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|Antidiabetic agents based on aryl and heteroarylacetic acids
|Adams et al.
|Antidiabetic agents
|Adams et al.
|Use of thiazolidinedione derivatives and related antihyperglycemic agents in the treatment of disease states at risk for progressing to noninsulin-dependent diabetes mellitus
|Antonucci et al.
|Systemic delivery of polypeptides through the eye
This application claims the benefit of U.S. Provisional Application, Ser. No. 60/361,559, filed Feb. 28, 2002, which is incorporated by reference.
1. Field of the Invention
This invention relates generally to a method for delivering insulin, insulinomimetic agents, and the like to the eye for treatment of diabetic retinopathy. More specifically, the method involves the periocular administration of these drugs via subconjunctival routes, sub-Tenon's routes, or intravitreal routes.
2. Background of the Related Art
Diabetes has reached epidemic proportions. Approximately 15 million people in the United States are currently afflicted with the disease, and that number is expected to rise to at least 21 million over the next 30 years.
In addition to (and as a consequence of) the metabolic disarray caused by the disease, diabetes causes a variety of other, organ-specific dysfunctions, including in particular diabetic retinopathy. Diabetic retinopathy affects half of all Americans diagnosed with diabetes. Diabetic retinopathy is an illness that occurs when diabetes damages tiny blood vessels in the retina, affecting vision, and is a leading cause of blindness. There are two clinical stages of retinopathy. The first stage is known as nonproliferative retinopathy, in which the blood vessels damaged by diabetes leak fluid and lipids onto the retina. When the fluid accumulates in the center of the retina (i.e., the macula) it leads to macular edema. The fluid makes the macula swell, which blurs vision. The second stage is the proliferative stage, where new blood vessels grow along the retina and in the clear, gel-like vitreous that fills the inside of the eye. These new blood vessels can bleed, cloud vision, and destroy the retina unless treated. There is also a preclinical phase in which patients will generally have no symptoms, nor will there be any findings on routine clinical examination. However, in the preclinical phase sensitive tests reveal reduced contrast sensitivity, electrical responses with an electroretinogram, or color vision.
There are several methods of treatment for diabetic retinopathy disclosed in the art. However, none of these treatment approaches have proven successful in addressing the primary metabolic disorder or in preventing retinopathy. Conventional diabetic retinopathy treatments are limited to controlling the diabetic state with systemic insulin administration or oral hypoglycemic agents. The problem with these systemic approaches is that they do not restore normal physiologic metabolic control or provide overall effective levels of the drug to the eye. Secondary treatment approaches include using diuretics to control blood pressure or intravascular fluid overload. Attempts have also been recognized in the arts for treating retinopathy with aldose reductase inhibitors, inhibitors of nonenzymatic glycation (aminoguanidine), corticosteroids or antihistamines. Methods of treatment for advanced retinopathy complications include vitrectomy surgery and laser treatment, exposing an intense beam of light to the small diseased areas of the retina. These methods are palliative in nature, and none of these methods is sufficiently effective to prevent or cure the disease.
Although diabetic retinopathy is extensively studied in the art, the direct effects of insulin or insulinomimetics on diabetic retinopathy are limited. It has been demonstrated that retinal neurons die in experimental diabetes in rats and in humans. Moreover, insulin has been shown to be a survival factor for retinal neurons in culture, and excess hexosamines impair insulin's survival-promoting effects. In vivo, systemically and intraocularly administered insulin activates the insulin receptor and downstream signaling cascades that are involved in cell function and survival. However, the ability to administer systemically sufficient insulin or other insulinomimetic agents to be effective for prevention of retinopathy is limited by the risk of hypoglycemia.
Accordingly, there is a great demand for safe and effective methods for delivering agents effective in treating diabetic retinopathy. In particular, there is a need in the art for treatment methods that maintain retinal cell function and survival in the face of persistent hyperglycemia.
The invention describes methods and reagents for treating retinal disorders, particularly retinal disorders having at least in part a metabolic etiology. As provided herein, the inventive methods and reagents permit compounds for treating ocular disorders, such as retinal detachment, retinitis pigmentosa, central retinal artery occlusion, central retinal vein occlusion, ischemic optic neuropathy, high tension glaucoma, low tension glaucoma, and cataract, to be administered locally in the eye. The invention specifically provides methods for preventing and treating nerve-related vision disorders, including in particular diabetic retinopathy. The inventive methods comprise periocular administration of a sufficient amount of a drug by a subconjunctival, sub-Tenon's or intravitreal route to be effective in treating such retinal disorders. In certain embodiments, the drug is administered to an eye under its mucous membrane or fascia.
Preferred drugs administered using the methods of the invention include formulations of insulin, insulinomimetic agents, or peptides. Formulations of insulin that may be used in the invention include, for example, formulations of native insulin, naturally derived insulin, recombinant insulin, any modification thereof containing buffers or modifying proteins, or any other known formulations of insulin. The concentration of the insulin formulation can range from 1 picomolar to 100 micromolar. If the insulin formulation is a gel or liquid, the volume thereof can range from 5 μL to 1 mL. In the practice of the inventive methods, a sufficient amount of any of these drugs is administered to the eye, wherein a sufficient amount of insulin ranges from 5 to 100 μL or 0.1 to 10 units of insulin. Formulations can also include augmenting drugs from the thiazolidinediones (TZD) class, such as rosiglitazone, pioglitazone, and troglitazone, as well as, non-peptide insulinomimetic agents, such as TLK16998 (Telik), KRX-613, and L-783,281 (Merck).
The invention further comprises methods of administrating drugs to the eye, where drugs are administered to more than one eye. These methods of administration include via a solution, a polymeric base, or a pump. Additionally, the method of administration may be by implanting a device, where the device releases a formulation of a drug, preferably insulin, an insulinomimetic agent or a peptide at a prescribed rate. One or more devices may be administered to one eye.
The invention also provides formulations of insulin, insulinomimetic agents or peptides adapted or prepared for use with the methods of the invention. Preferably, the formulations of the invention comprise pharmaceutical adjuvants, carriers, buffers or other components.
Specific preferred embodiments of the present invention will become evident from the following more detailed description of certain preferred embodiments and the claims.
FIG. 1 illustrates the invention's method for administration of drugs under the eye's surface membrane;
FIG. 2A presents a phosphotyrosine (PY) detecting Western blot from both muscle and retina in a rat that received either a vehicle (V) and insulin (I) injection;
FIG. 2B presents a graph quantifying Western blot analysis and expressing data as a graph for muscle tissue in terms of phosphotyrosine/insulin receptor beta-subunit (PY/IRβ) ratios;
FIG. 2C presents a graph quantifying the Western blots and expressing data as a graph for retina tissue in terms of PY/IRβ ratios;
FIG. 2D presents an immunoblot of phospho-Aktser473 (top) and total Akt (bottom) from vehicle, and insulin injected rats as well as quantification of the blot expressed in terms of phosphorylated to total Akt ratios;
FIG. 3A presents a Western blot comparing IRβ tyrosine phosphorylation in the retina and in other insulin responsive tissues under fasted and freely fed conditions;
FIG. 3B presents a graph quantifying Western blot analyses as disclosed above and expressed as a graph of PY/IRβ ratios for retina tissue;
FIG. 4 presents a PY immunoblot for autophosphorylation with (+) and without (−) addition of ATP to the kinase reaction in the retina and liver under freely fed and fasted conditions;
FIG. 5 presents a graph quantifying the Western blots shown in FIG. 4 and expressed as a graph of IRβ activity when IRβ immunoprecipitates were subjected to kinase assays;
FIG. 6 presents a PY immunoblot for retinas treated with IGF-1 or insulin and subjected to immunoprecipitation of the IGF-IRβ complex, with the arrowhead indicating the tyrosine phosphorylated band that corresponds to the IGF-1Rβ complex;
FIG. 7 illustrates the difference between intraportal insulin injection and explanted retina tissue; and
FIG. 8 presents a graph quantifying an immunoblot of insulin receptor tyrosine phosphorylation from retina of an anesthetized rat that received insulin in one eye and vehicle in the other eye.
The invention provides reagents, pharmaceutical compositions and methods for delivering drugs for treatment or prevention of nerve-related vision disorders, particularly diabetic retinopathy. The method specifically comprises periocular administration of insulin, insulinomimetic agents or peptides via subconjunctival, sub-Tenon's or intravitreal routes.
More specifically, the method of the invention comprises periocularly administering a sufficient amount of a formulation of insulin, insulinomimetic agents or peptides to both eyes. Periocular delivery is safer for the general health of an animal, preferably a human, undergoing treatment for a nerve-related vision disorder since it involves less ocular morbidity than laser or vitrectomy surgery.
The ability to systemically administer sufficient amounts or concentrations of insulin or other insulinomimetic agents to prevent retinopathy is largely limited by the risk of hypoglycemia. The invention overcomes the consequences of systemic administration by achieving direct local drug delivery of effective amounts of these agents by direct administration to the subconjunctiva, sub-Tenon's capsule, or intravitreous. Administering insulin or insulinomimetic agents via these routes also provides effective intraocular drug penetration to maintain retinal cell function and survival.
One aspect of this invention involves replacing a deficient insulin receptor ligand and increasing activation of a down-regulated insulin receptor, or its downstream signaling molecules. Specifically, the inventive methods comprise direct insulin administration to the eye, and specifically to cells of the retina. Any pharmaceutically acceptable insulin formulation can be used with the methods of the invention. Examples of useful insulin formulations include native insulin (preferably human insulin, particularly recombinantly-produced human insulin such as Humulin®, or insulin isolated from any other mammalian species), naturally derived or recombinant, and all of modifications thereof, such as Regular to NPH, Ultralente (Eli Lilly & Co.), insulin glargin (Lantus®, Aventis), Lispro®, (Eli Lilly & Co.), Novolin® (Novo-Nordisk) and formulations containing any modifying proteins (such as, for example, protamine) or buffers known or accepted in the art.
Moreover, the invention provides methods comprising administration of insulinomimetic agents or nucleotides (aptamers) that mimic some or all of insulin's actions. The invention further encompasses the administration of drugs that augment insulin along with the insulin. These augmenting drugs can be, inter alia, from the thiazolidinediones (TZD) class. They may also be small non-peptide insulinomimetic agents such as TLK16998 (Telik), KRX-613, and L-783,281 (Merck). Such compounds activate the proliferator-activator gamma (PPAR-gamma) receptor to provide necessary actions of insulin in the retina. Thus, their addition enhances the insulin effect on signaling to retina cells. Examples of augmenting drugs include rosiglitazone, pioglitazone, and troglitazone.
Concentrations of the drugs used in the invention can range from low picomolar to micromolar concentrations. If the drug is a liquid or gel insulin formulation, volumes can range from about 10 μL to about 1 mL. A sufficient dosage of the insulin will range from a few picomolars to micromolar.
The inventive treatment provided herein permits a number of different administration routes to be used to introduce an effective amount of a drug to the eye. These include administering the drug via a pump, a polymeric base, or a solution. The preferred method of administration is by a polymeric base, including but not limited to polyester (PET), polyethylene (PE), poly(L-lactic acid) (PLA), and polyurethane. Additionally, drugs may be administered by implantation of a formulation of the invention or a device that will release such a formulation at a prescribed rate. The invention advantageously provides methods for administering said formulation to both eyes simultaneously, although embodiments having administration to one eye, as well as embodiments having independent or non-contemporaneous administration to both eyes, are also encompassed by the invention.
Drug formulations of the invention advantageously can be administered under the mucous membrane of the eye or the Tenon's fascia of the eye. More specifically, the drugs can be delivered to the subconjunctival and/or sub-Tenon's space. As shown in FIG. 1, drug formulations of the invention are injected, or otherwise administered, under the eye's surface membrane so that the drugs are able to diffuse through the sclera into the retina, vitreous, and the anterior chamber.
The inventive methods for treatment of nerve-related retinal disorders, such as diabetic retinopathy, are suitable for prevention or treatment at any stage of such retinopathic disorders. Specifically, the inventive methods are equally effective for the preclinical, nonproliferative, macular edema stages of such retinopathic disorders, as well as for the proliferative stage of retinopathy. Other retinal disorders advantageously treated using the methods of the invention, include retinal detachment, glaucoma, retinitis pigmentosa, central retinal artery or central retinal vein occlusion, ischemic optic neuropathy, high tension glaucoma, low tension glaucoma, and cataract.
While the invention has been described with particular reference to diabetic retinopathy treatment and other retinal disorders, it will be understood by those skilled in the art that the invention has applications in other medical fields, in particular whenever local insulin or insulinomimetic agents are delivered to tissues at risk for complications. For example, deliveries to kidneys and nerves since patients with diabetes have impaired kidney function (nephropathy) and nerve function (neuropathy). Thus, local application of insulin adjacent to these organs and tissues may improve their function and prevent future deterioration.
The following Examples are intended to further illustrate certain aspects of the above-described method and advantageous results. The following examples are shown by way of illustration and not by way of limitation.
Intraportal insulin injection was performed to determine if a single bolus insulin injection, and therefore an acute elevation in circulating insulin, could activate retinal insulin receptors (IR) in vivo as it does in other tissues. Intraportal insulin injection was conducted as follows. Male Sprague-Dawley rats (Charles River, Mass.) weighing 200–350 g were fasted 18 hours prior to being anesthetized with a 10:1 ketamine:xylazine cocktail (53.5 mg/kg ketamine and 5.33 mg/kg xylazine) administered by intramuscular injection. The fasted rats were administered a 500 μg bolus of insulin, nothing (sham), or vehicle (0.9% saline) via the portal vein. At 15, 30, 45 and 60 minutes post injection (shown in FIG. 2A), hindquarter skeletal muscle and retina were snap-frozen under liquid nitrogen, and then stored at −80° C. pending analysis by immunoprecipitation and immunoblotting. There was no difference in insulin receptor beta-subunit (IRβ) phosphorylation between vehicle (V) and insulin (I) injection.
Tissue lysates were immunoprecipitated and immunoblotted as described by Barber et al. (2001, J. Biol. Chem. 276: 32814–32831). Tissues were homogenized in an immunoprecipitation (IP) lysis buffer (consisting of 50 mM HEPES, pH 7.3, 137 mM NaCl, 1 mM MgCl2, 2 mM NaVO4, 10 mM Na2H2P2O7, 10 mM NaF, 2 mM EDTA, 2 mM PMSF, 10 mM benzamidine, 10% glycerol, 1% NP-40, and 1 protease inhibitor tablet (Boehringer-Mannheim) per 10 mL of buffer. Homogenates were rocked 15 minutes at 4° C. and then centrifuged at 14,000 rpm at 4° C. Prior to immunoprecipitation and immunoblotting, the resulting supernatant was subjected to protein assay (Bio-Rad) and quantification.
Immunoprecipitations were performed as follows. Protein (250 μg) was diluted into 1 mL IP buffer containing one of the following antibodies: 5 μL of anti-IRβ or anti-IGF-IRβ (Santa-Cruz, Santa Cruz,), or 4 μL of anti-IRS-1 or IRS-2 (Upstate Biotechnology, Lake Placid, N.Y.), specific for these species of insulin responsive substrate, and 30 μL of a 50% protein A/Sepharose bead slurry (Amersham Pharmacia Biotech, Piscataway, N.J.). The Sepharose bead complex was rocked overnight at 4° C., washed twice with 200 μL of IP buffer, and boiled with 30 μL of 2× sample buffer (a solution of glycerol, SDS, TRIS buffer, bromophenol blue and betamercapto-ethanol). Fifty μg of protein per sample were analyzed by SDS-polyacrylamide gel electrophoresis (SDS-PAGE). Thereafter, gel-separated proteins were transferred to nitrocellulose membranes (blocked with a solution of 0.05% Tween-20 and 5% non-fat milk or 3% bovine serum albumin, dissolved in Tris-buffered saline) at room temperature for 1 hour. The membranes were probed overnight in blocking solution at 4° C. at 1:1000 dilutions of the primary antibody. The primary antibodies used in these assays included an anti-phosphotyrosine antibody (Upstate Biotechnology), and anti-Akt antibodies (Cell Signaling, Beverly, Mass.). Secondary antibodies were diluted 1:4000 (for horseradish peroxidase-conjugated anti-rabbit antibodies; obtained from Amersham Pharmacia Biotech, Piscataway, N.J.), or 1:1000 (for biotin-conjugated anti-mouse antibodies; obtained from Amersham Pharmacia Biotech). Tertiary incubations with streptavidin-linked alkaline phosphatase were diluted 1:4000 (Gibco, Gaithersburg, Md.). Positive signals were detected with electrochemiluminescence (ECL) kits (Cell Signaling) and electrochemifluoresence (ECF) kits (Amersham) each performed according to each manufacturer's protocol. Immunoblot quantitation was accomplished using ImageQuant (Molecular Dynamics), NIH Image 1.6 (NIH), or GeneTools (SynGene) software. Blots were re-incubated with different antibodies after being stripped, at 50° C. for 1 hour in a buffer containing 63 mM Tris (pH 6.8), 2% SDS, and 0.07% 2-mercapthoethanol.
Western blots interrogated with anti-phosphotyrosine (PY) antibodies showed a robust response in muscle, as expected. IRβ phosphorylation was also increased in retinal tissue, but only after a 30 minute delay. In addition, the response had a smaller magnitude than muscle. No difference in IRβ phosphorylation was found in sham-operated rats. These results indicated that retinal IRβ has greater levels of basal phosphorylation than muscle in vehicle treated rats.
The results of experiments quantifying this Western blot analysis are shown in FIG. 2B, presented as a ratio of phosphotyrosine (PY) levels to insulin receptor beta-subunit (IRβ) amounts (PY/IRβ). In these experiments, Western blots interrogated for muscle PY were stripped, reprobed for total IRβ, quantified and the data expressed in terms of PY/IRβ ratios. The zero time point was set to a ratio of 1. The results in FIG. 2B show a nearly 30-fold increase in phosphotyrosine content in muscle IRβ 15 minutes post-insulin injection, which increase peaked at 30 minutes and declined by 60 minutes post-injection. There was a significant increase in IRβ phosphorylation with insulin at all points examined. FIG. 2C shows the result obtained in parallel experiments performed on retinal tissue. Unlike the results shown in FIG. 2B, tyrosine phosphorylation did not significantly increase in retinal tissue until 30 minutes post injection, was maximal after 45 min and remained elevated 3–4 fold above vehicle-injected controls for 60 minutes. IRβ phosphorylation did not change in vehicle injected animals. The discrepancy in the fold increase in retinal tissue may be due to the relatively higher basal IRβ phosphorylation in the retinas of vehicle treated rats, or to the blood-retinal barrier limiting diffusion of insulin into the retina.
In addition, 45 min after insulin administration retinal lysates were analyzed for Akt activation by Western blotting specifically probed for phosphorylation of Akt (serine 473). These Western blot results, shown in FIG. 2D demonstrated that insulin induced a 48% increase in phosphoserine 473 content of Akt over vehicle injected controls when IRβ phosphorylation is maximal (45 minutes post-injection). Quantification of Western blots, also shown in FIG. 2D indicated there was no statistical difference between sham and vehicle injected controls. These results indicated that systemic insulin injection can effect changes in IRβ phosphorylation in retina, thereby demonstrating that insulin crosses the blood-retinal barrier. Insulin receptor phosphorylation and activation occurs in a different temporal manner than muscle, however, and insulin increases Akt phosphorylation in retina.
Thus, even though insulin penetrates the blood-retinal barrier, the delayed kinetics and lower phosphorylation differential between activated and inactive insulin receptor illustrates the limitations in systemic delivery for affecting retinal diseases related to or dependent on insulin levels, such as diabetic retinopathy.
Tyrosine phosphorylation in retinal IRβ and changes therein was compared with other insulin responsive tissues under freely fed and moderately fasted conditions as follows.
Six male Sprague-Dawley rats (Charles River) were fasted (18 hours) and were compared to 6 rats that were freely fed overnight. All rats weighed 200–350 g and were anesthetized with a 10:1 ketamine:xylazine cocktail as described in Example 1. Upon loss of motor reflex in the rats' retina, tissue samples from liver and hindquarter skeletal muscle were obtained, homogenized and immunoprecipitated as described in Example 1 and then subjected to Western blot analysis, also as described in Example 1. The blot in FIG. 3A shows that IRβ phosphorylation was unaltered in retina, but increased in muscle and liver compared to fasted rats. Phosphotyrosine-probed immunoblots were then reprobed for total IRβ content with the immunoprecipitating antibody as described in Example 1 to normalize the Western blot data.
The results of these experiments are shown in FIG. 3B as the ratio of PY to total IRβ. Plasma insulin levels were 1.95±0.36 ng/mL in fed rats versus 0.32±0.049 ng/mL in fasted rats (mean±SEM, p=0.011). Similarly, blood glucose levels were 95.5±2.6 mg/dL in fed rats versus 68.83±2.4 mg/dL in fasted rats (mean±SEM, p=0.000008). Image analysis (software from Molecular Dynamics, Sunnyvale, Calif.) of the Western blots from retinal tissue revealed no differences in IRβ phosphorylation between freely fed and fasted rats. In contrast, IRβ phosphorylation in liver and hindquarter skeletal muscle was diminished 23% and 38%, respectively in the fasted rats. On the other hand, IRβ phosphorylation in liver and muscle was significantly greater than in retinal tissue for freely fed rats.
In summary, retinal IR remained relatively constant in response to the physiological levels of insulin in circulation. Phosphotyrosine content of the IRβ in retina did not change, unlike in liver and muscle, despite changes in nutritional status and physiological increases in circulating insulin and blood glucose. IRβ from muscle and liver displayed increased tyrosine phosphorylation as expected in the freely fed state compared to fasted rats. These results were likely due to the fluctuations of circulating insulin in the freely fed condition.
Because tyrosine phosphorylation of the IR does not directly measure enzymatic activity, an IR kinase assay was developed.
The IRβ from fasted and fed rats was immunoprecipitated from retina and liver and analyzed by PY immunoblotting for autophosphorylation with (+) and without (−) the addition of ATP to the kinase reaction. IRβ immunoprecipitates obtained as described in Example 2 were subjected to IR kinase assays as follows. The Sepharose bead complex, obtained as described in Example 1, was washed three times with 200 μL of kinase buffer (50 mM HEPES, pH 7.3, 150 mM NaCl, 20 mM MgCl2, 2 mM MnCl2, 0.05% bovine serum albumin, and 0.1% Triton X-100). Western blotting was performed on these immunoprecipitates as described in Example 1; the results of these Western blot experiments (shown below) showed that washing the Sepharose bead/immune complex in kinase buffer did not diminish total bound IRβ. After the last (third) aspiration of kinase buffer, 500 μL of kinase buffer was added with or without 100 μM ATP (Sigma) to each aliquot of the washed Sepharose bead complex. These immune complexes were then rocked at ambient temperature for 1 minute, and the Sepharose beads then collected by brief centrifugation (approximately 3 seconds). The kinase buffer was aspirated, an equal volume of 2× Laemmli sample buffer was added and the samples were boiled for 3 min. SDS-PAGE and phosphotyrosine immunoblotting analysis was performed as described in Example 1.
Results of these assays are shown in FIG. 4. The PY immunoblot showed that retinal IRβ displays tonic tyrosine phosphorylation (− lanes), and the rate of phosphate incorporated into the IRβ is not different between fasted and fed rats (+ lanes). Liver IRβ, however, displays less basal tyrosine phosphorylation, which increases in the fed state (− lanes). As expected, the rate of IR autophosphorylation is significantly greater in the freely fed rat liver (+ lanes, p<0.05).
The results of these Western blot experiments shows that the kinase reaction proceeded linearly though 5 minutes of incubation (R2>0.9) and at a non-limiting dose of 100 μM ATP. The time course of IR autophosphorylation continued to proceed in a linear fashion over the course of these experiments, and the concentration of ATP used did not limit the rate of autophosphorylation.
These results further indicated that there was no change in retinal IRβ autophosphorylation rate between freely fed and fasted rats. These results also suggested a tonic level of tyrosine phosphorylation and kinase activity despite changes in circulating insulin and glucose levels. In contrast, in liver and skeletal muscle IRβ phosphorylation was increased in the freely fed state, leading to a significant increase in autophosphorylation activity. These results thus demonstrated the difference in insulin signaling physiology within the whole animal. Moreover, these results also indicated that the blood-retinal barrier may discretely regulate insulin flux, unlike in tissues that undergo rapid metabolic changes, the results having consequences for insulin administration in diabetic retinopathy.
A tissue explant culture system was used to characterize insulin-signaling transduction in retina without the hindrance of the blood retinal barrier present in whole animal models. Such a tissue explant culture system was developed as follows. Rats as described in Examples 1 and 2 were anesthetized using sodium pentobarbital (7.5 mg/kg), and then decapitated upon loss of motor reflexes. Rat retinas were removed by cutting across the cornea, removing the lens, and squeezing the eyeball to rapidly extract the retina. Retinas were pre-incubated in MEM (Sigma) supplemented with 5 mM pyruvate and 10 mM HEPES for 15 minutes at 37° C., 5% CO2, and with gentle shaking. Ten nM insulin or vehicle was added following pre-incubation. At 2, 5, 15, and 30 minutes after insulin addition, retinas were snap-frozen in liquid nitrogen for future use.
To examine the time course of insulin signaling events in the tissue, insulin-treated retinas were compared to retinas that received vehicle (0.9% saline) and to untreated retinas. Tissues were analyzed by immunoprecipitation and Western blotting as described in Example 1. Western blot data were quantified, as shown in FIG. 5, and revealed a significant increase in IRβ phosphorylation at all time points examined when normalized to total IRβ. Within 2 minutes of insulin stimulation, retinal IRβ exhibited a nearly 4-fold greater phosphotyrosine immunoreactivity, which remained elevated at levels 3-fold greater than baseline at the 30 minute time point. This analysis demonstrated that retinal IRβ undergoes increased tyrosine phosphorylation in response to a physiological dose of 10 nM insulin. These results from the explant retina system were similar to the results obtained using a cell culture model.
Insulin (10 nM) does not activate the IGF-1Rβ in retinal explants. Retinas were treated with either 1.3 nM IGF-1 or 0, 1, 10, 100, and 1000 nM insulin, and then retinal lysates were immunoprecipitated with an insulin-like growth factor I receptor (IGF-1Rβ)-specific antibody, followed by PY Western blotting (shown in FIG. 6). The IGF1-R was immunoprecipitated and PY Western blotting performed as described above. Insulin at 100 nM produced similar levels of IGF-1Rβ phosphorylation as were found when retinas were contacted with 1.3 nM IGF-1. These results demonstrated that IGF-1Rβ phosphorylation remained unchanged in the presence of 10 nM insulin, but increased with 100 nM insulin. These data further indicated that 10 nM insulin does not activate IGF-1Rβ in retinal explants, but has specific effects via the IR. Moreover, ATP levels over the time course experiments remained constant, indicating that the energy status of the tissue was not hindering the insulin signaling response.
These results suggested that isolated retinal tissue can respond robustly to physiological insulin concentrations, this response including IRβ tyrosine phosphorylation. The results also suggested that the blood-retinal barrier plays a significant role in regulating circulating insulin transport since the time course of the response is much faster than observed in vivo. Moreover, intraportal insulin injection experiments (Example 1) showed that insulin's access to the retina is limited by the retinal vasculature, the blood-retinal-barrier (BRB). In explanted retina tissue, in contrast, the BRB is essentially bypassed, and insulin signaling characteristics can be analyzed in a shorter time frame since insulin has direct access to the retina. A schematic comparison of intraportal insulin injection and explanted retina tissue is shown in FIG. 7.
In clinical diabetes, hypoglycemia is the major factor that limits the ability of patients to achieve the degree of intensive control of glycemia needed to prevent or reduce retinopathy. Retinal cells die by apoptosis in diabetes, and insulin is a survival factor for retinal neurons acting via the PI3-kinase/Akt pathway, which is inhibited by hyperglycemia. Systemically administered insulin activates the retinal insulin receptor, and the activities of the retinal insulin receptor, PI3-kinase and Akt are reduced after 4 weeks of streptozotocin-induced diabetes. Thus intensive insulin therapy has direct effects on retinal cell survival and function. Since intensive insulin therapy cannot be achieved by most patients due to the hypoglycemic effects of systemic insulin administration, direct application of insulin to the eye can provide the survival effects needed to maintain retinal cell health in the presence of imperfectly controlled systemic diabetes.
To demonstrate the efficacy of the methods of this invention, insulin was administered directly to the eye via the subconjunctival space of normal Sprague-Dawley rats. This route of administration bypasses the BRB for a more direct route of insulin action on retina. By injecting serial dilutions of insulin in this manner, it was discovered that a dose of 0.0325 U/100 g insulin activated the IR and Akt kinase pathway without lowering blood glucose values. As shown in FIG. 8, the IRβ is phosphorylated in the eye receiving insulin (right column), compared to the contralateral eye that received vehicle (left column). The retina was processed for IRβ PY content as described in Example 1. The results suggest it is feasible to administer insulin directly to the retina in doses that will not lead to potentially harmful hypoglycemic reactions and potently activate the insulin receptor.
These results demonstrated the in vivo efficacy of periocular insulin administration as a treatment for diabetic retinopathy.
It should be understood that the foregoing disclosure emphasizes certain specific embodiments of the invention and that alternatives equivalent thereto are within the spirit and scope of the invention as set forth in the appended claims.
The invention and the method of making it are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make the same. It is to be understood that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the invention as set forth in the claims.


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Warped View of the Weird Simpsons
Follow TheCruu!by "The Simpsons," a once-great animated sitcom that is no longer relevant, hasn't caught my attention in years, but the Weird Simpsons has. Directed and animated by Yoann Hervo, the Weird Simpsons re-imagines the opening sequence to the regular Simpsons in a style that Salvador Dali might enjoy. After …
A Song Sung Trump
Donald Trump certainly has been making the news lately. And now he has a new campaign song. "President Trump," written and performed by Mitchell Stone, is a nasally-twanged ode to the glories of Donald Trump. Watching this video, you're not quite sure if this should be taken seriously or if it's actually a parody of a crazy Trump-lover.
The Security Dinosaur Ate Lady Liberty!
Net Loss? Freedom combines audio clips of Edward Snowden with a backdrop of snazzy visuals that illustrate all the various ways the U.S. government can snoop on you. It also features a cartoon Lady Liberty walking a pet Security Dinosaur who soon turns on its master.
Begun the Drone Wars Have
The Drone Aviary offers a terrifying vision of a future with flying drones run amok. Oh wait, that future is already here. Created by The Superflux Lab, this film gave me acid reflux contemplating all the different ways drones may, and probably will, change society…
Warning: This Film May Give You Seizures
Follow TheCruu!by The Brain Hack involves many murky things happening murkily. And what do these murky things involve? Oh, nothing more than whether or not a couple of college students have discovered God or the Devil or just a new way to cause seizures. The film, written and directed by Joseph …
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The Boy Who Couldn't Sleep and Never Had To is the story of a teenage insomniac who has visions of terrifying creatures that come to life. And what are some of those terrifying creatures? Jawas.


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text: I was cleaning up my storage and noticed that the Twitter app was >500MB in size. I thought that was too much so I deleted and reinstalled it and it was <100MB. Two days later I noticed it was over 300MB in size and now it's at 570MB. The app says it's storing 530MB of Documents & Data, I don't think it's supposed to store anything at all. Anyone else run into this issue or have a fix?


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I am trying to keep costs down as much as possible for the show so that the PAWS Humane shelter can get as much $$ as they can for homeless cats and dogs. Many of the awards will be hand made, If you would like flat ribbons, you can sponsor a division by e-mailing the show hostess. Thank you!
- Places 1-2 in CM/AR/OF divisions will receive a handmade model horse traditional scale sized neck ribbon in the color of the judges' placing.
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- Places in 3-5 Paper ribbon flats in all divisions
- Division reserve and champions will receive a pretty printed certificate and a lovely gold or silver neck ribbon with a little bling
- Overall Grand and Reserve Champions will receive trophies and purple/gold, or purple/silver neck ribbon with big bling
- NOTE: Judges will not be allowed to place neck ribbons on your horse(s). They will be laid in front of your horse(s) for you to put on if you wish later when you are at your table for pictures.


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Episode 100 | Leadership, Workforce, Community, TechnologyGuests: Brian Panek, Jess Giudici, Bill Downey, Tom Simeone
Hello, Metalworking Nation! Today is an exciting day in the history of MakingChips as we release the highly anticipated Episode 100! We are coming to you live from the Technology & Manufacturing Association in Chicago, IL where we have assembled a round table panel of some of the most progressive manufacturing leaders in the Chicagoland
Podcast: Play in new window | Download | Embed


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New roundabout for busy intersection27 March 2017
One of Lavington's busiest four-way intersections will be replaced with a roundabout under a $1.165M contract awarded to local firm AP Delaney and Co.
Council to consider cat controls in new estate27 March 2017
AlburyCity is proposing to introduce restrictions for domestic cats in a new residential development in Thurgoona.
Dinosaur rEvolution: Secrets of Survival16 March 2017
Gondwana Studios is bringing an exciting and new travelling exhibition to the LibraryMuseum from Saturday 18 March - Sunday 21 May 2017.
Long-term community plan on exhibition28 February 2017
A long-term community plan which guides AlburyCity's planning and decision making is now on public exhibition.
New fence for iconic gardens16 February 2017
Albury's much loved Botanic Gardens is about to get a new façade, with work starting this week on the upgraded perimeter fence.
Creating Albury's own Ghost Story09 February 2017
AlburyCity Mayor, Kevin Mack has welcomed Federal Government funding support for the 2017 Write Around the Murray Festival through the Festivals Australia program.
Kerr Road upgrade to enter 3rd stage07 February 2017
Border based company, Excell Gray Bruni, has been awarded a $1.8M contract to continue a major upgrade of Kerr Road in Thurgoona.
Awards Honour Albury's Finest26 January 2017
A champion for cancer fundraising, a Xavier High School student, a tireless worker in volunteer services and a determined community service club have topped the honours at this year's Albury Awards.
Council disappointed at EPA fine05 January 2017
AlburyCity Mayor Kevin Mack has expressed disappointment at an $8,000 fine imposed on Council by the EPA over an odour complaint at the Albury Waste Management Centre (AWMC).


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|[p2-dev] p2 contributor gathering in Ottawa
Hi all,
A lot of people signed up to contribute to p2 (http://wiki.eclipse.org/Equinox_p2_3.5_contributions), therefore we were thinking that it would be good to meet in person in Ottawa for a couple of days to discuss, design and code some of the big items of the Galileo release.
Since most people interested in p2 are also interested in builds (okay, I am), the initial proposed date is the week of October 22nd in order to match with the Build workshop (http://wiki.eclipse.org/Build_Workshop_3:_Build_Hard_With_A_Purpose). That said, if there is a date that fits a bigger number of participants we can always arrange.
So here are a few questions that needs to be answered:
Do you think it worth having such a meeting?
Would you be interested in attending?
Which date would be the most convenient for you?
Thank you,


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Canadians of Iranian descent, victims of Iran-sponsored terrorism, and human rights advocates, are supporting S-219.
The precedent for sanctioning the Iranian regime for these violations was established in Canadian policy long before S-219 was introduced in the Senate. Here are several examples:
a) Prime Minister Brian Mulroney
The first precedent for sanctioning Iran's legislatively mandated and institutionalized discrimination towards minorities, was already established by Prime Minister Brian Mulroney who led the effort to sanction South Africa for its system of Apartheid in 1985.66 That legacy is a point of pride for Canadians and should be viewed as worthy precedent that needed to be established. While there certainly can be any number of considerations as to when or if to impose sanctions on another country, the legalized frameworks for severe systemic discrimination of the type found in Apartheid South Africa and as practised today in the Islamic Republic of Iran, should warrant considering sanctions as a policy option. As noted by Professor Winston Nagan, the founding director of the Institute for Human Rights and Peace Development at the University of Florida and a former chair of the board of directors of Amnesty International, USA (1989-91), Iran is a "Neo-Apartheid state". He explains that:
Having grown up with the indignities of the apartheid system in South Africa, I bristle whenever I hear anyone equate a government's treatment of a portion of its citizenry to apartheid. Usually, the claims are exaggerated. But in Iran today, the government's treatment of the Baha'i community bears striking similarities.67
While Iran has established a broad framework for discriminatory practices against its Muslim and non-Muslim minorities,68 Iran's mistreatment of the Baha'is occupies a special place in the current pantheon of state-mandated discriminatory practice. The Baha'is are banned as legislators; banned from universities; banned from 25 categories of employment; and their blood is considered "mobah" meaning that "it can be spilled with impunity".69 Baha'i "marriages are illegal, their children are illegitimate"; their cemeteries have been attacked, vandalized or closed,70 and in numerous cases the burial of Baha'is has been blocked or interfered with by authorities.71 As noted by Heiner Bielefeldt – U.N. Special Rapporteur on freedom of religion or belief – the discrimination "starts with kindergarten…."72
So, the precedent therefore has already been set for sanctions for Iran's "neo Apartheid" behaviours, and is particularly relevant in the case of the Iranian regime which in one of the most discriminatory on earth, and proudly and unabashedly impervious to change. (for more on this see FAQ #10)
b) Canada already sanctions three countries under SEMA for human rights violations:73
a) Syria – In 2011, Canada imposed SEMA sanctions on the Syrian regime. Syria's violent crackdown on peaceful protesters led to many civilian deaths and injuries. Thousands of civilians were detained arbitrarily and there were credible reports of summary executions and torture. These actions led thousands of Syrians to flee to neighbouring countries resulting in a serious humanitarian crisis in the region. The violent crackdown in Syria and the cross-border incursions into neighbouring countries resulting in fatalities and the mass exodus of refugees caused a grave breach of international peace and security that is likely to result in a serious international crisis. Further sanctions were then imposed between 2011 and 2017.
b) Myanmar/Burma – In 2007, SEMA came into force to respond to the human rights and humanitarian situation in Burma, which threatened peace and security in the entire region. DFAIT explained the sanctions as a Canadian response to "The abhorrent human rights and humanitarian situation in Burma is particularly dangerous as the government's actions not only oppress its own people, but also bring substantial transnational destabilizing effects which threaten peace and security in the entire region and undermine freedom, democracy, human rights and the rule of law." Canada's Foreign Minister justified the sanctions stating that:
People are being arrested, tortured and killed. Peaceful demonstrations by unarmed Buddhist monks were met with bullets. Each of these factors contravenes what our foreign policy stands for. Each is rejected by governments of countries we share our values of freedom, democracy, human rights and the rule of law. Each is an affront to the United Nations Charter.
c) Zimbabwe – In, 2008, SEMA regulations came into force. Events since March 2008, including a marked escalation in human rights violations and violence directed at the political opposition, a stolen election, the denial of a peaceful democratic transition and a worsening humanitarian situation toll the crisis in Zimbabwe to a new level. The Minister of Foreign Affairs gave the following rationale for the government's decision:
Zimbabwe has subjected opposition supporters to intimidation and state-sponsored violence…. Despite efforts by international mediators … the government has shown itself unwilling to negotiate in good faith, and uninterested in meaningful reform. Canada's targeted sanctions send a clear message that we abhor the current … regime's perversion of a legitimate democratic process and the continuing human rights violations….
In conclusion – Given Iran's complicity in the atrocities committed by the Assad regime; its documented status (by the UN, Amnesty, Human Rights Watch and a host of others) as one of the globe's most prolific violators of human rights; and that its human rights record far exceeds those of Burma and Zimbabwe which are currently sanctioned by SEMA – there is clearly precedent for Canada to consider sanctions against the Iranian regime.
This bill provides for strengthening of Canada's sanctions regime against Iran for its support of terrorism, incitement to hatred, and human rights violations; and for the identification of Iranian officials responsible for such activities. The Act has several key components: a. Government Report –...Read More
Iran's illegal and egregious actions against Canadian citizens; its status as the world's leading state sponsor of terrorism; its severe violation of the human rights of its own citizenry; and its flouting of the international community have generated these tensions with Canada and other countries. As outlined below, the difficulties ...Read More
What can sanctions achieve? – Despite clear limitations, sanctions have been utilized as an instrument of statecraft by Canada and other western countries in hundreds of cases over the last century – even when the sanctions themselves have not directly generated a "solution" for the crisis or behaviours being targeted. ...Read More
S-219 was introduced by Conservative Senator David Tkachuk and was seconded by Liberal Senator George Baker. S-219 is supported by a coalition of organizations and individuals committed to combatting terrorism, promoting human rights, and supporting the people of Iran in their struggle for democracy. Sen. Tkachuk worked closely with a ...Read More
This bill will not impose further hardship on ordinary Iranian citizens in Iran who have already been victimized by the regime's policies. As noted by Richard Nephew – an architect of the JCPOA who was critical of some aspects of S-219: In this case, the unintended consequences on the humanitarian impact of this bill are probably ...Read More
S-219 does not preclude a restoration of diplomatic relations with Iran or business dealings between Canada and the Iranian regime. It simply offers a framework for balancing Canada's stated concerns with Iran's egregious behaviours and the government's objective of reengagement. It seeks only to exclude those regime entities ...Read More
Iran is currently doing business with Canada despite being subject to Canadian sanctions under SEMA, and despite being listed by Canada as a State Supporter of Terror. (Iran for instance recently purchased $100 million in aircraft from Bombardier47). Furthermore, Iran is "engaging" other countries that also have imposed sanctions ...Read More
It is the Iranian regime which has put itself – with malice and forethought – on the margins of the civilized world by its own behaviors over the last 37 years. Most recently with the signing of the JCPOA the regime was provided yet another opportunity to demonstrate some semblance of good will on issues related to terrorism and ...Read More
There is little if any precedent suggesting that Iranian violations can be mitigated by merely engaging in diplomatic disapproval or issuing condemnatory statements ungrounded in a concrete legislative format: a) Past Precedents –The Iranian regime has made itself perfectly and unabashedly clear over the last 38 years, that it ...Read More
Canada already sanctions Iran under SEMA. S-219 simply stipulates that those sanctions already in place can be lessened only if Iran shows significant change with regard to terror sponsorship, human rights abuses and incitement to hatred. It also applies existing sanctions to additional targets as if they were persons whose names are listed in the ...Read More
Yes. a) As noted at greater length in FAQ #12, the precedents for sanctioning Iran under SEMA are clear. In the case of Burma for instance, SEMA regulations were imposed as a result of the abhorrent human rights and humanitarian situation in Burma is particularly dangerous as the government's actions not only oppress its own people,...Read More
Yes. a) In May 2017, the U.S. Treasury Department imposed the first human rights-related sanctions designations against Iranian individuals and entities since December 2014.62 b) In April 2017, the European Council has extended sanctions against Iran. The extended EU measures hitting Iran include a travel ban and asset-freeze ...Read More
Yes. a) On August 2, 2017, President Trump signed Congressional sanctions against Iran, known as the Countering America's Adversaries Through Sanctions Act. The law requires the president to extend a terrorism designation pursuant to Iran's Islamic Revolutionary Guard Corps (IRGC) and its foreign agents and affiliates by Oct. ...Read More
The precedent for sanctioning the Iranian regime for these violations was established in Canadian policy long before S-219 was introduced in the Senate. Here are several examples: a) Prime Minister Brian Mulroney The first precedent for sanctioning Iran's legislatively mandated and institutionalized discrimination towards minorities, ...Read More
a) While we support the passage of the Magnitsky Bill, we do not believe that the Magnitsky legislation could be a substitute for S-219 - or vice versa. We believe that each of these bills provides different tools for different albeit related issues -- and one cannot take the place of the other. Both are needed as part of ...Read More
Freedom House 2017 Report - Iran74 Iran's Aggregate Score – 17/100 (0=least free, 100=most free) Human Freedom Index 2016 – Iran75 Iran's Human Freedom ranking – Iran ranked 157 out of 159 countries Personal Freedom score – 3.9/10 World Justice Project Rule of Law Index ...Read More
Yes – it is essentially mandated in Iran's constitution. Euopean Parliament Report: "[Twelver Shia Islam is] – the only religion deemed 'revolution compliant' by the state. First, the Iranian Constitution itself enshrines discrimination by stating in its article 13 that the only recognised religious minorities...Read More
Yes. The UN Special Rapporteur on Human rights in Iran notes that the Government accepted only 2 out of the 25 recommendations regarding ethnic and religious minorities made during the 2014 universal periodic review.80 Amnesty International: Iran's disadvantaged ethnic minorities, including Ahwazi Arabs, Azerbaijani Turks, Baluchis, ...Read More
Professor Winston Nagan: "Having grown up with the indignities of the apartheid system in South Africa, I bristle whenever … anyone equate a government's treatment of a portion of its citizenry to apartheid. Usually, the claims are exaggerated. But in Iran today, the government's treatment of the Baha'i community...Read More
Speaking to commanders of the Iranian regime's State Security Forces Rouhani stated that: "When someone is condemned to death and he comes to the gallows according to the law, then we have no right to insult him as he is being taken to the gallows… in any case, the law has condemned him and he is punished and this has nothing to do...Read More
Yes. The UN Special Rapporteur (2017): "The Islamic Republic of Iran has reportedly executed the highest number of juvenile offenders worldwide, over the past decade. Despite an absolute ban on the practice under international law, the Islamic Penal Code still explicitly provides for the death penalty for boys of at least 15 lunar years of...Read More
Yes. The UN Special Rapporteur (2017) -- The Government did not accept any of the 20 recommendations of the UN Special Rapporteur regarding torture or other cruel, inhuman or degrading treatment or punishment made during the 2014 universal periodic review. As highlighted in previous UN reports, the Government rejects the notion that amputations ...Read More
UN Special Rapporteur (2017): "Child marriage remains legally possible for girls aged 13 years and boys aged 15 years. Even younger children can be married with the permission of the court but the marriage may not be consummated until puberty. In June 2016, a spokesperson for the Tehran-based Association to Protect the Rights of Children ...Read More
UN Special Rapporteur (2017): "…Certain provisions might even condone sexual abuse, such as article 1108 of the Civil Code, which obliges wives to fulfil the sexual needs of their husbands at all times. Similar concerns apply to provisions such as articles 301 and 612 of the Islamic Penal Code of 2013, which provide for lighter ...Read More
Yes. The increase was noted in a 2016 report by the European Parliament98, and Iran in fact has not denied it. See the following excerpt from an Iranian newspaper: Financial Tribune (Mar. 2017): An Iranian lawmaker said western intelligence services and spying networks are trying to "inflict damage on our country" by taking advantage ...Read More
Prof. Payam Akhavan – McGill University, Member of the Permanent Court of Arbitration at the Hague "Until very recently, Iran's biggest trading partner was the EU. …[M]ore than 200 Iranian dissidents were assassinated in the streets of Berlin and Paris and very rarely was the Iranian government held to account. So the ...Read More
No. According to most human rights experts the situation has remained unchanged or has worsened: The UN Special Rapporteur (2017): "The Special Rapporteur regrets that the information she received did not reveal any notable improvement in the situation of human rights in the country."103 The Hon. Irwin Cotler (Senate ...Read More
Report of the European Parliament (2017): "Similarly, the UN Special Rapporteur on the Human Rights Situation in Iran concluded that political and legislative reform has not produced tangible effects. More specifically, there is a major gap between the legislation that has been put in place and the practices implemented by the state in ...Read More
Apparently not – despite promises112 to do so. See below: Brigadier General Hossein Salami – Deputy Commander of the IRGC Tasnim News Agency (2016): "We warn the enemies of Islamic Republic of Iran: Do not make this mistake again as the revolutionary forces will chase them and kill them anywhere in the ...Read More
Hezbollah Leader Hassan Nasrallah (June 24, 2016) "Hezbollah's budget, its income, its expenses, everything it eats and drinks, its weapons and rockets, are from the Islamic Republic of ...Read More
The U.S. State Departments 2016 Country Report on Terrorism lists 58 "Foreign Terrorist Organizations," (many of them are also designated as terrorist entities by Canada) of which over a dozen are allied with Iran.125 Terrorism experts maintain that has Iran invested billions of dollars in terrorism: a) Congressional Report ...Read More
Yes. Iran is Listed in Canada as a State Supporter of Terror – Iran is listed in Canada (and in the U.S.) as a State Supporter of Terrorism. On July 1st, 2017, the Canada Gazette reported that after a review, the Foreign Minister determined that Canada will continue listing Iran and Syria as "State Supporters of Terrorism" ...Read More
Yes. Several Canadians were murdered in Hamas terrorist attacks, including Mr. Scott Goldberg, a father of seven who was murdered when a Hamas terrorist incinerated a busload of travelers in January 2004 in Jerusalem. Other Canadians have been injured in Hamas attacks, including Dr. Sherri Wise of Vancouver. Dr. Wise was severely injured in a...Read More
Yes. The list can be found below: a) Iranian-Canadian Abdolrasoul Dorri Esfahani – just sentenced to five years in prison for espionage, is an accountant involved in the financial aspects of the Iran nuclear deal (JCPOA). b) Canadian Permanent Resident Saeed Malekpour (2008 - ?) – Malekpour was arrested in October 2008...Read More
Public Safety Canada: "Hezbollah has networks around the world, including in Canada, and uses the networks for recruitment, fundraising and procurement."137 Hezbollah Expert Mathew Levitt: "Hezbollah has been active in Canada since the 1980s raising money through criminal activities and charity, procuring dual-use items, ...Read More
Yes. a) Iran's Spymaster: Lobbying Group for Iran is Active in Canada (2017) "Mahmoud Alavi, Iran's intelligence minister, in recent remarks bragged about the Islamic Republic's ability to operate an unnamed "lobby group" in the United States, Canada, and England, remain devoted to the ...Read More
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Happy 5th of July. I am stuffed from eating so much yesterday. I 'almost' ate as if it were Thanksgiving yesterday, nap after meal and all! Now I'm back at work and my stomach is grumbling asking me why my indulgent eating behaviour has suddenly stopped. I'm trying to distract myself by drinking juice and green tea, but I'm pretty sure I'll give in and try to find something 'semi' healthy to eat while I'm sitting here, 1 of 3 people who actually made it to work today.
On Monday, I had a blood draw for the regular check ups before IVF. On Tuesday my NP called and said I had elevated thyroid levels. uh oh. I thought 'oh is that why I've been gaining weight?' and then i snapped back into the reality that i have been eating hamburgers and carbs, whoopsies! Ok so elevated thyroids. I'm hoping that my thyroids were just elevated on a temporary basis due to stress. I go in today for my follow-up to see if I need to be put on thyroid medication – which i do NOT want to be put on. I spent yesterday and the day before trying my best to relax myself and to hydrate, hydrate, hydrate. I have been de-hydrated; and my last blood draw was painful. Needle in, poked in deep, and no blood coming out. The nurse told me to relax and squeeze the ball. After my 2nd deep breath, she said ok, it's starting to come out. not good (i do not like needles). So this morning I'm determined to hydrate, so that my veins are nice and plump for today's blood draw in about 2 hours. Think good thoughts that my thyroid levels are back to normal!
Onto juicing. I watched some documentaries this weekend! I don't usually watch documentaries as I prefer sappy dramas and romantic comedies, but I got into it, and watched 3 documentaries on food, 1 on 9/11, and 1 on Bill Cunningham of the NY Times (so cute!). My 3 food documentaries that I watched, somewhat inspired me. One in particular, 'Fat, Sick & Nearly Dead' which is about juicing and its awesome health benefits and healing powers! I recommend watching it if you haven't. After watching it over the wknd, I started googling juice machine reviews, (who knew there were so many out there) and was seriously thinking about getting one. Well on the fourth of July, I turned on the documentary and some of my family including Mr. Truffles, began watching it. An hour after the documentary was finished, I found myself in the car with Mr. Truffles on our way to pick up a juicer! Apparently the documentary inspired more than just myself haha! But to our dismay, the stores were closed (holiday – should have figured) so we came home empty-handed. But we are going to get one and start juicing within the next few days!
I'm excited to cleanse my body (in moderation) as I gear up for IVF, and fill myself with healthy micronutrients. You realize that the American way of eating is just horrid. Mr.Truffles and I are pretty healthy and eat healthily on most occasions. But when we fall of the band wagon sometimes, we fall hard. >.< I am still on birth control pills and will be on them until July 14, and start my Lupron on July 10, so I figure I have some time to do somewhat of a mild detox before I start stimming. (I've been googling, and it seems pretty safe to do). I think I'll try the No Food, Only Juice for only a few days, and then focus on eating clean foods and use the green juice concoction as a supplement or meal replacement. Not really sure this is 'the one' but we are thinking of getting this one… Breville 900 JEXL, isn't it pretty?
*edit*** we ended up getting an Omega juicer, and we are quite happy with it. Read the reviews for our Omega 330 juicer here.


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Aurora Lighting 1-Light CFL Swing Arm Wall Sconce - Polished Steel (STL-LTR463337)
Item #: 901-2231011ECM
Model #: STL-LTR463337
Brand: Aurora
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$104.99 Each
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Constructed with a thrilling polished steel finish and silver metal shade, this 1-light swing arm wall sconce is a great enhancement to any interior decoration and will brighten up your dwelling with shimmering warmth. Installation is truly painless with step by step instructions, perfect for any do-it-yourself project. Crafted with a contemporary setting and quality components, this fixture is painless to install and fits into any interior decoration and architectural styles. Indulge your practical side with the superior craftsmanship of this fixture. With low upkeep requirements, the Tubac Collection is a great addition to any space.
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- Dimensions: 6.5" H x 15" W x 22.5" L
- Features silver metal shade1 year limited warranty
- Compatible with any medium base, LED, halogen, CFL, or incandecent bulbs, 13 watts or less
- Features silver metal shade
- 1 year limited warranty
|Brand : Aurora
|Weight : 20.72 lbs. per Each


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1. That seems normal.
2. That seems normal.
1) It's normal to boot from USB by selecting "USB device," and from DVD by selecting "DVD/CDROM." It is abnormal to boot from USB and DVD by selecting "SATA HDD," which is what amrmohamed_95 has to do.
2) It's normal to be able to choose to boot from DVD or USB, after installing an operating system to the HDD. It's abnormal to be unable to choose to boot from USB or DVD, after installing an operating system to the HDD.
The only option in the Boot Menu that works, is the one that is highlighted in the above image. I imagine that when there is no installed operating system, the computer looks for another bootable device, and this is why the computer will boot from DVD or USB, by selecting the HDD, but only when the HDD has no operating system installed.


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Marcio De Sa scores a Brilliant century.
On Saturday 25 October 2014 Marcio De Sa scored a Brilliant 117 runs in the 1st XI Cricket fixture against Crawford College, Sandton.
We won by 44 runs, but this was a truly exceptional display of batting by a very good cricket player.
Well Done Marcio - Very proud of you!


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Easter tradition on Elba Island: the Festa della Sportella
- Published: 13-03-2017
- Category: Events
Land on a cosy and colourful island: this is the holiday that you desire. And Elba Island has exactly what you need: sea, art, history and, above all, traditions. If you decided to spend the Easter holidays in this lovely place, there's an event during which you can experience the fascinating atmosphere and the bucolic location: it's the Festa della Sportella, in the hermitage of Santa Caterina, near Rio nell'Elba.
Sportella: the cake of the lovers
It is a very ancient tradition. At the Hermitage of Santa Caterina in Rio nell'Elba, will take place the Festa della Sportella, on Easter Monday. The heart of everything is a love proposal. That's why it is a quite romantic tradition.
The sportella is a traditional cake. Its origin is a pagan ritual connected to the spring and fertility. During this festival, the sportella is blessed and given by girlfriends to their boyfriends. And it's certainly an excellent opportunity for a quiet picnic en plain air.
The feast
On Palm Sunday, the boyfriend gives a basket of flowers and a cake called cerimito to the girlfriend. If, on Easter Monday, the girlfriend give the sportella to this boyfriend, it's a real love proposal.
On Easter Sunday, in particular, the feast begins with the parade of the inhabitants, the parish priest and the band of the country, to celebrate the meeting of the two boys and enjoy, after the celebration of Mass, the sportella.
The Festa della Sportella is a great idea to spend Easter Monday on this island. But have you booked your ferry trip to Elba Island?
Image source: PixabayRelated articles


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Google+ (Google Plus) was launched by Google to give a tough competition to the social networking leader Facebook, but the former couldn't live up to the task that well. But the venture has still been a successful one with many visitors using it for marketing and promotional purposes. Google+ is a great way to promote your content. While this [Read More…]
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