text:
|Publication number
|Publication type
|Application number
|Publication date
|Jan 13, 1998
|Filing date
|Aug 31, 1994
|Priority date
|Aug 31, 1994
|Fee status
|Also published as
|Publication number
|Kouji Matsushima
|Original Assignee
|Chugai Pharmaceutical Co., Ltd.
|Export Citation
|BiBTeX, EndNote, RefMan
|Patent Citations (3), Non-Patent Citations (63), Referenced by (5), Classifications (19), Legal Events (6)
|External Links: USPTO, USPTO Assignment, Espacenet
The present invention relates to the prevention and/or the treatment of nephritis. More particularly, the invention concerns a method of suppressing neutrophil infiltration and protein excretion associated with glomerulonephritis comprising administering an antibody directed against interleukin 8 (IL-8).
Renal disorders can be classified pathologically into vascular disease, glomerular disease, tubulointerstitial disease and renal failure by the clinical state based on the major lesion site. At present, detection of urinary protein, especially urinary albumin has been recognized as an important diagnostic criterion of these disorders (see, for example, "Clinical Nephrology 2nd edition", 29-33, 1978, vitro, Brown and Company Inc.: "A Handbook of Kidney Nomenclature and Methodology", 167-195, 1975, vitro, Brown and Company Inc.")
All renal disorders with glomerular dysfunction as the main lesion are accompanied by remarkable abnormalities in the urinary protein level and urinary precipitates. These are induced by inflammation in the glomeruli. Glomerulonephritis is characterized by the infiltration of inflammatory cells into glomeruli and proliferation of mesangial cells (Pusey, C. D. et al., Diseases of the Kidney, ed. by Schrier, R. W. et al., Little, Brown and Company, Boston/Toronto, 1827-1884 (1988). The inflammation in the glomeruli occurs via various mechanisms. In particular, it is considered that glomerulonephritis may be mediated by an immunological mechanism at the acute phase (Germuth, F. G. et al., J. Exp. Med. (1953) 97:257-282; Dixon, F. J. et al. J. Exp. Med. (1961) 113:899-920; Fleuren, G. J. et al. Lab. Invest. (1978) 8:496-501; and Couser, W. G. et al. J. Clin. Invest. (1978) 62:1275-1287). This immunological mechanism involves two pathways; one is characterized by the deposition of immune complexes which have been preformed in circulating blood to the glomeruli and the other by the binding of a circulating antibody to an antigen which is on the surface of cells constituting the glomeruli. The deposition of immune complexes in the glomeruli by either mechanism induces the activation of the complement system and the infiltration of inflammatory cells including monocytes and neutrophils, and then glomerulus tissues are destroyed.
In several experimental animal models of immune complex-mediated glomerulonephritis, the infiltration of leukocytes, in particular, neutrophils is frequently observed at the site of the main lesion, in the early stage of the disease. The precise mechanism and the pathological role of the infiltration of leukocytes remain unclear. However, as an inflammatory reaction appears to be involved, and steroids are commonly used in the treatment of glomerulonephritis. This approach to treatment appears less than ideal since steroids exhibit a variety of undesirable side effects, some of them serious.
IL-8, formerly called monocyte-derived neutrophil chemotactic factor (MDNCF) (Yoshimura, T. Proc. Natl. Acad. Sci. USA (1987) 84:9233) or neutrophil attractant/activation protein-1 (NAP-1) (Peveri, P. et al. J. Exp. Med. (1988) 167:1547, is a chemotactic and activating polypeptide for human leukocytes (Ko, Y-C. et al. J. Immunol. Method (1992) 149:1227-1235). IL-8 is a potent neutrophil chemotactic cytokine and participates in the migration of neutrophils toward inflammatory sites. IL-8 activates neutrophils by accelerating degranulation and elevating the free Ca2+ concentration in the cytoplasm and also induces neutrophil migration (Hebert, C. A. et al. Cancer Investigation (1993) 11:743-750) to thereby destroy the infiltrated tissue. IL-8 is secreted by mesangial cells and endothelial cells in response to IL-1 or TNFα in vitro (Matsushima, K. et al. J. Exp. Med. (1988) 167:1883-1893; Abbot, F. et al. Kidney Int. (1991) 40:597-605; Kusner, D. J. et al. Kidney Int. (1991) 39:1240-1248; Zoja, C. et al. Am. J. Pathol. (1991) 138:991-1003; and Brown, Z. et al. Kidney Int. (1991) 40:86-90). Differential cleavage of the secreted IL-8 at N-terminus yields variants including the 79-, 77-, 72-, 71-, 70- and 69-amino acid forms. The relative proportion of IL-8 variants secreted depends on both the type of cell and the type of stimulus used (Hebert, C. A. et al. (supra).
The present inventor has found that in several recognized animal models, the administration of WS-4 antibody, which specifically neutralizes the biological activities of IL-8 by binding to IL-8, suppresses infiltration of neutrophils, and inhibits the neutrophil-dependent inflammatory reaction in LPS-induced dermatitis (Harada, A., et al. Int. Immunol. (1993) 5:681-690) and lung reperfusion injury (Sekido, N. et al. Nature (1993) 365:654-657). However, it remains unknown whether IL-8 is involved in nephritis.
The invention provides a new approach to preventing and/or treating nephritis. This approach is grounded in the inventor's hypothesis that IL-8 participates in neutrophil infiltration in glomerulonephritis and is responsible for elevated levels of protein excreted in the urine. The present inventor has verified this hypothesis in animal models and shown that administration of an antibody directed against IL-8 lower the levels of excretion of protein and albumin to normal as well as suppresses in part neutrophil infiltration into the glomeruli.
Thus, in one aspect, the invention is directed to a method to decrease the excretion of protein and/or albumin into the urine of a subject afflicted with nephritis, which method comprises administering to said subject antibodies immunoreactive with the IL-8 of the subject. Alternatively, or in addition, other moieties that interfere with the biological activity of IL-8 could be used. Similarly, the invention is directed to a method to suppress neutrophil infiltration of the glomeruli, which method comprises administering to said subjects antibodies immunoreactive with the IL-8 of the subject, or other moieties that interfere with IL-8. Immunoreactive fragments of the antibody may also be used. The methods of the invention may be combined with other treatments for nephritis.
In another aspect, the invention is directed to pharmaceutical compositions useful in the methods of the invention.
The invention method is thus useful in ameliorating at least one of the symptoms of nephritis, particularly glomerulonephritis, and more particularly inflammatory glomerulonephritis such as glomerulonephritis caused by the deposition of immune complexes or glomerulonephritis accompanied by the infiltration of neutrophils into the glomeruli.
FIGS. 1a, 1b and 1c are copies of photomicrographs (�3000 magnification) showing the results of a histological study on renal tissues of the BSA-immunized and control antibody-treated rabbit (FIG. 1a), BSA-immunized and anti-IL-8 antibody-treated rabbit (FIG. 1b) and normal rabbit (FIG. 1c).
FIG. 2 is a bar graph showing suppression of infiltration of neutrophils into the glomeruli by anti-IL-8.
FIGS. 3a and 3b are copies of photomicrographs (�300 magnification) showing the results of immunohistological observation on renal tissues of the BSA-immunized, control antibody-treated rabbit wherein anti-BSA antibody (FIG. 3a) or anti-rabbit IgG antibody (FIG. 3b) was used as an antibody for detecting the deposition of BSA and rabbit IgG in glomeruli.
FIG. 4 is a bar graph showing the effect of anti-IL-8 on deposition of the immune complex.
FIGS. 5a and 5b are copies of photomicrographs (�250 magnification) showing production of IL-8 protein in renal tissues by staining with WS-4 in untreated normal rabbit (FIG. 5a) and BSA-immunized rabbit (FIG. 5b).
FIG. 6 is a bar graph showing urinary IL-8 excretion in BSA-immunized, control antibody-treated rabbits.
FIG. 7 is a bar graph showing the effect of anti-IL-8 on the urinary protein excretion.
FIG. 8 is a bar graph showing the effect of anti-IL-8 on the urinary albumin excretion.
The invention takes advantage of the discovery by the inventor herein that IL-8 appears to mediate the infiltration of neutrophils into the glomeruli in the progress of the inflammatory kidney condition known as nephritis. The methods of the invention, designed to ameliorate or prevent the symptoms associated with this condition, therefore employ substances which interfere with the biological activity of IL-8. One class of such materials consists of antibodies immunoreactive with the IL-8 secreted by the cells of the afflicted subject or immunologically reactive fragments thereof. Certain IL-8 analogs containing amino acid substitutions or truncations at the N-terminus are IL-8 antagonists and also interfere with IL-8 activity. Moser, B. et al. J Biol Chem (1993) 268:7125-7128.
The antibodies, or immunologically reactive fragments, can be prepared in a variety of ways, as is generally known in the art. In general, such antibodies may be prepared by immunizing a suitable subject with IL-8 and monitoring the titers of IL-8 in the blood of the immunized animal. The antisera can be used directly optionally preceded by purification of the antibodies, or monoclonal antibodies may be prepared from the antibody-secreting B cells of the immunized animal using art-recognized methods.
While the IL-8 used for immunization is generally the IL-8 secreted by the species of which the subject to be treated is a member, it is not necessary that this be the case as long as antibodies raised against the injected IL-8 are cross-reactive with the IL-8 of the subject. For example, in the animal model illustrated below, antibodies raised against human IL-8 were shown to be immunoreactive with rabbit IL-8. Thus, the IL-8 used for immunization need only have the capacity to generate antibodies which are immunoreactive with the IL-8 of the subject to be treated.
In addition, recombinant methods for production of antibodies are known, and the antibodies useful in the invention can be prepared accordingly. In general, this could be approached by isolating DNA from immortalized B cells secreting the desired anti-IL-8 and using the relevant DNA for constructing suitable expression systems for production of these antibodies recombinantly.
In all of the foregoing cases, the antibodies may be treated to prepare only the immunologically reactive portions thereof, or the recombinant production systems may be designed to produce these fragments. The substitution of immunologically reactive fragments for whole antibodies, such as the Fab, Fab', F(ab')2, Fv, (or single-chain Fv portions having the H and L chain linked) is well known. See, for example, Byrd, et al. TIBTECH (1991) 132-137.
The antibodies or fragments useful in the method of the invention thus specifically bind to the IL-8 of the subject to be treated and inhibit the binding of such IL-8 to neutrophils. The antibodies can be produced in hosts other than those of the species of the subject to be treated and, indeed, this is commonly the case. For example, for treatment of humans, either human monoclonal antibodies or monoclonal antibodies derived from other sources such as mice can be used.. Exemplified herein is WS-4 described by Ko, Y. et al. J. Immunol. Meth. (1992) 149:1227-1235. WS-4 is an antibody secreted by hybridomas prepared from B cells of mice immunized with human IL-8 and is of the IgGlκ type. It has the ability to neutralize biological activities of human IL-8 by specifically binding thereto and by inhibiting the binding of human IL-8 to neutrophils.
Additional examples of such antibodies neutralizing the biological activities of IL-8 include antibody DM/C7 (Mulligan, M. S. et al. J. Immunology (1993) 150:5585-5595); antibody A5.12.14 (Boylan, A. M. et al. J Clin Invest (1992) 89:1257) and anti-Pep-1 antibody and anti-Pep-3 antibody disclosed in International Patent Application WO 92/04372.
By way of illustration, the anti-IL-8 for use in the method of the invention, when humans are the subjects, can be prepared by immunizing an animal, e.g., a mouse, rabbit or guinea pig, with IL-8 from humans or other appropriate species, recovering B cells, performing cell fusion, and isolating and cloning the resulting hybridomas producing the anti-IL-8 monoclonal antibody using standard methods.
Human IL-8, including IL-8 variants, (Matsushima, K. et al. J. Exp. Med. (1988) 167:1883-1893; Yoshimura, T. et al. Mol. Immunol. (1989) 26:87-93; Van Damme, J. et al. Eur. J. Biochem. (1989) 181:337-344) can, for example, be used as the sensitizing antigen. Immunization is generally conducted by intraperitoneal injection, preferably with the antigen diluted or suspended in PBS or a physiological saline, and administered with a suitable amount of a standard adjuvant several times, at intervals of 4 to 21 days until the desired antibody is detected in serum of the immunized animal. Spleen cells are preferably used as the immunocytes.
Various known cell lines such as P3 (P03X63Ag8. 653) (J. Immunol. (1978) 123:1548), pE-U1 (Current Topics in Microbiology and Immunology (1978) 81:17, NS-1 (Eur. J. Immunol. (1976) 6:511-519), MPC-11 (Cell (1976) 8:405-415), SP2/0 (Nature (1978) 276:269-270), FO (J. Immunol. (1980) 35:1-21), S194 (J. Exp. Med. (1978) 148:313-323) and R210 (Nature (1979) 277:131-133) may be suitably employed as the immortalizing myeloma cells to be fused with the immunocytes.
The cell fusion of the above-mentioned immunocytes with the myeloma cells can be carried out in accordance with standard methods, for example, the method of Milstein et al. (Methods Enzymol. (1981) 73:3-46).
Cell fusion is performed in a standard nutrient medium, for example, RPMI-1640 medium or MEM, optionally with a serum replenisher, such as fetal calf serum (FCS) as a supplement, in the presence of a facilitator of cell fusion such as polyethylene glycol (PEG) or Sendal virus (HVJ). If required, a reagent such as dimethyl sulfoxide may be used to elevate the fusion efficiency. A 1-to-10 ratio of immunocytes to myeloma cells is preferred.
In one illustrative protocol, the immunocytes are mixed with the myeloma cells in the medium supplemented with a PEG (MW 1000-6,000) solution, which has been preheated to about 37� C. and added to the medium at a concentration of about 30 to 60% (w/v). Medium is successively added, the obtained mixture is centrifuged and the supernatant is removed. After repeating this procedure, the desired hybridomas can be obtained.
Successful fusions can be selected by incubation in a standard selection medium, such as HAT (hypoxanthine, aminopterin and thymidine) medium for a time sufficient to remove unfused cells, usually several days to several weeks. Individual colonies are obtained by dilution and cloning.
Hybridomas capable of producing the desired antibody are screened in accordance with the conventional limiting dilution analysis, followed by cloning of successful hybridomas. Antibody which neutralizes the biological activities of IL-8 of the species to be treated can be screened for use in binding inhibition bioassay to human neutrophils as described in Schroeder, J.-M. et al. J. Immunol (1987) 139:3474-3483. The selected hybridoma clone is cultured in vitro or in mammalian hosts and recovered from the culture or from the ascites fluid, respectively. The immunoglobulins are then purified using standard purification techniques and, if desired, immunologically reactive fragments prepared.
The desired hybridomas can be stored in liquid nitrogen.
The availability of recombinant techniques for antibody production permits monoclonal antibodies which have been artificially modified to minimize the immunogenicity against humans to be used, such as a chimeric antibody consisting of the variable region of a monoclonal antibody of a nonhuman mammal, such as a mouse, and the constant region of a human antibody. A reshaped human antibody useful in the present invention can also be obtained using the method described in International Patent Application No. WO 92/19759. If necessary, amino acids in the framework region (FR) of the variable regions may be replaced in such a manner that the complementarity determining regions of the reshaped human antibody can form the proper antigen binding site (Sato, K. et al. Cancer Res (1993) 53:851-856).
The administration of substances which interfere with the functioning of IL-8 have been demonstrated to suppress the infiltration of neutrophils into the glomeruli and to lower the levels of excretion of protein and albumin in urine to normal in subjects that are afflicted with nephritis. Accordingly, these substances may be used to exert these effects in such subjects.
The subjects may be any animal subject having a condition of nephritis, in particular, glomerulonephritis, and more particularly of glomerularnephritis where deposition of antibody or an immune complex in the renal tissue can be observed. Enhanced susceptibility of the subjects to this treatment can therefore be assessed by assaying the glomeruli for such immune complexes or antibody by biopsy and immunohistochemical observation. However, the treatment is effective even in the absence of antibody or immune complexes in renal tissue. Animals subject to these conditions include humans, primates, domestic animals, livestock, and domestic fowl. Cross reactivity with particular antibodies not raised with respect to the IL-8 of the subject permits use of the raised antibodies in animals that have homologs of IL-8 from the subject. For example, antibodies to human IL-8 are immunoreactive with IL-8 of sheep, pig, rabbit and guinea pig.
For humans, the following disorders are representative: acute nephritis syndrome, in particular, poststreptococcal glomerulonephritis which occurs following infection with Streptococcus pyogenes and acute glomerulonephritis accompanying bacterial infections other than hemolytic streptococcus; rapidly progressive glomerulonephritis and nephritis accompanying Goodpasture's Syndrome (and showing similar symptoms thereto), IgA nephropathy, and nephritis accompanying Schoenlein-Henoch's purpura (and showing similar symptoms thereto); lupus nephritis caused by systemic lupus erythematosus which is a typical immune complex disease and nephritis accompanying progressive systemic sclerosis and showing similar symptoms; nephritis accompanying polyarteritis nodosa; nephritis accompanying Wegener's granulomatosis, idiopathic membranous glomerulopathy, membranoproliferative glomerulonephritis, interstitial nephritis, in particular, acute interstitial nephritis showing remarkable cell infiltration; nephritis accompanying serum sickness; and nephritis accompanying cryoglobulinemia.
The anti-IL-8 may be administered, preferably, by parenteral injection, for example, via intravenous, intramuscular, intraperitoneal, or subcutaneous injection, in a dosage range for humans of 1 to 1000 mg depending on the condition and age of the patient. This amounts to roughly 10 μg/kg-50 mg/kg of body weight for animals in general. Of course, optimization of dosage and of administration protocols for a particular species and for a particular subject are routine.
The anti-IL-8 may be formulated in a conventional manner as described in Remington's Pharmaceutical Sciences, latest edition, Mack Publishing Company, Easton, Pa. For example, a preparation for injection may be obtained by dissolving purified anti-IL-8 in a solvent such as a physiological saline or a buffer solution and then adding a substance such as Tween 80, gelatin or human serum albumin, to the solution to prevent nonspecific adsorption by the surfaces of the vessel containing the preparation. The preparation may be freeze-dried and reconstituted prior to use. Mannitol or glucose may be used as a filler for freeze-drying. The formulations may optionally also include additional active substances useful in the treatment of nephritis.
Effects of the administration of anti-IL-8 for the treatment of nephritis can be experimentally tested in animal models such as rabbits. A rabbit model recognized to be predictive of the effects of various treatments in humans has been developed. Rabbits are immunized with an antigen, for example, bovine serum albumin (BSA) to stimulate the animals to produce an antibody, then a large amount of BSA is administered to form an antigen (BSA)/antibody complex (immune complex), causing the animals to develop immune complex-mediated glomerulonephritis.
Test substance, such as anti-IL-8 or a control substance is also administered in accordance with the protocol. Various parameters including 1) the deposition of the antibody or the immune complex into glomerulus, 2) infiltrating neutrophil count in glomerulus and 3) changes in urinary protein level and urinary albumin level can be determined and compared between animals administered test substance and those administered control.
Hybridomas producing the antihuman IL-8 antibody WS-4 were prepared by fusing spleen cells of a BALB/C mouse immunized with human IL-8 with mouse myeloma cells P3X63-Ag8.653 by a conventional method with polyethylene glycol.
After screening by using the biological neutralization activity of human IL-8 as an indicator, the hybridoma WS-4 was established (Ko, Y. et al. (supra)).
Typing performed by using a mouse monoclonal antibody isotyping kit (Amersham International plc) showed WS-4 had κ type L-chain and γ1 type H-chain. In addition to recognizing human IL-8, WS-4 also recognizes rabbit IL-8.
The following example is intended to illustrate but not to limit the invention.
The murine hybridoma designated "WS-4" which produces the WS-4 monoclonal antibody was deposited at the Bioengineering Industrial Technology Research Institute of the Agency of Industrial Science and Technology (1-1-3 Higashi, Tsukuba, Ibarald, Japan) on Apr. 17, 1996, with the identifier "FERM BP-5507" under the terms of the Budapest Convention.
Japanese White rabbits weighing 2 kg (purchased from Sankyo Labo Service, Inc.) were quarantined for 1 week to confirm the absence of any disease before use. On day 0, each rabbit was immunized subcutaneously with 4 mg/kg body weight of crystallized bovine serum albumin (BSA) (Wako Pure Chemical Industries, Ltd.). The BSA was dissolved at 2 mg/ml in physiological saline and the solution mixed with an equal volume of complete Freund's adjuvant (CFA; Iatron). On day 7, each rabbit was subjected to a single intravenous (IV) injection of a mixture of both 500 mg of BSA with 10 μg of E. coli (Escherichia coli 055:B55) lipopolysaccharide (LPS; Difco Laboratories, Detroit, Mich.) dissolved in 2 ml of physiological saline. On day 8, 10 μg of LPS dissolved in 1 ml of physiological saline was injected IV. This protocol induces antigen (BSA)/antibody complex (immune complex)-mediated inflammatory glomerulonephritis in the rabbits.
10 mg of antihuman IL-8 antibody WS-4 (IgG1 κ type), prepared in Preparation A, was dissolved in 1 ml of physiological saline and intravenously injected into 10 test rabbits simultaneously with the BSA and LPS injection on day 7 referenced above and again with the LPS injection on day 8.
Mouse monoclonal antibody TpM-1 (IgG1 κ type), which recognizes a constituent of Toxoplasma gondii (Ogata, K. et al. J. Immunol. Methods (1983) 65:75-82) was injected into 9 control rabbits on days 7 and 8 in the same manner as anti IL-8.
Four hours after the administration of WS-4 or control antibody on day 8, the rabbits were sacrificed for histological and immunohistological examination of the renal tissues.
(1) Histological Findings
A part of the renal tissue obtained from each rabbit was fixed in 10% buffered formalin, embedded in paraffin, cut into 4 μm sections and stained with a periodic acid Schiff (PAS) reagent. These sections were observed under light microscope and then the severity and the range of glomerular lesions were evaluated by two criteria: 1) hypercellularity of cells constituting the glomeruli and 2) extent of infiltration of polymorphonuclear leukocytes (PMN) into the glomeruli.
The results are shown in FIGS. 1a-1c.
Hypercellularity: both the test group immunized with BSA and treated with WS4 (FIG. 1b) and controls immunized with BSA and treated with TPM-1 (FIG. 1a) showed little hypercellularity, similar to the results for normal, untreated rabbits (FIG. 1c). However, while the controls showed fused epithelial foot processes of the free wall of glomerular capillaries near the infiltrated leukocytes as indicated by the arrow in FIG. 1a, neither the untreated rabbits (FIG. 1c) nor the test group (immunized with BSA and treated with WS-4) (FIG. 1b) showed fusion of epithelial foot processes even if neutrophils accumulated in the glomerular capillaries (FIG. 1b).
Infiltration of PMN: controls (immunized with BSA and treated with TPM-1) showed extensive infiltration of PMN into the glomeruli (FIG. 1a). PMN infiltration into the glomeruli was reduced by 40% in the animals treated with WS-4 (62.7�7.6 vs. 37.7�3.7) (See FIG. 2). Thus, anti-IL-8 suppresses PMN infiltration in inflammatory glomerulonephritis induced by deposition of the immune complex, suggesting that IL-8 participates in this migration.
(2) Effects of Antibody Administration on Deposition of Immune Complex
Parts of the rabbit renal tissues obtained above were rapidly frozen in n-hexane, cooled with a mixture of dry ice with acetone and then cut into 4 μm sections with a cryostat (of the Tissue-Tek II system; Miles, Naperville, Ill.). The sections were reacted with either fluorescein isothiocyanate (FITC)-conjugated antirabbit IgG antibody or anti-BSA antibody (Cappel Laboratories, Malvern, Pa.) in accordance with the fluorescent antibody method of Camussi, G. et al. (Am. J. Pathol. (1988) 131:418-434).
The stained sections were observed under a fluorescence microscope. The amount and extent of fluorescence were evaluated in at least 50 glomeruli and were ranked in 4 grades of 0 to 3 (negative, scattered, weakly diffuse, strongly diffuse). The results are shown in FIGS. 3a, 3b and 4.
Both the control group treated with TPM-1 (FIGS. 3a and 3b) and the test group treated with WS-4 showed the deposition of BSA and rabbit IgG in the glomerulus. Semiquantified evaluation of the deposition of BSA and rabbit IgG indicated that there was no significant difference between the two groups. Thus, anti-IL-8 does not appear to affect immune complex deposition in inflammatory glomerulonephritis.
(3) Detection of IL-8 Production and Excretion
The production of IL-8 by the glomerular cells of rabbits with glomerulonephritis was assessed by direct immunohistochemical staining with avidin/biotin peroxidase and WS-4. IL-8 was detected in the glomerular mesangial cells, epithelial cells and monocytes in rabbits with nephritis induced as described above (FIG. 6), but not in normal rabbits (FIG. 5a).
The excretion of IL-8 in urine of the rabbits with glomerulonephritis induced as described above was also assessed. Samples were collected using a metabolic cage during 24 hours until the BSA-immunization at day 0 and for 28 hours from day 7 to time of sacrifice. At day 7, urinary IL-8 excretion significantly increased compared to day 0 in the control group treated with TPM-1 (FIG. 6). No IL-8 was detected in the plasma.
This suggests IL-8 might be locally produced in the glomerulus in immune complex-mediated inflammatory glomerulonephritis.
(4) Suppression of Urinary Excretion of Protein and Albumin
Urines of the rabbits with glomerulonephritis induced as described above were collected and the levels of protein and albumin were determined, by the pyrogallol red method (Thomas et al. J. Clin. Chem. Clin. Biochem. (1981) 19:203-208) and by turbidimmunometry with the use of rabbit serum albumin as a standard (Vittinghus., E. et al. Scand. J. Clon. Lab. Invert. (1981) 41:627-632), respectively. Protein and albumin excreted into the urines were expressed as total amount excreted in 1 hour (mg/hr).
Urines collected during 24 hours until the BSA-immunization at day 0 contained a small amount of protein (0.60�0.03 mg/hr) and a trace amount of albumin (0.01�0.01 mg/hr). In the control group treated with TPM-1 after the BSA-immunization at day 7, urines during 28 hours from day 7 showed remarkable increases in the urinary protein (3.20�0.97 mg/hr) and albumin (1.39�0.53 mg/hr). In contrast, the protein and albumin levels in urines of the BSA-immunized WS-4-treated group collected within 28 hours from day 7 after the BSA-immunization were significantly lowered to 0.89�0.15 mg/hr protein and 0.02�0.01 mg/hr albumin and were the same as normal levels (0.93�0.41 mg/hr protein and 0.01�0.01 mg/hr albumin).
Thus, while the administration of the anti-IL-8 does not completely prevent the migration and infiltration of PMN into the glomeruli, the excretion of urinary protein and albumin are suppressed to normal levels.
The mean and standard error were calculated on all the parameters determined in this example. Statistical analyses were performed by using Student's t-test and p<0.05 was accepted as statistically significant.
|Cited Patent
|Filing date
|Publication date
|Jan 6, 1987
|Aug 23, 1988
|Daiichi Seiyaku Co., Ltd.
|Process for treatment of nephritis with imidazoquinazolines
|Aug 25, 1987
|Jun 20, 1989
|Miles Laboratories, Inc.
|Treatment of glomerulonephritis
|Dec 28, 1989
|Jul 26, 1990
|Protein Design Labs Inc
|CHIMERIC IMMUNOGLOBULINS SPECIFIC FOR p55 TAC PROTEIN OF THE IL-2 RECEPTOR
|"Clinical Nephrology 2nd edition", Classification of Renal Disease, 29-33 (1978).
|Abbot, F. et al. Interleukin 1 Stimulates Human Mesangial Cells to Synthesize and Release Interleukins 6 and 8, Kidney Int. (1991) 40:597 605.
|Abbot, F. et al. Interleukin-1β Stimulates Human Mesangial Cells to Synthesize and Release Interleukins-6 and -8, Kidney Int. (1991) 40:597-605.
|Broaddus, V.C. et al, J. Immunol, 152:2960 2967, Feb. 15, 1994.
|Broaddus, V.C. et al, J. Immunol, 152:2960-2967, Feb. 15, 1994.
|Brown and Company Inc.: "A Handbook of Kidney Nomenclature and Methodology", 167-195, (1975).
|Brown and Company Inc.: A Handbook of Kidney Nomenclature and Methodology , 167 195, (1975).
|Brown, Z. et al. Cytokine activated Human Mesangial Cells Generate the Neutrophil Chemoattractant, Interleukin 8, Kidney Int. (1991) 40:86 90.
|Brown, Z. et al. Cytokine-activated Human Mesangial Cells Generate the Neutrophil Chemoattractant, Interleukin 8, Kidney Int. (1991) 40:86-90.
|Chun Tharapai, A. et al, J. Immunol, 152:1783 1789, Feb. 15, 1994.
|Chun Tharapai, A. et al, J. Immunol, 152:1783-1789, Feb. 15, 1994.
|Clinical Nephrology 2nd edition , Classification of Renal Disease, 29 33 (1978).
|Couser, W.G. et al. Experimental Glomerulonephritis in the Isolated Perfused Rat Kidney, J. Clin. Invest. (1978) 62:1275 1287.
|Couser, W.G. et al. Experimental Glomerulonephritis in the Isolated Perfused Rat Kidney, J. Clin. Invest. (1978) 62:1275-1287.
|Cronstein et al. The Adhesion Molecules of Inflammation Arthr. & Rheum. 36:147 1993.
|Cunningham & Harris AB Engineering How to be Human TIBTECH Apr. 1992 10.
|Cunningham & Harris AB Engineering-How to be Human TIBTECH Apr. 1992 10.
|Dixon, F.J. et al. Experimental Glomerulonephritis, J. Exp. Med. (1961) 113:899 920.
|Dixon, F.J. et al. Experimental Glomerulonephritis, J. Exp. Med. (1961) 113:899-920.
|Emery et al. Humanized mAbs for Therapeutic Applications Exp. Opin. Invest. Drugs 3:241 1994.
|Fleuren, G.J. et al. Experimental Glomerulonephritis in the Rat Induced by Antibodies Directed against Tubular Antigens, Lab. Invest. (1978) 8:496 501.
|Fleuren, G.J. et al. Experimental Glomerulonephritis in the Rat Induced by Antibodies Directed against Tubular Antigens, Lab. Invest. (1978) 8:496-501.
|Germuth, F.G. et al., A Comparative Histologic and Immunologic Study in Rabbits of Induced Hypersensitivity of the Serum Sickness Type, J. Exp. Med. (1953) 97:257 282.
|Germuth, F.G. et al., A Comparative Histologic and Immunologic Study in Rabbits of Induced Hypersensitivity of the Serum Sickness Type, J. Exp. Med. (1953) 97:257-282.
|Goding Mabs: Principles & Puncture Academic Press 1986 259 290.
|Goding Mabs: Principles & Puncture Academic Press 1986 259-290.
|Harada et al, International Immunology., vol. 5:681 690. Kincaid Smith, Kidney International 36:1108 1111, 1989.
|Harada et al, International Immunology., vol. 5:681-690. Kincaid-Smith, Kidney International 36:1108-1111, 1989.
|Harada, A., et al. Expression of Recombinant Rabbit IL 8 in E. coli and Establishment of the Essential Involvement of IL 8 in Recruiting Neutrophils into Lipopolysaccharide induced Inflammatory Site of Rabbit Skin, Int. Immunol. (1993) 5:681 690).
|Harada, A., et al. Expression of Recombinant Rabbit IL-8 in E. coli and Establishment of the Essential Involvement of IL-8 in Recruiting Neutrophils into Lipopolysaccharide-induced Inflammatory Site of Rabbit Skin, Int. Immunol. (1993) 5:681-690).
|Herbert, C.A. et al. Interleukin 8: A Review, Cancer Investigation (1993) 11:743 750.
|Herbert, C.A. et al. Interleukin-8: A Review, Cancer Investigation (1993) 11:743-750.
|Hisada, Y. et al., "The elevated production of interleukin-8 in glomerular diseases," The Journal of the American Society of Nephrology (ASN Program & Abstracts) (1993) p. 679, 108P.
|Hisada, Y. et al., The elevated production of interleukin 8 in glomerular diseases, The Journal of the American Society of Nephrology (ASN Program & Abstracts) (1993) p. 679, 108P.
|Ko et al. Asensitive Enzyme Line of Immunoabsorbent Assay for Human IL8 J. Immunol. Meth. 149:227, 1992.
|Ko et al. Elevated IL8 In Urine of Patients with UTI Infect. & Immun. Apr., 1993 61:1307.
|Ko, Y C. et al. A Sensitive Enzyme linked Immunosorbent Assay for Human Interleukin 8, J. Immunol. Method (1992) 149:1227 1235.
|Ko, Y-C. et al. A Sensitive Enzyme-linked Immunosorbent Assay for Human Interleukin-8, J. Immunol. Method (1992) 149:1227-1235.
|Kusner, D.J. et al. Cytokine and LPS induced Synthesis of Interleukin 8 from Human Mesangial Cells, Kidney Int. (1991) 39:1240 1248.
|Kusner, D.J. et al. Cytokine-and LPS-induced Synthesis of Interleukin-8 from Human Mesangial Cells, Kidney Int. (1991) 39:1240-1248.
|Matsushima, K. et al. Molecular Cloning of a Human Monocyte derived Neutrophil Chemotactic Factor (MDNCF) and the Induction of MDNCF mRNA by Interleukin 1 and Tumor Necrosis Factor, J. Exp. Med. (1988) 167:1883 1893.
|Matsushima, K. et al. Molecular Cloning of a Human Monocyte-derived Neutrophil Chemotactic Factor (MDNCF) and the Induction of MDNCF mRNA by Interleukin 1 and Tumor Necrosis Factor, J. Exp. Med. (1988) 167:1883-1893.
|Matsushima, K. et al., "Pathophysiological roles of interleukin 8 in inflammatory diseases," XIIth International Congress of Nephrology, Abstract (1993) p. 9 (or 74).
|Matsushima, K. et al., Pathophysiological roles of interleukin 8 in inflammatory diseases, XIIth International Congress of Nephrology, Abstract (1993) p. 9 (or 74).
|Peveri, P. et al. A Novel Neutrophil activating Factor Produced By Human Mononuclear Phagocytes J. Exp. Med. (1988) 167:1547.
|Peveri, P. et al. A Novel Neutrophil-activating Factor Produced By Human Mononuclear Phagocytes J. Exp. Med. (1988) 167:1547.
|Production & Application of Mabs In Cell Biology, Biochem. & Immunol.
|Pusey, C.D. et al., Immunopathology of Glomerular and Interstitial Disease, Diseases of the Kidney, ed. by Schrier, R.W. et al., Little, Brown and Company, Boston/Toronto, 1827 1884 (1988).
|Pusey, C.D. et al., Immunopathology of Glomerular and Interstitial Disease, Diseases of the Kidney, ed. by Schrier, R.W. et al., Little, Brown and Company, Boston/Toronto, 1827-1884 (1988).
|Reech et al, Cell 50:667, 1987.
|Sekido, N. et al. Prevention of Lung Reperfusion Injury in Rabbits by a Monoclonal Antibody against Interleukin 8, Nature (1993) 365:654 657.
|Sekido, N. et al. Prevention of Lung Reperfusion Injury in Rabbits by a Monoclonal Antibody against Interleukin-8, Nature (1993) 365:654-657.
|Wada et al. Detection of urine IL8 in Glomerular Diseases Kid. Int. 46:455, 1994.
|Wada et al. Prevention of Protein Urea by Administration at a IL8 A6 a Experimental Acute Immune Complex Indirect Glomerulonerphitus J. Exp. Med. Sep. 1994 180:1135.
|Wada et al. Prevention of Protein Urea by Administration at a-IL8 A6 a Experimental Acute Immune Complex-Indirect Glomerulonerphitus J. Exp. Med. Sep. 1994 180:1135.
|Wada, T. et al., "Prevention of experimental immune complex glomerulonephritis by the administration of a specific antibody against interleukin-8", The Journal of the American Society of Nephrology (ASN Program & Abstracts) (1993) p. 640, 21P.
|Wada, T. et al., "Prevention of proteinuria by the administration of anti-interleukin 8 antibody in experimental acute immune complex-induced glomerulonephritis", The Journal of Experimental Medicine (1994) 180(3) 1135-1140.
|Wada, T. et al., Prevention of experimental immune complex glomerulonephritis by the administration of a specific antibody against interleukin 8 , The Journal of the American Society of Nephrology (ASN Program & Abstracts) (1993) p. 640, 21P.
|Wada, T. et al., Prevention of proteinuria by the administration of anti interleukin 8 antibody in experimental acute immune complex induced glomerulonephritis , The Journal of Experimental Medicine (1994) 180(3) 1135 1140.
|Yoshimura, T. Proc. Natl. Acad. Sci. USA Purification of a Human Monocyte derived Neutrophil Chemotactic Factor that has Peptide Sequence Similarity to Other Host Defense Cytokines (1987) 84:9233.
|Yoshimura, T. Proc. Natl. Acad. Sci. USA Purification of a Human Monocyte-derived Neutrophil Chemotactic Factor that has Peptide Sequence Similarity to Other Host Defense Cytokines (1987) 84:9233.
|Zoja, C. et al. Interleukin 1 and Tumor Necrosis Factor Induced Gene Expression and Production of Leukocyte Chemotactic Factors, Colony stimulating Factors, and Interleukin 6 in Human Mesangial Cells, Am. J. Pathol. (1991) 138:991 1003.
|Zoja, C. et al. Interleukin-1β and Tumor Necrosis Factor-α Induced Gene Expression and Production of Leukocyte Chemotactic Factors, Colony-stimulating Factors, and Interleukin-6 in Human Mesangial Cells, Am. J. Pathol. (1991) 138:991-1003.
|Citing Patent
|Filing date
|Publication date
|Dec 16, 2003
|Oct 16, 2007
|Medarex, Inc.
|Human monoclonal antibodies against interleukin 8 (IL-8)
|Jun 27, 2007
|Nov 24, 2009
|Genmab A/S
|Human monoclonal antibodies against interleukin 8 (IL-8)
|Nov 11, 2009
|Jan 31, 2012
|Genmab A/S
|Human monoclonal antibodies against interleukin 8 (IL-8)
|Dec 27, 2011
|Dec 10, 2013
|Genmab A/S
|Methods of treating cancer with human monoclonal antibodies against interleukin 8
|Dec 16, 2003
|Oct 21, 2004
|Medarex, Inc.
|Human monoclonal antibodies against interleukin 8 (IL-8)
|U.S. Classification
|424/145.1, 530/388.23, 435/328, 435/326, 530/387.1, 435/325, 435/335, 424/158.1, 530/387.3, 530/388.1, 424/130.1, 424/133.1, 424/809
|International Classification
|Cooperative Classification
|European Classification
|Aug 31, 1994
Owner name: CHUGAI PHARMACEUTICAL CO., LTD., JAPAN
Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:MATSUSHIMA, KOUJI;REEL/FRAME:007163/0350
Effective date: 19940819
|Aug 10, 2001
|Maintenance fee reminder mailed
|Jan 4, 2002
|Fee payment
Year of fee payment: 4
|Jan 4, 2002
|Surcharge for late payment
|Jun 16, 2005
|Fee payment
Year of fee payment: 8
|Jun 10, 2009
|Fee payment
Year of fee payment: 12


text:
A picture I took this morning.. Could not sleep so I ended up changing the colors in ps Now its a purple tree
Deviant Art
Mind ChangingTrees growing in my garden.
It grows tall. It spreads out its a storm.
Everyday it changes, like an endless call.
Its a monday. Its friday.
Changing like the....
Changing like......
My mind is blooking. My mind is growing.
Growing like the hairs on my toes.
The color orange and yellow flashing.
My mind is here to listen. My mind is here for you.
Trees growing. It grows tall like my love for you.
I want to grab you. Kiss your neck. Share my mind with you.
Everyday it changes, like my love for you.
Its a monday. Its friday.
Changing like the color of your hair.
My mind is blooking. My mind is growing.
Colors flashing. Orange and yellow.
My mind is here for you.
Trees growing. Everyday its showing.
The smiles we share. The love that is there. I see your flaws.
Changing like the days.
I change, you change. We change together.
Its a monday. Its friday and im still in love with you.
In A FieldShe is sleeping next to me.
I get closer. Smell her fragrance.
Hair like champagne on a summer-day.
Her body i cover with mine.
I hold on.
I hold on to her.
The smell I love and her I adore.
Eyes watching me. She has that flirty stare and
I cant concentrate, I cant hear.
She is mine. My strawberry cookie in a winter-storm.
I glow whenever I see her. I know whenever I see her.
We belong. We are a song.
In a dream. I see us on a mountain.
I see us in a field. We are a movie. We are in love.
I see the house were we should live. I know there is much to give.
She gives me love. I give her love. Baby, we are a song.
She is sleeping next to me.
I get closer. Smell her fragrance.
Hair like champagne on a summer-day.
Her body I cover with mine.
I hold on.
I hold on to her.
The smell I love and her I adore.
Baby, you make me belong. Thats why Im writing this song.
In a dream. I see our kids walking around.
I see the sun on your tummy. I feel like a dummy, and Im your dummy. Im a dummy in love.
DecemberWake me up when December Comes.
Ill see you when the snow has fallen.
Ill see you when the month starts with a D.
Beautiful, terrifying and magic at once.
Making homebrew, having fun
and cuddling all night long.
I can't wait...So Wake Me Up When December Comes
HeartThe best songs are the ones I write to you.
Your eyes stole my heart. Your heart is off by a beat, from time to time.
With my heart I hope you will be complete.
Stitch you together so you can breath.
I would hollow my heart if you needed a part.
My heart is pumping the right way
so that someday I can have you name.
Empty body far away.
Far from warmth and far from play.
Far from the mouth that makes a smile.
Its blue now. Cold and winter around.
It will heat with time.
It's called foreplay
Written by Camilla Moen
|Sta.sh Submit

subset: commoncrawl


text:
Rod Mikinski, a Manhattan Mercury photographer for 34 years, has announced his retirement. Mikinski, in a written statement published in today's Mercury, called his tenure at the paper "a great joy," and thanked the "people of this community who let me get closer to the
Stan Ward, USD 383 coordinator of federal/state funds and grants, leaned back in his chair when the subject of money for homeless students came up. Ward and program coordinator Cheryl McCormick explained the dynamics of the program, which is designed to make sure homeless students
Sentiment and practicality are at odds with the planned destruction of a building at the Rock Springs 4-H Center looming next spring. The Water Wheel Ranch House, south of Junction City, will be demolished to make room for a new educational plaza. The building once
Notes from Monday's county commission meeting: • Road construction downtown has been delayed but is nearing its end. Gina Scroggs, executive director of Downtown Manhattan, Inc., said the installation of pedestrian signals is behind schedule. If they are not in place in time for Promenade
City commissioners Tuesday will be asked for feedback on an agreement between the city and Pottawatomie County governing water and sewer supplied by the city to Blue Township. The city has been working on a new contract for water and sewer service for the township
The dedication of the Pi Kappa Phi Fraternity Red Rose Garden, the first named campus landmark for a Kansas State Greek chapter, will be 10:30 am Saturday at the KSU Gardens on Denison Avenue. "It is a tradition of Pi Kappa Phi chapters nationwide to donate
What do a famous game show host, a man wearing purple pants, a Texas A&M booster and a room full of diehard TV fans have in common? They were all in attendance Sunday night for "The Price is Right Live." The stage show
Sure, zombies want to eat your flesh, but some of them are still softies at heart. Aggieville was invaded by a pack of 37 zombies and survivors — plus one zombie dog — during the third annual Zombie Walk for Hunger on Saturday. Participants donated canned goods to
Antonio Brown has been convicted of first-degree murder and other charges in the death of 14-month old Clayden Urbanek, according to reports in the Salina Journal. The trial was moved to Riley County earlier this month due to the intense media coverage the case
K-State's Marianna Kistler Beach Museum of Art is offering plenty of activities for patrons of all ages to enjoy during the month of October. The following events, all free unless otherwise indicated, are sponsored by the Beach Museum. They include: • "The World's Largest
Get the latest news, weather and sports updates from The Mercury sent to your phone.
You can download and print:
Terms of Service | Privacy Policy | The Manhattan Mercury, 318 North 5th Street, Manhattan, Kansas, 66502 | Copyright 2012
Reproduction of any kind is prohibited without written consent.


text:
City councilors will haul in executives from Ashkenazy Acquisition Corp. for another chat about the way they're running Faneuil Hall Marketplace - this time for their plans to start charging buskers up to $2,500 for performance space. Read more.
The Globe reports the operators of the one-time "festival" marketplace plan to start charging the street performers who provide much of the festival feeling a fee to entertain shoppers.
The Pittsburgh Business Times reports the for-profit school's parent company just isn't seeing enough profit in art education these days; will slowly close institute as students graduate its classes, rather than just shutting immediately.
H/t Dale Cruise.
for some common sense at 7-11. Went in there earlier for my daily chocolate fix, and saw notices by every register that they are now only accepting cash for scratch ticket purchases (no more debit cards).
Now,I typically stay far away from buying scratch tickets, but I'm still curious. Is this is a 7-11 policy or a Mass Lottery one? If it is a Lottery policy, perhaps the state could go one better and eliminate 90% of the current games - especially the ones that are so old the odds of winning any prize, especially the one remaining big prize, are almost next to nil.
CyPhy of Danvers, started by the co-founder of the equally local iRobot, today launched a Kickstarter campaign to raise $250,000 for making drones it swears any idiot with a smartphone can fly.
UPDATE: Mayor Walsh also got involved. His Roxbury liaison, Kaira Fox e-mailed neighborhood groups and other elected officials on Friday: "I wanted to let you know, the Mayor has heard the complaints and reached out to Clear Channel personnally to ask that they change the billboard. The City does not have control over the content of Billboards, but agrees this is in very poor taste to have in our neighborhood."
Dan O'Brien thought of Disneyworld when he saw the line of people waiting to get into the Downtown Crossing Roche Bros. on its opening day today.
The store is also accessible via the subway stop.
Councilors willing to sue to keep high-pressure natural-gas facility away from city's only active quarry
The City Council today unanimously called on the Boston Public Health Commission to study the possible ramifications of a proposed gas pipeline down Grove Street in West Roxbury and a proposed "metering and regulating station" for the pipeline right across the street from the West Roxbury Crushed Stone quarry, which still uses dynamite to dislodge the boulders it crushes.
Residents and the owners of a Blue Hill Avenue liquor store duked it out this morning over the store's request to start selling nips, at a hearing before the Boston Licensing Board.
The board decides tomorrow whether to let Blue Hill Liquors, 108 Blue Hill Ave., sell the tiny bottles.
The store's attorney, Ethan Schaff, said the store needs the nips to stay in business. He said that when the current owners took over the store two years ago, they agreed to a ban on nips to show the neighborhood they could clean the place up and run a respectable business.
A BU spinoff that is selling panels in a centralized solar farm is suing crowdsourcing site Indiegogo after the site blocked its campaign, the Boston Business Journal reports.
CloudSolar had raised nearly $450,000 in pledges before Indiegogo decided to halt the campaign and refund all the money, the Journal reports.
Blue Hill Liquors, 108 Blue Hill Ave., goes before the Boston Licensing Board next week seeking permission to sell nips.
The store currently has a license provision prohibiting it from selling the single-serving mini bottles of alcohol.
The board generally imposes nip bans on liquor stores at the request of local residents and police.
The board's hearings begin at 10 a.m. on Wednesday in its eighth-floor hearing room in City Hall.
WBUR reports Gov. Baker has submitted legislation that would require both background checks and minimum insurance levels for people who drive for services such as Uber and Lyft.
Legislators from Boston and Dedham are proposing a VFW Master Plan Commission to look at ways to improve the VFW Parkway from Centre Street in West Roxbury to the Dedham line and Providence Highway in Dedham between the Boston line and the Washington Street rotary.
State Sen. Mike Rush (D-West Roxbury) and state Reps. Ed Coppinger (D-West Roxbury) and Paul McMurtry (D-Dedham) want the commission to conduct:
Developer Nissim Shimon Trabelsi says he's talking to several hotel management companies - including the one that runs the King David Hotel in Jerusalem - about running the chain of hotels he hopes to start with one on VFW Parkway in West Roxbury at the Dedham line.
The BRA holds a public meeting Thursday on a developer's plans to build a kosher hotel and restaurant on the VFW Parkway at the Dedham line.
The meeting starts at 6:30 p.m. in the District E-5 community room.
Tony DeBenedictis, owner of Tony's Market on Washington Street, acknowledged today that he's seriously looking at moving from his longtime location in Roslindale Square to a spot up Washington at Durnell Avenue.
However, he said the deal is not 100% done and that he won't know for sure what he will do for about another month.
The Supreme Judicial Court today ruled today that Boston cabbies who "lease" cabs for daily shifts are independent contractors and so owed nothing under the state's minimum-wage and unemployment laws.
The state's highest court noted that the state law that defines "employees" explicitly excludes cab drivers.
The judges also rejected the cabbies' assertion that collectively the medallion and radio-assocation owners were "a singular employer exercising monolithic control over the taxicab industry."
Owner of Boston software company claims religious right to fire employee of company-funded foundation
The Globe reports on a lawsuit by a Chinese dissident living in the US against Boston-based Jenzabar, founder Ling Chai and two foundations founded and funded by the company.
Jing Zhang, who lives in New York, charges she was fired from one of the foundations because she grew reluctant to participate in weekly Christian prayer sessions on phone calls with headquarters in Boston.
While sauntering along Centre Street in West Roxbury the other day I noticed that the Data Doctors franchise had closed up shop. I peered in the windows and the storefront has been cleaned, swept, and is bare to the walls. The sign in the windows says they had to close up unexpectedly. The franchise was located in the block fo stores next to the hardware store by the Theodore Parker Church.
Makezine reports MakerBot shut its three retail stores, including the one in Boston, and laid off 100 workers.


text:
Forgot Password? | Not a User? Sign up
Your browser does not support iframes.
(Most) Homestead Critters
Enjoying Lazy Summer Days
Some of the barn critters are enjoying the summer days, namely Madricka, the mother donkey, and her young son, Buckwheat (aka baby Bucky).
They can often be seen stretched out in the sunshine, usually on their sides, soaking up the sunshine.
Samples gathered last week in two areas of Fayette County tested positive for West Nile virus.
Jodi Cyr, supervising sanitarian for Fayette County Health Department, said that first West Nile virus positive batches of mosquitoes in Fayette County were collected as part of routine testing by the department.
"These results demonstrate the continued need for people to ensure they are protected from mosquito bites," Cyr said.
The mosquito samples were collected in rural Ramsey and rural Shobonier/St. Peter last Tuesday and tested last Wednesday.
As Vandalia's mayor updated council members on the downtown demolition project on Monday, he also reported on another project, one on the city's north side.
Gottman told aldermen that the company leasing the property at the southwest corner of Eighth Street and Veterans Avenue from Larry Mabry has bought out the lease and turned the property back over to Mabry.
25 Years Ago
1990 – A Fayette County Child Sex Abuse Advocacy Board was formed. Doris Benefiel, chief managing officer of the Fayette County Probation Office, was chosen as chairman.
Charles and Gladys Fisher of Brownstown celebrated their 60th wedding anniversary.
Vandalia's 61-room Days Inn motel was ready to open. Eddie Lowry was named manager: The motel was owned and operated by Old Capital Hospitality Inc., a group of local investors.
This week's photo: This brother and sister were reared on a farm in Shafter. The brother still lives on the farm, and the sister lives in Vandalia and has a son.
Do you know them? If so, call The Leader-Union, 283-3374, by 5 p.m. next Monday.
Last week's photo: Ed and Tom Grubaugh.
Identifying her were: Ed
This week's Scrambler: tavictriye mseadnd eorm anth a dogo eida.
Can you unscramble it? If so, call The Leader-Union, 283-3374, by 5 p.m. next Monday.
William S. Wait was a visionary who died before he could see his vision become a reality.
As far back as 1835, Wait, of Greenville, was thinking of a rail line stretching across Illinois, from Terre Haute to St. Louis, linking Greenville to both Eastern and Western markets.
Vandalia Little Community Garden has a new feature this year an area designated as "The Educational Garden."
That new area has been created through local gardeners' creativity, commitment and desire to make the garden an attractive, pleasant and serene place to visit. It's also their love of gardening and just plain willingness to dig in the dirt, plant, weed and do whatever else is necessary to turn out the delicious fruits and vegetables to put on kitchen and dining tables.
Kanon Schaal does not seem to be excited about being photographed on his first day of pre-kindergarten at Vandalia Elementary School.
Vandalia's superintendent of schools told school board members on Tuesday that the district's new format for registering students, for the most part, "went very smooth."
That new format called for parents to preregister their students online, then show up on registration day to pay fees and pick up their children's schedules.
Copyright © 2015
The Leader Union is your source for local news, sports, events and information in Vandalia, Il, and the surrounding area.


text:
ODT Online
ODT /directory
Once international, always international.
Collecting for the Pink Ribbon appeal in the Exchange in
Dunedin yesterday are (from left) Kirsten Norquay, Andrew
Bird and Jan Waters.
The driver of a car involved in a crash described as a
''lucky escape'' had spent the day drinking in Dunedin before
attempting to drive home to Christchurch, police say.
The woman who received serious burns to the inside of her
throat in Wednesday's Saddle Hill fire has been discharged
from Dunedin Hospital.
Nearly one in five New Zealand parents are having to work two
jobs to make enough money to support their children's
learning, a Monash University and Australian Scholarships
Group Education Programmes survey has found.
When is a $5 note worth more than $5?
Login or Register
to add your business to the ODT/directory. Quick link to
more roadtests
& reviews
cars for sale
Submit your news & photos - Login or
Opinion? Have your say - Login or Register
Submit your
event or notice
Add a photo
Bookmark ODT
Make ODT my
Otago Daily Times print and digital edition, The
Star - Dunedin, The News - Central Otago, The
Ensign - Gore, Southland Express -
Invercargill, Southern Rural Life - Otago and
Southland, The Courier - Timaru, Courier Country - Canterbury and
West Coast, Queenstown Times - Queenstown, Mountain Scene -
Queenstown, The Oamaru Mail - Oamaru, The
Greymouth Star - Greymouth, Hokitika Guardian - Hokitika,
West Coast Messenger - West Coast, The Ashburton Courier -
Ashburton, The News - North Canterbury, Extra! schools
publication, Property
Times South Canterbury


text:
|Sign InHome
|Choose a puzzle cut
Solve times for this jigsaw puzzleShare your solve times with your buddies
The Small Tortoiseshell (Aglais urticae) is a colorful and well-known Eurasian butterfly in the family Nymphalidae. A dark colored slate wall is good place to absorb the warmth of the sun.
Share this Jigsaw Puzzle
Puzzle Postcard
E-mail this puzzle to a friend with your personal message and choice of puzzle cut.
Recent Puzzles
Tue Jasminum TortuosumMon Chain & SprocketSun Goldie on Sea WallSat Pont NeufFri Fall Rhus TyphinaThu Covered Bridge PWed AcornMore Previous Puzzles
Home|Puzzle Gallery|Daily Jigsaw|Site Map|Privacy Policy|Frequently Asked Questions


text:
Overall score
would recommend to a friend.
Reviewer score
Would recommend
Great Location!
Loved this hotel! Perfect location to walk the freedom trail and Quincy Market. Very Clean and terrific staff! Would love to come for a longer term stay!
Nice hotel, ideal Boston location
I attended a business conference near the Government Center. Helpful desk and valet service. Very quick check-in and out. Traveling alone, I felt safe. My walk to the conference was a short walk away.
Close to attractions and businesses in the heart of Boston
Great location; great facility!
I have already recommended this facility to several other parents! It is centrally located and is a very comfortable, amenable facility. Staff was quite responsive and very helpful. This is also a great place if one needs to work, as the
business amenities are great!
Great central location and accessible to North End, Back Bay, etc. One can either walk or ride the T.
Perfect Fit
This was the best location we could have hoped for. We didn't want to spend much, but wanted to be close to everything downtown. At first it looked like a mistake since we were right across from a night construction site, complete with jackhammers
and cranes. Though the hotel was full, they moved us into a room on the other side the very next day, and sent up earplugs in the meantime. Loved the water bottle fill up station, not big and luxurious, but had everything we needed, was clean, comfortable, staff was helpful. If you are looking for a 5 star hotel, this is not your place. If you are planning to be out and about and only sleeping in the hotel, this place is perfect!
Best location!Great staff! Excellant!
Upon arrival we were greeted by a friendly front desk person. It was nice room in a quiet area.The location of the hotel made our getting to points of interest in town so much easier.The restaurant attached to the hotel had great food. We walked
to most of our destinations or took the local transit which was a short walk from the hotel.All in all it was a great holiday made nicer by the location of the hotel and the staff there. Would definitely recommend the hotel to others visiting Boston and area.
Private hotel
this was a private hotel, no fancy resturants or pools, but it was great and I plan on using this hotel again, it had everything we needed with a great price.....great great great
great location but quiet at night, close to Quincy market, a favorite tourist spot and lots of places to eat, and the subway was 2 blocks away
Quiet, private, and great location.
We went to a concert at the TD Garden. It was about a 15 minute walk to the garden and about 10 minutes from other entertainment!
Perfect! From the coffee & printing of boarding passes in the lounge to helpful staff and internet connected/laptop ready well-appointed rooms located just blocks from Boston Common, Back Bay and Government Center. I stayed two nights to run the
Boston Marathon and celebrate with good friends. I could not have been more pleased. Both thumbs up. I shall return!
Elephant & Castle -- a great pub on the ground floor of the hotel.
Very comfortable, excellent service.
We needed a reasonably priced hotel in the area for a one-night stay. The hotel staff was extremely helpful and efficient, and the room was comfortable and well-appointed. For the price the hotel was an excellent choice.
Excellent Hotel, with a great location
The trip was great, the hotel staff was very friendly and acomodating.
Pleasant stay.
Enjoyable :
-two computers in the lobby with printer (useful to buy boarding pass)
-some books in the room
-free water refill
Orbitz guards your privacy and security. We're certified by TRUSTe and Verisign.© 2001 - 2015, Orbitz, LLC. All rights reserved.CST 2063530-50; Hawaii TAR-6881; Iowa 644; Washington 602-108-724


text:
Original Article
Elevated root-zone temperature hastens vegetative and reproductive development in Shiraz grapevines
Article first published online: 26 DEC 2013
DOI: 10.1111/ajgw.12053
© 2013 Australian Society of Viticulture and Oenology Inc.
Australian Journal of Grape and Wine Research
Volume 20, Issue 1, pages 123–133, February 2014
Additional Information
How to Cite
Rogiers, S.Y., Clarke, S.J. and Schmidtke, L.M. (2014), Elevated root-zone temperature hastens vegetative and reproductive development in Shiraz grapevines. Australian Journal of Grape and Wine Research, 20: 123–133. doi: 10.1111/ajgw.12053
Publication History
- Issue published online: 26 JAN 2014
- Article first published online: 26 DEC 2013
- Manuscript Accepted: 27 AUG 2013
- Manuscript Revised: 14 MAY 2013
- Manuscript Received: 9 FEB 2013
Funded by
- Grape and Wine Research Development Corporation
- Abstract
- Article
- References
- Cited By
- berry composition;
- canopy development;
- carbohydrate mobilisation;
- fruit ripening;
- soil temperature
Background and Aims
Springtime root-zone warming activates mobilisation of the root carbohydrate reserves, a critical source of carbon for early canopy and reproductive development in grapevines following winter dormancy. Seasonal variability in soil temperature during spring may result in inconsistent vegetative growth and fruitset with consequences for berry growth and ripening.
Methods and Results
We monitored flowering and berry ripening in Shiraz grapevines (Vitis vinifera L.) grown in large temperature-controlled pots. The vines were exposed to a cool, ambient and warm root-zone temperature from budburst to fruitset. Root starch mobilisation after budburst was linearly correlated to the cumulative heat units received by the soil. A warm root-zone temperature also hastened leaf expansion, net positive carbon assimilation, onset of flowering and fruit set, berry enlargement and the onset of veraison. At harvest, berry pH and nitrogen concentration as well as fresh and dry mass were higher for the vines exposed to a warm root-zone while berry acidity was lower.
Warm soil temperature in spring stimulated the mobilisation of carbohydrates in the roots and accelerated shoot and reproductive development, resulting in larger berries with lower acidity.
Significance of the Study
Because root-zone temperature is an environmental driver of berry size and composition, models predicting yield and berry composition can be fine-tuned to incorporate this critical parameter.


text:
Hotel Dorion
No prices found through our partners. Please contact the business directly or check some of our recommended alternatives.
How has this hotel rated in the past?
- Suites
- Continental Breakfast
- Free High-Speed Internet
- Kitchenette
Travelers also recommend:
TripAdvisor Reviews Hotel Dorion Montreal
Travel Blogs from Montreal
Saturday Explorations
... for dinner. St. Huberts is a restaurant chain in Montreal that specializes in rotisserie chicken. I had maple whisky chicken, which was delicious. After dinner, we grabbed crepes at the RoloPan.
RoloPan is a creperie that serves both savory and desert crepes. I used to think I knew how to make crepes. In France, I ate them all the time, but I never really got to see how they were made. The crepe maker (we saw the same guy ...
Montreal...no choice gotta stop here
... laughing his ass off at me. Least I can entertain...and this caused him to dig deep and find a bottle of dark rum tucked away...soooo you can guess what happened there. What didn't help next was I staggered upstairs and found the port. Saving grace was I could still tell time....and only had a bit of it to catch me flight. So with me best "Mmmmerky boooouuuukuts!" I gave a wave and staggered off....I still seemed to have a mastery of the language it would seem.
Montreal - 2nd Biggest Francophile City on Earth!
... this old country inn literally go up in smoke.
Scott and I now sit on the ViaRail train, heading through rural and forest scenes to Toronto. We arrive late tonight and have the following two days set aside to explore Canada's largest city. We're excited, among other things, about the prospects of developing a walk route amongst the islands that reside just offshore Toronto in Lake Ontario. Stay tuned for my next report of adventure planning in ...
La Fontaine park & The Botanical Gardens
... was at the same level as the seat. I then headed off to The Botanical Garden. I asked at the information desk if they have a map of the park. I then pointed to the Chinese garden and the lady said everything is closed for winter. Well I didn't come all this way to just walk off. She did warn me that only the main path is ok to walk on, but the small paths that lead to the Chinese & Japanese garden will be slippery ...
Exploring Cobblestones & Cathedrals
... Notre-Dame's towers ascend into the azure blue of an afternoon sky. Moving under three imposing arches, the tour line progresses until glimpses of the stunning interior gradually emerge. Designed and built by an Irish Protestant architect living in New York, James O'Donnell moved to Montreal to complete the new basilica. The holy work must have inspired O'Donnell himself, because by the time he was finished, he had coverted to Catholicism. After he died, the ...


text:
Dr. Stephanie C. Smith graduated from the University of Tennessee College of Medicine at Memphis in 2008. She works in Reno, NV and specializes in Neurology. Dr. Smith is affiliated with Banner Churchill Community Hospital.
Medical School: University of Tennessee College of Medicine at Memphis; Graduated 2008
15 McCabe Dr Ste 203
Reno, NV 89511
(775) 853-7669
Fax: (855) 313-0186
Practice Website: Not Available
Accepting New Patients: No
Medicare Accepted: No
Medicaid Accepted: No
Not Available
62 N Pecos Rd Ste B
Henderson, NV 89074
6630 S McCarran Blvd Ste A8
Reno, NV 89509
6630 S McCarran Blvd Ste A8
Reno, NV 89509
975 Kirman Ave Ste 292D
Reno, NV 89502
330 E Liberty St Ste 100
Reno, NV 89501


text:
GRAYSON, Ky. - The Kentucky county clerk jailed for refusing to issue marriage licenses to gay couples was released Tuesday after five days behind bars, emerging to a tumultuous hero's welcome from thousands of supporters waving large white crosses.
Odds have improved that many extremely premature U.S. infants will survive without major problems, although prospects remain poor for the smallest and youngest, born nearly four months too soon, a government-funded study found.
MINNEAPOLIS - The Minnesota dentist whose killing of Cecil the lion sparked a global backlash emerged for an interview in which he disputed some accounts of the hunt, expressed agitation at the animosity directed at those close to him and said he would be back at work within days.
NORWOOD, Mass. - Donald Trump insults and exaggerates.
HARLAN, Ky. - Kentucky coal miners bled and died to unionize.
GRAYSON, Ky. - They stood chanting outside the jail house, "Thank you, Kim; Thank you, Kim," and prayed that the defiant county clerk locked inside could hear them.
WASHINGTON - U.S. unemployment fell to a seven-year low of 5.1 percent last month, but hiring slowed - a mixed bag of news that offers few clues to whether the Federal Reserve will raise rock-bottom interest rates later this month.
ASHLAND, Ky. - A defiant county clerk went to jail Thursday for refusing to issue marriage licenses to gay couples, but five of her deputies agreed to issue the licenses themselves, potentially ending the church-state standoff in Rowan County, Kentucky.
ATLANTA - A man shot by police officers who went to the wrong Atlanta house ran bleeding outside, where a neighbor heard him asking, "Why did they come in my house? Why did they shoot me? Why did they shoot my dog?"
LOS ANGELES - Results for some of the states that participated in Common Core-aligned testing for the first time this spring are out, with overall scores higher than expected. But they are still below what many parents may be accustomed to seeing.
HOUSTON - The man accused of shooting and killing a suburban Houston officer has a history of mental illness and once lived in a homeless shelter, authorities said Monday.
NEW YORK - It's the LOL generation that appears most annoyed by bad grammar and spelling slips, according to a survey by Dictionary.com.
ROSEAU, Dominica - Tropical Storm Erika dissipated early Saturday, even as its remnants began drenching parts of eastern Cuba. But it left devastation in its path, killing at least 20 people and leaving nearly 50 missing on the small eastern Caribbean island of Dominica, authorities said.
A billion people logged in to Facebook on a single day this week, marking the first time that many members used the world's largest online social network in a 24-hour period. The number amounts to one-seventh of the Earth's population.
ROANOKE, Va. - On the day he was fired from a Virginia TV station, Vester Flanagan pressed a wooden cross into his boss' hand as two police officers walked him to the door. "You'll need this," he said.
WASHINGTON - The United States is prepared to increase the number of refugees it resettles by at least 5,000 next year as European countries struggle ...
© 2015 Statesboro Publishing - All Rights Reserved
Powered By


text:
Details: $100 Off RRP Super Deluxe Latex Sleeper Sofa Mattress
New • Add a Comment
Details: $160 Off RRP Sleeper Sofa Mattress Premium Memory Foam
100% Success • Add a Comment
Details: Save $50 Air-Dream-Air-Over-Coil-Sofa-Bed-Mattress
50% Success • Add a Comment
Details: Save $100 Super-Deluxe-Latex-Sleeper-Sofa-Mattress
50% Success • Add a Comment
Details: Receive free shipping with your order
25% Success • Add a Comment
5 coupon codes & deals for sofasleepermattress.com. Sofa Sleeper Mattress is the online shopping destination of choice for high quality mattresses. Choose from a great selection of sofa bed, RV and truck mattresses, air beds, mattress protectors and more. Browse the website to see available items.
Show More
Never miss a deal.
Be the first to know.
Plus get our best deals in our email newsletter. Privacy Policy
Show more popular stores
©2010 - 2015 RetailMeNot Inc. All rights reserved. Site Map | Terms of Use | Privacy Policy
RetailMeNot is a registered trademark of RetailMeNot, Inc. Third-party trademarks are the property of their respective third-party owners. Presence of a third-party trademark does not mean that RetailMeNot has any relationship with that third party or that the third party endorses RetailMeNot or its services.


text:
Auto Repair in Saint Germain
Our master mechanics identify the best auto repair shops in Saint Germain. Edit search×
There are 29 auto service shops and mechanics in Saint Germain. Edit search
RepairPal has not certified the following shops.
The shops listed below are not committed to the fair price guarantee and minimum warranty of RepairPal Certified shops. When taking your car to a shop that has not passed RepairPal's inspection, we recommend that you:
- Look for a shop with ASE-certified technicians.
- Request written estimates from multiple shops and check them with the RepairPal estimator
- Verify that the shop you select is willing and able to clearly explain the work being performed.
Auto repair shops and dealerships near Saint Germain.
322 W Pine St, Eagle River
Muffler & Exhaust, Service & Repair, Tire Sales/Repair
"These guys are great,they went out of there way too help get us back on the road and were honest and upfront with us...."
9736 Ray Place, Minocqua
Muffler & Exhaust, Oil Change & Lube, Service & Repair, Tire Sales/Repair, Transmission Repair
6663 Hwy. 8 West, Rhinelander
Roadside Assistance, Service & Repair
1874 North Stevens Street, Rhinelander
Service & Repair, Transmission Repair
8762 Hwy 51, Minocqua
Collision Repair & Paint, Service & Repair
1001 Coon Street, Rhinelander
Service & Repair, Transmission Repair
51598 Hwy 51, Manitowish
166 US Highway 51 North, Woodruff
4690 South Shore Drive, Rhinelander
8780 Blumenstein Rd, Minocqua
Muffler & Exhaust, Service & Repair
8627 Hwy 51 North, Minocqua
418 Hwy 51, Woodruff
897 Hwy 17 S, Eagle River
Roadside Assistance, Service & Repair, Tire Sales/Repair, Transmission Repair
209 W Davenport St, Rhinelander
1687 Justin St, Woodruff
1935 North Stevens Street, Rhinelander
- Buick
- Cadillac
- Chevrolet
- Toyota
Oil Change & Lube, Scheduled Maintenance, Service & Repair
1927 Apache Lane, Rhinelander
5501 Main St, Boulder Junction
7003 Hwy 45 N, Three Lakes
6251 Hwy. 70 E., St. Germain
9732 Hwy 70 West, Minocqua
406 Onieda, Minocqua
4246 Hwy B, Land O' Lakes
8240 US Highway 51 South, Minocqua
- Buick
- Chevrolet
- Pontiac
9760 Ray Place, Minocqua
"Save yourself a lot of time and do not use this place for service! Took my truck in to have a master cylinder replace..."
224 South 7th Street, Eagle River
Muffler & Exhaust, Service & Repair, Tire Sales/Repair
"Liars and Theives. Avoid at all costs
Took it in told them I was putting in a bootle of power steering fluid a day ..."
1390 State Road 155, St. Germain
5 East Monico Street, Rhinelander
9201 Cty Hwy J, Minocqua
RepairPal Certified Shops
pass a rigorous 42-point annual inspection by our master mechanics for quality work and fair prices.
Never Overpay
or RepairPal will refund you the difference.
Learn more
Guaranteed Quality Work
backed by a minimum 12-month / 12,000-mile warranty.
+ Search by Make in Saint Germain


text:
Last Week Tonight with John Oliver: Food Waste (youtube.com)
submitted by pnoque
Is dumpster diving illegal? (self.freeganism)
submitted by Moosekababs
New subreddit, /r/donateyourphone (self.freeganism)
submitted by ciaodanielle
Hungry 'freegan' in court for taking discarded out-of-date food from Tesco (sunderlandecho.com)
submitted by pnoque
Going To Waste | Against The Grain, a radical radio/webcast program. (againstthegrain.org)
submitted by anarchoaisthesis
Alternatives to dumpster diving? (self.freeganism)
submitted by mouse87
Free Fresnel Lens: used for solar cooking. (self.freeganism)
submitted by AnimalPix
An Interview with a Dumpster Diver (theglobalcatalyst.com)
submitted by ipsumoli
Do you think that freeganism makes you a bit of a hoarder? (self.freeganism)
submitted by chrisbluemonkey
Why we're wasting food in a hungry world (seattleglobalist.com)
submitted by anarcurious
The Real Freegan Lifestyle — Freedom, Solidarity, Independence vs Consumerism (medium.com)
submitted by StaceysWay
and yes, another new subreddit... (reddit.com)
submitted by parabill54s
New subreddit, /r/CrimethincCollective (reddit.com)
submitted by
Dumpster divers seek out free food as prices increase (bbc.com)
submitted by pnoque
How to eat like a king out of the trash (metrotimes.com)
submitted by pnoque
My wife's experiment: walk 100 miles with no money and no food (caredares.wordpress.com)
submitted by jomby
This food is from where?! (robgreenfield.tv)
submitted by robjgreenfield
Free-wheeling freegan bikes to promote sustainability (lacrossetribune.com)
submitted by pnoque
On hunger and homelessness in the land of plenty (thevillager.com)
submitted by pnoque
Merriam-Webster adds "freegan" to the dictionary (theguardian.com)
submitted by pnoque
Ideas for freegan home repair supplies? (self.freeganism)
submitted by chrisbluemonkey
My 'freegan' week in London (theecologist.org)
submitted by pnoque
Video: Meet the Dumpster Divers (nycitylens.com)
submitted by pnoque


text:
- ITV Report
- ITV Report
Race is on to repair Newquay by Easter
Live updates
A third of Cornwall visits triggered by TV dramas
More than a third of all visits to Cornwall have been triggered by television dramas like Doc Martin or Poldark.
The research by Visit Cornwall said the series had a significant influence on decisions to visit the county.
94% of those who took part in the survey said they wanted to visit the landscape and scenery showcased in the productions.
Eden Project named one of the world's top destinations
The Eden Project in Cornwall has been rated one of the 500 best places to visit in the world.
Travel guide Lonely Planet has put the iconic biomes at number 281. The number one spot was taken by the temples of Angkor in Cambodia.
The Ultimate Travelist is being published today, and has a reputation as a dream to-do list for many travellers.
Record-breaking interest in visiting Cornwall
The sun seems to be shining for tourism in Cornwall. The official online guide to visiting the county had a record-breaking half a million hits last month.
VisitCornwall.com says that's a huge increase on last year. Popular searches on the site were places to stay, things to do and local events - good news for local business and the region's reputation as a top summer destination.
Prince Charles shakes claws with giant lobster on Fistral Beach
The Duke and Duchess of Cornwall have completed a busy schedule of visits to the county, visiting all parts of the Duchy over the past three days.
The last day of the tour included a visit to Fistral Beach in Newquay.
Here they were shown how the marine litter which regularly washes up on our shores is now being recycled.
The Prince also had a close encounter with two giant creatures from the sea during the visit.
Steve Hardy reports.
Prince Charles & Camilla at Fistral Beach
It's the final day of the Duke & Duchess of Cornwall's visit to the Duchy and today they're at Fistral Beach, Newquay. They're seeing how local charities are tackling litter on our coastline.
The Duchess of Cornwall stops for a picture with 'Larry the Lobster' and 'Sally the Starfish', who are environmental campaigners from the Marine Conservation Society.
Prince of Wales & Duchess of Cornwall entertained on St Agnes
The Prince of Wales and the Duchess of Cornwall are continuing their tour of the Scilly Isles by visiting St Agnes.
Prince Charles and Camilla are currently taking part in their annual summer annual tour to the region.
With the focus of their three day visit on the region's tourism industry.
Prince Charles and Camilla were entertained by pupils from St Agnes school, who performed the famous story of St George slaying the Dragon for them in the sunshine.
They also visited the Island Fair where they were introduced to some local wildlife.
Day 2 of royal visit to Cornwall
The Duke and Duchess of Cornwall are spending a second day in the county today.
They're focusing on the tourism industry and local communities during this year's visit - stopping in Padstow in North Cornwall yesterday, meeting RNLI volunteers and visiting a restaurant run by celebrity chef Rick Stein. Today the royal couple will be on the Isles of Scilly, stopping by a local island fair on St Mary's.
- ITV Report
"I'm a royal celebrity"
Prince Charles is on his annual summer visit to Cornwall - and couldn't avoid an "I'm a celebrity" momentRead the full story ›
David Cameron expected to announce £5 million tourism investment
David Cameron is today expected to announce a £5 million investment in tourism in the region.
The move has been welcomed by the VisitEngland Chief James Berresford who said the five point plan to support tourism growth across the UK was further recognition of the enormous value and contribution of the industry.
Placing tourism at the heart of Government will do much to support plans to rebalance the economy.
We have invested £57m of Government funds in English tourism over the past five years which has to date generated over £1.5 billion growth in visitor spending and created over 28,000 jobs.
We aim to build on this success with both the Northern and South West Tourism Growth Funds, and the proposed Product Development Fund recommended in the Triennial Review of VisitEngland.
As part of a £5million South West Tourism Growth Fund announced by Government, a range of activity will take place to grow tourism, deliver economic growth and boost export earnings in the South West of England.
Our ambition for the South West Tourism Growth Fund is to work closely with VisitBritain and partner destinations to create an additional visitor spend of £60 million, supporting the creation of 1,000 jobs to boost the South West visitor economy.
'Gove effect' leaves the tourism industry out of pocket
A tourism business owner says the so-called Gove Effect is forcing her to sell off her holiday cottage.
Sarah Kitson from Lamerton near Tavistock says tougher rules where parents are fined for taking children out of school have had a drastic impact on holiday bookings.
It used to be from Easter til October we'd be fully booked but now we've got huge gaps. I've just had three weeks gap in a holiday cottage in Newquay, and it's just not worth keeping the holiday cottages running anymore as a holiday let business.
The rules brought in by Former Education secretary Michael Gove in 2013 mean parents can be fined £60 a day for taking their children out of school to go on holiday, or even prosecuted for it.
A recent report by the Tourism Society Westcountry said it's costing the industry £87 million a year.
The Tourism Society Westcountry and Visit Cornwall now calling for holidays to be staggered like in other European countries.


text:
Opportunity. Equity. Social Justice.
These are the guiding principles of the San José-Evergreen Community College District.
Student Success is the heart of our mission and we've hired the best and brightest faculty and staff to ensure that our students are well prepared when they transfer to a university, enter the workforce, or embark on a path of lifelong learning.
Welcome to San José-Evergreen Community College District where Student Success is our #1 priority. We invite you to join us by applying today to San Jose City College or Evergreen Valley College. Click on the campus image to Apply Today!
Congratulations to Dr. Rita M. Cepeda, SJECCD's Chancellor Emeritus, for being the recipient of HACU's (Hispanic Association of Colleges and Universities) Lifelong Leadership Award. The award ceremony will take place at the HACU 29th Annual Conference on October 10, 2015 at the Fountainebleau Miami Beach Hotel.
Congratulations for the well-deserved prestigious award, Dr. Cepeda!
evergreen valley COLLEGE AND san jose city COLLEGE maintained full accreditation status
Congratulations to Evergreen Valley College and San Jose City College for maintaining full accreditation status!
At its June 3 - 5, 2015, the Accrediting Commission for Community and Junior Colleges, Western Association of Schools and Colleges, reviewed the Follow-Up Reports submitted in March 2015 by Evergreen Valley College (EVC) and San Jose City College (SJCC). As a result, both EVC and SJCC have been removed from probation and maintained their full accredition status.
Congratulations to the Class of 2015
The largest graduating class in the history of SJECCD. Please see the following 3-minute videos of SJCC 2015 Graduation and EVC 2015 Graduation commencements.
SJCC : https://vimeo.com/sjeccd/sjccgraduation2015
EVC : https://vimeo.com/sjeccd/evcgraduation2015
SJECCD: https://vimeo.com/sjeccd/sjeccdgraduation2015
Chancellor Search
We are seeking a new Chancellor. The successful candidate must be a dynamic leader, a visionary, a listener. He/She must understand the struggle of community college students and embrace our community. The District is accepting applications and nominations. For details of this position opportunity, please click HERE.
The position has been extended from August 31, 2015 to open until filled. This is a confidential search process.
San José-Evergreen Community College District Saves Taxpayers $30 Million
The San José-Evergreen Community College District's successful refunding of selected bonds associated with its Measure G 2004 General Obligation Bond Program in June 2015 resulted in direct savings to the District's taxpayers in the amount of $10,203,044 or 9.67% in present value savings, which is well above the industry benchmark of 3%. These savings are in addition to the savings in April 2014, whereby the District successfully refunded selected bonds associated with its Measure G 2004 and Measure G 2010 General Obligation Bond Programs, providing $19,826,076 in direct savings to the District's taxpayers or 12.10% in present value savings.
The hard work and dedication of our students for their education and of our faculty and staff for their programs and services to increase student success are reflected in the following Annual Report 2014 and Appendices for each entity within the San José-Evergreen Community College District.
- SJECCD Annual Report 2014
- Report Appendices for:
* District Office
* Evergreen Valley College
* San Jose City College
* Workforce Institute
For more than 93 years, San José City College has been providing education and workforce opportunities to our district residents in San José; and for more than 40 years, Evergreen Valley College has educated our citizenry in south San José and Milpitas.
Our Workforce Institute is a training partner with many corporations as we work to develop and maintain a vital economy in the "South Bay".
Demographic changes, economic conditions, educational reforms, and the need for preparing students for postsecondary education prompted Measure G Bond funded initiative to build the Joint Use 21st Century Post-Secondary Education Center in Milpitas. This is a joint project between SJECCD and Milpitas Unified School District (MUSD) to be completed by Fall of 2016 with the following goals:
1. Promote a seamless system of higher education services2. Expand access to higher education in underserved areas of the District3. Improve regional economic development opportunities by providing access to career and technical education
Adult Education: The Board of Trustees and Chancellor Cepeda have undertaken a new strategic initiative to address the needs of adult learners by establishing a collaborative with local adult education schools and non-profit organizations. Through the Summer and Fall of 2013, the South Bay Consortium for Adult Education (SBCAE) was formed. The purpose of the Consortium is to develop plans for adult education for South Bay region.
Educating more than 20,000 students each year, our colleges are hubs of teaching, learning and innovation in one of the most exciting cities in the world.
SJECCD Global Ends Statement
The San José-Evergreen Community College District exists to ensure all students, especially those with educational and/or socioeconomic challenges, will have the skills and capabilities to be successful in the next stage of their life, sufficient to justify the use of available resources. Please click HERE for Ends Policy Dashboards.
These skills and capabilities can best be acquired through the following means:
Career Development Students will acquire skills sufficient to get, keep and progress in jobs with local employers, particularly in high wage/high growth areas, for all students, especially for: under-prepared students; older displaced students; and young people at the start of their careers.
Transferability All students, especially under-prepared students, will achieve academic success sufficient to transfer (EVC, SJCC) to a four-year post-secondary institution.
College Readiness Students will develop the language skills to succeed in college, the ability to analyze, synthesize, and evaluate information and will be able to effectively communicate with others and successfully work collaboratively in culturally diverse settings.
Institutional Excellence The District's governance board, staff and faculty (EVC, SJCC, DO, WI) will demonstrate through a culture of evidence commitment to excellence, equity and inclusion in every facet of its mission.
Student Success The San José-Evergreen Community College District will improve student success (EVC, SJCC) through enhanced educational services and programs (EVC, SJCC, WI) and strengthened community engagement.
College Experience Enrichment opportunities (EVC, SJCC, WI) will exist to enhance the learning environment and support student success.
We are seeking a new Chancellor. For details of this position opportunity, please click HERE
Employment Opportunities
Notice of Nondiscrimination and Contact Information for the Title IX Coordinator
Bid Opportunities
Citizens' Bond Oversight
Board Meeting
October 13, 2015 at 6:00 p.m.District Office Board Room40 S. Market St.San Jose, CA 95113
Agenda will be posted via Board Docs on October 8, 2015
We welcome your feedback regarding our website.
For comments or concerns please send an email to: email@example.com


text:
Reign of Fire
- Studio: Buena Vista Pictures
- Release Date: Jul 12, 2002
Critic Reviews
- Critic Score
- Most active
- Publication
- Most clicked
Often incomprehensible (a combination of jumpy editing and lots of thick British Isles accents) and hardly ever entertaining - even unintentionally.
It strains belief that nuclear weapons couldn't kill off the dragons, but three people with crossbows could.
The story doesn't clarify why the dragons hibernated for hundreds of years, nor why they awakened. Clearly, however, the filmmakers might have benefited from more sleep before penning the script.
Reign of Fire never comes close to recovering from its demented premise, but it does sustain an enjoyable level of ridiculousness.
Director Rob Bowman seems at a loss as to what to bring to the film, which, even with its good choice of leads, plods along from one dragon fight to the next, all of them staged to showcase Fire's impressive CGI dragons, but none choreographed with any real flair.
It's just silly, loud and goofy. The dragon needed a bigger part and the two stars smaller ones.
Peaks early with a vertiginous dogfight; thereafter, spotty CGI and a bamboozling plot conspire toward a colossal anticlimax.
One regards Reign of Fire with awe. What a vast enterprise has been marshaled in the service of such a minute idea. Incredulity is our companion, and it is twofold: We cannot believe what happens in the movie, and we cannot believe that the movie was made.
A disaster of a drama, saved only by its winged assailants. You know a picture's in trouble when you find yourself rooting for humankind to lose.
Dragons torch the earth as manly men with weird hair battle them in this colossally misconceived dud.
So what's not to like? There's the bad CGI, the choppy pacing, the comically intense acting, the repetition, the dullness and mostly the idiot plot about how there's only one male dragon and everything will be fine if they kill the Big Dick. Wha? Somebody get a hose and put this Fire out.
Awards & Rankings
User Score
Mixed or average reviews- based on 75 Ratings
User score distribution:
Positive: 28 out of 38
Mixed: 3 out of 38
Negative: 7 out of 38
Aug 19, 2010A stupid ending, with laughable dialogue and Matthew McConaughey looking and acting like something out of GI joe and yet I was never bored andA stupid ending, with laughable dialogue and Matthew McConaughey looking and acting like something out of GI joe and yet I was never bored and found it quite entertaining. I'm a bit annoyed though because it's never as epic or explosive as it should be and never as heartfelt as it wants to be. The cover and posters are misleading… Full Review »
TKNov 17, 2007Not the best movie ever... but mildly entertaining. The characters are somewhat likable and the story was predictable but decent. PS Aron, Not the best movie ever... but mildly entertaining. The characters are somewhat likable and the story was predictable but decent. PS Aron, your not cool and couldn't write a review worth reading to save your life... regardless of what Mindy might think.… Full Review »


text:
The hotel seems dated but was clean and close to JR Sendai Station."
This is a beautiful hotel. The lobby is a bit cold (reminds me of a castle) but the detail of the building is amazing and the rooms are just lovely. The furniture and bathroom remind me of something you might find in an English cottage - very romantic. The staff were friendly and one of desk staff we dealt with spoke very good English."
Rooms were smaller than I expected. I had a bigger room for the same price in the past. Professional baseball team stays there so there were many people in the lobby waiting to see their favorite players. If you like that kind of stuff it could be a perk, but if you hate crowds not so much."
The rooms were small but clean and perfectly good enogh. The hotel was 5 mins walk from the shinkansen and conventional rail station, with plenty of shops and restaurants nearby. Good breakfast, nice staff."
very nice I would come back in a moment everything was great!!!"
The hotel is close to the East Exit of the Koriyama JR station, away from the bustle of the town center. The room was clean, the breakfast buffet was fine, and I'd definitely stay there again."
the hotel is very comfort. The location is also convenience."
Nice and clean. People/staff are very helpful. This hotel to me looks alike a business hotel despite its size, it delivered what it could to customers very nicely. I look forward to staying in these hotels around Japan in the furture"
It takes about 10 mins walk from Akita JR station. It is a wonderful budget hotel because it comes with a real hot spring spa that you could enjoy almost anytime as you wanted. You could also enjoy free Ramen overnight during late night snack time. The room is modern, comfortable and clean. I really enjoy my stay. Only it doesn't included breakfast that you will need to pay around $13 CAD for the buffet which included some local delicacy. There is also matcha lattee if you are a big fans of it."