text:
The present invention provides methods and kits for diagnosing and treating glaucoma.
1. A method for treating glaucoma comprising administering to a patient in need thereof a composition comprising human bone morphogenic protein 4 (hBMP4), wherein the composition is administered by direct delivery to the eye of the patient.
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This application claims priority from U.S. Provisional Application Ser. No. 60/334,852 filed Oct. 31, 2001.
1. Field of the Invention
The present invention discloses methods and reagents for diagnosing and treating glaucoma and related disorders.
2. Description of the Related Art
"Glaucomas" are a group of debilitating eye diseases that are the leading cause of irreversible blindness in the United States and other developed nations. Primary Open Angle Glaucoma ("POAG"), the most common form of glaucoma, is characterized by the degeneration of the trabecular meshwork, leading to obstruction of the normal ability of aqueous humor to leave the eye without closure of the space (e.g., the "angle") between the iris and cornea (Vaughan, D. et al., (1992)). A characteristic of such obstruction in this disease is an increased intraocular pressure ("IOP"), resulting in progressive visual loss and blindness if not treated appropriately and in a timely fashion. The disease is estimated to affect between 0.4% and 3.3% of all adults over 40 years old (Leske, M. C. et al. (1986); Bengtsson, B. (1989); Strong, N. P. (1992)). Moreover, the prevalence of the disease rises with age to over 6% of those 75 years or older (Strong, N. P., (1992)).
Because increased IOP is a readily measurable characteristic of glaucoma, the diagnosis of the disease is largely screened for by measuring intraocular pressure (tonometry) (Strong, N. P. (1992); Greve, M. et al. (1993)). Unfortunately, because glaucomatous and normal pressure ranges overlap, such methods are of limited value unless multiple readings are obtained (Hitchings, R. A., (1993); Tuck, M. W. et al. (1993); Vaughan, D. et al., (1992); Vernon, S. A., (1993)). For this reason, additional methods, such as direct examination of the optic disk and determination of the extent of a patient's visual field loss are often conducted to improve the accuracy of diagnosis (Greve, M. et al., (1993)).
Glaucoma affects three separate tissues in the eye. The elevated IOP associated with POAG is due to morphological and biochemical changes in the trabecular meshwork (TM), a tissue located at the angle between the cornea and iris. Most of the nutritive aqueous humor exits the anterior segment of the eye through the TM. The progressive loss of TM cells and the build-up of extracellular debris in the TM of glaucomatous eyes leads to increased resistance to aqueous outflow (Lutjen-Drecoll and Rohen 1996; Rohen 1983; Rohen et al. 1993; Grierson and Calthorpe 1988), thereby raising IOP. Elevated IOP, as well as other factors such as ischemia, cause degenerative changes in the optic nerve head (ONH) leading to progressive "cupping" of the ONH (Varma and Minckler 1996; Hernandez and Gong 1996; Hernandez et al. 1990; Hernandez and Pena 1997; Morrison et al. 1990) and loss of retinal ganglion cells (Quigley et al. 2000; Quigley 1999; Quigley et al. 1995; Kerrigan et al. 1997) and axons. The detailed molecular mechanisms responsible for glaucomatous damage to the TM, ONH, and the retinal ganglion cells are unknown.
Current glaucoma therapy is directed to lowering IOP, a major risk factor for the development and progression of glaucoma. These therapies lower IOP, but they do not directly address the pathogenic mechanisms, and the disease continues to progress. At least half of patients with glaucoma are undiagnosed, and by the time patients are diagnosed with glaucoma, they have already lost approximately 40% of their retinal ganglion cells. Therefore, methods for earlier detection and diagnosis of glaucoma are needed.
In view of the importance of glaucoma, and the at least partial inadequacies of prior methods of diagnosis, it would be desirable to have an improved, more accurate method for diagnosing glaucoma in its early stages. In addition, it would be desirable to have new therapeutic agents that address glaucomatous pathogenic mechanisms.
The present invention overcomes these and other drawbacks of the prior art by providing methods and kits for the early diagnosis of glaucoma, for treating glaucoma, and for the identification of compounds useful in the treatment of glaucoma.
In certain specific embodiments, the invention provides a method for diagnosing glaucoma in a sample obtained from a cell or bodily fluid by detecting altered expression of a bone morphogenic protein family member gene. The method generally includes the steps of:
In general, the methods of the invention may include obtaining a sample from an individual and extracting DNA from said sample. Select PCR primers for specific members of the BMP gene family are then used to amplify relevant regions of the extracted gene to obtain a PCR product. The PCR product is resolved by a technique that effectively identifies DNA sequence differences between the normal and mutated form of the specific BMP family gene being evaluated (the extracted DNA). Identified differences between the sequences are indicative of glaucoma.
The tissue or fluid sample for use in the methods of the invention may be blood or buccal cells.
Typically, the primer sequences will have a length of between about 10, 15 or 18 nucleotides to about 20, or to about 30 nucleotides. Longer sequences, e.g., 40, 50, 80, 90, 95, 100, even up to full length, are even more preferred for certain embodiments. Lengths of oligonucleotides of at least about 18 to 20 nucleotides are well accepted by those of skill in the art as sufficient to allow sufficiently specific hybridization so as to be useful as a molecular probe, as described by Lathe (1985), which reference is specifically incorporated herein by reference for this purpose. Preferably, the nucleotide sequence will consist of from 20 to 100 contiguous nucleotides of SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, or SEQ ID NO:53. It is also contemplated that the primer sequences may consist of sequences of at least 10, 15 or 18 contiguous nucleotides from the sequences of BMP receptor genes and from BMP-associated proteins, the sequences of which are known.
Nucleic acid molecules having stretches of 10, 18, 20, 30, 50, 60, 65 or even up to and including 100 nucleotides or so, complementary to any one of SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, or SEQ ID NO:53, have utility as hybridization probes. Primers or probes having a nucleotide length of about 18 nucleotides are recognized by those of skill in the art to provide highly specific hybridization to a target sequence. The total size of the fragment, as well as the size of the complementary stretches, will ultimately depend on the intended use of application of the particular nucleic acid segment. Smaller fragments will generally find use in hybridization embodiments, wherein the length of the complementary region may be varied, such as between about 10, 18, 20 or 30 and about 50, 60, 70, 80, 80 or 100 nucleotides, or even full length according to the complementary sequences one wishes to detect.
In specifically preferred embodiments, the primers will consist of contiguous sequences from SEQ ID NO: 1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47, or SEQ ID NO:53. In other preferred embodiments, the primers will consist of contiguous sequences from BMP receptor genes (disclosed in ten Dijke et al. 1993; Astrom et al. 1999; Nohno et al. 1995, all incorporated herein by reference) or from BMP-associated genes, such as chordin (NCBI NM—029130), gremlin (Murphy et al. 1999; McMahon et al. 2000), follistatin (NCBI NM—003892) or bambi (NCBI NM—005791). Most preferably, the primers will consist of contiguous sequence from SEQ ID NO:3. In certain aspects, at least some of the primers may further include a detectable label.
In other embodiments, the invention provides a method for treating glaucoma by administering to a patient in need thereof a composition comprising a sequence consisting of at least one compound selected from the group consisting of a BMP2 agonist, a BMP4 agonist, a BMP5 agonist, a BMP7 agonist, a Smad 1/5 agonist, a chordin antagonist, a gremlin antagonist and a follistatin antagonist.
In additional aspects, the present invention provides a method for identifying a therapeutic agent for the treatment of glaucoma. Therapeutic agents may be identified, for example, by:
Another aspect of the invention are diagnostic kits containing sequences of the present invention and suitable reagents such as a detectable label linked to a protein, peptide or the antibody itself. Alternatively, the detectable label may be linked to a second sequence which selectively hybridizes to a sequence of the invention.
Related embodiments include therapeutic kits which include pharmaceutically-acceptable formulations of either the nucleic acid sequences or peptide or protein sequences disclosed herein. Such kits are useful in the detection of altered expression of the BMP genes and proteins in clinical samples for the diagnosis of glaucoma.
The drawings form part of the present specification and are included to further demonstrate certain aspects of the present invention. The invention may be better understood by reference to one or more of these drawings in combination with the detailed description of specific embodiments presented herein.
The trabecular meshwork has been proposed to play an important role in the normal flow of the aqueous humor, and has been presumed to be the major site of outflow resistance in glaucomatous eyes. Human trabecular meshwork (HTM) cells are specialized cells which line the outflow channels by which aqueous humor exits the eye. Altered synthetic function of the cells may be involved in the pathogenesis of POAG, steroid glaucoma, and other types of glaucoma.
Despite years of intensive research, the precise molecular mechanisms responsible for glaucomatous damage to the eye are not known. Recent research has suggested that growth factors may be important in maintaining normal homeostasis in the ocular tissues associated with glaucoma, and alterations in growth factor/growth factor receptors may play a role in glaucoma pathogenesis. Growth factors area very large family of polypeptides that control cell growth and differentiation. These molecules have a variety of cell-specific effects on gene expression, extracellular matrix composition and deposition, cytoskeletal organization, and regulation of cellular functions. The TM expresses a wide variety of growth factors, growth factor receptors (Tripathi et al. 1993a; Tripathi et al. 1993b; Tripathi et al. 1994a; Tripathi et al. 1994b; Wordinger et al. 1998; Wordinger et al. 1999) as well as neurotrophin/neurotrophic factors and their receptors (Liu et al. 2001; Wordinger et al. 2000). ONH astrocytes and lamina cribrosa cells, two cell types of the optic nerve head, express growth factors, neurotrophins and their receptors (Lambert et al. 2001; Pena et al. 1999). The aqueous humor also contains a variety of growth factors including FGF2, EGF, TGFβ, HGF (Tripathi et al. 1996; Tripathi et al. 1991; Tripathi et al. 1992; Hu and Ritch 2001) as well as neurotrophins (Chundru et al. 2000). Elevated levels of aqueous humor TGFβ-2 and HGF have been reported in POAG patients (Tripathi et al. 1994c; Inatani et al. 2001; Picht et al. 2001). Growth factors may be involved in glaucoma by altering the normal development and/or function of the TM and ONH.
The present invention stems in part from the recognition that bone morphogenic proteins (BMPs) not only induce bone and cartilage formation but are multifunctional cytokines having a wide range of effects on numerous cell types (Hogan 1996; Reddi 1997) and are expressed by both human trabecular meshwork (HTM) and optic nerve head (ONH) cells (Wordinger et al. 2002). BMPs are members of the TGFβ superfamily, and there are approximately 15-20 BMPs genes in man, 3 BMP receptors, and a number of BMP associated proteins that function as BMP antagonists (Yamashita et al. 1996). BMPs signal via a receptor complex consisting of BMPR-I and BMPR-II. It has been reported that superfamily members TGFβ and TGFβR (Agarwal et al. 1997; Lambert et al. 1997) and GDNF and GDNFR (Wordinger et al. 1999; Liu et al. 1999) are expressed by both HTM and ONH cells.
BMPs and BMP receptors are expressed in ocular tissues (Obata et al. 1999; You et al. 1999), but previous reports have focused on ocular development. The function of BMPs is important in ocular development since targeted disruption of genes encoding BMPs in mice leads to severe developmental defects in the retina and the lens (Jena et al. 1997; Luo et al. 1995; Dudley et al. 1995). BMP-2, BMP-4 and BMP-7 are involved in the development of the lens and retina (Jena et al. 1997; Furuta and Hogan 1998; Reddi 2000; Trousse et al. 2001). BMP-6 and BMP-7 also appear to play a role in protecting neurons from hypoglycemic or ischemic damage (Nonner et al. 2001; Liu et al. 2001), and BMP2 has been shown to enhance ganglion cell neurotrophin expression (Zhang et al. 1998). Heterozygous knock-out mice haploinsufficient for Bmp4 have ocular phenotypes including anterior segment dysgenesis, elevated IOP, and optic nerve abnormalities (Chang et al. 2001). There has been very limited information published concerning the role of BMPs in the human postnatal eye.
Mohan and colleagues (1998) reported that BMP-2 and BMP-4 and BMP receptors were expressed in cells of the adult cornea and suggested that BMP function might include corneal keratocyte proliferation and apoptosis. You and colleagues (1999) verified this study and also reported the expression of BMP-3, BMP-5, and BMP-7 in ex vivo and cultured corneal epithelium and stromal cells. They reported that the level of BMP transcription was higher in the stroma while the level for receptors was higher in cultured corneal epithelial cells.
Using RT-PCR, the present inventors discovered mRNAs for BMPs, BMP receptors BMPR-IA, BMPR-IB and BMPR-II, as well as BMP binding proteins gremlin, chordin, follistatin, and bambi, in HTM, lamina cribosa (LC) and ONH astrocyte cell lines and tissues (Wordinger et al. 2002). The present inventors further discovered that HTM and ONH cells express proteins BMP-2, BMP-4, BMP-5 and BMP-7.
Glaucoma will be diagnosed by characterization of genetic changes in genes of members of the BMP signaling family. As used herein, the phrases "bone morphogenic protein family member gene" and "BMP signaling family" refer to all BMPs, BMP receptors and associated proteins. The term "genetic changes" is well known by those skilled in the art. There are numerous examples of diseases associated with genetic changes in specific genes (for examples see Cummings 1997; Strachan, et al. 1996; Jorde, et al. 1999). Genetic changes in a specific gene (e.g. BMP) can be determined using a variety of techniques well known by those skilled in the art, such as: SSCP, DGGE, ASO, RFLP, heteroduplex analysis, CCM, PTT, and RNase cleavage (see Birren, et al. 1998).
Glaucoma may be caused by altered expression of one or more BMP family genes in the eye, which leads to elevated IOP and/or glaucomatous optic neuropathy. "Altered BMP gene expression" means expression of this gene product that is different from normal. The term may also refer to alterations in the sequence of the gene or protein. The normal BMP gene has been well characterized (see above), and the expression of BMP has been reported in a variety of tissues including the TM and ONH. Genetic changes in the coding region of BMP family genes may alter the function of these proteins. Genetic changes outside the coding region may also lead to glaucoma.
It is well known by those skilled in the art that "changes outside" of the coding region of a specific gene are important in the regulation of gene expression. For example, the region upstream (5′) of the coding region of most genes is known as the promoter region which "promotes" and regulates the expression of that gene. The promoter region contains numerous nucleotide sequences recognized by various transcription factors and DNA binding proteins that are responsible for activation or repression of gene expression. Regions downstream (3′) of the gene can determine poly-adenylation of the gene product, thereby regulating RNA processing and translation of the gene product.
The altered expression of BMP genes or mutations in the sequence of the genes that is indicative of glaucoma may be detected using techniques well known to those of skill in the art. For example, it is contemplated that a nucleic acid fragment of almost any length may be employed, with the total length preferably being limited by the ease of preparation and use in the intended protocol. The nucleic acid sequences disclosed herein may also have utility as probes or primers in nucleic acid hybridization embodiments. As such, it is contemplated that nucleic acid segments that comprise a sequence region that consists of at least a 14 nucleotide long contiguous sequence that has the same sequence as, or is complementary to, a 14 nucleotide long contiguous sequence of BMP-2A (SEQ ID NO:1), BMP-4 (SEQ ID NO:3), BMP-5 (SEQ ID NO:5), BMP-7 (SEQ ID NO:7), BMP-RIA (SEQ ID NO:37), BMP-RIB (SEQ ID NO:39), BMP-RII (SEQ ID NO:41), chordin (SEQ ID NO:43), gremlin (SEQ ID NO:45), follistatin (SEQ ID NO:47), or bambi (SEQ ID NO:53) will find particular utility. Longer contiguous identical or complementary sequences, e.g., those of about 20, 30, 40, 50, 100, 200, 500, 1000 nucleotides (including all intermediate lengths), and even up to full length sequences of about 1547 nucleotides (for BMP-2A), 1946 nucleotides (for BMP-4), 2153 nucleotides (for BMP-5) and 1878 nucleotides (for BMP-7), 2932 nucleotides (for BMP-RIA), 2032 nucleotides (for BMP-RIB), 3611 nucleotides (for BMP-RII), 3561 nucleotides (for chordin), 4049 nucleotides (for gremlin), 1386 nucleotides (for follistatin), and 1523 nucleotides (for bambi) will also be of use in certain embodiments.
It will be readily understood that "intermediate lengths", in this context, means any length between the quoted ranges, such as 14, 15, 16, 17, 18, 19, 20, etc.; 21, 22, 23, etc.; 30, 31, 32, etc.; 50, 51, 52, 53, etc.; 100, 101, 102, 103, etc.; 150, 151, 152, 153, etc.; including all integers through the 200-500; 500-1,000; 1,000-2,000 ranges, up to and including sequences of 2,001, 2002, 2050, 2051, and the like.
The ability of such nucleic acid probes and primers to specifically hybridize to BMP coding sequences and primers to specifically amplify BMP sequences will enable them to be of use in detecting the presence of complementary sequences in a given sample. However, other uses are envisioned, including the use of the sequence information for the preparation of mutant species primers, or primers for use in preparing other genetic constructions.
Nucleic acid molecules having sequence regions consisting of contiguous nucleotide stretches of 10, 20, 30, 50, or even of 100-200 nucleotides or so, identical or complementary to BMP-2A (SEQ ID NO:1), BMP4 (SEQ ID NO:3), BMP-5 (SEQ ID NO:5), BMP7 (SEQ ID NO:7), BMP-RIA (SEQ ID NO:37), BMP-RIB (SEQ ID NO:39), BMP-RII (SEQ ID NO:41), chordin (SEQ ID NO:43), gremlin (SEQ ID NO:45), follistatin (SEQ ID NO:47), or bambi (SEQ ID NO:53) are particularly contemplated as hybridization probes for use in, e.g., SNP evaluation and solid phase hybridization assays, in addition to Southern and northern blotting. This would allow BMP structural or regulatory genes to be analyzed, both in tissues and cells. The total size of fragment, as well as the size of the complementary stretch(es), will ultimately depend on the intended use of application of the particular nucleic acid segment. Smaller fragments will generally find use in hybridization embodiments, wherein the length of the contiguous complementary region may be varied, such as between about 10 and about 100 nucleotides, but larger contiguous complementary stretches of up to about 1547 nucleotides (for BMP-2A), 1946 nucleotides (for BMP-4), 2153 nucleotides (for BMP-5) and 1878 nucleotides (for BMP-7), 2932 nucleotides (for BMP-RIA), 2032 nucleotides (for BMP-RIB), 3611 nucleotides (for BMP-RII), 3561 nucleotides (for chordin), 4049 nucleotides (for gremlin), 1386 nucleotides (for follistatin), and 1523 nucleotides (for bambi) may be used, according to the length complementary sequences one wishes to detect.
The use of a hybridization probe of about 10-14 nucleotides in length allows the formation of a duplex molecule that is both stable and selective. Molecules having contiguous complementary sequences over stretches greater than 10 bases in length are generally preferred, though, in order to increase stability and selectivity of the hybrid, and thereby improve the quality and degree of specific hybrid molecules obtained, one will generally prefer to design nucleic acid molecules having gene-complementary stretches of 15 to 20 contiguous nucleotides, or even longer where desired.
Hybridization probes may be selected from any portion of any of the sequences disclosed herein. All that is required is to review the sequence set forth in SEQ ID NO:1, SEQ ID NO:3, SEQ ID NO:5, SEQ ID NO:7, SEQ ID NO:37, SEQ ID NO:39, SEQ ID NO:41, SEQ ID NO:43, SEQ ID NO:45, SEQ ID NO:47 or SEQ ID NO:53 and to select any continuous portion of the sequence, from about 10 nucleotides in length up to and including the full length sequence, that one wishes to utilize as a probe or primer. The choice of probe and primer sequences may be governed by various factors, such as, by way of example only, one may wish to employ primers from towards the termini of the total sequence, or from the ends of the functional domain-encoding sequences, in order to amplify further DNA.
The process of selecting, and preparing a nucleic acid segment that includes a contiguous sequence from within BMP-2A (SEQ ID NO:1), BMP4 (SEQ ID NO:3), BMP-5 (SEQ ID NO:5), BMP7 (SEQ ID NQ:7), BMP-RIA (SEQ ID NO:37), BMP-RIB (SEQ ID NO:39), BMP-RII (SEQ ID NO:41), chordin (SEQ ID NO:43), gremlin (SEQ ID NO:45), follistatin (SEQ ID NO:47), or bambi (SEQ ID NO:53) may alternatively be described as preparing a nucleic acid fragment. Of course, fragments may also be obtained by other techniques such as, e.g., by mechanical shearing or by restriction enzyme digestion. Small nucleic acid segments or fragments may be readily prepared by, for example, directly synthesizing the fragment by chemical means, as is commonly practiced using an automated oligonucleotide synthesizer. Also, fragments may be obtained by application of nucleic acid reproduction technology, such as the PCR™ technology of U.S. Pat. NoS. 4,683,202 and 4,682,195 (each incorporated herein by reference), by introducing selected sequences into recombinant vectors for recombinant production, and by other recombinant DNA techniques generally known to those of skill in the art of molecular biology.
Accordingly, the nucleotide sequences of the invention may be used for their ability to selectively form duplex molecules with complementary stretches of BMP genes or cDNAs. Depending on the application envisioned, one will desire to employ varying degrees of selectivity of hybridization to achieve varying degrees of selectivity of probe towards target sequence. For applications requiring high selectivity, one will typically desire to employ relatively stringent conditions to form the hybrids, e.g., one will select relatively low salt and/or high temperature conditions, such as provided by 0.02M-0.15M NaCl at temperatures of 50° C. to 70° C. Such selective conditions tolerate little, if any, mismatch between the probe and the template or target strand, and would be particularly suitable for examining BMP genes.
Of course, for some applications, for example, where one desires to prepare or identify mutants employing a mutant primer strand hybridized to an underlying template or where one seeks to isolate BMP encoding sequences from related species, functional equivalents, or the like, less stringent hybridization conditions will typically be needed in order to allow formation of the heteroduplex. In these circumstances, one may desire to employ conditions such a 0.15M-1.0M salt, at temperatures ranging from 20° C. to 55° C. Cross-hybridizing species can thereby be readily identified as positively hybridizing signals with respect to control hycbridizations. In any case, it is generally appreciated that conditions can be rendered more stringent by decreasing NaCl concentrations or by the addition of increasing amounts of formamide, which serves to destabilize the hybrid duplex in the same manner as increased temperature. Thus, hybridization conditions can be readily manipulated, and thus will generally be a method of choice depending on the desired results.
In certain embodiments, it will be advantageous to employ nucleic acid sequences of the present invention in combination with an appropriate means, such as a label, for determining hybridization. A wide variety of appropriate indicator means are known in the art, including fluorescent, radioactive, enzymatic or other ligands, such as avidin/biotin, which are capable of giving a detectable signal. In preferred embodiments, one will likely desire to employ a fluorescent label or an enzyme tag, such as urease, alkaline phosphatase or peroxidase, instead of radioactive or other environmental undesirable reagents. In the case of enzyme tags, colorimetric indicator substrates are known that can be employed to provide a means visible to the human eye or spectrophotometrically, to identify specific hybridization with complementary nucleic acid-containing samples.
In general, it is envisioned that the hybridization probes described herein will be useful both as reagents in solution hybridization as well as in embodiments employing a solid phase. In embodiments involving a solid phase, the test DNA (or RNA) is adsorbed or otherwise affixed to a selected matrix or surface. This fixed, single-stranded nucleic acid is then subjected to specific hybridization with selected probes under desired conditions. The selected conditions will depend on the particular circumstances based on the particular criteria required (depending, for example, on the G+C contents, type of target nucleic acid, source of nucleic acid, size of hybridization probe, etc.). Following washing of the hybridized surface so as to remove nonspecifically bound probe molecules, specific hybridization is detected, or even quantified, by means of the label.
It will also be understood that this invention is not limited to the particular nucleic acid and amino acid sequences of BMP-2A (SEQ ID NO:1), BMP4 (SEQ ID NO:3), BMP-5 (SEQ ID NO:5), BMP7 (SEQ ID NO:7), BMP-RIA (SEQ ID NO:37), BMP-RIB (SEQ ID NO:39), BMP-RII (SEQ ID NO:41), chordin (SEQ ID NO:43), gremlin (SEQ ID NO:45), follistatin (SEQ ID NO:47), or bambi (SEQ ID NO:53). Recombinant vectors and isolated DNA segments may therefore variously include the BMP coding regions themselves, upstream or downstream regions of the genes, coding regions bearing selected alterations or modifications in the basic coding region, or they may encode larger polypeptides that nevertheless include BMP coding regions or may encode biologically functional equivalent proteins or polypeptides that have variant amino acid sequences.
The DNA segments of the present invention encompass biologically functional equivalent BMP proteins and polypeptides. Such sequences may arise as a consequence of codon redundancy and functional equivalency that are known to occur naturally within nucleic acid sequences and the proteins thus encoded. Alternatively, functionally equivalent proteins or polypeptides may be created via the application of recombinant DNA technology, in which changes in the protein structure may be engineered, based on considerations of the properties of the amino acids being exchanged. Changes designed by man may be introduced through the application of site-directed mutagenesis techniques, e.g., to introduce improvements to the antigenicity of the protein or to test BMP mutants in order to examine binding activity at the molecular level.
The therapeutic agent for the treatment of glaucoma can be: a peptide or protein, a peptide mimetic, an oligonucleotide or derivatized oligonucleotide, or small drug-like molecule, all which affect one or more aspects of the ocular BMP pathways. Preferred therapeutic agents are those that are: (1) BMP2, BMP4, BMP5, or BMP7 agonists; (2) chordin, gremlin, follistatin, or bambi antagonists; and/or (3) Smad1, Smad5 and/or Smad4 agonists.
The agent may be delivered directly to the eye (for example: topical ocular drops or ointments; slow release devices in the cul-de-sac or implanted adjacent to the sclera or within the eye; periocular, conjunctival, sub-Tenons, intracameral or intravitreal injections) or parenterally (for example: orally; intravenous, subcutaneous or intramuscular injections; dermal delivery; etc.) using techniques well known by those skilled in the art. The following are examples of possible formulations embodied by this invention.
It is further contemplated that the compounds of the invention could be formulated in intraocular insert devices.
A. Assay for Therapeutic Agents
This invention is also useful for the discovery of new anti-glaucoma therapeutic agents that are involved in the BMP signaling pathway (see
The BMP/Smad signaling pathway is negatively regulated by several mechanisms. Certain BMP-binding proteins (such as gremlin, BAMBI, or follistatin) bind BMPs and inhibit their interaction with BMP receptors. In addition, there are inhibitory Smad proteins (e.g. Smad 6 and Smad 7), which bind and inactivate BMP receptors. (Kowabata et al. 1998; Itoh et al. 2000; Miyazono 2000). The present inventors have discovered that human TM cells, ONH astrocytes and lamina cribrosa cells express message and protein for the BMP receptor complex. Thus, these cells could respond to endogenous BMP ligands.
Various methods may be used to discover new anti-glaucoma therapeutic agents, and these techniques are well known to those skilled in the art. For example, peptide or peptide mimetic agents that act as agonists or inhibitors of BMPs can be discovered through molecular modeling of BMP/BMP receptor structures (Nickel et al. 2001). BMP signal transduction involves select sets of Smad proteins (Kawabata et al. 1998; Itoh et al. 2000; Attiseno et al. 2000). Select BMP agonists and Smad agonists can be discovered using cell based assays. The test cell should express the appropriate BMP receptor(s) and possess the appropriate BMP signaling pathway. Because one of the major effects of BMP signaling is the alteration of gene expression, BMP agonists and Smad agonists can be discovered by screening for BMP-induced genes. The induction of BMP regulated genes also may be assayed by quantitating levels of mRNA using quantitative RT-PCR (Wang et al. 2001), DNA microarrays, or reporter gene constructs. There are natural inhibitors of BMP signaling, the BMP binding proteins (also known as BMP-associated proteins), such as chordin, gremlin, and follistatin. Antagonists of the protein inhibitors can be discovered using ligand binding assays. For example, test agents can be added to recombinant purified gremlin, and those agents that bind to gremlin are identified using a variety of techniques known to those skilled in the art. To determine whether these agents are gremlin antagonists, a cell based assay similar to that described above is used.
It is contemplated that any known in vitro and in vivo screening models may be used in conjunction with the present invention to identify new glaucoma therapies directed to the BMP family of genes. Such models are well known to those skilled in the art and their practice has become routine. Small peptides or peptide mimetics can be designed based on structure/function knowledge of the BMP, BMPR, and/or BMP binding protein gene products. Ligand binding assays can be used to detect small molecules that bind to BMPs, BMPRs, or BMP binding proteins. Cell based assays can look at the effects of various agents on BMP signaling pathways. Knock-in cell lines containing BMP family gene promoters coupled to a reporter gene can be generated to look for agents that alter BMP family member gene expression. These assays can be used to identify both agonist and antagonist molecules. Ex vivo assays, such as perfusion cultured anterior segments from human eyes (Clark et al. 1995a; Pang et al. 2000), can be used to examine the effects of agents on IOP and on BMP signaling in TM tissue. Rodent models of glaucoma can be generated using well-known techniques to create stable BMP family member transgenic, knockout, or knock-in strains of mice and rats. These rodent models can be used to screen for agents that alter the glaucoma-like phenotype(s) (e.g. tonometry to evaluate effects on IOP, histology to evaluate effects on glaucomatous optic neurology).
B. Kits
The present invention provides methods, compositions and kits for the early detection of glaucoma. The kits can contain a nucleic acid segment encoding a BMP polypeptide or protein. The kit can further contain reagents for detecting an interaction between a sample and a nucleic acid or peptide of the present invention. The provided reagent can be radio-, fluorescently- or enzymatically-labeled. The kit can contain a known radiolabeled agent capable of binding or interacting with a nucleic acid or peptide or protein of the present invention.
The reagent of the kit can be provided as a liquid solution, attached to a solid support or as a dried powder. Preferably, when the reagent is provided in a liquid solution, the liquid solution is an aqueous solution. Preferably, when the reagent provided is attached to a solid support, the solid support can be chromatography media, a test plate having a plurality of wells, or a microscope slide. When the reagent provided is a dry powder, the powder can be reconstituted by the addition of a suitable solvent, that may be provided.
In still further embodiments, the present invention concerns diagnostic methods and associated kits for the diagnosis of glaucoma. It is proposed that the BMP associated peptides and nucleic acids of the invention may be employed to detect polymorphisms or mutations in the BMP nucleic acids from patient samples. In general, these methods will include first obtaining a sample suspected of containing such a polymorphism or mutation, contacting the sample with a peptide or nucleic acid of the present invention, as the case may be, under conditions effective to allow the formation of a complex, and then detecting the presence of the complex.
In general, the detection of complex formation is quite well known in the art and may be achieved through the application of numerous approaches. For example, the present invention contemplates the application of ELISA, RIA, indirect fluorescence techniques and the like. Generally, complex formation will be detected through the use of a label, such as a radiolabel or an enzyme tag (such as alkaline phosphatase, horseradish peroxidase, or the like). Of course, one may find additional advantages through the use of a secondary binding ligand.
The following examples are representative of the techniques employed by the inventors in carrying out aspects of the present invention. It should be appreciated that while these techniques are exemplary of preferred embodiments for the practice of the invention, those of skill in the art, in light of the present disclosure, will recognize that numerous modifications can be made without departing from the spirit and intended scope of the invention.
Cell culture: Human TM cells and ONH cells were generated from donor eyes as described (Steely et al. 1992; Steely et al. 2000; Wilson et al. 1993; Clark et al. 1994; Clark et al. 1995b; Clark et al. 1995c; Clark et al. 1996; Clark et al. 2001a; Clark et al. 2001b; Dickerson et al. 1998; Wordinger et al. 1998; Wordinger et al. 1999; Wordinger et al. 2000; Wordinger et al. 2002; Lambert et al. 2001; Agarwal et al. 1999; Liu et al. 2001). TM cells were grown from TM explants of donors ranging in age from 6 days to 90 years. Human optic nerve head astrocytes and lamina cribrosa (LC) cells were generated from carefully dissected optic nerve heads (donors aged 2 days to 90 years) and characterized according to previous reports (Lambert et al. 2001; Clark et al. 1995a). The cells wers grown to confluency in the following media: Ham's F10 media (JRH Biosciences, Lenexa, Kans.) containing 10% fetal bovine serum (HyClone, Logan, Utah) and antibiotics (Gibco BRL-Life Technologies, Grand Island, N.Y.) for TM cells; Dulbecco's modified Eagle's media (DMEM, HyClone) containing 10% FBS for LC cells; and astrocyte growth medium (AGM, Clonetics, San Diego, Calif.) containing 5% FBS for ONH astrocytes.
RT-PCR: Human TM and ONH tissues also were dissected from donor eyes (Wordinger et al. 1998; Wang et al. 2001). Total RNA was extracted from the TM and ONH cells and tissues using TRizol extraction (Gibco BRL-Life Technologies), and cDNA prepared by reverse transcription using standard procedures (Wordinger et al. 1998; Wordinger et al. 1999; Wordinger et al. 2000; Wordinger et al. 2002). PCR primers were designed using the Oligos 4.0 software program (see primer pairs in Table 1). All primer pairs were designed so that amplification of potentially contaminated genomic DNA sequences would produce mRNA PCR products that would be substantially larger than expected, because intron sequences that were excised during RNA processing would be included in genomic DNA. The β-actin PCR primers, AGGCCAACCGCGAGAAGATGACC (upstream) (SEQ ID NO: 55) and GAAGTCCAGGGCGACGTAGCAC (downstream) (SEQ ID NO: 56) with an annealing temperature of 55° C. yielded a PCR product of 350 bp.
PCR reactions were run as described (Wordinger et al. 1998; Wordinger et al. 1999; Wordinger et al. 2000; Lambert et al. 2001; Wordinger et al. 2002) using Taq Start Antibody Hot Start with the following cycle conditions: 2 minutes at 94° C., 2 minutes at 92° C., and 40 cycles of 30 seconds at the optimal annealing temperature, extension for 90 seconds at 72° C. and denaturation for 45 seconds at 92° C. The amplified PCR products were examined by horizontal electrophoresis in 1.5% agarose gels. To ensure specificity of the RT-PCR products, Southern blot analysis was performed with probes designed using Oligo 4.0 that hybridized to a region within the amplified PCR product. PCR products were sequenced to verify the specificity of the PCR reactions. Table 2 lists the members of the BMP family that are expressed in the human TM and ONH.
Western immunoblotting: Protein was extracted from cultured cells using lysis buffer, and proteins were separated by denaturing polyacrylamide gel electrophoresis prior to electrophoretic transfer to nitrocellulose membranes (Lambert et al. 2001). The membranes were blocked with 5% milk (for BMPs) or 3% gelatin (for BMPRs) and incubated with the following primary antibodies: BMP2, BMP4, BMP5, BMP7 (all from Santa Cruz, Santa Cruz, Calif.), or BMP-RIA, BMP-RIB, BMP-RII (from Jackson Immuno Research, West Grove, Pa.). The membranes were washed, incubated with secondary antibodies (goat anti-mouse IgG-horseradish peroxidase for BMPs, Santa Cruz; donkey anti-goat-horseradish peroxidase for BMP receptors, Jackson Immuno Research), and developed using the WesternBreeze chemiluminescence immunodetection system (Invitrogen, Carlsbad, Calif.).
Expression of BMPs, BMPRs mRNA in human TM cells and tissues: Amplification products of expected for BMP-2, BMP-4, BMP-5 and BMP-7 primer pairs in human TM cells and tissues are shown in
Expression of BMP and BMP receptor mRNA in human ONH cells and tissues: Amplification products of expected size for BMP-2, BMP-4, BMP-5 and BMP-7 primer pairs in human ONH astrocytes and ONH tissues are shown in
Amplification products of expected size for BMP-RIA, BMP-RIB, and BMP-RII primer pairs in human ONH astrocytes and ONH tissues are shown in
Expression of BMP proteins and BMP receptor proteins in human TM and ONH cells and tissues:
Expression of BMP associated protein mRNAs in cultured human TM cells and in human ONH cells: Amplification products of expected size for BMP associated protein primer pairs in human TM cell lines are shown in
Amplification products of expected size for BMP associated protein primer pairs in ONH astrocytes and LC cell lines are shown in
All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. More specifically, it will be apparent that certain agents which are both chemically and structurally related may be substituted for the agents described herein to achieve similar results. All such substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
The following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference.
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Company Overview of American Forest & Paper Association Inc
Company Overview
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Key Executives for American Forest & Paper Association Inc
American Forest & Paper Association Inc Key Developments
American Forest & Paper Association Inc. reported production results for the month of December 2013. The company reported that Total boxboard production increased 1.4% when compared to December 2012 and increased 1.1% from last month. Unbleached Kraft Boxboard production decreased over the same month last year and decreased compared to last month. Total Solid Bleached Boxboard & Liner production increased compared to December 2012 and increased compared to last month. The production of Recycled Boxboard was flat compared to December 2012 and decreased when compared to last month.
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Despite the uncertainty surrounding the implementation date for ICD-10, HIMSS remains committed to providing the industry with the tools and resources to ensure successful transition. The HIMSS ICD-10 PlayBook contains tools, guidelines, and information to help with your ICD-10 implementation.
The ICD-10 PlayBook provides critical information, resources, and toolkits to assist hospitals, ambulatory centers, practitioners, and their staff in transitioning to ICD-10.
ICD-10 Speakers Bureau May 2015
To help you with your ICD-10 transition, members of the HIMSS ICD-10 Task Force are available to share their knowledge and experience on ICD-10 implementation. Should you be interested in inviting a speaker to present to your organization, please contact Pam Jodock at email@example.com or 312-507-9924.
Operationalizing ICD-10: It's October 1, 2015 . . . Now What? Apr 2015
In order to continue to operate smoothly after the implementation of ICD-10, it is important to have a plan in place like that which is suggested here and to fully execute it. This paper addresses what you need to do to make certain your organization will be ready to weather the transition and minimize any operational and financial disruptions.
Operationalizing ICD10 - A HIMSS15 Presentation Apr 2015
A HIMSS15 presentation that asks what happens immediately before, during, and after implementation of the ICD-9 to ICD-10 transition?
Successful ICD-10 Implementation from a Provider Perspective Apr 2015
A HIMSS15 presentation that brings together three different provider organizations who share their insights and tips for testing for a successful ICD-9 to ICD-10 Implementation.
Talk Ten Tuesday: An Interview with Hamilton Todd, HIMSS ICD-10 Task Force Apr 2015
Listen to this webinar for information on how you can prepare your organization for a post ICD-10 launch world.
ICD-10: Curse or Blessing for Small Practices Mar 2015
Health care is transitioning from fee-for-service to value-based reimbursement. The better we take care of our patients, the higher our income. Hear from a small provider practice as she discusses ICD-10.
As a benefit of membership, HIMSS Corporate Members are invited to share thought leadership pieces on topics of their choice. The views and opinions expressed in these White Papers are those of the authors and do not necessarily reflect the views and opinions of HIMSS.
View Corporate Member White Papers related to the ICD-10 Transition.
The ICD-10 National Pilot Program, an industry-wide healthcare collaborative effort co-led by HIMSS and WEDI, was established in 2013 to develop a standard set of testing scenarios for the healthcare community and to identify an "asynchronous" testing model for small and large organizations who must test for ICD-10. The goal is for you to begin testing early and remediate your systems well in advance of the compliance date.
If you are interested in joining the HIMSS ICD-10 Task Force, contact Joanne Bartley
CMS is accepting additional July volunteers from May 11 through 22, 2015. Don't miss your chance to participate in end-to-end testing with Medicare prior to the October 1, 2015, implementation date.
The Centers for Medicare & Medicaid Services (CMS) shares five facts dispelling misconceptions about the transition to ICD-10.
CMS has released ICD-10 testing results.


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Leak-resistant packaging ensures a drier retail poultry caseCryovac poultry films, bags, absorbent pads and trays allow retailers to create a more appealing display and relieve shoppers from handling wet, sticky poultry packages. Cryovac also supplies vacuum shrink wraps and tray lidding for hundreds of retail food applications.
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+Vote List
by AdamThomas * Ranker
Staff tags 76 votes 28 voters 80,921 views 10 items
Staff tags 76 votes 28 voters 80,921 views 10 items
The 10 Most Disgusting Video Game Heroes
As gamers, we really ARE unaware of how hideous some of our heroes are. I mean, if you took some of them into reality and thought about what they would really look like, smell like and feel like, you'd find it difficult not to lose your lunch over their bright happy faces. In honor of these heroes, here are the downright raunchiest faces in gaming that aren't villains, but beloved heroes (or at least protagonists.)
By the way, it's just the ones you play as for now. No NPCs, villains or supporting characters because that would be just too damned easy.
Check out Ranker's other lists like the Most Disgusting Movies of all Time.
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- Tip: Navigate with your { left and right } arrow keys1«»+ 13- 1Super Meat Boy is an amazing game. The superb level design. The brutal difficulty. The hilarious cut-scenes. The cameos and bonuses... It's a pure joy to play.
Meat Boy himself though - he's horrifying.
He's a short (I think) humanoid, who I assume may have actually been a human boy. He has no skin, and bleeds EVERYWHERE HE GOES. To make matters even the slightest bit worse on an appearance scale he lost one of his teeth when the title screen hit him in the face, and one of his eyes is probably gone too. Just imagine a twelve year old boy running around your house without skin, grinning maniacally everywhere, and you have pictured what Meat Boy would look like on our plane of reality.
Hell if you watch the attached fan video, even though it keeps his cartoonish appearance, he's still fairly disgusting.
But it's that "skinless kid" version that's nightmarish. I'm not the only one to envision this, Magic the Gathering artist Dave Rapoza created this image for the game's PC cover:
Yeah, the whole cast of characters in the game is pretty awful actually.
Then there's the horror of his existence. Unlike most platformers, where the deaths of your guy aren't dwelled upon or really taken account of, in SMB, you actually get to go to hell, and discover the many dead versions of yourself in the pit of the dark lord Beezlebub. They even form into a giant dead body boss in order to stop you!
This means that maybe Meat Boy has powers similar to Mr. Immortal of the Great Lakes Avengers. That his entire life is a series of awful, painful deaths which he'll never be able to escape from.
Wow. That's just . . . yipes.l< << PREV 1 of 10 NEXT >>


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A People That Dwells Alone
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Thursday, November 15, 2012


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im obsessed with these. Easy to make too! Shoes+ rhinestones+glue. Funky laces or Ribbon. 2 funky hair bows. Easy to change up. - Couldn't find the instructions but I think this can be done visually. I think I've got an old pair of kids shoes that I can practice on.
So cute to make for little girls. Shoes, rhinestones, glue, funky laces or ribbon, & 2 funky hair bows.
RAINBOW SHERBERT Converse Bling Pink High Tops for Infants and Toddlers with Boutique Bows and SPECTACULAR Swarovski Crystals...
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The Kylee Set Aqua pink Lace Diaper Cover Headband by KutieTuties infant, toddler, 1st birthday, birthday, newborn, baby, girl bow leggings
Pretty sure every little girl needs these. These could be the most precious tights ever! So adorable!!
Inspiration (photo)~ This is the photo that turned me onto Matilda Jane. Scouts Closet #matildajaneclothing, #MJCdreamcloset
Adorable little girl. To learn how to grow your hair longer click here - blackhair.cc/1jSY2ux
This hairstyle is a perfect alternative for a artsy outfit... do artsy hair and a simple outfit! Perfect for a photoshoot
Fun 4th of July hairdo for girls. {If you know the correct link please let me know so I give credit to t his adorable idea!}


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Portuguese martyr. Hewas an archpriest of Siure. Born in Auranca, near Coimbra, he answered the desire for a priestly vocation and served the Church until captured by the Saracens. He died in Cordoba, Spain, as a result of cruel treatment by his captors.
St. Matthew, one of the twelve Apostles, is the author of the first Gospel. This has been the constant tradition of the Church and is confirmed by the Gospel itself. He was the son of ... continue reading | shop
St. Thomas was a Jew, called to be one of the twelve Apostles. He was a dedicated but impetuous follower of Christ. When Jesus said He was returning to Judea to visit His sick friend ... continue reading
St. Martin de Porres was born at Lima, Peru, in 1579. His father was a Spanish gentleman and his mother a coloured freed-woman from Panama. At fifteen, he became a lay brother at the ... continue reading | shop
Miguel Jose Serra was born on the island of Majorca on November 24, 1713, and took the name of Junipero when in 1730, he entered the Franciscan Order. Ordained in 1737, he taught philosophy and ... continue readingMore Saint of the Day
Elizabeth Bayley Seton was the first native born American to be canonized by the Catholic Church. Born two years before the American Revolution, Elizabeth grew up in the "cream" of New York society. She was a prolific reader, and read everything from the ... continue readingMore Female Saints
St. Michael the Archangel - Feast day - September 29th The name Michael signifies "Who is like to God?" and was the warcry of the good angels in the battle fought in heaven against satan and his followers. Holy Scripture describes St. Michael as "one of the chief ... continue reading
The name Gabriel means "man of God," or "God has shown himself mighty." It appears first in the prophesies of Daniel in the Old Testament. The angel announced to Daniel the prophecy of the seventy weeks. His name also occurs in the apocryphal book of Henoch. He was the ... continue reading
All we know of Barnabas is to be found in the New Testament. A Jew, born in Cyprus and named Joseph, he sold his property, gave the proceeds to the Apostles, who gave him the name Barnabas, and lived ... continue reading
If one had to choose one saint who showed the humorous side of holiness that would Philip Neri. Born in 1515 in Florence, he showed the impulsiveness and spontaneity of his character from the ... continue reading
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During his visit to the United States this coming September, Pope Francis will canonize Blessed Junipero Serra, the heroic 'Apostle of California.' Once that happens, the Golden State will have its own patron saint and the Church will have another great missionary role ... continue readingMore Christian Saints & Heroes


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I am writing a Flex application for use on a private intranet with no external Internet access. I want to use Google's 3D Maps Flex API, but it must be connected to the internet to download map tiles on demand.
Is there a way to locally cache the 3D map tiles and data so that I can run this app without an internet connection? And if not, is there a 3D GIS that supports Flex integration and allows for a local map cache?


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Zheng Jie, Henri Kontinen lose 0-2 at French OpenZheng Jie (L) of China and Henri Kontinen of Finland compete during the mixed doubles semifinal against Lucie Hradecka of the Czech Republic and Marcin Matkowski of Poland at 2015 French Open tennis tournament in Paris, France on June 3, 2015. Zheng ... People.com.cn, 1 month ago
UPDATE 1-Tennis-French Open mixed doubles quarterfinal results - Reuters UK, 1 month ago
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China's Zheng Jie vows to fight on
Chinese star Zheng Jie said here on Wednesday that she has not thought about retiring from the tour despite a shoulder injury has prevented her from playing the singles events. Zheng, 32, won her first round mixed doubles match with Finland's Henri ...China.org.cn, 1 month ago XINHUA - China's Zheng Jie vows to fight on Namibia Press Agency, 1 month ago
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Taiwan's Chan Yung-jan and Zheng Jie advanced to the doubles final at the Aegon International in Eastbourne, England, on Friday when their semi-final opponents, second-seeded Russian duo Ekaterina Makarova and Elena Vesnina, withdrew. The ...Taipei Times Online, 1 week ago Chan and Zheng edge tight battle, advance to semis Taipei Times Online, 1 week ago Taiwan's Chan advances in Eastbourne Taipei Times Online, 1 week ago Chan and Zheng ousted in semis Taipei Times Online, 2 weeks ago
A Reference-Free Method for Brightness Compensation and Contrast Enhancement of Micrographs of Serial Sections
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Bach1 Represses Wnt/{beta}-Catenin Signaling and Angiogenesis [Original Research]
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Body's Response to Spicy Foods Guides Design of New Pain Relief Drugs
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Establishment and Validation of SSCLIP Scoring System to Estimate Survival in Hepatocellular Carcinoma Patients Who Received Curative Liver Resection
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- In Champoussin
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Self-Catered Ski Apartment in Champoussin, Switzerland
Sleeps up to 6, from ₤387 per week. Save up to ₤157.
Price Includes :- Accommodation Only
Le Sportif is in the Swiss ski resort of Champoussin and has Les Crosets within reach for a days skiing.
Sports and Outdoors
Biking - Hiking - Ice Rink - Mountain Biking - Riding - Skiing - Snowboarding
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Map of Ski Chalets and Apartments in Champoussin
NOTE: Locations provided to us are not always precise; please check Accommodation Location when booking!
Le Sportif is convenient for Skiing and Snowboarding in Swiss Ski Resorts including Champoussin and Les Crosets.


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Play any type of Game at Y8.com. The biggest Game Collection to play free online. Flash, Unity 3D, Html5, Android, Java and Shockwave.
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Thanks for that info. I'll see if/when it is coming downunder and if I can afford it.
Does anyone know why the UK DVDs are so expensive? (I'm talking about in comparison to the US shows.) For some strange reason you can pay twice as much for a UK series that has only half the number of episodes. Well that's how it is in Australia anyway. Hopefully it's not so bad elsewhere.
While I'm here, was that it for this Series - 6 Episodes? I didn't think I'd seen very many but didn't realise it was so few.
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Taylor Swift has more power than many of us were willing to admit.Apple's soon-to-launch music subscription service may have sounded good on paper to execs, but it was causing bad blood among musicians and artists — until one of them swiftly challenged Apple head on and, basically, won.
By Wade AllenMore Content NowDidn't know Hilary Duff was still recording? You're not alone.
It's been more than a half-century since Chubby Checker jubilantly danced onto the American Bandstand stage and introduced to the world to "The Twist." He changed music history in two minutes and 42 seconds.
It's hard to believe it has been 25 years since Mariah Carey arrived on the music scene.
Call off Ponce de León — I've found the Fountain of Youth. A couple of weeks ago, I wrote that I'm comfortably middle-aged. I am, but that doesn't mean that it's not nice to feel young again every once in a...
I should probably mention that I'm a complete sucker for the country soul that came out of FAME Studios in Muscle Shoals, Alabama, and to which Amy Black pays tribute on her latest, "The Muscle Shoals Sessions" (Reuben Records).
Chris Botti now travels the world, leaving audiences in awe of his trumpeting skills and smooth, world-class musicianship. But he won't soon forget his start and it wasn't nearly as glamorous.
What do each of these songs have in common? "We Belong Together" (Mariah Carey, 2005), "Umbrella" (Rihanna, 2007), and "I Gotta Feeling" (Black Eyed Peas, 2009).
Now that we've had a couple weeks to digest the sad news of Fox's decision to cancel "American Idol" after next season, let's look at the big picture, and also take time to congratulate season 14 winner Nick...
If you're fortunate enough to have a hit song, you might find yourself at the Billboard Music Awards.
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If the fancy tech on TV crime shows makes you chuckle, keep in mind that there are many other ways real cases differ from the TV versions. Deb Shinder offers tips for working with ...
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Habayit Hayehudi seeking to moderate budget cuts to ultra-Orthodox
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I was born in a a log cabin in Corbin Kentucky. No wait! the Log Cabin part was a dream. I started playing guitar when I was about 12. Then years later, I joined the Army and got married. Didn't play as much for about 15 years. Now I play every day. I keep improving, but its a race against time. That's OK, it's all about the journey.


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Take A Second Look!
Dear Readers: Your faithful Mexican is putting the final touches to his coming magnum opus, Taco USA: How Mexican Food Conquered America (out April 2012) and is thus at the rancho, getting handmade tortillas made by his chica in pigtails while I work on rewrites. But instead of a Best Of columna, I've decided to revisit one of my all-time favorite reader interactions. Remember back in 2007, when I asked ustedes who are half-Mexican and half-something else to tell us what you call yourselves? The brilliant, hilarious responses offered show how genius the Mexi brain truly is. You can find the full list online—in the meanwhile, enjoy and see you in una semana!
Ask the Mexican at firstname.lastname@example.com, be his fan on Facebook, follow him on Twitter or ask him a video question at youtube.com/askamexicano!
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Betty Earlene Saunders
Betty Earlene Saunders, 77, passed away Thursday, May 23, 2013, in Wichita Falls, Texas. Memorial services will be held at 2 p.m. Thursday, May 30, 2013, at First Baptist Church in Bowie, Texas, with Pastor Mike Henson and Alicia Shelton assisting.
Mrs. Saunders was born Betty Earlene Richardson on February 6, 1936, in Montague, Texas, to Earl and Sue (Reed) Richardson. She was a lifelong residence on Montague County living in Bowie for 52 years. She worked as a jeweler for the Time Shop for over 30 years until she retired in 1998. Betty was a member of the First Baptist Church and loved God, her family and her many friends. She treasured the time with her family, especially her great grandson Connor.
She was preceded in death by her parents and her husbands, Jack Curnutte in 1984 and Byron Saunders in 2000.
Betty is survived by her four children, Cheryl Botkin and her husband Michael of Wichita Falls, Debra Funkhouser and her husband Rich of Frisco, Texas, Earl Curnutte and his wife Phyllis of Adkins, Texas, and Cindy Sims of Fort Worth, Texas. She is also survived by a sister, Pearlene Eldred of Nocona, Texas; five grandchildren, Craig White, Marisa White, Cory Curnutte, Lisa Stockton, and Chad Stockton; as well as her great-grandson, Connor White.
Memorials may be made to Legacy Garden Walkway - Hospice of Wichita Falls, 4909 Johnson Road, Wichita Falls, Texas, 76310.
Condolences may be sent to the family at www.fallsfuneralhome.com.
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What are the applications for your personal use that needs a small database like SQLite? I am thinking of trying a few popular databases and SQLite is surely the first one I am planning to try since I know barely nothing about database except some simple programming years ago.
I learned that SQLite is good for personal use. But embarrassingly I do not see any application except maybe managing my list of phone numbers/contact info, which has probably a few hundred items. What's your experience?
FYI, I use EndNote for my reference and softcopy of books, and I feel iTunes' music/media management is ok since I am not a frequent user anyway. And others? I do lots of coding, but I just use some simple etags tools for that. And I pretty much use .txt file (sometimes in the asciidoc style) for my notes. I have quite a bunch of notes, but not that many either.
So, really, what are your personal applications that need a small database instead of existing tools and plain text files?


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100% PROOF Pope Francis is ANTICHRIST______
There are 595735 comments on the CBC News story from Jul 10, 2007, titled Roman Catholic church only true church, says Vatican. In it, CBC News reports that:The VaticanA issued a document Tuesday restatingA its belief that the Roman Catholic Church is the only true church of Jesus Christ.
Join the discussion below, or Read more at CBC News.
#453119 Jun 17, 2013
100% PROOF Pope Francis is ANTICHRIST______
#453120 Jun 17, 2013
The Gospel of FSM does say that He (accidentaly) drowned the world except for Noah and the ark. That's the part that made me laugh the hardest.
#453121 Jun 17, 2013
Ezekiel 31
Pharaoh to Be Slain
1 In the eleventh year, in the third month, on the first day of the month, the word of the Lord came to me: 2 Son of man, say to Pharaoh king of Egypt and to his multitude:Whom are you like in your greatness?
3 Behold, Assyria was a cedar in Lebanon,
with beautiful branches and forest shade, and of towering height, its top among the clouds.
4 The waters nourished it; the deep made it grow tall, making its rivers flow around the place of its planting, sending forth its streams to all the trees of the field.
5 So it towered high above all the trees of the field; its boughs grew large and its branches long
from abundant water in its shoots.
6 All the birds of the heavens made their nests in its boughs; under its branches all the beasts of the field gave birth to their young, and under its shadow lived all great nations.
7 It was beautiful in its greatness, in the length of its branches; for its roots went down to abundant waters.
8 The cedars in the garden of God could not rival it, nor the fir trees equal its boughs; neither were the plane trees like its branches; no tree in the garden of God was its equal in beauty.
9 I made it beautiful in the mass of its branches,
and all the trees of Eden envied it, that were in the garden of God.
10 Therefore thus says the Lord God: Because it towered high and set its top among the clouds, and its heart was proud of its height,
11 I will give it into the hand of a mighty one of the nations. He shall surely deal with it as its wickedness deserves. I have cast it out.
12 Foreigners, the most ruthless of nations, have cut it down and left it. On the mountains and in all the valleys its branches have fallen, and its boughs have been broken in all the ravines of the land, and all the peoples of the earth have gone away from its shadow and left it.
13 On its fallen trunk dwell all the birds of the heavens, and on its branches are all the beasts of the field.
14 All this is in order that no trees by the waters may grow to towering height or set their tops among the clouds, and that no trees that drink water may reach up to them in height. For they are all given over to death, to the world below, among the children of man,with those who go down to the pit.
15 Thus says the Lord God: On the day the cedar went down to Sheol I caused mourning; I closed the deep over it, and restrained its rivers, and many waters were stopped. I clothed Lebanon in gloom for it, and all the trees of the field fainted because of it.
16 I made the nations quake at the sound of its fall, when I cast it down to Sheol with those who go down to the pit. And all the trees of Eden, the choice and best of Lebanon, all that drink water, were comforted in the world below.
17 They also went down to Sheol with it, to those who are slain by the sword; yes, those who were its arm, who lived under its shadow among the nations.
18 Whom are you thus like in glory and in greatness among the trees of Eden? You shall be brought down with the trees of Eden to the world below. You shall lie among the uncircumcised, with those who are slain by the sword.
This is Pharaoh and all his multitude, declares the Lord God."
Since: Sep 09
Vanderhoof, Canada
#453122 Jun 17, 2013
You can keep on believing that as a Catholic you are special if it so pleases you ... but it's common sense that a god that favored Jews would not betray or confuse the Jews by claiming they must become Catholic.
The god would command that they stop straying FROM Judaism, and practice Judaism as Judaism should be practiced.
Of course religion is all based on hearsay from the get-go, so the idea that it confuses people is a given.
Myths were created by theologians TO confuse (divide and conquer)... and they succeeded.
#453123 Jun 17, 2013
Excellently put.
Since: Sep 09
Vanderhoof, Canada
#453124 Jun 17, 2013
The ex-Jew Catholics opened up the old testament ... changed meanings of the words, added their story of a Jesus-myth and presto ... up came a supposed new testament based on new lies that claimed truth as it's own.
Your religion is nothing special. Lies can't BE special.
Religion is theory from the get-go ... nothing more ... nothing less. You no more know the future than does a butterfly.
Since: Sep 09
Vanderhoof, Canada
#453125 Jun 17, 2013
Gee, they must be in the same religion cult. They agree on the dogmas.
#453126 Jun 17, 2013
OldJG wrote:
Oxbow wrote:
<quoted text>
Scripture alone (from the Reformation slogan Sola Scriptura) is the teaching that Scripture is the Church's only infallible and sufficient rule for deciding issues of faith and practices that involve doctrines. While the Bible does not contain all knowledge, it does contain that which is necessary for salvation. Indeed, if something is not found in Scripture, it is not binding upon the believer. This view does not deny that the Church has the authority to teach God's Word. Furthermore, while tradition is valuable, it but must be tested by the higher authority of the Scriptures.
<quoted text>
Let's ask this question as well. Did the Bible stand up, open it's mouth and declare which of your popes was correct in their interpretation? Please do not lie and tell us your theology has never changed. We can and have presented the fallacy of that argument over and over and over and over and over and over and over again. Comprende'
You said, quote, "The Catholic Church wasn't started because a group of people opened up the Bible and said, "duh, it looks like Peter was the leader... we'll call him 'Pope', and duh ik looks like Jesus says the bread is his body..." End quote.
Please use the correct names when describing the "church" as you call it. The Christian church not the Roman Catholic church....
You said, quote, "The Catholic Church came before the NT was written." End quote.
Again, The Christian church and not the Roman Catholic church.
You said, quote, "Say, how come Catholicism looks remarkably similar before Constantine than post Constantine." End quote.
Yes, Roman Catholicism is exactly as Constantine left it. Corrupt and confused.
You said, quote, "Bottom line, if you were speaking truth, I would join ya." End quote.
Bottom line. You would not know the truth if it fell in your lap.
You said, quote, "I do not catch the Catholic Church doing it - because they don't need to. Truth is truth." End quote.
The Roman Catholic church has changed it's theology like you would change your clothes. One day this is truth and the next day something else is truth. Over and over and over and over and over and over again since Satan established your cult. The truth is not in the Roman Catholic church and apparently not in you.
#453127 Jun 17, 2013
Simmer down and stop slandering. Don't you know that you will be judged as well?
You will have to account for every idle word you say and every lie you spout.
Since: Sep 09
Vanderhoof, Canada
#453128 Jun 17, 2013
Luther changed the dogmas in the pretense that a god wanted members of clergy to marry.
You are trying to claim that the reformation was not about Luther wanting to get married.
I believe all religion is a lie, so no matter what you try to support in concern with the words of your favorite theologians it will based on lies ... not ownership of truth.
Since: Sep 09
Vanderhoof, Canada
#453129 Jun 17, 2013
If all the supposed holy books did not exist ... preachers could not fight over the meanings of the words.
Imagine how dull their lives would be if they couldn't PREACH and fight over who is right.
Just imagine.
#453130 Jun 17, 2013
I suppose you are correct, in that confusion is the norm, in any age.
The problem of which you speak is a common one as well, and generally one needs to first eat some humble pie before they go questing after truth, and then eat another piece of that pie after finding it.
I love humble pie.
Since: Apr 07
Location hidden
#453131 Jun 17, 2013
June VanDerMark wrote:
<quoted text>
You can keep lying if it so pleases you ... but if there is a god that serves only Jews ... you are in over your head with lies upon lies.
I suggest you keep THAT in mind.
You can manipulate other people, but you can't manipulate a god ... if that god just HAPPENS to exist.
Of course, you have NOT told June any lies respective to Luther.
Luther posted his 95 THESES in 1517 in Wittenberg, Germany, and the Pope of the day excommunicated him in 1520. Meanwhile, his teachings had spread like wildfire throughout Germany.
In 1523, a group of 12 nuns, inspired by Luther's teachings, escaped their cloister ("escaped" because they would never have been PERMITTED to leave) with the help of a respected merchant and leading citizen, one Leonard Kopp, and Luther himself.
Once they had escaped, what was to be done with them? Three of them returned to their own homes, while the remaining nine waited for arranged marriages. Naturally, since Luther was single, his friends repeatedly suggested that he marry one of the ex-nuns himself. He rejected the idea, "not because he was a sexless stone, nor because he was hostile to marriage, but because he expected daily the death of a heretic."--"HERE I STAND: A LIFE OF MARTIN LUTHER, Roland H. Bainton
By 1525, all the nuns had been married except one, a 26 year old woman named Katherina von Bora. In the 16th century, 26 was considered a bit long in the tooth for a first marriage :) so her position was delicate. Although two or three matches had been attempted for Katherina, all had fallen through for one reason or another. The latest suggestion was one Dr. Glatz, whom she couldn't stand :) Finally, she asked the help of a visitor to Wittenberg, a Dr. Magdeberg, who conveyed a message to Luther. She would accept either Magdeberg himself or Luther.
Luther had never had any intention of marrying. His father, however, had other ideas. He was a very successful merchant who had been deeply displeased when his son Luther chose the Church as his career instead of becoming a merchant like his father. When Luther told him about the idea of his marrying Katherina, he meant it as a joke, but his father took it seriously :) He wanted to pass on the family name. And Luther began to see the idea in a different light. He fully expected to be burned at the stake within a year, so starting a family THEN could only be seen as defiance at anything that might happen to him. Also, he would rescue Katherina from her dilemma.
"He summed up by giving three reasons for his marriage: to please his father, to spite the Pope and the Devil, and to seal his witness before martyrdom." --"HERE I STAND: A LIFE OF MARTIN LUTHER, Roland H. Bainton
In short, Luther's reasons for marrying were practical in nature, not for love. But he and Katie (whom he called "my rib"!) fell genuinely and deeply in love after they were married. Katherina was an excellent housekeeper, which as Luther's household was continually expanding through the years (many students, etc. lived with the Luthers), having a well-run domestic life was in itself a considerable contribution to Luther's work.
The Luthers had six children together. And by the way, Katherina was no doormat. She fully supported her husband's work, but she was never afraid to speak her mind to him.
I absolutely LOVE their story! Always have :)
#453132 Jun 17, 2013
Sure, accidents happen. Silly me.
Thank you for calling that to my attention. This allows me to correct my beliefs.
No one has died because of my God, except through accidents.
Since: Aug 08
He Gave His SON to Save us
#453133 Jun 17, 2013
And hey what about all those Catholic politicians who are fervently pro voice in their voting.
Ann Counter does not speak for all Christians .
#453134 Jun 17, 2013
Jesus did do "something magnificent and beautiful" while on Earth. He established His Church which has been a light to the whole world illuminating the way to Him.
He didn't wave a magic wand and take away free will. If He had of done as you think He should have, He would have been the biggest tyrant ever.
You are thinking like the Jews thought, that the Savior King was going to come as a mighty ruler here on earth and solve everyone's earthly/material problems. That's not what Jesus came to do. The perfect utopia is not going to happen until His second coming and there will be a new heaven and a new earth.
#453135 Jun 17, 2013
I'm not sure that the Reformation was anchored in the desire for clerical marriage.
Can you cite evidence to support this claim you're making?
#453136 Jun 17, 2013
Ok, so you must believe that preborn babies have sinned? Newborns have sinned? The profoundly retarded have sinned? Ancephalic babies have sinned?
And also Jesus has sinned?
The verse does say "ALL", doesn't it?
#453137 Jun 17, 2013
Black Thunder 42:
Sorry. I misunderstood your post. And so I went around to another direction, to challenge your understanding. It is often difficult to challenge another's understanding, or broaden their way of thinking, which was my intention, and still is, without some misunderstandings in the attempt.
So, for one to have memories, there must be an object of that memory. Likewise, for there to be a reflection in a mirror, there must be an object as well.
Can you agree to these two points, that there must be objects?
#453138 Jun 17, 2013
I think you give religion too much credit. A theory is a rational type of abstract or generalizing thinking, usually put forth for the purpose of further measuring and testing.
Religion is based on myth, with no rational, real world evidence required. Few believers seek to test or measure a religious myth.
If evidence appears to refute a theory, then that theory is reworked or dismissed as refuted.
No amount of real-world, real-life evidence will cause true believers to dismiss their chosen myth.
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« March 25 March 27 » Wednesday, March 26, 2008
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March 26, 2008 in Business on Page A10 NEW YORK – Home prices plunged by record levels in January from a year ago, with almost no major cities immune from the spiraling market. Analysts worried that even the …
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March 26, 2008 in Business on Page A10 NEW YORK – American consumers are gloomier about the economy than at any point since just before the U.S. invasion of Iraq, as slumping housing prices and soaring fuel costs …
In brief: Tribe to pay $9.5 million for 600 gambling machines
March 26, 2008 in Business on Page A10 The Spokane Tribe of Indians plans to buy 600 slot-style electronic gambling machines and accessories, worth an estimated $9.5 million, an Austin-based game manufacturer announced. Multimedia Games Inc. will deliver …
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Even Las Vegas feels the economic pinch
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Clear Channel stock plunges after report
March 26, 2008 in Business on Page A11 Shares of Clear Channel Communications Inc. plummeted in late trading Tuesday, following a report that the media company's private buyout is on the brink of collapse. Shares fell $1.89, or …
Sirius-XM merger creates questions for customers
March 26, 2008 in Business on Page A11 More than 17 million satellite-radio subscribers heard about the proposed XM and Sirius merger, looked at their radios and saw expensive doorstops. According to the companies' proposed merger, the current …
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March 26, 2008 in City on Page B1 More than $100,000 has been recovered and two people arrested following a safe heist at a rural home. The arrests were made Monday after sheriff's deputies discovered two suspects had …
City ends year with $6.7 million extra
March 26, 2008 in City on Page B1 In a sea of depressing economic data, the city of Spokane has some good news. Spokane's Chief Financial Officer Gavin Cooley reported this week that the city ended 2007 with …
Accuracy watch
March 26, 2008 in City on Page B1 For 03-26-2008
Lakeland levy passes easily
March 26, 2008 in Idaho on Page B2 RATHDRUM – Lakeland School District voters have been so consistent in supporting tax measures that school officials have a hard time remembering when one last failed. Once again, voters came …
In brief: Bush pardons Spokane attorney
March 26, 2008 in City on Page B3 President Bush pardoned 15 people Tuesday, including a Spokane attorney, and commuted the prison sentence of another. The pardon list includes William L. Baker, of Spokane, who was convicted of …
Message in a bottle found 21 years later
March 26, 2008 in City on Page B3 SEATTLE – Merle Brandell and his black lab Slapsey were beachcombing along the Bering Sea when he spied a plastic bottle among the Japanese glass floats he often finds along …
Troy Mine may face over $90,000 in fines
March 26, 2008 in City on Page B3 MISSOULA – Federal mine regulators have proposed over $90,000 in fines against Troy Mine, based on inspections carried out after a mine worker was killed in a cave-in last summer. …
Judge upholds arsonist's records requests
March 26, 2008 in City on Page B3 SEATTLE – A man who's serving 24 years for having the cars of two lawyers firebombed might be creeping out prosecutors by seeking information about them under the Public Records …
Area IRS office open Saturday
March 26, 2008 in City on Page B3 Looking for help on your tax return? Spokane's IRS office will be open from 8 a.m. to 3 p.m. Saturday to help people file their returns, which could bring an …
Senate panel backs primary reform
March 26, 2008 in Idaho on Page B4 BOISE – Idaho would move to a "modified-closed" primary election system, under legislation sent to the full Senate on a party-line vote Tuesday. The measure, proposed by the nonpartisan citizen …
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Washington Records
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B.C. pine beetle epidemic runs out of trees
March 26, 2008 in City on Page B5 VANCOUVER, B.C. – The mountain pine beetle epidemic in British Columbia is coming to a close, but only because the pests have run out of trees. The voracious beetle has …
Parachute may have been hijacker D.B. Cooper's
March 26, 2008 in City on Page B5 SEATTLE – The FBI said Tuesday it's analyzing a torn, tangled parachute found buried in southwest Washington to determine if it might have been used by legendary plane hijacker D.B. …
Good old days are gone
March 26, 2008 in Opinion on Page B6 I would be a lot more worked up about getting Michigan and Florida delegates seated at the Democratic National Convention this summer if we were hearing a coherent economic policy …
Our View: Dorm upgrades help with recruiting, retention
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