The present invention provides an isolated DNA molecule that codes for a cell-surface binding protein in human monocytes and macrophages. In addition, an amino acid sequence derived from the nucleotide sequence is provided. The newly-identified cell-surface binding protein described herein is instrumental in the apoB-mediated cellular uptake of plasma chylomicrons and remnants and hypertriglyceridemic triglyceride-rich lipoproteins in an ApoE- and lipoprotein lipase- and heparin sulfate proteoglycan-independent pathway. The new human macrophage receptor has been cloned and uniquely, binds TGRLP via apolipoprotein B48, the marker of dietary TGRLP (apoB48R). This process rapidly converts macrophages and apoB48R-transfected Chinese hamster ovary cells in vitro into lipid-filled xe2x80x9cfoam cells,xe2x80x9d hallmarks of atherosclerotic lesions. The apoB48R cDNA (3744 bp) encodes a novel protein with no known homologs. Its xcx9c3.8 kb mRNA is expressed primarily by reticuloendothelial cells. Immunohistochemical studies indicate that foam cells of human atherosclerotic lesions express the apoB48R.

1. Field of the Invention
The present invention relates generally to the fields of molecular biology, cardiovascular medicine and cellular nutrition. More specifically, the present invention relates to DNA encoding the human monocyte-macrophage and placental triglyceride-rich lipoprotein/apolipoprotein B (apoB) receptor gene(s) and protein(s).
2. Description of the Related Art
Hypertriglyceridemia is a common, heterogeneous disorder. When chylomicrons persist in the fasting state, lipid-filled monocyte-macrophage-derived foam cells can accumulate in the spleen, liver, bone marrow, atherosclerotic lesions, and skin (Fredrickson, 1978). Many, but not all, early studies (Carlson, 1972; Brunzell, 1976; Grundy, 1988; Schaefer, 1988; Austin, 1991) indicate elevated plasma triglycerides are a risk factor for coronary heart disease and myocardial infarction, sequelae of atherosclerosis. The possibility that triglyceride-rich lipoproteins (hepatic as well as dietary) are involved in atherosclerosis has been strengthened recently. Both the Procam study and a follow-up of the Helsinki Heart Study implicate elevated triglycerides (and therefore triglyceride-rich lipoproteins) as an important risk factor in atherosclerosis (Assmann, 1992). Havel et al. demonstrated that plasma very low density lipoprotein and intermediate density lipoprotein cholesterol levels correlated with progression of coronary atherosclerosis disease, whereas low density lipoprotein cholesterol level did not (Phillips, 1993). Moreover, very low density lipoprotein-intermediate density lipoprotein particles enter the artery wall and are found in human atherosclerotic plaques (Rapp, 1994). Elevated postprandial chylomicron remnants of Sf less than 400 are significantly higher in subjects with coronary heart disease but with normal fasting lipid levels than in matched control subjects without this disease (Patsch, 1992; Weintraub, 1996). Thus, there is increasing biochemical as well as epidemiologic evidence that the major carriers of plasma triglycerides, very low density lipoproteins and plasma chylomicrons and their remnants, are atherogenic.
Monocytes and macrophages play a key role in atherogenesis, accounting for many lipid-filled xe2x80x9cfoam cellsxe2x80x9d in atherosclerotic lesions (Gerrity, 1981; Faggiotto, 1984). Many studies on foam cell formation have focused on uptake of modified and oxidized low density lipoprotein by the macrophage scavenger receptor and putative oxidized low density lipoprotein receptors (van Berkel, 1994). However, monocytes and macrophages also take up intestinally-derived plasma chylomicrons, which contain apoB48, and hepatically-derived very low density lipoprotein (apoB-100). Zilversmit and colleagues demonstrated extrahepatic uptake of xcx9c40% of chylomicrons in rabbits (Ross, 1977) that was decreased by inhibition of the reticuloendothelial system (Nagata, 1987). Furthermore, studies in marmosets (a primate) and rabbits demonstrated substantial uptake (20-40% of total) of chylomicrons in vivo by accessible, peripheral macrophages, particularly in bone marrow (both animals) and spleen (marmosets) (Hussain, 1989a, 1989b). This would suggest that triglyceride-rich lipoproteins serve as a non-modified, native source of lipid for monocytes"" and macrophages"" nutrition in the normal state.
Triglyceride-rich lipoproteins are involved in the pathological conversion of monocytes and macrophages into foam cells in humans, a process seen in bone marrow, spleen, etc. in types 1, 3 and 5 hypertriglyceridemia (Fredrickson, 1978). Triglyceride-rich lipoproteins are also involved in formation of monocyte-macrophage-derived foam cells in eruptive xanthomas in untreated hypertriglyceridemic diabetic subjects. These foam cells contained triglyceride-rich lipoprotein core lipids, triglycerides and cholesteryl esters, following chylomicron uptake (Parker, 1970).
Chylomicrons and hypertriglyceridemic-very low density lipoproteins (including xcex2-very low density lipoproteins) are the only known native human lipoproteins, without modification, which directly cause rapid, receptor-mediated macrophage lipid accumulation in vitro, causing macrophages to resemble foam cells histologically (Gianturco, 1982b, 1986a, 1986b, 1988; Brown et al., 1983; Ostlund-Lindqvist, 1983; Bersot, 1986). The lipid that accumulates in macrophages after receptor-mediated uptake of a lipoprotein in vitro reflects the lipid composition of the lipoprotein (Gianturco, 1982b; Brown et al., 1983). Therefore, as seen in vivo, triglyceride is the predominant lipid which accumulates initially in macrophages exposed to hypertriglyceridemic-very low density lipoproteins or chylomicrons, but cholesterol and cholesteryl esters also accumulate even in short term incubations (Gianturco, 1986a). Triglyceride-rich lipoproteins enter the arterial wall in animals (Nordesgaard, 1994) and in man (Rapp, 1994). Since one triglyceride-rich lipoprotein Sf greater than 100 contains 5 times or more cholesterol and cholesteryl esters than one low density lipoprotein (Shen, 1978), each triglyceride-rich lipoprotein that enters a monocyte, macrophage or the arterial wall is equivalent to 5 or more low density lipoprotein particles in terms of cholesterol delivery.
A number of plausible mechanisms for the above-described observations exist, many involving apoE. Very low density lipoproteins from hypertriglyceridemic subjects were first shown to be abnormal and potentially atherogenic in studies which showed that very low density lipoproteins from hypertriglyceridemic, but not from normal subjects, deliver cholesterol to cultured fibroblasts via the low density lipoprotein receptor (Gianturco, 1978). The abnormality in hypertriglyceridemic-very low density lipoproteins is primarily in the Sf greater than 60 subfraction which, in contrast to normal very low density lipoproteins fraction Sf greater than 60, contains extra apoE of an accessible conformation that specifically binds to the low density lipoprotein receptor; apoB of Sf greater than 60 particles does not bind to the LDL receptor (Gianturco, 1982a, 1983; Bradley, 1984; Hui, 1984; Krul, 1985; Eisenberg 1988). ApoE also mediates triglyceride-rich lipoprotein binding to other widely-distributed receptors in the low density lipoprotein receptor gene family, such as the low density lipoprotein receptor-related protein/xcex12-macroglobulin receptor (Beisiegel, 1989; Kowal, 1989) and a very low density lipoprotein receptor expressed primarily in heart, muscle, and adipose (Takahashi, 1992). One of these could account for apoE-mediated very low density lipoprotein uptake observed in monocytes and macrophages (Wang-Iverson, 1985).
In contrast, apoB mediates the binding of low density lipoprotein (Goldstein, 1977), intermediate density lipoproteins (Sf12-20), and the predominant very low density lipoprotein in normal subjects, very low density lipoprotein3 (Sf20-60) (Bradley, 1984; Krul, 1985), the only very low density lipoprotein subclass from normal subjects that binds to the low density lipoprotein receptor of fibroblasts (Gianturco, 1980a, 1982a, Eisenberg, 1988) or of U937 monocytes (Sacks and Breslow, 1988). The domain of apoB that binds to the low density lipoprotein receptor is in the C-terminal portion not present in apoB-48 (Yang, 1986; Milne, 1989).
Lipolysis of normal very low density lipoprotein Sf greater than 60 permits binding of the lipolytic remnant to the low density lipoprotein receptor (Catapano, 1979; Schonfeld, 1979). Lipoprotein lipase secreted by macrophages (Khoo, 1981) hydrolyzes very low density lipoproteins and enhances its cellular uptake (Lindquist, 1983). This facilitation may occur through localization of triglyceride-rich lipoproteins to membrane heparin sulfate proteoglycan (Eisenberg, 1992) and/or through binding to low density lipoprotein receptor-related protein (Beisiegel, 1991).
The substantial and rapid uptake of triglyceride-rich chylomicrons in vivo by bone marrow and spleen macrophages in marmosets and rabbits was not accelerated by infusion of apoE (Hussain, 1989a). This is surprising, since apoE is a necessary ligand for the uptake of large triglyceride-rich lipoproteins by members of the low density lipoprotein receptor gene family. Indeed, infused apoE diverted much of the uptake from the peripheral macrophages to the liver, suggesting that the observed peripheral macrophage chylomicron uptake was not mediated by apoE and that these macrophages have an apoE-independent uptake mechanism. The rate and magnitude of triglyceride-rich chylomicron uptake by bone marrow monocytes and macrophages (20-40% of chylomicrons cleared from the plasma at 20 minutes (Hussain, 1989a)) suggests this uptake is receptor mediated. Rapid, receptor-mediated delivery of intestinally-derived, triglyceride-enriched chylomicrons may be necessary to assure delivery of sufficient energy and fat-soluble vitamins and other essential compounds to sustain hematopoiesis. In addition, and in contrast to inactivation of the apoE gene, loss of apoB by homologous recombination caused embryonic lethality in the homozygous state. ApoB is normally expressed early in yolk sak visceral endodermal cells for the synthesis of apoB-containing lipoprotein which are apparently necessary for the transport of lipids and lipid-soluble vitamins to embryonic tissues.
Moreover, homologous recombinant (xe2x80x9cknockoutxe2x80x9d) mice that completely lack apoE accumulate very low density lipoprotein and chylomicron remnants in their plasma (Plump, 1992; Zhang, 1992). These mice develop atherosclerosis that is accelerated by high fat diets. The lesions are characterized by monocyte-macrophage-derived foam cells, as in human lesions, demonstrating unequivocally that apoE is not necessary for the conversion of monocytes and macrophages into foam cells in vivo (Nakashima, 1994; Reddick, 1994). Taken together, these in vivo studies suggest strongly the existence of an apoE-independent pathway for the uptake of triglyceride-rich lipoproteins by monocytes and macrophages, which would result in foam cell formation in hypertriglyceridemia.
In vitro evidence for an apoE- and lipoprotein lipase-independent, apoB-mediated triglyceride-rich lipoprotein receptor pathway in murine macrophages has been reported (Gianturco, 1988). Because of the potential importance of an apoE-independent, receptor-mediated pathway for triglyceride-rich lipoproteins in the formation of foam cells in human pathology, particularly in hypertriglyceridemic subjects, the human monocyte-macrophage receptor from the monocytic cell line THP-1 was characterized and purified and receptor-specific antibodies were produced. Briefly, this unique apoE- and lipoprotein lipase-independent pathway and binding site is in murine macrophages, human monocytes and macrophages, and in the human monocytic cell lines THP-1 and U937, but not in human fibroblasts or hepatoma cell lines or in Chinese hamster ovary (CHO) cells (Gianturco, 1988, 1994a). Further, ligand blotting studies in bovine and porcine aortic endothelial cells also were positive. Thus, endothelial cells specifically bound chylomicrons followed by hydrolysis and uptake of their cholesteryl esters (Fielding, 1978) and very low density lipoproteins from hypertriglyceridemic subjects, but not from normal subjects, delivered cholesterol to cultured endothelial cells (Gianturco, 1980).
Since the apoE-independent and lipoprotein lipase-independent receptor also binds xcex2-very low density lipoproteins, but with lower affinity, it was once referred to as a xcex2-very low density lipoprotein receptor (Goldstein, 1980; Gianturco, 1986a). Subsequent studies, however, demonstrated that uptake of triglyceride-rich lipoproteins independent of apoE was not inhibited by anti-low density lipoprotein receptor antibodies that inhibited the low density lipoprotein receptor-mediated uptake of rabbit xcex2-very low density lipoproteins in the same cells, nor did anti-low density lipoprotein receptor antibodies bind to the candidate receptor (Gianturco, 1988). The apoE-independent receptor differs from the low density lipoprotein receptor family or the scavenger receptor family in many properties including (1) unchanged expression during differentiation, (2) slower intracellular ligand degradation, (3) ligand specificity, (4) apparent molecular weight of the candidate receptors, and (5) cellular distribution.
The prior art is deficient in the lack of the sequence of the DNA encoding for the monocyte-macrophage apoB receptor gene and protein, in the genomic structure and chromosomal localization and in the understanding of its expression in the placenta, human coronary, carotid, and aortic macrophage-derived foam cells in atherosclerotic lesions and in other immune tissues including peripheral blood leukocytes, bone marrow, spleen, tonsils and appendix. The present invention fulfills this longstanding need and desire in the art.
Monocyte-macrophage-derived foam cells accumulate in atherosclerotic lesions and throughout the body in some types of hypertriglyceridemia. Uptake of plasma chylomicrons and hypertriglyceridemic triglyceride-rich lipoproteins by an apoE-independent human monocyte and macrophage receptor, distinct from previously-described lipoprotein receptors, may be involved in foam cell formation in vivo. Two cell-surface membrane binding proteins (MBPs) of xcx9c200 and xcx9c235 kDa, in human monocytes and macrophages and THP-1 monocytes and macrophages, were characterized as the likely receptors. It was determined that both MBPs share a common xcx9c200 kDa ligand binding subunit. This ligand-binding subunit was purified and internal tryptic peptide sequences were obtained. Receptor-specific antipeptide antibodies were generated against a 10-residue unique and unambiguous internal sequence (to which no matches were found in GenBank, Swiss Pro, etc) that binds the active receptor forms MBP200, MBP200R and MBP235. Antibodies against the C-terminal xcx9c47 kDa receptor domain and other domains were produced and shown to bind to all active forms of the receptor. Overlapping partial cDNAs from a xcexgt10 THP-1 library and from a xcexgt10 human placental library corresponding to the receptor were obtained and sequenced.
The present invention shows that cell-surface MBP200 and MBP235 are unique monocyte, macrophage, placental and endothelial cell receptors for apoB in plasma chylomicrons and some hypertriglyceridemic-triglyceride-rich lipoproteins and their remnants; other apoB-containing lipoproteins also bind to the receptor with varying, generally much lower, affinities. The present invention also shows that said receptors bind to apoB-48 and to the N-terminal portion of apoB-100 at or near the lipoprotein lipase binding site and not in a heparin-binding domain. Normally, the MBPs may be involved in nutrition of circulating monocytes and accessible, peripheral macrophages, e.g. bone marrow; in lipemic states, the pathway can be overwhelmed and contribute to foam cell formation and endothelial cell dysfunction. Therefore, diminished triglyceride-rich lipoprotein uptake by this receptor, due either to receptor defects or to triglyceride-rich lipoprotein defects leading to altered receptor affinity, may be involved with metabolic abnormalities associated with increased risk for cardiovascular disease, such as modest hypertriglyceridemia and small, dense low density lipoproteins (pattern B) and/or persistence of chylomicron-derived, (i.e., apoB-48-containing) lipoproteins in the fasting state. Diminished activity of the receptor in the placenta could result in fetal abnormalities due to reduced delivery of dietary fat-soluble vitamins (A, E, D) and essential fatty acids and other essential nutrients that are carried in chylomicrons.
To clone the cDNA for MBP200R, PCR with degenerate primers were used and a THP-1 xcexgt10 cDNA library to produce a 631 bp product (pcr631) (SEQ ID No. 3) which contains three peptide sequences found in amino acid sequence from MBP200R. pcr631 was used to identify several distinct cDNA clones. One clone, THP-1 xcex73-3 (SEQ ID No. 9), contains an 1851 bp insert with a 1381 bp open reading frame (ORF) and 470 bp untranslated region including the stop codon, the polyadenylation signal and the poly-A tail. PCR on a 5xe2x80x2 stretch human placenta xcexgt10 cDNA library using antisense primers derived from the 5xe2x80x2 end of THP-1 xcex73-3 resulted in a 1466 bp clone with an open reading frame that overlapped the open reading frame of THP-1 xcex73-3 (pcr1466) (SEQ ID No. 8) resulting in a 3071 bp sequence with a 2601 bp open reading frame. Glutathione-S-transferase fusion proteins were expressed using the pcr631, THP-1 xcex73-3, and pcr1466 pGEX constructs. Polyclonal antibodies were produced to each protein domain. Immunoblots demonstrate that the antibodies specifically recognize the GST-fusion products and all receptor activities (MBP200, MBP235 and MBP200R). Additional 5xe2x80x2 sequence obtained by PCR of the human placenta xcexgt10 cDNA library with antisense primers from the 5xe2x80x2 end of pcr1466 resulted in a 751 bp clone (pcr751) (SEQ ID No. 7) that contained a 10 bp untranslated 5xe2x80x2 end, a Kozak consensus start sequence and the initial ATG start codon. The sequences obtained from multiple clones from THP-1 monocyte genomic DNA and the cDNA library result in 3744 bases of cDNA sequence (SEQ ID No. 1) with an open reading frame of 3264 bp encoding a 1088 residue protein for the human monocyte apoB48 receptor. Northern analysis of THP-1s, human placenta, bone marrow, peripheral blood leukocytes, spleen, tonsils, appendix, and lymph node reveal a messenger RNA of approximately 3.8 kb, indicating the complete cDNA sequence has been determined. A full-length cDNA was constructed in a pCDNA vector. Chinese hamster ovary (CHO) cells transfected with the vector containing the receptor cDNA, in contrast to the pCDNA vector alone, expressed full receptor activity as determined by rapid, high affinity binding and uptake of fluorescent DiI-labeled trypsinized VLDL and, in stably transfected CHOs, by rapid cellular triglyceride mass accumulation and by the rapid (xcx9c1.5 hour) accumulation of cytoplasmic lipid droplets visualized by light microscopy after staining with the neutral lipid Oil Red 0, after incubation with chylomicrons containing apoB48 as the B species, HTG-VLDL and tryp VLDL but not with normal VLDL or LDL.
One object of the present invention is to provide an isolated DNA molecule encoding a monocyte-macrophage cell surface apoB48R binding protein selected from the group consisting of: (a) a DNA molecule comprising a sequence SEQ ID No. 1 and which encodes the monocyte-macrophage cell surface apoB48R binding protein (the apoB receptor) (SEQ ID No. 2) or a portion of the monocyte-macrophage cell surface apoB48R binding protein; and (b) a DNA molecule differing from the DNA molecule of (a) in codon sequence due to the degeneracy of the genetic code, and which encodes the monocyte-macrophage cell surface apoB48R binding protein (SEQ ID No. 2) or a portion of the monocyte-macrophage cell surface apoB48R binding protein. Embodiments of this object of the invention include provisions for a vector containing the isolated DNA molecule encoding a monocyte-macrophage cell surface apoB48R binding protein and regulatory elements necessary for expression of said isolated DNA molecule in a cell, the vector adapted for expression in a recombinant cell, as well as a host cell containing the vector.
An additional object of the present invention is to provide a vector comprising an isolated DNA for a monocyte-macrophage cell surface apoB48R GST fusion binding protein having the sequence SEQ ID No. 2 or portions thereof.
A further object of the present invention is to provide a method of cell-specific delivery of therapeutic compounds to human monocytes, macrophages, other reticuloendothelial cells that express the receptor or embryos comprising the steps of: providing a peptide or antibody(s) having the ability to bind to an isolated monocyte-macrophage cell surface apoB48R binding protein having the sequence SEQ ID No.2, or a portion of said sequence or comprising a related protein of the same gene family; and incorporating the peptide into liposomes containing said therapeutic compound. Yet another method of cell-specific delivery may utilize a receptor-specific antibody or an antibody fragment (Fab) that binds to an isolated monocyte-macrophage cell surface apoB48R binding protein having the sequence SEQ ID No.2, or a portion of the sequence, or comprising a related protein of the same gene family; and incorporating the antibody into liposomes.
Yet another object of the present invention is to provide a method of inhibiting foam cell formation and increased monocyte adhesion to endothelial cells, comprising the step of treating a monocyte-macrophage with an agent which binds an isolated monocyte-macrophage cell surface apoB48 receptor protein having the sequence SEQ ID No.2, thereby blocking or inhibiting binding of apoB-containing lipoproteins to the receptor. Gene therapy such as adenoviral delivery of the receptor proteins of the present invention to LDL-receptor deficient subjects is also contemplated.
Another object of the present invention is to provide delivery of the novel sequences disclosed herein, e.g., in an adenoviral vector, to the liver or elsewhere, for the purpose of correcting metabolic defects that cause abnormal accumulation of apoB-containing lipoproteins in the plasma.
Yet another object of the present invention is to provide a method of evaluating an individual at risk for cardiovascular disease, comprising the steps of: (a) extracting a sample of monocytes-macrophages and triglyceride-rich lipoproteins from the plasma of the individual and from a control individual not considered at risk for cardiovascular disease; and (b) comparing the binding affinity (Kd) of the apoB receptor of the monocytes-macrophages for triglyceride-rich lipoproteins between the individual at risk and the control individual, whereby a difference in the binding affinity between the individual at risk and the control individual is indicative of an alteration in either or both the apoB cell-surface receptor protein and triglyceride-rich lipoproteins, and the alteration in the apoB cell-surface receptor protein or triglyceride-rich lipoproteins is indicative of dyslipidemias, abnormal postprandial triglyceride metabolism or Pattern B phenotype in the individual at risk. Alternatively, one may compare the rapid, receptor mediated monocyte-macrophage lipid accumulation induced by standardized tryp VLDL vs. normal TGRLP vs the patients TGRLP by quantifying lipid mass changes and by Oil Red 0 staining.
This objective may also be accomplished by performing a Western blot analysis on proteins of the monocytes-macrophages using an antibody directed towards the protein of SEQ ID No. 2, or fragments thereof, or alternatively performing a Northern blot analysis on RNAs of the monocytes-macrophages using a DNA probe selected from the group consisting of SEQ ID No. 1, SEQ ID No. 3, SEQ ID No. 7, SEQ ID No. 8 and SEQ ID No. 9, or fragments thereof, whereby a difference in the migration or mobility of the proteins and/or RNAs between the individual at risk and the control individual is indicative of an alteration in the apoB cell-surface receptor protein, and the alteration in the apoB cell-surface receptor protein is indicative of dyslipidemias, abnormal postprandial triglyceride metabolism or Pattern B phenotype in the individual at risk.
As atherosclerotic plaques are enriched with ApoB48-receptor expressing cells, the instant invention may also be directed toward delivery of therapeutic agents to atherosclerotic plaques. These agents may include label to localize said plaques, inhibitors of apoB48 receptor to inhibit further development of the plaques, or agents designed to eliminate the plaques.

DNA encoding human apoB48R: a monocyte-macrophage apolipoprotein B48 receptor gene and protein


Disclosed is a control device for a 3D printer, which controls the 3D printer including a supply unit for supplying a forming material and a degradable agent, and a printing unit for printing a 3D object. The control device includes a display unit and a controller. The display unit outputs screen information for setting a use period of the 3D object. The controller controls the addition amount of the degradable agent, based on the set use period.

1. Field of the Invention
The present disclosure relates to a control device for a three-dimensional (3D) printer outputting digitized 3D products.
2. Description of the Conventional Art
In general, a 3D printer uses a printing technique of producing a 3D object by stacking consecutive layers of a material. The 3D printer can quickly produce a 3D object, based on user's desired 2D information, and thus is applied to production of a prototype sample, and the like.
The technique of the 3D printer includes a modeling process of forming a design drawing of a 3D object, a printing process of actually producing the object by stacking a material, and a treating process of hardening or surface-treating the printed object. A method of implementing the 3D printer according to the printing process may be generally divided into a method of stacking the material by irradiating an ultraviolet (UV) laser onto a liquid material film and curing the liquid material film, a method of stacking the material by dropping material ink using an ink-jet head and curing the material ink, and a method of staking the material by irradiating a UV beam onto a material layer in a desired pattern using a projector and curing the material layer. The implementation method of the 3D printer may be divided into a method using liquid, a method using powder, a method using solid, and the like.
Various shapes desired by users can be freely printed by 3D printers, and thus the 3D printers can be variously applied to manufacturing, medical and IT fields.
Accordingly, the use of disposable products printed by the 3D printers is generalized, and therefore, environmental pollution caused by an increase in waste with respect to objects easily printed by the 3D printers increases.
In addition, food formed with edible materials by the 3D printers may be produced, and accordingly, people's health may be threatened.


Embodiments disclosed herein provide systems and methods for processing events using existing computer event capture modules. In a particular embodiment, a method provides a primary event module communicating with an operating system to detect application events generated by user input and processing the application events to determine if a primary event has occurred. The method further provides a secondary event module communicating with the primary event module to obtain an indication of the application events detected by the primary event module and processing the application events to determine if a secondary event has occurred.

Entities such as businesses, educational institutions, and individuals use computers routinely to accomplish tasks. The tasks can vary widely depending on the user and what the user needs to perform. Usually the tasks are accomplished using various computer applications that may each be used in various ways. Thus, there may be more than one way for a user to accomplish a task using the applications on the computer of the user. Having multiple ways of accomplishing tasks may make it difficult to track the activity of the user or may also make it difficult for the user to determine whether the user is accomplishing the task appropriately.

Event processing using existing computer event capture modules


A connector for connecting wooden beams to one another, in which the capacities of a conventional toothed plate to transfer tensile and compressive forces have been improved by securing one or several toothed plates (3, 4, 5) to a mutual frame plate (2).

It is previously known to use various types of toothed plates for interconnecting wooden beams. Such a plate is known from, for example, U.S. Pat. No. 2 606 666. The "teeth", i.e. the protrusions serving as nails in the toothed plate, are in such devices produced by punching out and bending arrow-shaped protrusions in the plate. This procedure limits the thickness of the plate used. With steel plates over about 2 mm thick it is very difficult to produce in a simple way the punches and bendings referred to. The disadvantage of this toothed plate is thus its poor capacity to transfer high tensile, compressive and shear forces. In the device according to U.S. Pat. No. 3,498,170, the toothed plate produced thus by punching is reinforced by placing on the tooth-side of the plate a separate perforated plate which supports the teeth. The reinforcing effect of this separate additional plate does not, however, correspond to, for example, the increased weight, and the structure requires a very high manufacturing precision in order to work at all.
In order to solve the above-mentioned problem, a new connector is disclosed in, for example, Finnish Patent Application No. 833 655, the connector having a very thick steel plate to which a large number of teeth have been secured by, for example, welding. By this solution it is possible to produce a joint capable of transferring very high forces. This solution has, however, a disadvantage in its relatively expensive manufacturing method. Also the connector is very heavy and the material costs are high.

Connector for connecting wooden beams to one another


The present disclosure provides a display panel including a display area and a non-display area, a base substrate, a plurality of thin film transistors, a plurality of touch signal lines, a first test signal line area, an array substrate row driving circuit, a second test signal line area, a ground line area and an insulating layer. The thin film transistor includes a gate, a gate insulating layer, a source and a drain. The non-display area includes a first side and a second side; the array substrate row driving circuit respectively forms a first gap and a second gap with the first test signal line area and the second test signal line area, an orthographic projection of the ground line area on the base substrate is in the projection of the second test signal line area in the base substrate. The present disclosure also provides a display device.

In the current field of lighting and display, due to the high mobility of low-temperature polysilicon (LTPS), more and more research has been widely used to develop the lighting products and the panel industry to meet the needs of the industry of ultra-narrow bezel.
For ultra-narrow bezel display panels, antistatic striking capability is an important factor in the quality of display panels. In the current display panel industry, mainly by adding a circle around the panel ground line, the driving signal is wrapped in the loop surrounded by a loop inside, in the antistatic test on the panel, the static discharge will be released by the ground line loop. However, because of the antistatic striking capability and the distance from the panel to the ground line, the width of the ground line and the distance between the ground line and the signal are proportional, the design of the ultra-narrow bezel will result in a narrower width of the three, so that greatly reduces the antistatic striking capability of the panel.

WUHAN CHINA STAR OPTOELECTRONICS TECHNOLOGY CO., LTD.


The present invention describes a method of treating restless leg syndrome by eliminating venous reflux in an underlying vein. The malfunctioning vein can be removed or ablated by inserting a catheter into the vein that transmits sufficient energy to coagulate or ablate the lining of the vein causing it to permanently close, eliminating the source of venous reflux and the symptom of restless leg syndrome.

RLS is a poorly understood disorder in which patients experience compelling urges to move the legs usually accompanied by intense, unpleasant sensations in their legs. RLS affects 5-15% of the American and European populations. RLS affects the general population with a mean age at onset of 27.2 years. Onset of RLS is often before age 20 in 38.3% of patients. Women are twice as likely to be affected. The earliest description of an RLS case was by English physician and anatomist Sir Thomas Willis in 1672. RLS lingered in anonymity until 1944, when Swedish neurologist Karl Ekbom first described the salient features. In 1945 he coined the phrase "restless legs". The addition of the word "syndrome" designates this malady as a condition defined by clinical symptoms rather than by any specific pathological process.
Most patients find they cannot describe the nature of their sensations. It is frequently unrecognized or misdiagnosed and therefore widely undertreated. Dr. Ekbom felt that "this is evidently due to the fact that the sensations do not resemble any known phenomenon that can be used as a comparison." They are variably described as heebie-jeebies, antsy, Jimmy legs, or as creeping-crawling, pulling, drawing, boring, wormy, etc. The sensations are painful in about 30% of patients. Patients experience intense unpleasant sensations deep in the legs that are accompanied by an irresistible urge to move the affected limbs. The sensations are usually located in the calf area, but may be felt anywhere from the ankles to the thighs. The arms are rarely involved.
There is a wide variation in severity with some patients experiencing only occasional mild symptoms, while others struggle with disabling episodes on a nightly basis. Symptoms of RLS are worse in the evening and during periods of relaxation or decreased activity, especially while lying down or reclining. Patients are often completely asymptomatic in the morning. The reason for this is unknown. The desire to relieve the symptoms can lead to a compulsion involving excessive limb movements. The sensations and the compulsion to relieve them frequently become terribly distressing. As RLS symptoms are stronger at bedtime, sleep-onset insomnia is common. RLS sufferers often find they cannot sleep until the early morning hours. Patients with severe RLS experience nightly attacks that lead to chronic sleep-deprivation with its accompanying psychological and cognitive deficits.
Investigators have made great strides in the understanding and treatment of RLS over the last two decades, to the nightly relief of millions of victims. The etiology of RLS remains elusive, however, and a final common pathway has yet to be described. According to Dr M. J. Thorpy, primary RLS "may represent a heterogeneous group of disorders because no single pathophysiologic mechanism explains all the clinical features exhibited."
There are no classic physical findings, no conclusive blood assays, and no standard radiological or sleep studies to diagnose RLS. Because there is no known biomarker, the diagnosis of RLS can only be made based on clinical history. In an attempt to more clearly define RLS, the IRLSSG developed RLS diagnostic criteria in 1995. An IRLSSG consensus panel at the National Institutes of Health (NIH) modified these criteria to their present form in 2003. These four criteria are necessary and sufficient for the diagnosis of RLS. They include: 1) Urges to move the limbs with or without unpleasant sensations, 2) worsening of symptoms at rest, 3) improvement of symptoms with movement, and 4) worsening of symptoms at night. The IRLS questionnaire (FIG. 1) was developed by the IRLSSG and validated in 2003 as a consistent, reliable tool to objectively measure RLS severity.
RLS is divided into primary (idiopathic) and secondary causes. Primary RLS is felt to be the most common form and is suspected to be a sensorimotor abnormality associated with central nervous system dysfunction involving abnormal brain iron metabolism and irregularity of central dopaminergic neurotransmitter pathways. Primary RLS likely represents a heterogenous group because no single pathophysiologic mechanism explains all the clinical features exhibited. Secondary RLS occurs in such disparate conditions as back pain, iron deficiency, renal failure, pregnancy, neuropathy, and venous disease. Various medications are known to precipitate RLS attacks. The fact that RLS is a "mixed bag" diagnosis has complicated research, confounded investigators, and frustrated clinicians; in that various medications work in only a percentage of affected patients. Current treatment therefore focuses on nightly management of symptoms rather than on cure.
In 1995, Dr. A. H. Kanter's groundbreaking study suggested that sclerotherapy in patients with varicose veins and RLS is 98% effective in initial relief of RLS. This is the first article to describe operative treatment of RLS. Dr Kanter concluded that all RLS patients with varicose veins should be considered for phlebological evaluation and possible treatment before being consigned to chronic drug therapy.
Secondary RLS is known to occur in and is secondary to such disparate conditions as iron deficiency, renal failure, pregnancy, neuropathy, and venous insufficiency. Various medications are known to exacerbate existing RLS, even precipitate RLS, and other causes are likely.
Because RLS is a "mixed bag" diagnosis, research investigators have been confounded when treatments only work on a portion of the test subjects. Treatment of the secondary causes of RLS can frequently cure patients of this distressing malady. Because venous insufficiency is a secondary cause, treatment of this cause may cure the patient of RLS.
Venous insufficiency is quite common, affecting 10-15% of adult men and 20-25% of adult women. Duplex ultrasound studies reveal that saphenous vein reflux is the most common form of venous insufficiency and is the underlying condition in most patients suffering with varicose veins. Sclerotherapy in patients with varicose veins and RLS has been shown to be 98% effective in initial relief of RLS with recurrence rate of 8% and 28% at one and two years, respectively. Sclerotherapy is not a very effective treatment for varicose veins. While effective for tiny surface veins, the injection of liquid sclerosant into the large veins responsible for venous insufficiency has a low success rate. This method requires multiple injections, can be very painful, and the veins often reopen in a few years requiring, continual treatments. Most RLS patients are not willing to undergo this therapy. Although prior art consists of drug therapy and occasionally the use of compression stockings, surgery in the form of vein stripping has also not been considered a treatment for this condition because of the significant morbidity associated with the procedure. This invention discloses the use of a new minimally invasive treatment for venous insufficiency that is benign enough to be considered as a treatment and a cure for RLS with a significantly improved benefit to cost ratio.
Varicose veins have been treated in a similar manner except that the clinical symptoms of varicose veins are much more evident. Bulging veins, ulcers, pain and leg tiredness are all symptoms of varicose vein disease. This invention also relates to otherwise healthy legs that do not necessarily show these symptoms but rather an early stage of venous disease that causes RLS without bulging and painful varicose veins.
This connection between venous insufficiency and restless leg syndrome has been noted in the literature but the root cause of the disease and the connections to the venous system is not obvious. It was only through anecdotal comments by patients who had restless leg syndrome and were also successfully treated for varicose veins that the connection became clear. The restless leg symptoms disappeared after treatment for varicose Veins. This invention takes this one step farther and claims that restless legs can be successfully treated even without the symptoms of varicose veins by eliminating venous reflux in a segment adjacent to the twitching or skin movement.
US Pub No. US20030176822A1, published Sep. 18, 2003 to Morganlander discloses a method of treating restless leg syndrome, the method comprising the steps of eliminating reflux from an underlying vein by applying pressure to the leg of the patient. However, it does not teach or anticipate a method of treating restless leg syndrome comprising the step of eliminating reflux from an underlying vein by closing the underlying leg vein permanently as described in present invention.
U.S. Pat. No. 6,797,259, issued Sep. 28, 2004 to Rabinowitz et al. also teaches a method and device to "for delivery of muscle relaxants through an inhalation route which are typically used for the treatment musculoskeletal pain or restless leg syndrome." However, the "applying energy, such as microwave or laser light" described in Rabinowitz et al. is for "the heating of the muscle relaxant compositions" in an inhalation device, not "to the treatment site". Applicant submits that Rabinowitz does not teach or anticipate a method of treating restless leg syndrome comprising the step of eliminating reflux from an underlying vein by closing the underlying leg vein permanently.

This patent is subject to a terminal disclaimer.


A laser diode stack includes a serially connected plurality of laser diode bars mounted on heat sinks. Connected in parallel with each laser diode is a respective safety diode which has a higher band gap than its associated laser diode. The safety diode remains nonconductive so long as the associated laser diode is operational. Should the laser diode fail in an open circuit condition, the respective safety diode responds to the open circuit voltage to restore continuity to the serially connected chan of laser diodes.

This invention relates to high power laser applications in which the required optical output power is greater than can be obtained from a single laser or laser bar as a consequence of which multiple laser devices must be assembled in stacks.
Certain applications in the printing and welding industries, for example, require high intensity, high power laser beams. To provide the requisite power it is the practice to make an electrical connection of the assemblage of laser diode bars in the stack so that they are in series with each other. For example, certain high power diode pumped solid state laser applications may require up to 100 diodes to be connected in series in one cavity and up to 8 cavities may be needed. The typical current through a laser diode in a stack is 60A at a forward voltage of 1.8V. While such a stack assemblage permits the desired optical output power to be achieved, there is a problem should the heat incidentally generated in the stack cause any of the solder connections to melt. The resulting open circuit interrupts current to the laser stack and shuts down the laser""s optical output. The shut down of the optical output power is at least inconvenient to the user and also may have more serious consequences in ruining the product being operated upon.
U.S. Pat. No. 5,550,852 has heretofore shown that it can be advantageous to connect a reverse laser diode in parallel with each operative laser diode to provide a path for reverse currents which may occur during testing, power-up, etc., that otherwise would be damaging to the active laser diode. In the ""852 patent the reverse diode has electrical properties similar to those of the operative laser diode so that the reverse diode and the active diode could be fabricated at the same time. While the reverse diode is therefore useful, it does not solve the problem of maintaining operational continuity of a laser bar stack should one of the series connected laser diodes fail in an open-circuit condition.
In accordance with the principles of the present invention a stack serially connected laser diodes is prevented from failing in operational continuity when one of the laser diodes fails in an open circuit condition by proving an individual safety diode for each diode in the stack connected in parallel with its corresponding laser diode. The safety diode is fabricated so that it exhibits a higher forward voltage (higher band gap) than its corresponding laser diode. Should the laser diode fail in an open circuit condition, the voltage impressed across the open circuit will rise since it is no longer shunted by the low resistance of the failed laser diode. The higher voltage is sufficient to allow the safety diode to take over the function of the failed laser diode thereby maintaining continuity of the current path through the serially connected laser diodes of the stack. Advantageously, the safety diode is mounted on the same heat sink as its companion laser diode so that it can receive efficient cooling when it is called into operation. The light output from the safety diode when it turns on in response to the failure of its associated laser diode may advantageously be used to provide a different color light to signal the status of the assembly of multiple diode lasers.


A ventilated enclosure comprising a substantially vertical side wall, a roof including at least one roof section, a ridge vent formed adjacent a portion of the roof section and side vent formed adjacent a portion of the substantially vertical side wall, a first elongated inflatable member disposed adjacent the ridge vent and a second elongated inflatable member disposed adjacent the side vent, the first and second elongated inflatable members each movable between a first and second position disposed in operative relationship relative to the ridge vent and side vent respectively to selectively control air flow through the ridge vent and side vent respectively and to permit air circulation through the ventilated enclosure when the first and second elongated inflatable members are each in the first position and to seal the ridge vent and side vent respectively when the first and second elongated inflatable members are each in the second position.

1. Field of the Invention
A ventilated enclosure including a first and second elongated inflatable member each movable between a first and second position to selectively seal a ridge vent and side vent or vents respectively to control air circulation through the ventilated enclosure.
2. Description of the Prior Art
Numerous efforts have been undertaken to provide greenhouse or enclosure construction with selective venting and circulation therethrough to control humidity and temperature within the greenhouse or enclosure.
It is common to ventilate a greenhouse or enclosure with a ridge opening in combination with side wall openings to provide air flow using shutters or other closure means to control air flow through the greenhouse or enclosure.
U.S. Pat. No. 4,399,738 discloses a ventilation means including an elongated tubular inflatable member disposed adjacent a ridge vent extending along the ridge of the enclosure and a side vent along extending the side wall of the enclosure having an elongated tubular inflatable member disposed adjacent thereto such that the elonfated tubular inflatable members when deflated permit circulation of air through the side vent and ridge vent and the elongated tubular inflatable members seal the ridge and side vents when inflated.
U.S. Pat. No. 4,438,680 shows an enclosure comprises a glazing structure and blazing bars including a ridge to support the glazing structure. The ridge includes vents opening into the enclosure defined by the glazing structure and into the ambient atmosphere. A blower exhausts air from the enclosure into the ambient atmosphere.
U.S. Pat. No. 3,791,076 shows means for affixing or securing a flexible membrane to a tubular section.
United Kingdom 1,250,065 discloses a ventilating apparatus including a pair of solid rollers disposed at opposite ends of the roof line to seal vents formed therein in cooperation with corresponding pairs of substantially flat surfaces.
Japanese 84,944 teaches overlapping spaced roof sections.
U.S. Pat. No. 1,070,434 disclosed a greenhouse with sash bars extending from the lower edge of one side of the roof to the peak of the roof and thence to the lower edge of the other side of the roof.
U.S. Pat. No. 3,401,621 shows the venting of an interior structure by means of a blower mounted near the ridge line of the structure.
U.S. Pat. No. 3,063,191 discloses an artificially climatized greenhouse including a ridge ventilation. Similarly, U.S. Pat. No. 3,562,972 shows a greenhouse construction for environmental or climate control.
Additional examples of similar construction are shown in U.S. Pat. Nos. 2,046,600; 3,274,730; 3,874,114; 3,063,195; 3,777,425; 4,027,437; 4,055,030; 4,141,798; 4,196,544; 4,216,618; 4,262,656; 4,283,889; 4,301,626; 4,316,405; 4,318,251; 4,352,259; 4,366,646; 4,387,533; 4,452,230; 4,470,405; 4,505,066; 4,510,921; 4,515,150; 4,565,230; 4,567,732; and 4,569,150.


Embodiments of the instant invention are directed to a system, apparatus and method for monitoring a user""s activities and displaying and presenting unsolicited content to users over a wide area network. Embodiments of the instant invention include a monitoring system comprising an activity monitor and a content transfer and display means, wherein the activity monitor comprises an event identifier and a timer. The monitoring system monitors user activities, identifies trigger events, measures the elapsed time of inactivity of the user and initiates the presentation of unsolicited data, or content, to the user computer. In general, the monitoring system identifies trigger events and measures the elapsed time between trigger events. If the elapsed time between the trigger events exceeds a predefined time period the monitoring system causes unsolicited data to be presented on the user computer.

This invention is directed to a system, apparatus and method for monitoring a user""s activities, and displaying content to the users on a wide area network with minimal disruption in the user""s activity. More specifically, embodiments of the invention direct and display content to users on inactive windows so as to reduce disruption of the user""s activities.
Wide area networks, such as the World Wide Web (xe2x80x9cWWWxe2x80x9d) or the Internet, have become increasingly popular modalities for the advertisement of products or to present unsolicited content to users. Indeed, much like broadcast medium, for example, radio and television, advertisers sponsor content in exchange for the right to present unsolicited content to users, such as, for example, an advertisement. Indeed, advertisers sponsor most of the content on the WWW. The sponsorship provided by the advertiser supports the host providers and facilitates free hosting for individual users.
In exchange for free content support, and therefore, free hosting of individual web sites, advertisers desire to display their advertisements as frequently as possible. Current advertising on the WWW is typically in the form of a small banner or a pop-up window. The banner advertisements are usually placed at the top or bottom of the page. The banner itself is usually insufficient in its advertising message to the consumer. As such, to review the banner advertisement, the user must click on the banner and load the advertisement.
The pop-up window is another form of advertisement. Pop-up advertisements open when a new browser window is opened, wherein the pop-up advertisement appears in front of the user""s primary window. As with the banner advertisements, the user must click on the advertisement to view the advertisement.
As evinced above, current advertisement methods require some affirmative action on from the user. Further, current advertising methods are intrusive and interrupt the user""s activities. Indeed, unlike broadcast medium, wherein the advertisements are placed in between the content of the main programming, advertisements on the WWW, which can be displayed at any time, are usually displayed over, or with, the content that the user is viewing, and require affirmative action by the user. As most users do not desire to be interrupted in their activities, most users avoid reviewing the advertisements. Indeed, some users avoid sites with highly intrusive advertisements.
A need in the industry exists for a modality of presenting unsolicited content to users wherein the user is not required to affirmatively respond to view the content. A further need exists for a modality of displaying unsolicited content wherein the presentation of the content does not interrupt the user""s activities, but rather, occurs during a disruption in the user""s review of desired content.
Embodiments of the instant invention are directed to a system, apparatus and method for monitoring a user""s activities and displaying and presenting unsolicited content to users, wherein the user is not required to affirmatively respond in order to review the content. Furthermore, embodiments of the instant invention are directed to a method for presenting unsolicited content such that the presentation of the content does not disrupt the user""s review of other content that the user has chosen to review. Other method and apparatus for accomplishing similar objectives are disclosed in the co-pending application Ser. No. 09/419,698, filed by the inventor hereof on Oct. 14, 1999, which is incorporated herein by reference.
Embodiments of the instant invention include a monitoring system 30 comprising an activity monitor 32 and a content transfer and display means 34, wherein the activity monitor 30 comprises an event identifier 36 and a timer 38. The monitoring system 30 monitors user activities, identifies trigger events, measures the elapsed time of inactivity of the user and initiates the presentation of unsolicited data, or content, to the user computer 12. In general, the monitoring system 30 identifies trigger events and measures the elapsed time between trigger events. If the elapsed time between the trigger events exceeds a predefined time period the monitoring system 30 causes unsolicited data to be presented on the user computer 12.
A feature of preferred embodiments of the invention is an activity monitor. An advantage to this feature is that the activity of the user can be monitored to determine whether the user has suspended his activities. A further advantage of this feature is that the user can be presented with unsolicited content during the period of suspended activities.
Another feature of preferred embodiments of this invention is that the unsolicited data is presented in its full format to the user. An advantage to this feature is that the user is not required to affirmatively access the data to review the data.

System, apparatus and method for presenting and displaying content on a wide area network


This invention comprises a prosthetic implant having a metal base with a layer of metallic wire screen bonded to the upper surface of the base, and further having a polyethylene portion molded about the upper surface of the base. The polyethylene portion penetrates the porous openings in the screen to enhance the securement of the polyethylene portion to the base. The screen is fully encapsulated between the metal base and the polyethylene portion. The base further includes a plurality of notches spaced around the peripheral edge. The screen layer overhangs over at least a portion of the notches. In addition, the lower surface of the base includes a porous metallic layer providing an exposed porous surface. The construction of the screen layer on the upper surface of the base is different from the construction of the porous layer on the lower surface.

The present invention relates to a prosthetic implant device, and more particularly to such implants which include a polyethylene portion secured to a metal base. This invention is particularly suitable for use as a patellar prosthesis or a tibial prosthesis although it is not limited thereto.
Heretofore, various means have been used to provide secure attachment of a polyethylene implant portion to a metal base. U.S. Pat. No. 4,501,031 to McDaniel et al. discloses a metal base which includes notches about its peripheral edge to help secure a plastic bearing portion via molding to the base. U.S. Pat. No. 4,205,400 discloses a metal base which includes tapered holes therethrough which diverge away from the upper surface and a plastic bearing portion molded to the base and through the tapered holes to secure the plastic to the metal U.S. Pat. No. 3,506,982 includes a metal anchor 3 fixed into the plastic portion 4.
In addition, a metal-backed polyethylene patella known as the AMK Patella (described in a Depuy ad.RTM. in the July 1989 JBJS, p.68) utilizes a Porocoat porous coating on the upper surface of the metal base between the plastic and metal to lock the poly surface to the metal backing. This component also uses the Porocoat porous coating on the lower exposed surface of the base. The Porocoat coating consists of a plurality of small ball-shaped metallic particles as described by U.S. Pat. No. 3,855,638 to Pilliar.
The utilization of various porous materials to select exposed or outer surfaces of implants is well known to enhance to fixation of such outer surfaces to bone for bony ingrowth or, if a bone cement material is used for fixation, to more securely fix such outer surfaces to the bone cement. Other examples of various porous materials utilized on select outer surfaces of metal or poly implants are disclosed in U.S. Pat. Nos. 3,605,123 to Hahn; U.S. Pat. No. 3,906,550 to Rostoker et al.; U.S. Pat. No. 4,454,612 to McDaniel et al; U.S. Pat. No. 4,589,883 to Kenna; and 4,636,219 to Pratt et al. In addition, U.S. Pat. No. 4,479,271 to Bolesky et al. discloses a bottom base layer of porous fiber metal material, an intermediate metal reinforcing layer including at least one opening therein, and a top non-metal surface (such as polyethylene) which is molded to the base layer. The portion of the top polyethylene layer that is in contact with the base layer penetrates into the interstices of the porous metal material, hence securing the non-metal layer to the porous metal base layer.
U.S. Pat. No. 3,720,996 to Tschermak discloses a method of producing a tight connection between a synthetic body and a metal body which comprises inserting a porous sintered metal body into the synthetic body and then pressing them together so the plastic of the synthetic body penetrates the pores of the sintered metal body, and then connecting an additional metal body to the exposed portion of the porous sintered metal body.
U.S Pat. No. 4,007,494 to Sauer discloses a bone cap comprising a porous body adapted for bone ingrowth that is partially covered by a coating of non-porous biocompatible material such as polyethylene.
U.S. Pat. No. 4,213,816 to Morris discloses a method for bonding a porous coating of polymeric material to a rigid structural member that employs an intermediate substrate layer of material that is chemically compatible with the polymeric material, but has a lower melting temperature so as to flow into the pores of the polymeric material.
In addition, it is noted that it is known in the art of implants to separately manufacture a polyethylene portion and a metal portion and subsequently attach them by various mechanical means of locking. Often these separately manufactured poly and metal components enable the poly portion to be removably secured to the metal base. Examples of such devices are disclosed in U.S. Pat. Nos 4,795,468 to Hodorek et al. and U.S. Pat. No. 4,207,627 to Cloutier. However, it is not the intention of the present invention to address such removable attachment features, but rather to address the permanent interlock of a plastic portion to a metal portion.

Metal-backed prosthetic implant with enhanced bonding of polyethylene portion to metal base


An image reading device is provided which can read an image at a wide dynamic range and which can be constructed at low cost. Film images which are recorded on a photographic film undergo a preliminary reading by an area CCD. On the basis of the image data obtained from the reading, the density of each LCD cell of an LCD when performing the main scanning of the image can be calculated so that the amount of incident light on the area CCD is as great as possible without saturation of the accumulated charge in each photoelectric conversion cell occurring. The film image then undergoes the main reading with the density of each LCD cell of the LCD controlled so as to be the above calculated density.

1. Field of the Invention
The present invention relates to an image reading apparatus and an image reading method and, in particular, to an image reading method in which an image is read by photoelectrically converting incident light from the image in units of single pixels when the image to be read has been divided into a plurality of pixels and to an image reading apparatus in which the above image reading method can be applied
2. Description of the Related Art
Conventionally, an image scanner is known in which an image is read (i.e. image data representing density values of each pixel in an image) in the following manner. Light emitted from a light source and transmitted through an image recorded on a photographic film or the like is measured (photoelectrically converted) in units of single pixels by a charge accumulation sensor (for example, a CCD). Photometric signals output from the CCD through an electronic circuit constructed so as to include an amplification circuit are then amplified and the amplified photometric signals are converted into digital data by an A/D converter.
In this type of scanner, generally (in the first reading method), the amount of light from the light source is adjusted (the amount of light for each component color is adjusted for a color scan) so that photometric values obtained from incident light when no photographic film has been set in place substantially conform to the maximum photometric value and so that no saturation of the values occurs. The amplification factor of the amplification circuit for amplifying the photometric signals output from the CCD is also adjusted and, image reading is performed after the CCD charge accumulation time has been adjusted (this is sometimes adjusted for each component color in a color scan).
In the first reading method, the dynamic range DR of analog photometric signals output from the amplification circuit is found by
DR=Vsat/Vdrk
when Vsat is the maximum level and Vdrk the black level of the photometric signals. In order to read an image at a wider dynamic range, the black level Vdrk may be reduced and the maximum level Vsat increased, however, the black level Vdrk, in particular, is dependent on: (1) the dark current output from the CCD; (2) noise output from the CCD; (3) the drift of the amplification circuit; and (4) noise output from the amplification circuit.
Consequently, the above (1) to (4) are factors that inhibit the widening of the dynamic range when reading a photographic film. (1) and (3) out of the above (1) to (4) can be substantially removed by correcting the dark current (i.e. by correcting the level of the photometric signals by the amount of the difference between the ideal level of the photometric signals when reading optical black (normally 0) and the actual level thereof).
When dark current correction is performed, because the black level Vdrk is replaced by the noise level of the CCD and the amplification circuit Vnoi, the dynamic range of the photometric signals is found by
DR=Vsat/Vnoi
Accordingly, in order to widen the dynamic range of a reading in a scanner with the above structure, it is necessary to reduce (2) the noise output from the CCD and (4) the noise output from the amplification circuit in addition to performing dark current correction. Thus it is necessary to use a CCD having low noise and high performance and to design an amplification circuit also having low noise. The problem is thus that costs are high.
Moreover, when the analog section of a scanner having a CCD and an amplification circuit is designed to have a wide dynamic range, it is also necessary to use an A/D converter which separates and converts the level of input signals into multibit data as the A/D converter for converting photometric signals into digital data. However, the cost of the A/D converter increases the greater the number of multibits. In particular, when dealing with image data comprising a plurality of pixels such as that from an image scanner, high speed analog digital conversion is demanded. As a result, the analog digital converter ends up being extremely expensive. Accordingly, currently, the specifications of each section of an image scanner are determined so that the widest dynamic range possible under the constraints of cost is obtained. Consequently, the performance of the scanner (i.e. the photometric dynamic range and the image reading speed possible from the analogxe2x80x94digital conversion speed) is not always satisfactory.
Further, high performance negative scanners are also known which read negative images with a high level of accuracy by separating negative images recorded on a color negative film into a plurality of pixels (for example, 1000 pixels) and separating each pixel into each component color and measuring the light thereof in order to determine exposure conditions used when a photograph printer exposes the images onto a photosensitive material such as photographic paper or the like. In this type of high performance negative scanner, the light of each negative image is preliminary measured under photometric conditions in which it is certain that saturation will not occur (prescan) and the density of the lowest density pixel in the negative image is detected. A main photomeasurement (fine scan) is then performed in which the charge accumulation time of the CCD is adjusted for each of the negative images (adjusted for each component color in a color scan) so as to be the longest possible time without the output being saturated by the light from the lowest density pixels, thus ensuring the maximum dynamic range (second reading method).
In the second reading method, often the density of the lowest density pixel is comparatively high relative to, for example, an over exposed negative image which has high density. Therefore, the charge accumulation time for a fine scan is adjusted so as to be long. Moreover, often the density of the lowest density pixels is comparatively low (namely, is close to or identical to the film base density) relative to an under exposed negative image which has a low density. Therefore, the charge accumulation time for a fine scan is also adjusted so as to be short.
Because the gradient of the change in the density relative to the change in the exposure amount in a negative film is small (xcex3 less than  less than 1), the gradation of a negative image is a soft gradation and the contrast of the negative image is low. Moreover, because the above high performance negative scanner uses a CCD having a comparatively rough photometric point density (pixel density), the contrast of the light incident on the CCD from each pixel of the negative image becomes still lower. As a result, by adjusting the charge accumulation time in accordance with the density of the low density pixels, as in the second reading method, negative images of any state of exposure type (over exposed negative images/normally exposed negative images/under exposed negative images) can each be read at a wide dynamic range.
However, in the second reading method, reading negative images having high contrast at a wide dynamic range such as negative images of scenes photographed using reverse light, negative images photographed using strobe lighting, and negative images in which light sources are contained in the image is difficult. Moreover, the dynamic range of the reading is also insufficient when reading images recorded on reversal film which has a large gradient of the change in the density relative to the change in the exposure amount (xcex3≈1), or when making high accuracy readings of images which have been separated into a plurality of pixels (for example, several hundreds of thousands of pixels). This is because the contrast of the light incident on the CCD from each pixel of the image is extremely high.
The present invention has been achieved in order to solve the above problems. It is an object of the present invention to provide a low cost image reading apparatus and image reading method which make possible the reading of an image at a wide dynamic range.
In order to achieve the above objectives, in the image reading apparatus according to the first aspect of the present invention, there is provided: a reading apparatus for reading an image in units of single pixels, after the image to be read has been separated into a plurality of pixels, by photoelectrically converting incident light from the image; determination device for determining suitable reading conditions for the image for each pixel or for each of small areas comprising a plurality of pixels, based on the result of the image reading; and a control apparatus for performing, based on the result of the determination by the determination device, a control process so that output image data identical to the image data obtained if each pixel or each small area of the image were read under the reading conditions determined to be suitable for each is obtained from the results of the image reading by the reading apparatus.
The reading apparatus according to the first aspect reads an image in units of single pixels, after the image to be read has been separated into a plurality of pixels, by photoelectrically converting incident light from the image. Note that, the reading apparatus can also be structured so as to include, for example, a reading sensor provided with a plurality of cells which reads the image with each cell by photoelectrically converting incident light from the image to be read (for example, a charge accumulation type reading sensor which accumulates signal charges obtained by photoelectric conversion). Note also that the incident light from the image being read may be light transmitted through the image or light reflected from the image.
In the reading of the image by the reading apparatus, when the amount of incident light (alternatively, the integral value of the amount of incident light within a reading period) is too great compared to the sensitivity of the reading apparatus, the reading accuracy is decreased due to saturation of the photoelectric conversion output. When the amount of incident light is too small compared to the sensitivity of the reading apparatus, the reading accuracy is decreased due to the photoelectric conversion output being too small. Consequently, when considering the dynamic range of a reading, it is desirable that the reading conditions are controlled so that the amount of incident light is as large as possible without being so large as to cause saturation of the photoelectric conversion output. However, because the density values or luminance values of the image being read vary from pixel to pixel or from small area to small area, they also differ for each pixel in an image with regard to the suitable reading conditions.
To counter this, the determination device of the first aspect, determines suitable reading conditions for the image for each pixel or for each small area comprising a plurality of the pixels of the image, based on a result of reading the image. Note that the result of a preliminary reading of the image being read by the reading apparatus (known as a prescan) may be used for the above result of reading the image. Alternatively, when the determination device is structured so as to include an image reading apparatus separate to the reading apparatus, the result of reading the image by the image reading apparatus (prescan) may be used for the above result of reading the image. Moreover, as will be described in the tenth aspect, it is also possible to use the results when the image is read a plurality of times by a reading apparatus under different reading conditions.
Furthermore, the reading conditions can include at least one of a physical amount relating to the sensitivity of the reading apparatus (for example, the length of time of the reading by the reading apparatus (corresponding to the charge accumulation time in a charge accumulation type image sensor: even if the amount of incident light is constant, because the value of the output of the reading apparatus changes due to the length of time of the reading, the sensitivity of the reading apparatus appears to change)) and a physical amount relating to the amount of incident light. It is also possible to obtain the suitable reading conditions by calculating and setting values representing the suitable reading conditions for the image as the values of the above physical amounts.
The control apparatus of the first aspect performs, based on the result of the determination by the determination device, a control process so that output image data identical to when each pixel or each small area of the image is read under the reading conditions determined to be suitable for each is obtained from the results of the image reading by the reading apparatus.
The control process for obtaining the above output image data can be achieved by, in the second aspect, for example, controlling the reading apparatus such that, when the reading apparatus is structured such that the reading conditions can be varied between units of pixels or small areas comprising a plurality of pixels, the reading conditions for each pixel or for each small area during the image reading by the image reading apparatus each match the suitable reading conditions determined by the determining means. As a result, in a single image reading by the reading apparatus, the image being read is read under suitable reading conditions both for pixel units and for small area units. The results of the reading by the reading apparatus can be used as output image data.
The control process for obtaining the above output image data can also be achieved by, as is described in the tenth aspect, for example, selecting for each pixel or each small area data which corresponds to the most suitable reading conditions determined by the determining means from the image data obtained from each of the plurality of image readings made under different reading conditions by the reading apparatus, and synthesizing this as output image data. In this case, the output image data which is equal to that when the image being read is read under suitable reading conditions for both pixels units and small area units is synthesized from the results of the plurality of image readings by the reading apparatus.
In the method described above, because output image data which is equal to that when the image being read is read under reading conditions determined as suitable for both pixels units and small area units (reading conditions in which the amount of incident light is as large as possible without saturation of the photoelectric conversion output occurring) is obtained, output image data equivalent to the result of the image being read at a wide dynamic range can be obtained even in cases such as when the image being read has a high level of contrast.
Moreover, in the first aspect, because output image data which is equal to that obtained when the image is read under reading conditions determined as suitable for both pixels units and small area units is obtained by selecting reading conditions in pixel units or small area units, an image reading apparatus with the equivalent of the dynamic range necessary for reading the image can be constructed at low cost without it being necessary to construct the reading apparatus with high cost sections such as low noise reading sensors.
The image reading apparatus according to the second aspect of the present invention comprises: reading means which reads the image by photoelectrically converting incident light from the image in units of single pixels when the image to be read has been separated into a plurality of pixels and which is able to change the image reading conditions in units of pixels or in units of small areas each comprising a plurality of pixels; determination device which determines suitable reading conditions for the image for each pixel or for each small area comprising a plurality of pixels based on a result of reading the image; and a control apparatus for performing control such that the reading conditions for each pixel or each small area during the image reading by the image reading apparatus match the suitable reading conditions determined by the determination device.
In the second aspect, the reading apparatus is able to change the image reading conditions for units of single pixels or for units of small areas comprising a plurality of pixels. The determination device determines suitable reading conditions for each pixel or each small area based on the result of the image reading. The control means performs control processing such that the reading conditions for each pixel or each small area during the image reading by the reading apparatus match each of the determined suitable reading conditions. As a result, in the same way as in the first aspect, it is possible to read an image at a wide dynamic range and to construct the image reading device cheaply.
Note that the construction of an image reading apparatus capable of altering the reading conditions of an image in units of single pixels or in units of small areas comprising a plurality of pixels can be achieved by including in the image reading apparatus a reading sensor for reading the image by photoelectrically converting each pixel of the incident light from the image, and an incident light amount alteration apparatus capable of altering the amount of incident light striking the reading sensor in pixel units or in small area units.
The incident light amount alteration apparatus can be constructed from, for example, a transmission light amount adjustment device such as an LCD which is provided with a plurality of cells and which is capable of altering at each cell the amount of transmission light or, alternatively, from a reflection light amount adjustment device such as a DMD (digital micromirror device) which is provided with a plurality of cells and which is capable of altering at each cell the amount of reflection light. By corresponding these cells to pixels or small areas and controlling the amount of transmission light or reflection light of the devices at each cell, the amount of incident light striking the reading sensor can be altered in units of single pixels or in units of small areas.
When the reading apparatus has the above structure, the control by the control apparatus of the reading conditions can be achieved by independently controlling the amount of incident light striking the reading sensor via the incident light amount alteration apparatus in units of single pixels or in units of small areas. The effect achieved by the third embodiment is that there is no longer any need to use as the reading sensor of the reading apparatus a structurally complicated reading sensor such as a charge accumulation type reading sensor capable of independently altering the charge accumulation time for units of single pixels or units of small areas.
The construction of a reading apparatus capable of altering the reading conditions of an image in units of single pixels or in units of small areas comprising a plurality of pixels can be achieved, as described, for example, in the sixth aspect of the present invention, by including in the image reading apparatus a charge accumulation type reading sensor for reading the image by photoelectrically converting incident light from the image for each pixel and accumulating this as a charge, and capable of independently altering the charge accumulation time for pixel units or for small area units.
When the reading apparatus has the above structure, the control of the reading conditions by the control apparatus is performed by independently controlling the charge accumulation time of the reading time for pixel units or for small area units. According to the sixth aspect, although the structure of the reading sensor is complicated, the incident light amount alteration apparatus described in the third aspect is no longer a necessary part when controlling the image reading conditions for pixels units or for small area units each of which comprises a plurality of pixels, thus allowing the number of parts to be reduced.
Moreover, the image reading apparatus according to the present invention is structured such that light other than from the image being read is also incident on the reading sensor (for example, is structured such that, when the image being read is recorded on a recording medium such as a photographic film, light which has passed through or been reflected from regions other than the regions where the image is recorded on the photographic film is also incident of the reading sensor). In particular, when the amount of incident light other than from the image being read is greater than the amount of incident light from the image being read, if the reading sensor is, for example, a charge accumulation type reading sensor, then the incident light other than from the image being read has an adverse effect on the image reading, such as the charge accumulated in the reading sensor from the incident light other than from the image being read being saturated.
It is possible to prevent the incident light other than from the image being read having an adverse effect on the reading by, for example, shutting out incident light other than from the image being read using a mask or the like. However, as in the third aspect, in an aspect in which a second reading apparatus is constructed so as to have an incident light amount alteration means and a second control apparatus controls the reading conditions by controlling the amount of incident light incident on the reading sensor in units of pixels or small areas using the incident light amount alteration apparatus, then, as described in the fourth aspect, it is preferable that the second control apparatus controls the amount of incident light on the reading sensor in units of pixels or small areas using the incident light amount alteration apparatus such that the amount of incident light other than from the image being read from among the incident light incident on the reading sensor is below a predetermined value.
In contrast, in the sixth aspect of the present invention, in an aspect in which the second reading apparatus is structured so as to include a charge accumulation type reading sensor capable of altering the charge accumulation times for stand-alone pixel units or small area units, and the second control apparatus controls the reading conditions by controlling the charge accumulation time of the reading sensor in stand-alone units of pixels or small areas, then, as described in the seventh aspect, it is preferable that the second control apparatus controls the charge accumulation time of the reading sensor in units of pixels or small areas such that the charge accumulation time in the photoelectric conversion of incident light other than from the image being read from among the incident light incident on the reading sensor is below a predetermined value.
By controlling the charge accumulation time or incident light amount as described above, there is no need to make the structure more complex such as by providing a mask for shutting out incident light other than from the image being read and incident light other than from the image being read can be prevented from having an adverse effect on the reading of the image.
Further, irregularities in pixel units which are caused by the image reading apparatus are sometimes generated in the results of an image reading by the reading sensor. Examples of the causes of these irregularities are unevenness in the amount of light illuminating the image being read;
aberration in the optical system irradiating the light from the image onto the reading sensor; and irregularities in the sensitivity for each pixel of the reading sensor. Moreover, when the image being read is one that has been made visible by performing developing processing and the like on a photographed object which has been recorded on a photographic film by photography using a camera, density unevenness in the image being read is generated due to aberrations in the optical system of the camera. Therefore, aberrations in the optical system of the camera are also a cause of irregularities in pixel units in the results of an image reading by a reading sensor.
It is possible to avoid irregularities in pixel units in the results of an image reading by a reading sensor by, for example, performing a correction processing to correct the image reading results in units of each pixel.
However, as in the third aspect, in an aspect in which the second reading apparatus is constructed so as to include an incident light amount alteration apparatus and the second control apparatus controls the reading conditions by controlling the amount of incident light on the reading sensor in units of pixels or small areas using the incident light amount alteration apparatus, then, as described in the fifth aspect, it is preferable that the second control apparatus controls the reading conditions by controlling the amount of incident light on the reading sensor in units of pixels or small areas using the incident light amount alteration apparatus such that density unevenness in an image being read and irregularities in each pixel unit in the results of an image reading by a reading sensor caused by the image reading apparatus are corrected.
In contrast, as in the sixth aspect of the present invention, in an aspect in which the second reading apparatus is constructed so as to include a charge accumulation type reading sensor capable of altering the charge accumulation time for stand-alone units of pixels or small areas, and the second control apparatus controls the reading conditions by controlling the charge accumulation time of a reading sensor in stand-alone units of pixels or small areas, then, as described in the eighth aspect, it is preferable that the second control apparatus controls the reading conditions by controlling the charge accumulation time of a reading sensor in units of pixels or small areas such that density unevenness in an image being read and irregularities in each pixel unit in the results of an image reading by a reading sensor caused by the image reading apparatus are corrected.
By controlling the charge accumulation time or incident light amount as described above, it is possible to avoid irregularities in pixel units in the results of an image reading and there is no need to perform correction processing on the results of the image reading for each pixel unit.
Note that, in the third and fourth aspects, it is also possible, as is described in the ninth aspect, to construct the reading apparatus such that it contains a light amount adjustment apparatus capable of adjusting the amount of light of at least one of illumination light illuminating an image and incident light incident onto a reading sensor from an image. In this case, the control apparatus is able to control the reading conditions by controlling the amount of light of at least one of illumination light and incident light via the light amount adjustment apparatus.
The light amount adjustment apparatus may be formed from a diaphragm, a light reduction filter, or the like, and, generally, these optical parts are provided in the structure of an image reading apparatus. Accordingly, according to the ninth aspect of the present invention, by controlling the light amount via a light amount adjustment apparatus, it is possible to reduce the width of the alteration of the incident light by the incident light amount alteration apparatus described in the third aspect, or to reduce the width of the alteration of the charge accumulation time by the reading sensor described in the sixth aspect. In addition, an increase in the number of parts can be avoided by using a diaphragm or light reduction filter already present in the apparatus as the light amount adjustment apparatus.
The image reading apparatus according to the tenth aspect of the present invention comprises: a reading apparatus which is provided with a light amount adjustment apparatus capable of adjusting the amount of light of at least one of illumination light illuminated onto an image being read and incident light from the image, and which reads the image a plurality of times by photoelectrically converting incident light incident from the image in units of single pixels when the image has been divided into a plurality of pixels and also causes the reading conditions to be varied for each reading by adjusting the amount of incident light using the light amount adjustment apparatus; determination device which determines the most suitable reading conditions for each pixel or for each small area comprising a plurality of pixels from among the reading conditions for each image reading, based on image data obtained from each of the plurality of image readings by the reading apparatus; and a control apparatus which selects for each pixel or each small area data corresponding to the most suitable reading conditions determined by the determination device from the image data obtained from each of the plurality of image readings by the reading apparatus and synthesizes this as output image data.
The reading apparatus according to the tenth aspect reads the image a plurality of times by photoelectrically converting incident light incident from the image being read in units of each single pixel when the image has been divided into a plurality of pixels and also causes the reading conditions to be varied for each reading by adjusting the amount of incident light using the light amount adjustment apparatus. Note that it is possible to use an existing diaphragm, light reduction filter, or the like as the light adjustment apparatus of the tenth aspect as well.
The determination device determines the most suitable reading conditions for each pixel or for each small area comprising a plurality of pixels from among the reading conditions for each image reading by the reading apparatus, while the control apparatus selects for each pixel or each small area data corresponding to the above determined most suitable reading conditions from the image data obtained from each of the plurality of image readings and synthesizes this as output image data. As a result, because output image data equivalent to when the image being read is read under the suitable reading conditions for each pixel or small area unit is synthesized from the results of the plurality of image readings by the reading apparatus, it is possible to read the image at a wide dynamic range and to construct the image reading apparatus cheaply.
Note that when the reading conditions are varied by adjusting the amount of incident light, if, for example, the reading apparatus includes a charge accumulation type reading sensor, saturation of the accumulated charge amount occurs in at least a portion of the cells during the plurality of image readings. However, if a charge accumulation type sensor having anti-blooming characteristics (for example, a sensor having an overflow drain structure) is used, the overflow charge from the cell in which the accumulated charge saturation occurred can be prevented from having adverse effects, which is naturally preferable. Moreover, when the above reading sensor is used in the tenth aspect, the determination of the most suitable reading conditions can be made on the basis of whether or not saturation of the accumulated charge occurred in each cell.
In the image processing method according to the eleventh aspect of the present invention, suitable reading conditions for the image to be read are determined for each pixel or for each small area comprising a plurality of pixels. Then, based on the above determination results, control is performed such that output image data equivalent to that obtained when the image is read under the suitable reading conditions for each pixel unit or each small area unit is obtained from the results of reading the image by photoelectrically converting incident light from the image in units of single pixels when the image to be read has been divided into a plurality of pixels. Therefore, in the same way as in the first aspect, an image can be read at a wide dynamic range without any major increase in the costs being incurred.

Image reading apparatus and image reading method