device according to the invention is a pressing roller that is different from a rubber or blanket cylinder, i.e., it is not a rubber or blanket cylinder.
The cylinder packing may be a printing plate, for example, an offset printing plate, or a flexographic printing plate used for varnishing or a rubber blanket used, for example, for varnishing. Accordingly, the cylinder is a plate or blanket cylinder.
Advantageous developments of the pressing device according to the invention are noted hereinbelow.
One development is distinguished by the fact that the first flap is mounted so as to be adjustable into a pressing position, wherein the first flap bears on the cylinder packing.
The content of a further development is that in the pressing position the first flap is received in or dips into a cylinder gap of the cylinder.
According to a further development, in the pressing position, the cylinder packing is held by the first flap on a clamping pad of a clamping device of the cylinder.
The fact that, in the pressing position, the cylinder packing is held bent by the first flap in the cylinder gap formed in the cylinder distinguishes a further development.
The content of a further development is that, in the protective position, a rolling or sliding element disposed on the first flap is held by a spring in contact with a guide track.
A further development is that the first flap is mounted so that it is swivelable about the joint from the protective position into a switching position, wherein the rolling or sliding element is raised off the guide track when overcoming the force of the spring.
According to one development, provision is made for the rolling or sliding element to be seated in a latching recess in the guide track when in the protective position. The guide track may be a curved cam track of a cam, and the rolling or sliding element may be a cam follower element.
Other features which are considered as characteristic for the invention are set forth in the appended claims.
Although the invention is illustrated and described herein as embodied in a pressing device for a printing press or varnishing machine, it is nevertheless not intended to be limited to the details shown, since various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims.
The construction and method of operation of the invention, however, together with additional objects and advantages thereof will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings.

Pressing device for a printing press or varnishing machine


The present invention relates to a fire sprinkler head that once activated can be shut off via a built-in ball-type cutoff valve without requiring the flow of fire retardant in the feeding pipe to be cut off.

1. Field of the Invention
The present invention relates to a fire sprinkler head that once activated can be shut off via a built-in ball-style cutoff valve without requiring the flow of fire retardant in the feeding pipe to be cut off.
2. Background of the Invention
When commercial and residential fire sprinklers are activated by heat, fire retardant flows freely through the sprinkler. Usually that fire retardant is water. Once the fire or fire risk has been suppressed, continued retardant flow causes considerable damage. In many cases the damage from water or other retardant grossly exceeds the damage caused by fire. It would be beneficial for firefighters and building support personnel to be able to shut off an individual fire sprinkler quickly. The current primary method for cutting off the flow of water or other retardant is to shut the retardant off at the source for the sprinkler system. This is time-consuming, as finding the riser room and then the correct shutoff valve can take many minutes. It is also dangerous, as the entire sprinkler system or subsystem is disabled until the fire sprinkler is repaired or replaced and water pressure is reestablished.
In certain buildings with fire prevention systems, such as college dormitories or commercial buildings, occupants or invitees might be tempted to tamper with sprinklers featuring a manually operated valve. For any sprinkler system including such a feature, it therefore becomes important to provide a tamper-resistant operation feature whereby only authorized personnel are given access to the valve.
The inclusion of a manually operated cutoff valve in a fire sprinkler has the potential to alter or enlarge the size of the sprinkler housing and/or assembly, making such housing or assembly difficult or impossible to mount within existing fire prevention systems and supply pipes. Such a feature also has the potential to unreasonably increase the cost of manufacture and installation of each such sprinkler. Inclusion of a cutoff valve within a standard sprinkler assembly and housing would be beneficial to combat such incompatibility and to keep costs in line with standard sprinklers.
Capasso et al. U.S. Pat. No. 4,638,866 discloses an apparatus for stopping the flow of water through the opening in a fire sprinkler head after the failure of an originally installed triggering device, which apparatus thereafter serves as a substitute triggering device. The apparatus is provided with a meltable body portion having a first bore formed therein with a shoulder formed at one end of the first bore and a second bore formed generally transverse to and in contact with the first bore at the shoulder end of the first bore, a spring positioned in the first bore, a piston positioned within the spring and having a slot at one end which is alignable with the second bore and a pin inserted through the second bore and engaging the piston slot. Thus, after placement in a sprinkler head, transverse movement of the pin results in the release of the piston which is moved by the spring into the sprinkler head opening, stopping the flow of water.
Capasso, U.S. Pat. No. 4,830,117 discloses a thermally responsive device for terminating the discharge of fire-extinguishing fluid from an activated sprinkler head of the pendent and sidewall type. The device includes a recessed seat which, when impressed onto an activated sprinkler head, returns the shut-off valve to the water emitting conduit to obturate fluid flow. The device is secured by a frictional locking means which allows it to remain in place as a guard against inadvertent discharge.
DeGennaro, U.S. Pat. No. 4,923,013 discloses an automatic shut-off valve arrangement for a fire sprinkler system includes a set of auxiliary pipe fittings interconnected between the water distribution pipes and the sprinkler heads. Each fitting houses a multi-vane paddle wheel rotatably mounted under an eccentric valve opening normally unobstructed by a movable valve member, and the paddle wheel axle is connected by a gear train to an actuator for the valve member. When water flows from the distribution pipe through the fitting and exits therefrom via the sprinkler head to douse a fire, the paddle wheel rotates rapidly and drives the actuator via the gear train so that the valve member is shifted to close the valve opening and interrupt the flow of water therethrough after a prescribed time interval, thereby minimizing the risk of water damage to the protected premises.
Reed, U.S. Pat. No. 6,575,252 discloses a tool for deactivating a sprinkler head. The tool includes a housing, a first arm supported by the housing and a second arm supported for movement relative to the first arm. A first engagement surface is supported by the first arm and a second engagement surface is supported by the second arm. The first and second engagement surfaces are adapted for positioning intermediate a valve and a receiving support of the sprinkler head. A biasing member is operably connected to the second arm for urging the second engagement surface away from the first engagement surface. A handle is supported by the second arm and is moveable relative to the housing.
Wancho et al., U.S. Pat. No. 6,854,668 discloses a sprinkler that discharges a column of water downwardly onto a deflector that has a plurality of peripheral tines with a respective non-radial tapered notch separating each adjacent pair of tines. Opposed cutouts with tabs in the central portion of the deflector combine with the notches and with depressed peripheral tabs to produce a predetermined spray pattern.
Fischer, U.S. Pat. No. 6,976,543 discloses a low pressure, extended coverage, fire protection sprinkler, i.e. of the upright type, suitable for use in protection of extra hazard and high piled storage occupancies, in accordance with the 1999 Edition of NFPA 13, that has a body with an internal passageway extending between an inlet end and an opposite outlet end, and a deflector mounted to the body by at least one support arm and disposed in alignment with the axis and generally spaced from the outlet end of the internal passageway. The sprinkler has a predetermined K-factor, i.e. of greater than about 16.0. The sprinkler is configured and arranged to deflect flow of water generally radially outwardly and downwardly of the sprinkler in a predetermined spray pattern. Preferably, the predetermined spray pattern has a generally polygonal shape, e.g., a rectangular shape, when viewed at a predetermined distance below the deflector.
Dade, U.S. Pat. No. 7,422,072 discloses a sprinkler wedge designed for inhibiting water discharge from an open or activated sprinkler head. The sprinkler wedge generally comprises a main body having proximal and distal ends, a handle assembly connected toward the proximal end for easy grasping by a human hand, and a forked tip toward the distal end. The sprinkler wedge is designed for improved single-handed insertion into the water stream of an activated sprinkler head.
Flynn, U.S. patent application Ser. No. 12/359,880, Pub. No. 20100186973, discloses a sprinkler with a built-in cone plug-style cutoff valve manually operated from a screw head disposed on the underside of the sprinkler, within the center of the deflector shield. By turning the screw head using a standard or modified screwdriver, the operator moves the cone plug along the central axis of the sprinkler, from an open position into a closed position wherein the cone engages with a seal and blocks fire retardant from exiting the sprinkler.

Fire sprinkler with ball-type cutoff valve and tamper-resistant features


A raw material supply device (105) includes an introduction pipe (152a) which introduces a carrier gas into a raw material vessel (151), a transport pipe (152b) which transports a source gas fed out from the raw material vessel, a supply pipe (155a) which is branched from the transport pipe and supplies the source gas to a film forming chamber (101), a circulation pipe (155b) which is branched from the transport pipe (152b) and returns the source gas to the introduction pipe (152a), an introduction valve (156a) which is attached to the introduction pipe, a supply valve (156b) which is attached to the supply pipe, a circulation valve (156c) which is attached to the circulation pipe, and a controller (157) which controls opening/closing of the valves. The controller controls the supply valve and the circulation valve to be in opposite open/closed states. The source gas can be supplied more stably while suppressing the waste of the raw material.

Recently, ALD (Atomic Layer Deposition) capable of forming a thin film for each of atomic and molecular layers is receiving attention as a technique having various features including one capable of forming a high-quality thin film more uniformly at a temperature as low as about 300° C. The ALD method is an epitaxial growth technique of forming a thin film for each atomic layer by alternately supplying, to a substrate, the source gases of respective elements which constitute a film to be formed.
In the formation of a thin film using the ALD method, for example, the gas of an organic compound of a metal which constitutes a film to be formed is used as a source gas. Most organic metal compounds are liquids at room temperature (about 20° C.). Thus, an epitaxial growth technique such as ALD evaporates a liquid of an organic metal compound by so-called bubbling and uses it as a source gas (Japanese Patent Laid-Open Nos. 5-074758 and 5-251348). The method of evaporating a liquid raw material by bubbling is a simply raw material supply means for evaporating and supplying a liquid raw material because the structure is simple and a gas used for bubbling can be used as a carrier gas for an evaporated source gas.

Mitsui Engineering & Shipbuilding Co., Ltd.


A method of and apparatus for supplying power during EDMing in which reverse polarity pulses are used to inhibit electrolytic activity. A main voltage pulse of a certain polarity and an auxiliary voltage pulse, preceding the main voltage pulse of the same or reverse polarity, are applied across a machining gap during the on time of a main gate signal and until a discharge is detected. The ratio of the number of auxiliary voltage pulses of regular polarity to those of reverse polarity is set to a desired value depending upon machining conditions, to thereby obtain a good compromise between the conflicting requirements of achieving a high machining rate, while inhibiting undesirable electrolytic activity.

In EDM's, including both wire-cut EDM's and die-sinking EDM's, various problems may arise due to the electrolytic phenomenon associated with the dielectric fluid used.
For example, when applying voltage pulses of a so-called regular polarity across a machining gap of a die-sinking EDM, i.e., wherein the machining electrode is negative and a workpiece is positive, for machining workpieces made of hard alloys, such as tungsten carbide, deionization of the dielectric in the machining gap may become difficult as machining proceeds. Particularly in portion(s) of the machining gap, such as near the center of the bottom of the machining electrode, where it is difficult to carry away the machined particles, the resistivity of the dielectric fluid may locally decrease.
In addition, when using water-based dielectric fluids which include a high polymer in a die-sinking EDM, there is a tendency to produce tar in the machining gap. Since the tar has a greater electrical conductivity than the dielectric, the resistivity of the gap may locally decrease. When electrolytic or arc currents flow through such low-resistivity portions of the gap, an oxide adherent may be quickly produced. The insulating property of this oxide adherent causes the machining rate to dramatically decrease and adversely affects the quality of the machined surface.
When using a kerosene-based dielectric fluid in a die-sinking EDM, there also is the tendency to produce tar in the machining gap, which may result in arcing. Such arcing may cause cracks on the surface of the workpiece, which will tend to shorten the useful life of die or mold being produced.
When machining a workpiece using a wire-cut EDM, in which water or a water-based dielectric fluid is used, when repeatedly applying voltage pulses across a regularly poled machining gap, i.e., one in which the machining electrode is negative and the workpiece is positive, the dielectric fluid may become electrolyzed, resulting in an electrolytic current flowing across the low-resistivity portion(s) of the gap; which in turn results in the formation of an affected layer on the workpiece surface. Particularly when machining a workpiece made of a hard alloy, such as tungsten carbide, substances susceptible to electrolysis, such as cobalt, may dissolve out of the workpiece resulting in the formation of an affected layer on the workpiece surface, which in turn may damage the workpiece and shorten the life of any die or mold being produced.
In Japanese Patent Publication No. 63-17569, a power supply for a wire-cut EDM is disclosed which has a main power source for generating a discharge across the machining gap with the machining electrode being negatively poled and the workpiece being positively poled, i.e., of regular polarity, and an auxiliary power source for generating a discharge across the gap with the machining electrode being positively poled and the workpiece being negatively poled, i.e., of reverse polarity. In this device, a voltage is first applied in reverse polarity from the auxiliary power source to initialize a discharge. After detecting the occurrence of a discharge, the main power source maintains the discharge in regular polarity while interrupting the power from the auxiliary power source. As a result, the undesirable effects of electrolytic activity are decreased, although at the cost of a reduced machining rate, since the current flow across the gap reverses direction.

Method and apparatus for supplying power for electric discharge machining


A power-supply apparatus includes a power-supply circuit to which an input voltage and an input current are input, to include a switching element to be controlled by a control signal so as to generate an output voltage and an output current, a memory, and a processor coupled to the memory and the processor to calculate a first duty ratio of the control signal so that the output voltage approaches a target voltage, calculate a second duty ratio of the control signal for the switching element, based on the input voltage, the input current, the output voltage, and the output current, detect deterioration of the power-supply circuit, based on the first duty ratio and the second duty ratio, generate the control signal of the first duty ratio when the power-supply circuit has not deteriorated, and generate the control signal for stopping the power-supply circuit when the power-supply circuit has deteriorated.

A power-supply apparatus has been known that has a duty-ratio determiner that determines a duty ratio of a control signal for a switching element in a power supply circuit so that an output voltage of the power supply circuit gets close to a target voltage (see Japanese Laid-open Patent Publication No. 2017-085820). A permissible-range calculator calculates a permissible range of the duty ratio, based on a current output from the power supply circuit and detected by a current detection circuit. When the duty ratio determined by the duty-ratio determiner is within the permissible range, an output portion outputs the duty ratio determined by the duty-ratio determiner, and when the duty ratio determined by the duty-ratio determiner is outside the permissible range, the output portion causes the power supply circuit to stop. Thus, in the power-supply apparatus, even when the current detection circuit fails, the power supply circuit can be stopped when overcurrent flows to the power supply circuit.

Power-supply apparatus and power-supply method


An implantable valve prosthesis is provided. The valve prosthesis includes a frame structure having first and second independent frame elements. A graft member is attached to both the first and second frame elements and includes a closure member, such as a valve leaflet. The closure member is movable between a first position that allows fluid flow through the prosthesis in a first, antegrade direction and a second position that restricts flow through the prosthesis in a second, retrograde direction.

Many veins of the human body or animals include natural valves that aid in the return of blood flow toward the heart. These natural valves may prevent blood from pooling in the lower legs and feet. The proper function of these venous valves is especially important during standing or sitting when the weight of blood in the vein can slow blood flow toward the heart. Problems can arise when these venous valves fail to function properly. For example, venous valves can become incompetent or damaged by disease such that the backflow of blood is not prevented. When this occurs, blood pressure builds up and the veins and their valves become dilated, particularly in the lower extremities. If enough pressure builds up, the condition of venous insufficiency may develop. The severity of this condition is substantial, resulting in swelling, extensive pain, deformities, and, in the most severe cases, the development of ulcers can occur. If these ulcers become infected, amputation may ultimately be necessary to save the patient's life.
Currently, there is no proven cure for venous insufficiency. Basic treatments include elevation of the legs or the use of compression stockings. If surgery is determined to be necessary, vein stripping is typically performed, which involves the removal of the incompetent or damaged vein(s). Other surgical methods involve valvular reconstruction or transplantation.
The development of artificial and biological valves has been employed in an attempt to return normal pressure to the veins. There are a variety of these valves described in the art, which are generally designed to allow normal flow of blood back to the heart, while preventing retrograde flow. However, blood flow within a vein is intermittent and bidirectional, subject to constant fluctuation in pressure and volume. As a result, the shape of a lumen of a vein can undergo dramatic dynamic change resulting from these varying blood flow velocities, pressures and volumes therethrough. Many design considerations, consequently, regarding artificial valves for the venous system are taken into account. One primary consideration includes the ability of the frame and the valve to conform to the dynamic fluctuations in the shape of the lumen of the vein. Another primary consideration is the ability of the valve to be implanted in a body vessel having a variable diameter along the length of a site of implantation, or a branched body vessel site of implantation.
What is needed is an intraluminally-placed valve prosthesis, including a frame and valve, or closure member, that is compliant to be delivered percutaneously and, upon implantation, configured to prevent migration within the body vessel and minimize irritation of the body vessel. In addition, there remains a need for a valve prosthesis to conform to the changing shape of the lumen of the vein. There also remains a need for valve devices having a support frame configured with a radial strength to maintain patency of a body vessel while supporting a means for regulating fluid within the body vessel.

Implantable valve prosthesis with independent frame elements


A placement guide apparatus with an improved hydration inducing plug used in coupling a noninvasive analyzer to a sampling site to determine analyte in the human body is disclosed. The hydration inducing plug includes at least one fluoropolymer that may be used as a coupling agent. The guide apparatus may further include an automated or semi-automated coupling fluid delivery system. Use of either of these couplers mitigates issues associated with related technology and enhances noninvasive analyte measurements, such as a near-IR diffuse reflectance based noninvasive glucose concentration analyzer.

1. Field of the Invention
The invention relates generally to the technology of noninvasive analyte determination in the human body. More particularly, the invention relates to the use of a placement guide in conjunction with a diffuse reflectance based near-IR glucose analyzer. The placement guide couples to a glucose analyzer and has at least one of a hydration inducer and a reservoir for a coupling agent used for automatic or manual delivery of the coupling agent to the sampling site.
2. Description of Related Art
Spectroscopy based noninvasive analyzers deliver external energy in the form of light or rays to a specific sampling site or region of the human body where the photons interact with the chemistry and physiology of the sampled tissue. A portion of the incident photons are scattered or transmitted out of the body where they are detected. Based upon knowledge of the incident photons and detected photons, the chemical and/or structural basis of the sampled site may be deduced. Several distinct advantages to a noninvasive system are the analyses of chemical and structural constituents in the body without the generation of a biohazard in a pain free manner with limited consumables. The technique may also allow for multiple analytes or structural features to be determined at one time. Some common examples of noninvasive analyzers are magnetic resonance imaging (MRI), X-rays, pulse oximeters, and noninvasive glucose analyzers. With the exception of X-rays, these determinations are performed with relatively harmless wavelengths of radiation. Examples herein focus on noninvasive glucose determination, but the principles apply to other modes of noninvasive analyses.
Diabetes
Diabetes is a chronic disease that results in improper production and utilization of insulin, a hormone that facilitates glucose uptake into cells. While a precise cause of diabetes is unknown, genetic factors, environmental factors, and obesity appear to play roles. Diabetics have increased risk in three broad categories: cardiovascular heart disease, retinopathy, and neuropathy. Diabetics may have one or more of the following complications: heart disease and stroke, high blood pressure, kidney disease, neuropathy (nerve disease and amputations), retinopathy, diabetic ketoacidosis, skin conditions, gum disease, impotence, and fetal complications. Diabetes is a leading cause of death and disability worldwide. Moreover, diabetes is merely one among a group of disorders of glucose metabolism that also includes impaired glucose tolerance, and hyperinsulinemia, or hypoglycemia.
Diabetes Prevalence and Trends
Diabetes is an ever more common disease. The World Health Organization (WHO) estimates that diabetes currently afflicts 154 million people worldwide. There are 54 million people with diabetes living in developed countries. The WHO estimates that the number of people with diabetes will grow to 300 million by the year 2025. In the United States, 15.7 million people or 5.9 percent of the population are estimated to have diabetes. Within the United States, the prevalence of adults diagnosed with diabetes increased by 6% in 1999 and rose by 33% between 1990 and 1998. This corresponds to approximately eight hundred thousand new cases every year in America. The estimated total cost to the United States economy alone exceeds $90 billion per year. Diabetes Statistics, National Institutes of Health, Publication No. 98-3926, Bethesda, MD. (Nov. 1997).
Long-term clinical studies show that the onset of complications can be significantly reduced through proper control of blood glucose levels. The Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, N Eng J of Med, 329:977-86 (1993); U.K. Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes, Lancet, 352:837-853 (1998); and Y. Ohkubo, H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, M. Shichizi, Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study, Diabetes Res Clin Pract, 28:103-117 (1995).
A vital element of diabetes management is the self-monitoring of blood glucose levels by diabetics in the home environment. However, current monitoring techniques discourage regular use due to the inconvenient and painful nature of drawing blood through the skin prior to analysis. The Diabetes Control and Complication Trial Research Group, supra. As a result, noninvasive measurement of glucose has been identified as a beneficial development for the management of diabetes. Implantable glucose analyzers eventually coupled to an insulin delivery system providing an artificial pancreas are also being pursued.
Sampling Methodology
A wide range of technologies serve to analyze the chemical make-up of the body. These techniques may be broadly categorized into two groups, invasive and noninvasive. For the purposes of this document, a technology that acquires any biosample from the body for analysis or if any part of the measuring apparatus penetrates into the body, the technology is referred to as invasive.                Invasive: Some examples of invasive technologies for glucose determination in the body are those that analyze the biosamples of whole blood, serum, plasma, interstitial fluid, and mixtures or selectively sampled components of the aforementioned. Typically, these samples are analyzed with electrochemical, electroenzymatic, and/or colorimetric approaches. For example, enzymatic and calorimetric approaches may be used to determine the glucose concentration in interstitial fluid samples.        Noninvasive: A number of approaches for determining the glucose concentration in biosamples, have been developed that utilize spectrophotometric technologies. These techniques include: Raman and fluorescence, as well as techniques using light from the ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)].Noninvasive Glucose Determination
There exist a number of noninvasive approaches for glucose determination. These approaches vary widely, but have at least two common steps. First, an apparatus is utilized to acquire a signal from the body without obtaining a biological sample. Second, an algorithm is utilized to convert this signal into a glucose determination.
One type of noninvasive glucose determination is based upon spectra. Typically, a noninvasive apparatus utilizes some form of spectroscopy to acquire the signal or spectrum from the body. Utilized spectroscopic techniques include, but are not limited to: Raman and fluorescence, as well as techniques using light from ultraviolet through the infrared [ultraviolet (200 to 400 nm), visible (400 to 700 nm), near-IR (700 to 2500 nm or 14,286 to 4000 cm−1), and infrared (2500 to 14,285 nm or 4000 to 700 cm−1)]. A particular range for noninvasive glucose determination in diffuse reflectance mode is about 1100 to 2500 nm or ranges therein. K. Hazen, Glucose Determination in Biological Matrices Using Near-infrared Spectroscopy, doctoral dissertation, University of Iowa (1995). It is important to note that these techniques are distinct from the traditional invasive and alternative invasive techniques listed above in that the interrogated sample is a portion of the human body in-situ, not a biological sample acquired from the human body.
Typically, three modes are utilized to collect noninvasive scans: transmittance, transflectance, and/or diffuse reflectance. For example the signal collected, typically being light or a spectrum, may be transmitting through a region of the body such as a fingertip, diffusely reflected, or transflected. Transflected here refers to collection of the signal not at the incident point or area (diffuse reflectance), and not at the opposite side of the sample (transmittance), but rather at some point on the body between the transmitted and diffuse reflectance collection area. For example, transflected light enters the fingertip or forearm in one region and exits in another region typically 0.2 to 5 mm or more away depending on the wavelength utilized. Thus, light that is strongly absorbed by the body such as light near water absorbance maxima at 1450 or 1950 nm would need to be collected after a small radial divergence and light that is less absorbed such as light near water absorbance minima at 1300, 1600, or 2250 nm may be collected at greater radial or transflected distances from the incident photons.
Noninvasive techniques are not limited to using the fingertip as a measurement site. Alternative sites for taking noninvasive measurements include: a hand, finger, palmar region, base of thumb, wrist, dorsal aspect of the wrist, forearm, volar aspect of the forearm, dorsal aspect of the forearm, upper arm, head, earlobe, eye, tongue, chest, torso, abdominal region, thigh, calf, foot, plantar region, and toe. It is important to note that noninvasive techniques do not have to be based upon spectroscopy. For example, a bioimpedence meter would be considered a noninvasive device. Within the context of the invention, any device that reads a signal from the body without penetrating the skin and collecting a biological sample is referred to as a noninvasive glucose analyzer. For example, a bioimpedence meter is a noninvasive device.
Calibration
Glucose analyzers require calibration. This is true for all types of glucose analyzers such as traditional invasive, alternative invasive, noninvasive, and implantable analyzers. One fact associated with noninvasive glucose analyzers is that they are secondary in nature, that is, they do not measure blood glucose levels directly. This means that a primary method is required to calibrate these devices to measure blood glucose levels properly. Many methods of calibration exist.
One noninvasive technology, near-infrared spectroscopy, requires that a mathematical relationship between an in vivo near-infrared measurement and the actual blood glucose value be developed. This is achieved through the collection of in-vivo NIR measurements with corresponding blood glucose values that have been obtained directly through the use of measurement tools like a HEMOCUE or a YSI (YSI INCORPORATED, Yellow Springs Ohio), or any appropriate and accurate traditional invasive reference device.
For spectrophotometric based analyzers, there are several univariate and multivariate methods that may be utilized to develop the mathematical relationship between the measured signal and the actual blood glucose value. However, the basic equation being solved is known as the Beer-Lambert Law. This law states that the strength of an absorbance/reflectance measurement is proportional to the concentration of the analyte which is being measured, as in equation 1,A=εbC  (1)where A is the absorbance/reflectance measurement at a given wavelength of light, ε is the molar absorptivity associated with the molecule of interest at the same given wavelength, b is the distance that the light travels, and C is the concentration of the molecule of interest (glucose).
Chemometric calibration techniques extract the glucose signal from the measured spectrum through various methods of signal processing and calibration including one or more mathematical models. The models are developed through the process of calibration on the basis of an exemplary set of spectral measurements known as the calibration set and associated set of reference blood glucose concentrations based upon an analysis of capillary blood or venous blood. Common multivariate approaches requiring an exemplary reference glucose concentration vector for each sample spectrum in a calibration include partial least squares (PLS) and principal component regression (PCR). Many additional forms of calibration are known, such as neural networks.
There are a number of reports on noninvasive glucose technologies. Some of these relate to general instrumentation configurations required for noninvasive glucose determination. Others refer to sampling technologies. Those most related to the present invention are briefly reviewed here:
As outlined above, there have been a number of studies documenting the need for an accurate and precise noninvasive glucose analyzer.
R. Barnes, J. Brasch, D. Purdy, W. Lougheed, Non-invasive determination of analyte concentration in body of mammals, U.S. Pat. No. 5,379,764 (Jan. 10, 1995) describe a noninvasive glucose analyzer that utilizes data pretreatment in conjunction with a multivariate analysis to determine blood glucose concentrations.
General Instrumentation:
P. Rolfe, Investigating substances in a patient's bloodstream, UK Patent Application No. 2,033,575 (Aug. 24, 1979) describe an apparatus for directing light into the body, detecting attenuated backscattered light, and utilizing the collected signal to determine glucose concentrations in or near the bloodstream.
C. Dahne, D. Gross, Spectrophotometric method and apparatus for the non-invasive, U.S. Pat. No. 4,655,225 (Apr. 7, 1987) describe a method and apparatus for directing light into a patient's body, collecting transmitted or backscattered light, and determining glucose from selected near-IR wavelength bands. Wavelengths include 1560 to 1590, 1750 to 1780, 2085 to 2115, and 2255 to 2285 nm with at least one additional reference signal from 1000 to 2700 nm.
M. Robinson, K. Ward, R. Eaton, D. Haaland, Method and apparatus for determining the similarity of a biological analyte from a model constructed from known biological fluids, U.S. Pat. No. 4,975,581 (Dec. 4, 1990) describe a method and apparatus for measuring a concentration of a biological analyte such as glucose using infrared spectroscopy in conjunction with a multivariate model. The multivariate model is constructed form plural known biological fluid samples.
J. Hall, T. Cadell, Method and device for measuring concentration levels of blood constituents non-invasively, U.S. Pat. No. 5,361,758 (Nov. 8, 1994) describe a noninvasive device and method for determining analyte concentrations within a living subject utilizing polychromatic light, a wavelength separation device, and an array detector. The apparatus utilizes a receptor shaped to accept a fingertip with means for blocking extraneous light.
S. Malin, G Khalil, Method and apparatus for multi-spectral analysis of organic blood analytes in noninvasive infrared spectroscopy, U.S. Pat. No. 6,040,578 Mar. 21, 2000) describe a method and apparatus for determination of an organic blood analyte using multi-spectral analysis in the near-IR. A plurality distinct nonoverlapping regions of wavelengths are incident upon a sample surface, diffusely reflected radiation is collected, and the analyte concentration is determined via chemometric techniques.
Specular Reflectance:
R. Messerschmidt, D Sting Blocker device for eliminating specular reflectance from a diffuse reflectance spectrum, U.S. Pat. No. 4,661,706 (Apr. 28, 1987) describe a reduction of specular reflectance by a mechanical device. A blade-like device "skims" the specular light before it can impinge on the detector. A disadvantage of this system is that it does not efficiently collect diffusely reflected light and the alignment is problematic.
R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. Pat. No. 5,636,633 (Jun. 10, 1997) describe a specular control device for diffuse reflectance spectroscopy utilizing a group of reflecting and open sections.
R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. Pat. No. 5,935,062 (Aug. 10, 1999) and R. Messerschmidt, M. Robinson Diffuse reflectance monitoring apparatus, U.S. Pat. No. 6,230,034 (May 8, 2001) describe a diffuse reflectance control device that can discriminate between diffusely reflected light that is reflected from selected depths. This control device may additionally act as a blocker to prevent specularly reflected light from reaching the detector.
Malin et. al., supra describe the utilization of specularly reflected light in regions of high water absorbance such as 1450 and 1900 nm to mark the presence of outlier spectra wherein the specularly reflected light is not sufficiently reduced.
K. Hazen, G. Acosta, A. Abul-Haj, R. Abul-Haj, Apparatus and method for reproducibly modifying localized absorption and scattering coefficients at a tissue measurement site during optical sampling, U.S. Pat. No. 6,534,012 (Mar. 18, 2003) describe a mechanical device for applying sufficient and reproducible contact of the apparatus to the sampling medium to minimize specular reflectance. Further the apparatus allows for reproducible applied pressure to the sampling site and reproducible temperature at the sampling site.
Temperature:
It is well known that many physiological constituents have near-IR absorbance spectra that are sensitive in terms of magnitude and location to localized temperature. This has been reported as impacting noninvasive glucose determinations. Hazen, et. al., supra.
Coupling Fluid:
Index of fraction matching between the sampling apparatus and sampled medium is well known. Glycerol is a common index matching fluid for optics to skin. A number of patents disclose more specific coupling fluids with important sampling parameters.
R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 5,655,530 (Aug. 12, 1997), and R. Messerschmidt Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 5,823,951 describe an index-matching medium for use between a sensor probe and the skin surface. The index-matching medium is a composition containing perfluorocarbons and chlorofluorocarbons.
M. Robinson, R. Messerschmidt, Method for non-invasive blood analyte measurement with improved optical interface, U.S. Pat. No. 6,152,876 (Nov. 28, 2000) and M. Rohrscheib, C. Gardner, M. Robinson, Method and apparatus for non-invasive blood analyte measurement with fluid compartment equilibration, U.S. Pat. No. 6,240,306 (May 29, 2001) describe an index-matching medium to improve the interface between the sensor probe and skin surface during spectroscopic analysis. The index-matching medium is preferably a composition containing chlorofluorocarbons. The composition can also contain perfluorocarbons.
T. Blank, G. Acosta, M. Mattu, S. Monfre, Fiber optic probe guide placement guide, U.S. Pat. No. 6,415,167 (Jul. 2, 2002) describe a coupling fluid of one or more perfluoro compounds where a quantity of the coupling fluid is placed at an interface of the optical probe and measurement site. Notably, perfluoro compounds do not have the toxicity associated with chlorofluorocarbons.
Guide:
Blank et. al., supra describe the utilization of a guide in conjunction with a noninvasive glucose analyzer in order to increase precision of the location of the sampled site resulting in increased accuracy and precision in a noninvasive glucose determination.
In all of the related technology of this section, no suggestion of automated analysis is made. Further, no suggestion is made for a fluoropolymer hydration inducer or for a coupling fluid reservoir within the guide. Both of these guide features ease the use of a bioanalyzer such as a near-IR based noninvasive glucose analyzer. In addition, to date no FDA device has been approved for the utilization by an individual or a medical professional for noninvasive glucose concentration determination.
The Problem
Noninvasive glucose analyzers reported to date generally require precision in sampling in order to accurately determine glucose concentrations in the body. The measurement is complicated by every manual step required in the spectral acquisition process utilized in a given glucose determination. Complications include any of a requirement of time, a step requiring manual dexterity, or movement of measurement apparatus that may be bulky, fragile, or sensitive in terms of returned analytical signal. Elimination or automation of steps required for a noninvasive glucose determination is beneficial for at least one of increasing marketability of the analyzer, increasing the number of people who may utilize the analyzer, reduction in time requirements associated with a glucose determination, and increased precision and/or accuracy of a glucose determination. Specifically, preparation of the sampling site in terms of temperature, historesis of applied pressure, hydration, and optical scattering parameters involving actions from the user that may be any of technically challenging, time consuming, and error inducing.
What is desired is a mechanism for reducing user input through methods and apparatus such as a hydration inducer and a coupling agent enhancement integrated into a guide used in conjunction with a noninvasive glucose analyzer.

Apparatus and method for easing use of a spectrophotometric based noninvasive analyzer