text:
info@nexusacademicpublishers.com
Books & Thesis
Teacher/Student Portal
Instruction for book & thesis
Journals Menu
Free eTOC Alerts
Article in Press
Open Special Issues
Research Journal for Veterinary Practitioners
Download PDF Download ePUB
RJVP_7_2_39-52
Effect of Renoprotective Amino Acids and a Dipeptide on Disease Progression, Nutritional Status, and Blood-Serum Phosphate Concentration in Cats with Chronic Kidney Disease
James D. Archer*
Applied Research Laboratory-Veterinary Studies Project, Villa Pompeii Campus, 4848 Olive Hill Road (28 Rolling View), Fallbrook, CA 92028, USA.
Abstract | Low-protein, low-phosphorus therapeutic diets (TDs) are often recommended for cats (Felis catus) with chronic kidney disease (CKD) in an attempt to slow disease progression. Studies in humans with CKD reveal that dietary supplementation with certain amino acids slows or prevents time-related increases in blood-serum creatinine concentration (SCr) and phosphate concentration (PHOS). The objectives of this study were to assess the influence of a renoprotective amino acid and a dipeptide complex (AB070597) on disease progression, PHOS, and protein oxidation/nitrogen-balance in non-protein, non-phosphorus-restricted diet cats with CKD. The treatment group included 67 privately-owned domestic cats with SCr and clinical signs consistent with CKD. A retrospective control group included 57 non-AB070597-treated CKD cats. Cats in the treatment group received 300-mg oral bi-daily doses of AB070597 for up to 104 weeks. SCr and PHOS were measured at approximate 12-week intervals.Treated cats experienced significantly reduced SCr (mg/dL) from baseline during all observation periods (P≤0.004), except week 12 (P=0.054). The overall least squares mean (LS-mean) difference between treatment and control groups was –0.5 (P<0.001). When International Renal Interest Society (IRIS) disease stage was expressed as LS-means change-from-baseline, treatment values were negative, whereas control values were positive, indicating a decline in stage for treatment and an increase for controls. The overall difference at 104 weeks for treatment was –0.4 (P<0.001). Treatment group mean and median PHOS (mg/dL) declined from baseline -1.3 (P < 0.002) and -0.2 (P <0.002), respectively, at 104 weeks, whereas control group mean and median values increased 0.14 (P<0.004) and 0.3 (P<0.002), respectively. Treatment group cats' body weights (kg, standard deviation [SD]) remained stable: mean change (0.0, 0.75), P<0.001; while controls lost weight: mean change (-0.9, 1.07), P <0.001.Oral supplementation of renoprotective amino acids and a specific dipeptide prevented disease progression, maintained nutritional status, and preserved PHOS homeostasis in treated cats and may benefit the greater population of companion cats diagnosed with CKD.
Keywords | Cats, Chronic kidney disease, Supplement, Amino acid, Progression
Editor | Muhammad Abubakar, National Veterinary Laboratories, Islamabad, Pakistan.
Received | March 04, 2019; Accepted | March 25, 2019; Published| June 26, 2019
*Correspondence | James D Archer, Applied Research Laboratory-Veterinary Studies Project, Villa Pompeii Campus, 4848 Olive Hill Road (28 Rolling View), Fallbrook, CA 92028, USA; Email: jarcher@appliedresearchlaboratory.us
Citation | Archer JD (2019). Effect of renoprotective amino acids and a dipeptide on disease progression, nutritional status, and blood-serum phosphate concentration in cats with chronic kidney disease. Res. J. Vet. Pract. 7(2): 39-52.
DOI | http://dx.doi.org/10.17582/journal.rjvp/2019/7.2.39.52
ISSN (Online) | 2308-2798
Copyright © 2019 Archer et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The prevalence of CKD rises with age, and approximately 5%, 7-10 years old, 10%,11-14 years old, and 30% of cats over 14 years of age develop CKD (Polzin et al., 1992). The mean age at diagnosis is 12.8 years (Boyd et al., 2008); however, cats have been diagnosed with CKD as early as 9 months and as late as 22 years (DiBartola et al., 1987). The course of the disease is variable, with some cats progressing to end-stage within months while others survive for years (Chakrabarti et al., 2012). Medical consensus considers CKD progressive and irreversible,
Table 1: IRISaCKDb Disease Stages in Cats
Stage Serum Creatinine Comments
mg/dL umol/dL
Normal range 0.6–2.2 53–194 No clinical signs of renal disease.
At risk <1.6 <140 No clinical signs of renal disease, but increased risk due to factors such as age, breed, exposure to nephrotoxins, etc.
1 <1.6 <140 Non-azotemic, but has at least one renal abnormality such as proteinuria, low urine specific gravity or abnormal imaging results.
2 1.6–2.8 140–249 Mild azotemia, often with mild or absent clinical signs.
3 2.9–5.0 250–439 Moderate azotemia. Extrarenal clinical signs may be present.
4 >5.0 >440
Increasing risk of systemic clinical signs and uremic crises.
aIRIS = International Renal Interest Society; bCKD = chronic kidney disease.
Source: http://www.iris-kidney.com/pdf/3_staging-of-ckd.pdf; accessed 24 May 2018.
thus treatments are supportive or palliative. Treatments may include hydration maintenance, calcium, vitamin D, erythropoietin supplementation; TDs, enteral phosphate binders, anti-hypertensive therapy, and histamine H2-receptor blockers to manage secondary gastritis.
The IRIS developed guidelines to categorize the severity of CKD (IRIS, 2016). The initial assessment is based on at least 2 measurements of fasting SCr, patient history, and the results of clinical examination. The IRIS stages are shown in Table 1.
Veterinarians often recommend TDs for cats with CKD. Restriction reduces PHOS, blood-urea nitrogen, and parathyroid hormone concentrations, and increases survival time in cats that accept the diet, when compared with cats on non-TDs (Elliot et al., 2000). Poor acceptance is common, however; with one study showing that 59.13% of cats rejected change from their former diet to TDs (Caney, 2017). TDs generally have decreased protein, phosphorus, increased carbohydrate, and variable fat content, compared with non-TDs.
A study by Salaun et al. (2017) confirmed an earlier finding by Hewson-Hughes et al. (2011) that a carbohydrate-consumption ceiling exists in cats which limits daily food intake based on daily carbohydrate intake; thereby creating deficits in protein and fat consumption, compared to their metabolic energy requirement, when fed high carbohydrate foods. Once they consumed food equivalent to 3 g carbohydrate/kg body-weight/day, they stopped eating.The carbohydrate-consumption ceiling established by Hewson-Hughes et al. was higher at 4.1 g carbohydrate/kg body-weight/day.
In a study by Bryan Kestenbaum et al. (2005) of humans with CKD, PHOS was independently and significantly related to mortality. For each 1mg/dL PHOS increase, there was a significant 23% increased risk of death (P < 0.001, 95% CI, 1.12-1.36). PHOS above the mid-range value of 3.5 mg/dL correlated with increased mortality risk, with an approximately linear relation for increased risk for each 0.5 mg/dL PHOS increase.
Cats with CKD that experience a PHOS increase of 1 mg/dL, within 1 year of diagnosis, have a 41% increased risk of progression to higher IRIS stages (Chakrabarti et al., 2012) and an 11.8% increase in the risk of death for the same increase over any time period. In a study by Boyd et al. (2008), PHOS was the only biochemical parameter that was predictive of survival.
Inorganic phosphate (Pi) absorption and reabsorption/excretion in all mammals are controlled by 3 Na+-dependent Pi cotransporter proteins (NaPiIIb, which mediates absorption in the small intestines, and NaPi-IIa and NaPiIIc, which control reabsorption/excretion in renal proximal tubules (Foster et al., 2006), so knowledge regarding PHOS homeostasis gained from studies in rodents and humans can apply to cats.
Regardless of the inciting cause, CKD evolves to progressive tubulointerstitial fibrosis accompanied by deteriorating renal function. L-carnosine, the dipeptide in AB070597, has been shown to increase bone morphogenetic protein-7 (BMP-7) gene expression in human periodontal ligament cells (Ito-Kato et al., 2004). Zeisberg et al. (2003) demonstrated that BMP-7 counteracts transforming growth factor-B1-induced epithelial-to-mesenchymal transition and reverses chronic kidney injury. Our laboratory organized an in vitro microarray experiment using human renal primary proximal tubule epithelial cells (hRPTEC) (feline cells were not available) that showed cells incubated with L-carnosine at 1.763 ug/mL increased BMP-7 messenger ribonucleic acid (mRNA) expression 2.13-fold while cells incubated with AB070597 at 3.125 ug/mL showed a 3.29-fold increase. L-carnosine blood-serum concentration in healthy cats is 10.17 ug/mL (Sabatino et al., 2013).
Studies of humans with CKD demonstrate that dietary supplementation with certain amino acids and keto-amino acids slows or prevents time-related SCr increase, disease progression, and significantly reduces PHOS in some patients (Yatzidis, 2004; Mitch et al., 1984). Further studies in humans and animals have determined that specific amino acids produce a protective effect on renal function; these include L-arginine (Reyes et al., 1994), L-aspartic acid (Tada et al., 2008), L-glutamic acid (Yatzidis, 2002), L-glutamine (Sadar et al., 2016), glycine (Yin et al., 2002), L-histidine (Watanabe et al., 2008), and the dipeptide L-carnosine (β alanyl-histidine) (Aldini et al., 2011).
AB070597 is a complex of these amino acids and dipeptide. A previous study of oral AB070597 supplementation to 27 cats with CKD showed a significant decrease in median SCr and lower median disease severity as assessed by IRIS Stage, compared with untreated controls (Archer, 2015). The objectives of this study were to assess the influence of the amino acids and dipeptide in AB070597 on disease progression, protein oxidation/nitrogen balance, and PHOS in cats with CKD fed non-protein and non-phosphorus-restricted diets.
This study was open-ended. Qualified subjects entered as they became available from referring clinics; therefore, baseline and successive observation period (OP) times were asynchronous; thus, no relationship existed between the number of cats observed for any OP and survival or removal. Data collection extended to 104 weeks. The treatment group consisted of 67 privately-owned domestic cats that ranged in age from 4 to 21 years (median=14 years) and weighed 4.12 (1.2) kg. Cats were neutered males (33, 49.3%) and spayed females (34, 50.7%). Breeds represented were Domestic Short Hair (51, 76.1%), Domestic Medium Hair (6, 9.0%), Domestic Long Hair (6, 9.0%), and Exotic (4, 6.0%).Treatment group cats included 27 (40.3%) in Stage 2, 26 (38.8%) in Stage 3, and 14 (20.9%) in Stage 4. Owners provided informed consent before enrollment. Cats remained under the care of their owners and received standard care throughout the study, which exceeded requirements defined in United States Congressional Public Law 89-544 (Animal Welfare Act of 1966), including flea and tick prophylaxis, subcutaneous fluids, and antibiotics as prescribed by their supervising veterinarians. All cats had been fed commercial non-TDs before the study and continued their original diets so protein and phosphorus would not be restricted, which would have lowered amino acid and phosphorus intake from pre-study baseline values; as well as created a daily metabolic energy deficiency in some animals because of the carbohydrate-consumption ceiling. From within the United States, 46.7% and 73.3% of wet TDs (N=15; Salaun ceiling and Hewson-Hughes ceiling, respectively) and 100% and 100% of dry TDs, (N=9; Salaun ceiling and Hewson-Hughes ceiling, respectively) contain carbohydrate percentages that limit protein and fat intake, thus creating metabolic energy requirement deficiencies (Archer, unpublished work). Owners were instructed to notify Applied Research Laboratory of any diet change and were polled monthly for compliance verification. Cats were eligible for enrollment if serial SCr was persistently ≥2.3 mg/dL (or if serial SCr was<2.3 mg/dL but incrementally increased over time and was≥ 2.3 mg/dL at inclusion), and if history of clinical signs was consistent with CKD (e.g., chronic polyuria, polydipsia, or small kidneys on abdominal palpation). Cats with suspected or verified disease, including diabetes mellitus, neoplasia, bacterial pyelonephritis, systemic hypertension, uncontrolled hyperthyroidism, acute renal failure, or other comorbidities unrelated to CKD were excluded. Complete blood count, blood chemistry, and weight profiles were determined before or at enrollment to establish SCr, PHOS, and weight baselines.
A retrospective control group of 57 non-treated CKD cats, that ranged in age from 3 to 20 years (median = 13 years) and weighed 4.1 (1.6) kg, was selected from medical records at 5 participating clinics (A, B, C, D, E.). Cats and their respective IRIS stages were distributed at clinics as follows:
A = 20 stage 2, 4 stage 4
B = 7 stage 2, 4 stage 3, 2 stage 4
C = 6 stage 2, 4 stage 3
D = 2 stage 2, 1 stage 4
E = 4 stage 2, 3 stage 3
Control cats were neutered males (23, 40.4%), spayed females (18, 31.6%), intact males (10, 17.5%), and intact females (6, 10.5%). Breeds represented were Domestic Short Hair (43, 75.4%), Domestic Medium Hair (1, 1.8%), Domestic Long Hair (2, 3.5%), and Exotic (11, 19.3%). Control group cats included 39 (68.4 %) in Stage 2, 11 (19.3%) in Stage 3, and 7 (12.3%) in Stage 4.
Amino acids and dipeptide were purchased from Nutriland Group, Inc. (Paramount, California, USA) and Dongyu USI (Irvine, California, USA), respectively. Each 300-mg dose included 25 mg L-arginine, 50 mg glycine, 50 mg L-glutamine, 25 mg L-histidine, 50 mg L-aspartic acid, 50 mg L-glutamic acid, and 50 mg L-carnosine. Cats were dosed twice daily. Each dose was mixed with 1.5 mL of water and was given by syringe directly into the subject's mouth or sprinkled on a small amount of food.
Body weights were recorded at entrance, at the last clinic visit, and at various times between. Control group cats' body weights were taken from their respective medical records.
Table 2A: Data-Recording Example
Entry Points (days) 0 1 2 3 >>>>>>644 (92 weeks)
SCra or PHOSb (mg/dL)
n.n n.n n.n n.n n.n n.n n.n n.n n.n
2 " n.n n.n n.n n.n
3 " n.n n.n n.n n.n n.n n.n
4 " n.n n.n n.n n.n n.n n.n n.n n.n n.n
" n.n n.n n.n n.n n.n n.n n.n n.n
7 " n.n n.n n.n n.n n.n
8 " n.n n.n n.n n.n n.n n.n n.n n.n
9 " n.n n.n n.n n.n n.n n.n n.n n.n n.n n.n
10 " n.n n.n n.n n.n n.n n.n n.n n.n
12 " n.n n.n n.n n.n n.n n.n n.n n.n n.n n.n
13 " n.n n.n n.n n.n n.n n.n n.n n.n n.n
Entry points for each animal (Table 2A) were translated to Synchronized-Baseline Cohorts (Table 2 B).
aSCr = blood-serum creatinine concentration; bPHOS = blood-serum phosphate concentration.
Table 2B: Translation to Synchronized-Baseline Cohorts
Observation Period (weeks) 0 12 24 36 48 60 72 84 96 104
n.n n.n n.n n.n n.n n.n n.n n.n n.n n.n
2 " n.n n.n n.n
n.n
Example Population 13 13 13 13 12 11 11 11 7 6
Treatment Popc
aSCr = blood-serum creatinine concentration; bPHOS = blood-serum phosphate concentration; cPop = Population.
Blood Sample Collection
A blood sample (2.0-3.0 mL) was collected from the jugular or saphenous vein at each regularly-scheduled clinic visit and placed into a serum-separator tube. The whole blood sample was allowed to clot at room temperature and then centrifuged. Serum was separated and dispensed into a labelled transport tube. Each sample was sent to a local veterinary diagnostic reference laboratory (Antech Diagnostics, Headquarters, Irvine, California, USA or Idexx Laboratories, Headquarters, Westbrook, Maine, USA) for SCr and PHOS analysis.
Laboratory Measurements
SCr and PHOS were measured approximately every 12 weeks, up to 104 weeks or death, whichever occurred first. Measurements were performed at Idexx or Antech laboratories using an Olympus AU2700 Chemistry Analyzer and Beckman-Coulter AU5431 Chemistry Analyzer, respectively.
SCr and PHOS coefficients of variation (CV), as determined by Idexx Laboratories, were 3.33%, 1.88% and 3.51%, 3.08% (low end, high end of normal range), respectively; and less than 3% for within-run samples at Antech Diagnostics, with a total precision of less than 5%.
Control group SCr and PHOS analyses were also performed by Antech Diagnostics and Idexx Laboratories, except for 1 clinic that used in-house instrumentation supplied by Antech Diagnostics. Some laboratory reports were more than 4 years old, so the CV of the instrumentation used then is not known.
BMP-7 mRNA Expression and hRPTEC Viability Assays
BMP-7 mRNA expression and hRPTEC viability assays for L-carnosine and AB070597 were performed by Cyprotex US, LLC, Watertown, MA 02472, USA. hRPTEC (Catalog #: CC-2553) and Renal Epithelial Cell BulletKit™ (Catalog #: CC-3190) were purchased from Lonza Walkersville, Inc., Walkersville, Maryland 21793, USA.
BMP-7 mRNA Expression Assay
Cells were cultured at 37°C, 5% CO2 in renal epithelial cell growth medium, and passaged to 2 96-well plates with a density of 4000 cells/well. After 24 h culture, varying concentrations of L-carnosine and AB070597 were added to each well and incubated for 6 days. Total RNA was extracted from hRPTEC using MagMax™-96 Total RNA Isolation Kit (ThermoFisher Scientific, Waltham, MA, USA). Complementary deoxyribonucleic acid (cDNA) was synthesized from total RNA with High Capacity RNA-to-cDNA Kits and a Veriti thermal cycler (ThermoFisher, Waltham, MA, USA). Real-time-quantitative PCR (RT-qPCR) was performed in Applied Biosystems Real-Time Quantitative polymerase chain reaction system (Thermo Fisher, Waltham, MA, USA). Expression of BMP-7 mRNA in treated cells was determined by RT-qPCR and compared with reference vehicle treated hRPTEC. Peptidylproprolyl isomerase-A was used as an internal control.
hRPTEC Viability Assay
hRPTEC were plated on 384-well tissue culture treated polystyrene plates at 1.5 x 10^4 cells. After overnight incubation at 37°C, cells were dosed with AB070597 in a range of concentrations and incubated for 72 h at 37°C. Cell viability was measured using the Promega Cell Titer 96 Non-Radioactive Cell Proliferation Assay (MTT) kit (Promega Corporation, Madison, WI, USA) by adding dye solution to each well and incubating for 3 h at 37°C. After incubation, Promega Solubilization Solution/Stop Mix was added to each well. Plates were incubated at 37°C for 1 h and mixed on a plate shaker for 10 minutes. Spectrophotometric absorbance was read at 370 nm. The IC50 was calculated using GraphPadPrism (GraphPad Software, San Diego, CA, USA).
Baseline (time 0) was the moment each cat entered the study. SCr and PHOS measurements were assembled into synchronized-baseline OP cohorts to adjust for asynchronous baseline entry dates, with the result that earlier OP cohorts included more cats than later cohorts, as shown in Table 2. Table 3 shows the number of treatment and control cats, versus length (OPs) of observation.
Table 3: Number of Cats vs. Time Observed*
OP (weeks) Control
Cats Observed
0 Baseline 57 67
*Declining numbers at increasing observation periods do not correlate with removal or survival but result from an open-ended study design with asynchronous entry dates.
IRIS Stage data were analyzed by converting SCr measurements to disease stages: Stage 1 (SCr< 1.6 mg/dL), Stage 2 (SCr, 1.6–2.8 mg/dL), Stage 3 (SCr, 2.9–5.0 mg/dL) and Stage 4 (SCr> 5.0 mg/dL).
Data for SCr and IRIS stage were analyzed using the same method. For each endpoint, the change-from-baseline value was calculated for each OP as Week N–Week 0. Descriptive statistics were calculated by treatment and OP for each endpoint and for the change-from- baseline values for each endpoint. For each endpoint, the change-from-baseline values were modeled using a repeated measure analysis of covariance model, with an autoregressive first-order covariance structure. The following covariates were evaluated for inclusion in the repeated measures model: study (secondary-analysis data, included in Archer (2015), versus data from the current study), age, baseline value, gender, sterilized (spayed or neutered versus intact), and breed. The fixed effects for treatment, time, and treatment by time interaction were included in the model. LS-means for treatment and control SCr and IRIS stage change-from-baseline, for each OP, along with the 95% confidence intervals (CI) for the LS-means, were calculated. The same statistics for overall treatment over 104 weeks were calculated. In addition, the differences in LS-means between treatment and control for each OP and over the entire 104-week treatment period were determined, along with the corresponding 95% CIs and P-values for the differences. In addition, the counts and percentages for each IRIS stage for each OP were calculated for treatment and control groups. The P-value from the Cochran-Mantel-Haenszel (CMH) statistic, testing the alternative hypothesis that there was a linear association between treatment and stage, was calculated by OP. Normality assumptions were evaluated for each endpoint and, if the assumptions appeared violated, a sensitivity analysis was conducted using a ranked analysis of variance model like the original model used. The difference between these two models was that the change-from-baseline was ranked within OP and then the model was fit on these ranked values. A two-sided, 2-sample t-test,with Satterthwaite approximation for unequal variances, was employed to compare the change-from-baseline body weights between treatment and controls.Treatment and control PHOS change-from-baseline were analyzed with the Wilcoxon Signed Rank Test. Statistical power for SCr LS-means change-from-baseline and IRIS LS-means stage change-from baseline at each OP was calculated from control and treatment means, sampling ratio, and pooled standard error of mean (SEM). Analyses were conducted using SAS Institute, Inc. 9.4 analytics software (SAS Institute Inc., Cary, NC, USA) at significance level 0.05. AB070597 and L-carnosine induced BMP-7 mRNA fold-change in hRPTEC cells were analyzed with Applied Biosystems, QuantStudio Real-Time PCR Software (ThermoFisher Scientific, Waltham MA, USA).
Results are reported as mean (SD); LS-mean (SEM); median (minimum, maximum).
Mean SCr was 4.2 (2.66) mg/dL at week 0 for treatment cats, and 2.9 (0.89) mg/dL for control cats. Mean SCr was lower in the treatment group, when compared with controls, at all OP, from week 12 to week 104. Values are plotted in Figure 1 and Table 4. Treated cats exhibited significantly reduced SCr from baseline at all OP (P <0.001 at 7 OP, P <0.004 at 1 OP), except for week 12 (P=0.054). The overall difference at week 104, between treatment group and controls, was –0.5 (CI: –0.8, –0.2; P <0.001). There were some OPs where underlying normality assumptions may have been violated so a sensitivity analysis was performed on the ranked data. There was a significant difference for ranked data at all OPs including week 12. Thus, the data suggest that treatment significantly lowered SCr as compared with no treatment. The SCr LS-mean change-from-baseline over time is shown in Figure 2 and Table 5.
Figure 1: Mean SCra vs. Time
aSCr = blood-serum creatinine concentration.
Table 4: Mean SCra vs. Time
OP (weeks)
SCr (mg/dL) mean (SDb)
Control Treatment n-Treatment/Control
0 2.9 (0.89) 4.2 (2.66) 67/57
12 3.1 (0.93) 3.1 (1.31) 67/57
104 4.6 (2.67) 2.7 (0.97)
a SCr = blood-serum creatinine concentration; bSD = standard deviation
OPs and IRIS Distribution
Mean IRIS Stage for treated cats was 2.8 (0.76) and 2.3 (0.68) at weeks 0 and 104, respectively (Figure 3). Stage 2, 3, and 4 cats were observed for 75 (32), 65 (34), and 39 (33) weeks, respectively (data not shown).
Table 5: SCra LS-Meanb Change-from-Baseline vs. Time
LS-Mean (SEMc)
P n-Treatment/
Statistical Power (%)
Control Treatment
0 67/57
12 0.0 (0.21) –0.5 (0.20) 0.054 67/57 40.2
24 0.7 (0.21) –0.6 (0.21) < 0.001 59/57 >99
48 0.7 (0.22) –0.4 (0.23) < 0.001 45/51 92.8
104 1.7 (0.36) –0.6 (0.38) < 0.001 18/19
aSCr = blood-serum creatinine concentration; bLS-Mean = least squares mean; cSEM = standard error of mean.
Mean IRIS Stage for controls was 2.3 (0.57) and 2.9 (0.88) at weeks 0 and 104, respectively (Figure 3). Stage 2, 3, and 4 cats were observed for 80 (27), 66 (28), and 65 (57) weeks, respectively (data not shown).
Figure 2: SCra LS-Meanb Change-from-Baseline vs. Time
aSCr = blood-serum creatinine concentration; bLS-Mean = least squares mean.
Figure 3: Mean IRISa Stage vs. Time
aIRIS = International Renal Interest Society.
IRIS Stage
A comparison of averages showed that treated cats started at a numerically higher mean SCr and IRIS stage compared with controls. At week 12, treatment group stage declined whereas control group values increased (Figure 3). As time progressed, a gradual shift in the treatment group to lower mean IRIS stage compared with controls was observed. A CMH statistic test for linear association between treatment and reduced disease stage was significant at baseline, with the treatment group having higher stage values than the control group. At weeks 24, 48, 60, 72, 84, 96, and 104 a significant linear association was observed between treatment and disease stage, with lower disease stage values observed in the treated cats compared with controls (Table 6).
Table 6: CMHa Test for Linear Association of Decreased Disease Stage with Treatment vs. Time
OP (weeks) P
0 Baseline <0.001
aCMH = Cochran-Mantel-Haenszel.
When IRIS Stage was expressed as LS-mean change-from-baseline, weeks 12, 24, 36, 48, 60, 72, 84, 96, and 104 showed significant reductions (P = 0.006 at week 12, P<0.001 weeks 24 to 104) as shown in Figure 4 and Table 7. The overall difference at week 104, between treatment and controls was –0.2 (CI: –0.3, –0.1; P <0.001). The treated group showed negative LS-mean change in IRIS
Table 7: IRISa LS-Meanb Stage Change-from-Baseline vs. Time
Least Squares Mean (SEMc)
P n-Treatment/Control Statistical Power (%)
104 0.7 (0.12) –0.4(0.12) < 0.001 18/19
aIRIS = International Renal Interest Society; bLS-Mean = least squares mean; cSEM = standard error of mean.
stage score at each OP compared to baseline. In contrast, controls showed positive change at each OP. The data indicate that treatment significantly lowered disease stage over time.
Treatment and Control IRIS-Stage Distribution vs. Time
At baseline, the control group had a larger proportion of cats classified as IRIS Stage 2 (68.4 %) than did the treat
ment group (40.3%). At all subsequent OP the proportion of cats classified as IRIS Stage 2 was greater in treated cats compared with controls, as shown in Figure 5. Controls moved from predominantly Stage 2 to predominantly Stages 3 and 4 at week 104, whereas treated cats moved from a nearly equal distribution between Stages 2 and 3 to mostly Stage 2, with a small percentage of Stage 3 and 4 cats at week 104. Cats returned to IRIS Stage 1 only in the treatment group. Figures 5, 6, and 7 and Table 8 show the distribution of animals in each IRIS stage versus time.
Figure 4: IRISa LS-Meanb Stage Change-from-Baseline vs. Time
aIRIS = International Renal Interest Society; bLS-Mean = least squares mean.
Figure 5: Cumulative IRISa Stage Frequencies in Treatment and Control Groups vs. Time
Figure 6: Treatment IRISa Stage-Distribution vs. Time
aIRIS = International Renal Interest Society; bOP = observation period.
Treated cats showed an overall LS-mean PHOS difference at 104 weeks, when compared with controls, of -0.3 (CI: -1.2, 0.6; P = 0.5; data not shown). However, treatment group mean and median PHOS declined from baseline
Table 8: Number and Percentage of Cats in IRISa Stages per OP
OP (weeks) 0 12 24 36 48 60 72 84 96 104
Stage 1 N Cats
Stage 1 % 0.0 1.5 3.4 2.0 0.0 0.0 0.0 0.0 0.0 5.6
Stage 2 N Cats 27 40 36 30 25 23 18 21 15 12
Stage 2 % 40.3 59.7 61.0 58.8 55.6 59.0 56.3 67.7 65.2 66.7
Stage 3 N Cats 26 22 20 19 19 15 13 9 7 4
Stage 4 N Cats 14 4 1 1 1 1 1 1 1 1
Stage 4 % 20.9 6.0 1.7 2.0 2.2 2.6 3.1 3.2 4.3 5.6
Stage 1 N Cats 0 0 0 0 0 0 0 0 0 0
Stage 1 % 0 0 0 0 0 0 0 0 0 0
Stage 2 N Cats 42 31 28 27 22 17 12 10 7 8
Stage 2 %
Stage 3 N Cats 12 23 20 20 20 14 15 16 14 5
Stage 4 % 5.3 5.3 15.8 11.3 17.6 20.5 20.6 16.1 12.5
Figure 7: Control IRISa Stage-Distribution vs. Time
-1.3 (CI:-1.11, -1.34, P=0.002), and -0.2 (CI: -0.15, -0.25, P<0.002), respectively , whereas control group mean and median values increased 0.14 (CI: 0.45, 0.03, P=0.004), 0.3 (CI: 0.20, 0.10, P<0.002, respectively (Figures 8, 9). Mean and median values remained within reference range for both groups through all OPs.
Safety and Palatability
The cell viability assay revealed no cytotoxicity to hRPTEC when exposed to AB070597 for 72 h at 37°C, over the concentration range (100.00, 50.00, 25.00, 12.50, 6.25, 3.13, 1.56, 0.78, 0.39, and 0.2 ug/mL), as shown in Figure 10; therefore, no IC50 was calculated. Treated cats accepted AB070597 as a single oral dose and on food. Treatment diaries were not used in this study, but there were no reports of digestive distress or diarrhea. Some cats displayed symptoms consistent with CKD, but no observed adverse effects attributable to supplementation were reported by owners or veterinarians. There were no adverse changes in serum chemistries or complete blood counts traceable to supplementation in treated cats (data not shown).
Figure 8: Treatment PHOSa Change-from-Baseline vs. Time: Median (P = 0.002), Mean (P = 0.002)
aPHOS = blood-serum phosphate concentration; bOP = observation period.
Baseline body weights were recorded in 57 treated cats. Body weights were recorded in 41 of those cats at their final study-related clinic visit. Baseline and time-equivalent
Table 9: Summary of Body Weights (kg)
n 53 57
Mean (SDa)
4.5 (1.28) 4.1 (1.17)
Median (minb, maxc)
4.1 (2.3, 8.4) 3.9 (2.2, 7.2)
Last Clinic Visit
Mean (SD) 3.7 (1.14) 4.1 (1.30)
Median (min, max) 3.5 (2.1, 7.2) 4.0 (1.9, 7.7)
Weight Change-from Baseline to Last Clinic Visit
P-value < 0.001
< 0.001
aSD = standard deviation; bmin = minimum; cmax = maximum
Table 10: Mean BMP-7 mRNA Fold-Change for Concentrations of AB070597 and L-Carnosine Measured by qRT-PCR in hRPTEC
AB070597 L-carnosine
(ug/mL)
MFCa
(ug/mL) MFC SD
100 3.957982 1.532254 113.12 3.261911 1.356335
50 1.612641 * 56.56 2.409648 0.300896
25 5.771671 3.169783 28.28 2.153824 1.316414
12.5 1.238226 0.519722 14.14 2.128198 2.963974
6.25 1.892023 1.228735 7.07 1.443206 0.901008
3.125 3.286329 2.052426 3.535 2.364290 1.241926
1.56 1.451196 0.490564 1.764 2.128385
aMFC = mean fold-change; bSD = standard deviation; * Zero division error.
Figure 9: Control PHOSa Change-from-Baseline vs. Time: Median (P = 0.002), Mean (P = 0.004).
aPHOS = blood-serum phosphate concentration, bOP = observation period.
body weights were available from medical records for 53 and 46 control group cats, respectively. Control group cats lost an average of 0.9 kg (P < 0.001), while cats in the treatment group showed a mean body weight change of
0.0 kg ( P < 0.001). Changes in body weight are shown in
Figure 10: hRPTECa Viability vs. AB070597 Concentration
ahRPTEC = human renal primary proximal tubule epithelial cells.
Figure 11: AB070597-Induced Fold-Change in BMP-7a mRNAb in hRPTECc, Measured by qRT-PCRd.
aBMP-7 = bone morphogenetic protein-7; bmRNA = messenger
ribonucleic acid; chRPTEC = human renal primary proximal tubule epithelial cells; dqRT-PCR = quantitative real time-polymerase chain reaction.
Overall, BMP-7 mRNA fold-change increased with rising concentrations of AB070597 and L-carnosine. BMP-7 mRNA was increased and significantly different from controls in all culture wells, except 1, at all concentrations (P < 0.05) (supplemental data). Changes were small, however, and no significant trend was established. Table 10 and Figures 11 and 12 show the mean fold-change at varying concentrations.
Figure 12: L-carnosine-Induced Fold-Change in BMP-7a mRNAb in hRPTECc,Measured by qRT-PCRd
Current controversy exists over whether TDs provide adequate nutrition for CKD cats (Scherk and Laflamme, 2016). Commercial TDs, with decreased protein, phosphorus, and increased carbohydrate percentages, were not fed in this study because they would have lowered baseline oral amino acid and phosphorus intake and prevented some cats from reaching their daily metabolic energy requirement (Salaun et al., 2017; Hewson-Hughes et al., 2011). SCr was chosen as an indicator of renal function because it correlates strongly with disease severity (Elliott and Barber, 1998). PHOS was selected because increased levels associated with accelerated disease progression and poor prognosis (Boyd et al., 2008). The IRIS disease staging system was used because it is an accepted tool for categorizing disease stage and monitoring progression. Body-weight was an important variable used as an estimate of protein oxidation and nitrogen balance.
Mean SCr dropped dramatically in treated cats from baseline to week 12 and continued a generally negative slope to week 104. Control cats experienced the opposite trend, with mean SCr rising from baseline through week 104. Treatment group median body weight, over the same time remained stable, which was likely the result of their diet providing adequate nutrition by not restricting protein and fat. Had treatment cats lost weight, there might be reason to question SCr improvement, but that was not the case.
There are biological mechanisms that might explain these differences: SCr correlates positively with increased plasma levels of the endogenous L-arginine derivatives, asymmetrical and symmetrical dimethylarginine, in cats with CKD (Jepson et. al., 2008). Both competitively block cellular uptake of L-arginine, the exclusive biological substrate for nitric oxide synthesis, thereby inhibiting its production. The pathogenic role of blocked nitric oxide synthesis in human CKD patients was discussed by Zoccali et al. (2001) and Bode-Boger et al. (2006). In diverse models of renal disease, oral L-arginine supplementation consistently improves glomerular filtration rate (Klahr, 1999).
Treatment resulted in significant improvements in mean IRIS stage at week 24 onward. Treatment also created significant improvements (P<0.001, except for week 12 [P = 0.006]) in LS-mean IRIS stage change-from-baseline compared with controls, suggesting that treatment arrested, and to some extent, reversed disease.The reduction in IRIS stages conflicts with those observed in cats treated with conventional therapies, whose stages increase with time.
Mean and median PHOS remained within reference range for both treatment and control groups through 104 weeks. There were, however, significant differences in change-from-baseline, with PHOS falling below baseline from week 12 through week 104 in the treatment group and PHOS rising from week 24 through 104 in controls (Figures 8, 9). The steady decline in treatment group PHOS might seem unusual, since cats were fed non-protein, non-phosphorous restricted diets. One explanation is that amino acids increase glomerular filtration rate, which would increase phosphate excretion. Another is that cats preferentially use amino acids for gluconeogenesis to maintain glucose needs (Eisert, 2011). The amino acids in AB070597 are gluconeogenic and might have elevated insulin levels in response to increased blood-serum glucose. Increased insulin lowers PHOS by stimulating cellular uptake (Riley et al., 1979).This was observed in humans when circulating L-arginine levels were increased by infusion, resulting in a highly significant fall in PHOS that was significantly correlated to increased insulin (Massara et al., 1980). Finally, increased BMP-7 expression might have played a role in the treatment group's persistent PHOS decline from baseline. BMP-7 gene expression declines in early stages of renal fibrosis and continues to decline with disease progression in the rat model (Xuhua et al., 2007). Gravesen et al. (2018) showed that exogenous BMP-7 treatment created a significant PHOS decrease in CKD rats that had been fed a high phosphorus diet (1.2%) for 14 weeks. Even though BMP-7 mRNA fold-change was not statistically significant in this study's BMP-7 mRNA expression assay, there was a positive trend with rising AB070597 concentrations. It is possible that increased endogenous BMP-7 expression induced non-functional nephrons to differentiate and regain their normal phenotype, thereby adding to the total functional nephron number, resulting in increased fractional PHOS excretion.
Cats are unable to maintain nitrogen balance when protein intake is below their protein requirement (Green et al., 2008), resulting in negative nitrogen balance and weight loss.Treatment group cats maintained stable mean and median body weight and were not fed TDs, implying that they preserved nitrogen balance as a result of their non-restrictive diets. Diet data was not available from all control-referring clinics, but from clinics that kept diet records, 60.4% of cats were prescribed TDs, which was 66.7% of all controls, presenting a possible explanation for the group's significant mean and median weight loss. Freeman et al. (2016), showed that weight loss in CKD cats accelerates after diagnosis, across all IRIS stages, which implies that a common underlying intervention at diagnosis might be responsible (e.g., TD prescription). Markovich et al. (2015) found that 51% of owners were compliant when TDs were recommended, so it is reasonable to expect that many control cats at clinics that did not have diet records were also fed TDs. Data is convincing, however, that TDs extend survival, but at a cost. Green et al. (2008) showed that when cats were fed low protein TDs, protein oxidation exceeded energy intake by approximately 39%, whereas oxidation and energy intake were adequately matched with medium and high protein diets. Ross (2016) conducted a study, where feeding tubes were placed in 34 CKD cats to control TD intake for long-term body-weight maintenance. Body weight stabilized or increased slightly, despite continued disease progression. Median survival was 178 days, and Kaplan-Meyer survival curves showed that approximately 74% died within one year. When this current study's results are viewed as a whole, there is reason to hypothesize that weight control and longevity might be enhanced with a normal diet and amino acid/dipeptide supplementation.
Treated cats exhibited significant overall reductions in SCr LS-mean change-from-baseline and IRIS stage compared with untreated controls. Treatment group IRIS LS-mean stage change-from-baseline was negative at each OP, indicating disease stage reduction, whereas control group IRIS LS-mean stage change-from-baseline was positive at each OP, indicating disease stage advance. PHOS change-from-baseline persistently declined in treated cats and persistently increased in controls, suggesting that treated cats increased fractional excretion, increased glomerular filtration rate, or both. Treated cats maintained body weight, suggesting stable nitrogen balance. Oral supplementation of renoprotective amino acids and dipeptide in AB070597 prevented, and to some extent, reversed disease progression in treated animals that were fed non-protein and non-phosphorous restricted diets. Clinical use of this compound may benefit the greater population of companion cats diagnosed with CKD.
The author gratefully acknowledges the staff at Whitsell Innovations, Inc. for their assistance with manuscript preparation and to PharPoint Research, Inc. for their expertise and insight with data analysis and figure design. He also acknowledges the professional scientific capabilities of Cyprotex US, LLC staff for their BMP-7 mRNA and cell viability analyses.
This study was made possible by generous support from the John T. Fulton Trust.
The author declares no financial conflict of interest.
•	Aldini G, Orioli M, Rossoni G, Savi F, Braidotti P, Vistoli G, Yeum KJ, Negrisoli G, Carini M (2011). The carbonyl scavenger carnosine ameliorates dyslipidaemia and renal function in Zucker obese rats. J. Cell Mol. Med. 15(6):1339-1354. https://doi.org/10.1111/j.1582-4934.2010.01101.x
•	Archer JD (2015). Effect of AB070597 on blood-serum creatinine concentration in cats with chronic kidney disease. Res. J. Vet. Pract. 3(3):58-68. https://doi.org/10.14737/journal.rjvp/2015/3.3.58.68
•	Bode-Boger SM, Scalera F, Kielstein JT, Martens-Lobenhoffer J, Breithardt G, Fobker M, Reinecke H (2006). Symmetrical dimethylarginine: a new combined parameter for renal function and extent of coronary artery disease. J. Am. Soc. Nephrol. 17:1128-1134. https://doi.org/10.1681/ASN.2005101119
•	Bartges JW (2012). Chronic kidney disease in dogs and cats. Vet. Clin. North Am. Small Anim. Pract. 42(4):669-692. https://doi.org/10.1016/j.cvsm.2012.04.008
•	Boyd LM, Langston C, Thompson K, Zivin K, Imanishi M (2008). Survival in cats with naturally occurring chronic kidney disease (2000–2002). J. Vet. Intern Med. 22(5):1111-1117. https://doi.org/10.1111/j.1939-1676.2008.0163.x
•	Caney SM (2017).An online survey of dietary and phosphate binder practices of owners of cats with chronic kidney disease. J. Feline Med. Surg. 19(10):1040-1047. https://doi.org/10.1177/1098612X16672999
•	Chakrabarti S, Syme HM, Elliott J (2012). Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease. J. Vet. Intern Med. 26(2):275-281. https://doi.org/10.1111/j.1939-1676.2011.00874.x
•	DiBartola SP, Rutgers HC, Zack PM, Tarr MJ (1987). Clinicopathologic findings associated with chronic renal disease in cats: 74 cases (1973-1984). J. Am. Vet. Med. Assoc. 190(9):1196-1202.
•	Elliott J, Barber PJ (1998). Feline chronic renal failure: clinical findings in 80 cases diagnosed between 1992 and 1995. J. Small Anim. Pract. 39(2):78-85. https://doi.org/10.1111/j.1748-5827.1998.tb03598.x
•	Elliott J, Rawlings JM, Markwell PJ, Barber PJ (2000). Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J. Small Anim. Pract. 41(6):235-242. https://doi.org/10.1111/j.1748-5827.2000.tb03932.x
•	Eisert R (2011). Hypercarnivory and the brain: protein requirements of cats reconsidered. J. Comp. Physiol. B. 181(1):1-17. https://doi.org/10.1007/s00360-010-0528-0
•	Foster IC, Hernando N, Biber J, Murer H (2006). Proximal tubular handling of phosphate: A molecular perspective. Kidney Int. 70(9):1548-1559. https://doi.org/10.1038/sj.ki.5001813
•	Freeman LM, Lachaud MP, Matthews S, Rhodes L, Zollers B (2016). Evaluation of Weight Loss Over Time in Cats with Chronic Kidney Disease. J. Vet. Intern. Med. 30(5):1661-1666. https://doi.org/10.1111/jvim.14561
•	Gravesen E, Lerche Mace M, Nordholm A, Hofman-Bang J, Hruska K, Haagen Nielsen C, Kjaer A, Olgaard K, Lewin E (2018). Exogenous BMP7 in aortae of rats with chronic uremia ameliorates expression of profibrotic genes, but does not reverse established vascular calcification. PloS One. 13(1): e0190820. https://doi.org/10.1371/journal.pone.0190820
•	Green AS, Ramsey JJ, Villaverde C, Asami DK, Wei A, Fascetti AJ (2008). Cats are able to adapt protein oxidation to protein intake provided their requirement for dietary protein is met. J. Nutr. 138(6):1053-1060. https://doi.org/10.1093/jn/138.6.1053
•	Hewson-Hughes AK, Hewson-Hughes VL, Miller AT, Hall SR, Simpson SJ. Raubenheimer D (2011).Geometric analysis of macronutrient selection in the adult domestic cat, Felis catus. J. Exp. Biol. 214(Pt6):1039-1051. https://doi.org/10.1242/jeb.049429
•	International Renal Interest Society (2016).http://www.iris-kidney.com/pdf/3_staging-of-ckd.pdf; accessed 24 May 2018.
•	Ito-Kato E, Suzuki N, Maeno M, Takada T, Tanabe N, Takayama T, Ito K, Otsuka K (2004). Effect of carnosine on runt-related transcription factor-2/core binding factor alpha-1 and Sox9 expressions of human periodontal ligament cells. J. Periodontal. Res. 39(3):199-204. https://doi.org/10.1111/j.1600-0765.2004.00725.x
•	Jepson RE, Syme HM, Vallance C, Elliot J (2008). Plasma asymmetric dimethylarginine, symmetric dimethylarginine, l-arginine, and nitrite/nitrate concentrations in cats with chronic kidney disease and hypertension. J. Vet. Intern. Med. 22(2):317-324. https://doi.org/10.1111/j.1939-1676.2008.0075.x
•	Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL, Young B, Sherrard DJ, Andress DL (2005). Serum phosphate levels and mortality risk among people with chronic kidney disease. J. Am. Soc. Nephrol.16(2):520-528. https://doi.org/10.1681/ASN.2004070602
•	Klahr S (1999). Can L-arginine manipulation reduce renal disease? Semin Nephrol. 19(3):304-309.
•	Markovich JE, Freeman LM, Labato MA, Heinze CR (2015). Survey of dietary and medication practices of owners of cats with chronic kidney disease. J. Feline. Med. Surg. 17(12):979-983. https://doi.org/10.1177/1098612X14563097
•	Massara F, Martelli S, Cagliero E, Camanni F, Molinatti GM (1980). The hypophosphatemic and hyperkalemic effect of arginine in man. J. Endocrinol. Invest. 3(2): 177-180. https://doi.org/10.1007/BF03348247
•	Mitch WE, Walser M, Steinman TI, Hill S, Zeger S, Tungsanga K (1984). The effect of a keto acid–amino acid supplement to a restricted diet on the progression of chronic renal failure. N. Engl. J. Med. 311(10):623-629. https://doi.org/10.1056/NEJM198409063111002
•	Polzin DJ, Osborne CA, Adams LG, Lulich JP (1992). Medical management of feline chronic renal failure. In: Kirk RW, Bonagura J eds.Current Veterinary Therapy XI. Philadelphia:W.B. Saunders, 848.
•	Reyes AA, Karl IE, Klahr S (1994). Role of arginine in health and in renal disease. Am. J. Physiol. 267(3 Pt 2):F331-346.
•	Riley MS, Schade DS, Eaton RP (1979). Effects of insulin infusion on plasma phosphate in diabetic patients. Metabolism. 28(3):191-194. https://doi.org/10.1016/0026-0495(79)90063-5
•	Ross S (2016). Utilization of feeding tubes in the management of feline chronic kidney disease. Vet. Clin. North Am. Small Anim. Pract. 46(6): 1099-1114. https://doi.org/10.1016/j.cvsm.2016.06.014
•	Sabatino BR, Rohrbach BW, Armstrong PJ, Kirk CA (2013). Amino acid, iodine, selenium, and coat color status among hyperthyroid, Siamese, and age-matched control cats. J. Vet. Intern. Med. 27(5):1049-1055. https://doi.org/10.1111/jvim.12165
•	Sadar S, Kaspate D, Vyawahare N (2016). Protective effect of L-glutamine against diabetes-induced nephropathy in experimental animal: role of KIM-1, NGAL, TGF-β1, and collagen-1. Ren. Fail. 38(9):1483-1495. https://doi.org/10.1080/0886022X.2016.1227918
•	Salaun F, Blanchard G, Le Paih L, Roberti F, Niceron C (2017). Impact of macronutrient composition and palatability in wet diets on food selection in cats. J. Anim. Physiol. Anim. Nutr. (Berl). 101(2):230-328. https://doi.org/10.1111/jpn.12542
•	Scherk MA, Laflamme DP(2016). Controversies in Veterinary Nephrology: Renal Diets Are Indicated for Cats with International Renal Interest Society Chronic Kidney Disease Stages 2-4: The Con View. Vet. Clin. North Am. Small Anim. Pract. 46(6): 1067-1094. https://doi.org/10.1016/j.cvsm.2016.06.007
•	Tada Y, Yano N, Takahashi H, Yuzawa K, Ando H, Kubo Y, Nagasawa A, Uehara S, Ogata A, Nakae D(2008).Toxic effects of L-aspartic acid at high dose levels on kidneys and salivary glands in Fischer 344 rats detected in a 90-day feeding study. Food Chem. Toxicol. 46(8):2789-2795. https://doi.org/10.1016/j.fct.2008.05.013
•	Watanabe M, Suliman ME, Qureshi AR, Garcia-Lopez E, Bárány P, Heimbürger O, Stenvinkel P, Lindholm B (2008). Consequences of low plasma histidine in chronic kidney disease patients: associations with inflammation, oxidative stress, and mortality. Am. J. Clin. Nutr. 87(6):1860-1866. https://doi.org/10.1093/ajcn/87.6.1860
•	Xuhua M, Sen L, Xingyi M, et al (2007). The expression of bone morphogenic protein-7 and its significance in renal tissue of unilateral ureteral obstruction rat model. Sichuan Med. J. 2007-07.
•	Yatzidis H (2002). A new, superior, single and stable, amino acid and bicarbonate-based, glucose-free solution for peritoneal dialysis. Dialysis Transplant. 31(3):143-149.
•	Yatzidis H (2004). Oral supplement of six selective amino acids arrest progression renal failure in uremic patients. Int. Urol. Nephrol. 36(4):591-598. https://doi.org/10.1007/s11255-004-8782-2
•	Yin M, Zhong Z, Connor HD, Bunzendahl H, Finn WF, Rusyn I, Li X, Raleigh JA, Mason RP, Thurman RG (2002).Protective effect of glycine on renal injury induced by ischemia-reperfusion in vivo. Am. J. Physiol. Renal. Physiol. 282(3):F417-423. https://doi.org/10.1152/ajprenal.00011.2001
•	Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R (2003). BMP-7 counteracts TGF-beta1-induced epithelial-to mesenchymal transition and reverses chronic renal injury. Nat. Med. 9(7):964-968. https://doi.org/10.1038/nm888
•	Zoccali C, Bode-Boger S, Mallamaci F, Benedetto F, Tripepi G, Malatino L, Cataliotti A, Bellanuova I, Fermo I, Frolich J, Boger R (2001). Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet. Dec 22-29. 358(9299): 2113-7
© Copyrights 2019. Nexus. All rights reserved until stated otherwise. Design & Developed By ZG Technologies


text:
package org.onosproject.mcast.api;

import com.google.common.annotations.Beta;
import org.onosproject.event.AbstractEvent;

import java.util.Objects;

import static com.google.common.base.MoreObjects.toStringHelper;

/**
 * An entity representing a multicast event. Event either add or remove
 * sinks or sources.
 */
@Beta
public class McastEvent extends AbstractEvent<McastEvent.Type, McastRouteUpdate> {

    /**
     * Mcast Event type enum.
     */
    public enum Type {
        /**
         * A new mcast route has been added.
         */
        ROUTE_ADDED,

        /**
         * A mcast route has been removed.
         */
        ROUTE_REMOVED,

        /**
         * A set of sources for a mcast route (ie. the subject) has been added.
         */
        SOURCES_ADDED,

        /**
         * A set of sources for a mcast route has been removed.
         */
        SOURCES_REMOVED,

        /**
         * A set of sinks for a mcast route (ie. the subject) has been added.
         */
        SINKS_ADDED,

        /**
         * A set of sinks for a mcast route (ie. the subject) has been removed.
         */
        SINKS_REMOVED
    }

    private McastRouteUpdate prevSubject;

    /**
     * Creates a McastEvent of a given type using the subject.
     *
     * @param type        the event type
     * @param prevSubject the previous mcast information
     * @param subject     the current mcast information
     */
    public McastEvent(McastEvent.Type type, McastRouteUpdate prevSubject, McastRouteUpdate subject) {
        super(type, subject);
        this.prevSubject = prevSubject;
    }

    /**
     * Gets the previous subject in this Mcast event.
     *
     * @return the previous subject, or null if previous subject is not
     * specified.
     */
    public McastRouteUpdate prevSubject() {
        return this.prevSubject;
    }

    @Override
    public int hashCode() {
        return Objects.hash(type(), subject(), prevSubject());
    }

    @Override
    public boolean equals(Object other) {
        if (this == other) {
            return true;
        }

        if (!(other instanceof McastEvent)) {
            return false;
        }

        McastEvent that = (McastEvent) other;

        return Objects.equals(this.subject(), that.subject()) &&
                Objects.equals(this.type(), that.type()) &&
                Objects.equals(this.prevSubject(), that.prevSubject());
    }

    @Override
    public String toString() {
        return toStringHelper(this)
                .add("type", type())
                .add("prevSubject", prevSubject())
                .add("subject", subject())
                .toString();
    }
}

redpajama_set_name: RedPajamaGithub


A family serving event! We're hosting a two-day family food packing event here at 7 Whatney on Friday, May 17 from 6-8pm, and Saturday May 18 from 9-11am. Sponsored by SuperNove Kids, in partnership with Kids Around the World, we'll package 100,000 meals for orphanages in Swaziland. This is a great event for all ages, and leading up to the big weekend, we will be raising funds to purchase the meals that we will pack and send out! Save the date and sign-ups will be open soon!


text:
Indianapolis, IN (Massachusetts Ave / N Rural St)
Massachusetts Ave / N Rural St
About Indianapolis, IN (Massachusetts Ave / N Rural St)
Massachusetts Ave / N Rural St median real estate price is $113,277, which is more expensive than 38.9% of the neighborhoods in Indiana and 20.5% of the neighborhoods in the U.S.
The average rental price in Massachusetts Ave / N Rural St is currently $963, based on NeighborhoodScout's exclusive analysis. Rents here are currently lower in price than 50.6% of Indiana neighborhoods.
Massachusetts Ave / N Rural St is a suburban neighborhood (based on population density) located in Indianapolis, Indiana.
Massachusetts Ave / N Rural St real estate is primarily made up of small (studio to two bedroom) to medium sized (three or four bedroom) single-family homes and townhomes. Most of the residential real estate is occupied by a mixture of owners and renters. Many of the residences in the Massachusetts Ave / N Rural St neighborhood are relatively historic, built no later than 1939, and in some cases, quite a bit earlier. A number of residences were also built between 1940 and 1969.
Vacant apartments or homes are a major fact of life in Massachusetts Ave / N Rural St. The current real estate vacancy rate here is 27.1%. This is higher than the rate of vacancies in 92.5% of all U.S. neighborhoods. In addition, most vacant housing here is vacant year round. This can sometimes be the case in neighborhoods dominated by new construction that is not yet occupied. But often neighborhoods with vacancy rates this high are places that can be plagued by a protracted vacancy problem. If you live here, you may find that a number of buildings in your neighborhood are actually empty.
Notable & Unique: Modes of Transportation
If your dream is to be able to ride your bike to work each day, look no further than this unique neighborhood. With 6.3% of residents in the Massachusetts Ave / N Rural St neighborhood commuting on a bicycle to and from work daily, this neighborhood has more bicycle commuters than 98.3% of all neighborhoods in the U.S., according to NeighborhoodScout's exclusive analysis.
One of the most interesting things about the Massachusetts Ave / N Rural St neighborhood is that it has a greater concentration of residents who live alone than most all neighborhoods in America. With 46.4% of the households here made up of people living alone, NeighborhoodScout's research reveals that this is a larger proportion of people living alone than in 95.1% of the neighborhoods in America.
In addition, according to NeighborhoodScout's research, Massachusetts Ave / N Rural St is better suited for first-time home buyers than 85.6% of neighborhoods in the state. Most homes here are priced below the state's median house value, yet maintain comparably good appreciation rates over the last decade relative to other neighborhoods in Indiana. Along with an exclusive multi-metric measure of neighborhood quality developed by NeighborhoodScout that scores high here in this neighborhood, this means that buying into the neighborhood is not only an accessible option but considered a decent first time home buyer choice for building equity in your first home, while being in a quality neighborhood
Do you watch 'This Old House' on Public Television? Do you love the idea of fixing up a Colonial or Victorian era home, complete with the charm of yesteryear? Do you like to stroll or drive streets lined with gracious older residences? If you found yourself nodding yes to any of these questions, you are going to be interested in this unique neighborhood. The Massachusetts Ave / N Rural St neighborhood stands out on a national scale for the sheer concentration of historic residences it contains: 73.2% of the residential real estate here was built from 1939 or earlier, some much earlier. This is a greater concentration of historic homes than 98.6% of the neighborhoods in the United States.
Significantly, 1.1% of its residents five years old and above primarily speak Greek at home. While this may seem like a small percentage, it is higher than 97.2% of the neighborhoods in America.
The neighbors in the Massachusetts Ave / N Rural St neighborhood in Indianapolis are low income, making it among the lowest income neighborhoods in America. NeighborhoodScout's research shows that this neighborhood has an income lower than 91.7% of U.S. neighborhoods. With 39.2% of the children here below the federal poverty line, this neighborhood has a higher rate of childhood poverty than 85.2% of U.S. neighborhoods.
The old saying "you are what you eat" is true. But it is also true that you are what you do for a living. The types of occupations your neighbors have shape their character, and together as a group, their collective occupations shape the culture of a place.
In the Massachusetts Ave / N Rural St neighborhood, 32.2% of the working population is employed in sales and service jobs, from major sales accounts, to working in fast food restaurants. The second most important occupational group in this neighborhood is executive, management, and professional occupations, with 31.4% of the residents employed. Other residents here are employed in manufacturing and laborer occupations (22.5%), and 13.9% in clerical, assistant, and tech support occupations.
The most common language spoken in the Massachusetts Ave / N Rural St neighborhood is English, spoken by 93.4% of households. Some people also speak Spanish (6.2%).
In the Massachusetts Ave / N Rural St neighborhood in Indianapolis, IN, residents most commonly identify their ethnicity or ancestry as German (12.8%). There are also a number of people of English ancestry (10.6%), and residents who report Irish roots (5.1%), and some of the residents are also of Mexican ancestry (4.4%), along with some French ancestry residents (2.7%), among others.
How you get to work – car, bus, train or other means – and how much of your day it takes to do so is a large quality of life and financial issue. Especially with gasoline prices rising and expected to continue doing so, the length and means of one's commute can be a financial burden. Some neighborhoods are physically located so that many residents have to drive in their own car, others are set up so many walk to work, or can take a train, bus, or bike. The greatest number of commuters in Massachusetts Ave / N Rural St neighborhood spend between 15 and 30 minutes commuting one-way to work (42.4% of working residents), which is shorter than the time spent commuting to work for most Americans.
Here most residents (73.6%) drive alone in a private automobile to get to work. In addition, quite a number also carpool with coworkers, friends, or neighbors to get to work (8.0%) and 7.0% of residents also ride the bus for their daily commute. In a neighborhood like this, as in most of the nation, many residents find owning a car useful for getting to work.
AGE OF Indianapolis, IN (Massachusetts Ave / N Rural St) HOMES
TYPE OF Indianapolis, IN (Massachusetts Ave / N Rural St) HOMES
SIZE OF Indianapolis, IN (Massachusetts Ave / N Rural St) HOMES
Employment Industries in Massachusetts Ave / N Rural St
in Massachusetts Ave / N Rural St
in Indianapolis
in Indiana
Indianapolis VIOLENT CRIMES
Indianapolis Property CRIMES
INDIANAPOLIS PUBLIC SCHOOLS
District Quality Compared to Indiana
Better than of IN school districts.
Indianapolis-Carmel-Anderson, IN Metro Area regional investment potential
Housing Affordability Trends: Indianapolis-Carmel-Anderson, IN Metro Area
Popular real estate near Massachusetts Ave / N Rural St
Carmel, IN (Northern Beach)
Indianapolis, IN (Broad Ripple)
Indianapolis, IN (Butler U / N Meridian St)
Indianapolis, IN (Central Ave / E 49th St)
Indianapolis, IN (E 54th St / N Meridian St)
Indianapolis, IN (Kessler Boulevard East Dr / E Westfield Blvd)
Indianapolis, IN (Shore Acres)
Indianapolis, IN (Traders Point)
Indianapolis, IN (W 56th St / Dandy Trl)
Meridian Hills, IN
89% Match ‐ Indianapolis, IN (Brookside Parkway South Dr / N Sherman Dr)
89% Match ‐ Indianapolis, IN (Fletcher Ave / Shelby St)
86% Match ‐ Indianapolis, IN (E 10th St / N Sherman Dr)
86% Match ‐ Indianapolis, IN (Prospect St / S State Ave)
85% Match ‐ Indianapolis, IN (Madison Ave / E Morris St)

redpajama_set_name: RedPajamaCommonCrawl


text:
Photo Credit: Facebook / Canadian Press
IndigiNews is fed up—and they have every right to be
Two hunters in Alberta were shot dead by strangers. Alberta's Superior Court just charged the killers with murder. But from a CBC headline, you'd swear the case was about something else.
CBC chose to focus on a text from the wife of one of the hunters. What was the text about, you ask? She was worried he'd been drinking. She didn't want him to drive. That's the kind of concern anyone would have about a loved one.
But what did CBC do with that information? They made it the main headline. They jumped straight for a stereotype.
Let's review the facts:
Two men were murdered. They happened to be Métis. They were murdered after they were celebrating.
The murderers assumed the two hunters were thieves. But they had zero evidence.
IndigiNews is a local news agency that focuses on VanIsle. And they're fed up. They're fed up because mainstream media uses Indigenous stereotypes instead of treating Indigenous people like people.
They published an open letter to CBC, and to mainstream media outlets that use racist coverage of Indigenous folks.
"Mainstream media has engaged in propaganda that has been used to normalize the genocide that this country capitalizes on," they say in the letter.
So the two hunters had a few beers that night. They'd just bagged a moose!
Did that mean they deserved to be murdered? Was drinking really the problem here?
"This headline serves as another reminder that major players in the journalism industry have not been listening, nor have they grown."
"It reminds us that our humanity is not valued as Indigenous people. This piece is beyond ignorance—it is racism."
IndigiNews
The Alberta Superior Court said the murderers took the law into their own hands. The hunters did nothing wrong.
So why did the headline focus on a wife's worried text about drinking?
The editors at IndigiNews say they don't often make big statements when media outlets use racism to get clicks. They normally send private emails to writers.
"It's what we call a 'calling in,' rather than a 'calling out,'" they said.
But in the face of the brutal murder of these two men, they say the CBC's article went too far.
"In the recent case of CBC Edmonton publishing a racist story with an equally egregious headline, we decided to use an Open Letter to address it."
This is not the first time mainstream media has been racist when reporting about murdered Indigenous people. In the open letter, IndigiNews brought up coverage of Tina Fontaine and Colten Boushie. Both of these young Indigenous people were murdered, and their cases were widely covered in the news.
They ended the heartfelt letter by saying, "Your ignorance is a part of our ongoing genocide and we are calling it out here and now."
We've had an inquiry about the thousands of murdered and missing Indigenous women in this country. Folks are finding hundreds of buried children around residential schools. You'd think the country's national broadcaster would be able to do better on this.
The CBC should not be the lens of racism in Canadian media.
It's now on the CBC to not say sorry, but to never do this again.
So far, CBC Edmonton and the Canadian Press haven't responded to the letter.
PrevPreviousIs There Really a "Witch Hunt" on Strathcona Regional Directors?
NextNorthIsle Hospital Closures Just Keep ComingNext
Drug Poisoning Overdose Warning
With drug decriminalization coming into play, more safety measures are needed
Hard Work From Unlikely Crew Helps Salmon To Thrive
The next restoration poster child.
"Baby Boy Shaw" Still Has No Official Name
At least according to our government
Wild Salmon Deserve Better
The Cohen Inquiry, recommended removing fish farming from DFO's oversight, but it never happened.
Chips ahoy! – 'Namgis Logging Chip Plant Fills First Barge
It's like turning logging waste into gold


One of the best puzzle games I've played. The puzzles are fantastic, but what really makes it cool is how you can take any spite/pixel art and turn it into an actual puzzle and it just works really well all because of the gaming mechanics. Here are a few I did. Scan these QR codes and check them out! They aslo work on the 3DS.


text:
The 1989 Utah Utes football team represented the University of Utah as a member of the Western Athletic Conference (WAC) during the 1989 NCAA Division I-A football season. In their fifth and final season under head coach Jim Fassel, the Utes compiled an overall record of 4–8 record with a mark of 2–6 against conference opponents, finished in seventh place in the WAC, and were outscored by their opponents 524 to 365. The team played home games at Robert Rice Stadium in Salt Lake City.

Utah's statistical leaders included Scott Mitchell with 3,211 passing yards, Clifton Smith with 681 rushing yards, and Dennis Smith with 1,091 receiving yards.

Schedule

Personnel

Season summary

at BYU

After the season

NFL Draft
One Utah player was selected in the 1990 NFL Draft.

References

Utah
Utah Utes football seasons
Utah Utes football

redpajama_set_name: RedPajamaWikipedia


text:
Q: jQuery: passing $(this) to named function event handler I note that it's recommended to use named functions when binding an event handler to a javascript event. How can I do this when my function needs to be passed the this object?
For example, how would I replace the anonymous function below by directly calling doFancyStuff:
$(document).on('change', 'input.fancy-textbox', function () {
    doFancyStuff($(this));
});

function doFancyStuff($textbox) {
    // fanciness
}

Extra points if you point out other conventions I might be breaking with the above code.

To clarify, I want to call the doFancyStuff() method in my example from multiple places, otherwise yes, I could just do something like this:
$(document).on('change', 'input.fancy-textbox', doFancyStuff);

function doFancyStuff() {
    var $textbox = $(this);

    // fanciness
}

A: Just pass the function as is:
$(document).on('change', 'input.fancy-textbox', doFancyStuff);

function doFancyStuff() {
    $(this).fancy(); // :-P
}

jQuery will automatically invoke your function with the proper context set.

As for other conventions you might be breaking: are you sure you need event delegation? If not, this would be much better:
$('input.fancy-textbox').on('change', doFancyStuff);

or you could even use the short-hand version:
$('input.fancy-textbox').change(doFancyStuff);

A: You will actually be able to use $(this) inside your method doFancyStuff if you define it as your event handler. The .on() method will set the context (this) accordingly:
$(document).on('change', 'input.fancy-textbox', doFancyStuff);

function doFancyStuff() {
    // 'this' will be the changed input.fancy-textbox
}

A: You have to change doFancyStuff to expect the same signature as your anonymous function. The way you've coded this, it looks like it expects a single parameter of a jQuery object, and ignores "this."  But the parameter of an event is something else (the event object) and "this" is the target. If you want to use a function as an event target, then it's got to expect the same data. So rewrite:
$(document).on('change', 'input.fancy-textbox', doFancyStuff);

function doFancyStuff(e) {
    var $textbox = $(this);
    // fanciness
}

A: I would say that's a matter of opinion.  I see no problem using an anonymous function here.  If this is the only place doFancyStuff is called, you could do this:
$(document).on('change', 'input.fancy-textbox', doFancyStuff);

function doFancyStuff() {
    // fanciness
    var $textbox = $(this)
}

However, if this function is called from multiple places and you can't change the way it works, you would have to do something like this:
$(document).on('change', 'input.fancy-textbox', doFancyStuffFromEvent);

function doFancyStuffFromEvent() {
    // fanciness
    doFancyStuff($(this));
}

function doFancyStuff($textbox) {
    // fanciness
}

Which is messy.

A: I use $.proxy to solve this issue:
$(document).on('change', 'input.fancy-textbox', $.proxy(doFancyStuff, myChoiceofThis);

function doFancyStuff(event) {

    // $el is the same as $(this) when using anonymous functions
    var $el = $(event.currentTarget);

    // me === myChoiceOfThis
    var me = this; // me === myChoiceOfThis
}

If doFancyStuffis an object method, then being able to give a reference such as myChoiceOfThis is very useful.

redpajama_set_name: RedPajamaStackExchange


Many thanks for stopping by our website.
Presently, you are reading the about us page. I'm not too sure what you are after by visiting this page since most web sites really have different uses with regards to the about us page. I'm going to use this page to inform you a little bit more about me and why I put this website together.
For me it is all about passion. I've got a passion for discussing subjects that are dear to me, ask anyone who knows me and they'll certainly concur with that.
The topics that I love to talk about will always be linked to everything and anything about computers. My connection with computers actually began in the days when the Commodore 64 was still very popular. I could claim that many of you have no idea anything concerning this, but it'll let you know about my age ever since I have been in this industry for so long as I could remember.
Through the years, I've been a Windows man simply because I like to tweak and tinker whatever I'm able to reach. Apple has always kept everything about their operating system a secret.
For quite some time, it has been an enjoyment for me to help folks master the computer, programming and coding. In the modern world the computer has grown to be a complete necessity and not an odd luxury reserved for geeks to play with.
I could state that my parents who are both in their 70s are a great example of how individuals have accepted this new technology.
It really amazed me how they were able to adapt to computer technology because they seek out question and answers on the internet, watch videos, do some photo editing and use emails and social to talk with our family members.
My son is already 10 years old and he was really comfortable in using computer technology for the last 3 to 4 years. It is really easy for him to use his phone, tablet or laptop to complete his homework, play games and watch videos.
I'm sure that today, you already get the whole explanation why I am attracted to computer technology and the other topics related to this. This is also among the reasons why I developed this blog. I also want to reach out to as many folks as feasible who also have the same passion. If I could be able to help individuals with their concerns, enjoyment and fascination on the world of computers, it would mean that my time is wisely spent on this website. If you need to know anything that is relevant to computer topics, you can me le know instantly. You could always drop an email or you could also leave a comment to my blog posts because I am always reading them.


The 2019 fees include a non-refundable $100 Enrolment Security Deposit required upon confirmation of a place (offset against Term 1 fees). The 4-year-old term fee in brackets is the reduced term fee applicable to eligible Concession Card Holders.
(payable with Term 1 fees) Refundable Maintenance Levy - $50 per family per year (3yo), $100 per family per year (4yo) refundable following attendance of TWO working bee.
You may be eligible for government Child Care Benefit (CCB) for the 3 and 4 year old programmes as Deepdene Preschool is a registered child care provider.
The Victorian Government provides per capita funding to support children to access a kindergarten program in the year before they start school. This funding is a contribution towards meeting the cost of our 4yo kindergarten program and is based on the number of children enrolled in the 4yo program at Deepdene Preschool. The preschool meets the balance of the costs of delivering the 4yo program through fees. Our 3yo program is not funded, and the preschool meets the whole of the costs of delivering the 3yo program through fees.
support of the Victorian Government.


text:
Q: Generate SessionId in WCF I want to generate a unique SessionId every time when the user Login. I have read various articles and found the below line useful
 var sessionId = OperationContext.Current.SessionId;

But still I am getting null in SessionId.
Please give me some useful way.


text:
Q: auto complete in jquery with different display text I am trying the following autocomplete logic. but its not working. my desired output is the display text and the value that is being sent should be different(example Cricket should be sent as cri.)
here is the markup:

Just Web Code (www.justwebcode.com)

 Enter any Sport Name: <input type="text" id="autocomplete" />

and the jquery is:
$(function(){

 var games = [
   { value: 'cricket', data: 'cri' },

   { value: 'chess', data: 'che' }
];

$("#autocomplete").autocomplete({
source: {games.value ;games.data}
});

});

A: Please check JQuery documentation for Autocomplete
It says, that source can be

An array of objects with label and value properties: [ {
  label: "Choice1", value: "value1" }, ... ]


text:
The Plant Based Eatery Gone Mobile
Find The J. Mobile!
Come see us at one of our many events this season! We will be at festivals, breweries, distilleries, and more. You can find a full calendar of events here!
About The J. Mobile
As the popularity of the plant-based restaurant, J. Selby's, has grown during its first year and a half, so too the number of customers pushing owner Matt Clayton to launch a food truck. In response, Clayton and team rolled out the J. Mobile, a 100-percent plant-based food truck, in August 2018.
"The J. Mobile is receiving the same enthusiastic response as our 100-percent plant-based food in the restaurant," Clayton said. "Though our menu on the truck differs from the fare offered at J. Selby's, what remains the same is our commitment to offering a delicious plant-based spin on familiar foods."
Impressed by her unique, creative flare, devotion to making food people want to eat, and her intense desire to master the food truck format, Clayton chose Diane Satriano to lead the J. Mobile. A J. Selby's line cook since the restaurant opened, Satriano is a veteran of the local restaurant scene.
"When it became clear to me that the time was right for the truck," Clayton said, "it was equally clear that Diane was just the person to put in charge. And ever since she began developing the menu, everyone on staff has been hungrily anticipating the rollout."
The J. Mobile was on hand at the 2018 Twin Cities Veg Fest in September. Stationed near J. Selby's annual chocolate chip cookie give away, the food truck enjoyed non-stop business as Satriano was joined by several members of the restaurant staff.
"Few things are better than feeding people and seeing them love it," said the J. Mobile's chef. "We kept making food, moving the line, and to receive so many compliments was very gratifying."
The plan for the J. Mobile includes two to three days of traditional street service with special events rounding out another two to three days per week.
"A food truck is meant to be out there finding a place alongside a curb somewhere, serving quick, quality, carry-away meals for folks," Satriano said. "To that end, we'll be hitting many of the same food truck spots in St. Paul and around the area. But in keeping with Matt's mission to bring delicious plant-based food to all, we will be available, for hire, year-round to serve all types of special events like weddings, birthdays, grad parties, you name it."
J.Selby's, founded by Matt Clayton and opened in 2017, is a restaurant offering customers 100-percent plant-based takes on American classics, like burgers, chili dogs, wings, desserts and more. J. Selby's is a part of The Plant Based Eater, Inc. and the J. Mobile is part of Mobile Vegan Foods LLC.
The J. Mobile


Gomez Carmenza. A peculiar bicycle linked to Carlos' character would become the instrument to mark history in a time when the craze for cycling and their idols began to write an unforgettable chapter in Colombia. For his successful portrayal in "Pharaoh", director Julio Cesar Luna gave him the opportunity to star alongside another promising actress, Amparo Grisales, in the soap opera "Your Heart Is Mine". From here, music would pave the way and help him make history on Colombian television.
Thanks to writer David Sanchez Juliao, Carlos Vives would move on to his first leading role. A funny love story of a boxer from Cartagena, Carlos Vives played the leading role of Gallito Ramirez alongside leading actress Margarita Rosa de Francisco The success of the soap opera and his character made him one of the hottest Latin exports in television in both the US and Puerto Rico.
From this moment on he directed his passion and talent to music. He recorded two ballad albums under Sony Music, and in 1987 was nominated for a Premio Lo Nuestro for "Breakthrough Artist". At the same time, he alternated his work in both worlds. In 1991 he returned to Caracol TV to star in a musical about the life and work of the famous vallenatocomposer Rafael Escalona, a role that would lead him to earn later that year the Simon Bolivar award for "Best Actor".
Carlos wowed crowds in America and Europe with the infectious beat of "Clásicos de La Provincia". He broke his own sales record (triple gold and triple platinum in 1993 and 1995) previously held by the Escalona soundtrack,and managed to reach the top of sales charts, making his mark in a musical arena dominated by local popular artists Emiliano Zuleta, Juancho Polo Valencia, Luis Enrique Martinez, and Carlos Huertas, among many others.
Meanwhile, he starred alongside Venezuelan actress Rudy Rodriguez in a story of the origins of the Republican era in which he played one of the first Creole patriots in the soapopera "The Double Woman."
In 1994 he undertook yet another project, and created a factory of ideas, characters, criticism, music, interviews, news, satire and humor that would impact Colombian television onc again. This time he would direct one of the first night shows in Colombian television, a show titled "La Tele".
triple platinum in 1996, and was labeled by critics as the most important album in the Colombian music industry in the last 50 years.
Then came "Tengo Fe", a multi-gold record in 1997.Moving forward, then came "Amor de Mi Tierra", GOLD + PLATINUM record in 1999 in the USA. In 2000, the album reached double platinum in Colombia and triple platinum in Spain (September 2000). In this album the song "Fruta Fresca" remained at #1 on Billboard Magazine – USA (1999/2000).
In the body of work that followed, he introduced electric guitars, bass and drums and rock to the traditional vallenato sound, a hitherto risky and undreamt fusion, and in turn, made a claim of popular lyric All this and more led to "El Rock de mi Pueblo". The risk proved to be worthy as the new album would move on to win a Latin Grammy for "Best Contemporary Tropical Album", and was nominated for "Best Tropical Song" ("Como Tu", November 3, 2005).
Carlos Vives magnifiedthe country's cultural heritage and opened the doors for a future generation of Colombians artists that have brought a new stream of local music and have become the new faces of Colombia around the world. He also gave a space to children's music by taking poems by popular author Rafael Pombo to another level. "Pombo Musical" would be awarded with a Latin Grammy in 2009 for "Best Children's Album."


If you need soft lenses for astigmatism, we have Acuvue Oasys for Astigmatism lenses in stock and ready for you. They're sold here in a six-pack for each eye at the low price of $40 per six-pack. If some other manufacturer's lens works better for you, you can be sure we'll provide you with an equally good value!


text:
Q: android code is crashing no errors hi to all can any one please tell me what is the problem from this logcat
once the app opens the image gallery to pick an image the app crashes
(what the code does: it opens the image gallery and loads the image as a wall paper then the user can ad an hair or a star ...etc to the image....)
thanks to all :)
E/dalvikvm(14530): Could not find class 'com.google.ads.AdView', referenced from method com.owleyes.moustache.Viewer.basicInit
W/dalvikvm(14530): threadid=1: thread exiting with uncaught exception (group=0x4001e578)
E/AndroidRuntime(14530): FATAL EXCEPTION: main
E/AndroidRuntime(14530): java.lang.VerifyError: com.owleyes.moustache.Viewer
E/AndroidRuntime(14530):    at java.lang.Class.newInstanceImpl(Native Method)
E/AndroidRuntime(14530):    at java.lang.Class.newInstance(Class.java:1409)
E/AndroidRuntime(14530):    at android.app.Instrumentation.newActivity(Instrumentation.java:1024)
E/AndroidRuntime(14530):    at android.app.ActivityThread.performLaunchActivity(ActivityThread.java:1565)
E/AndroidRuntime(14530):    at android.app.ActivityThread.handleLaunchActivity(ActivityThread.java:1667)
E/AndroidRuntime(14530):    at android.app.ActivityThread.access$1500(ActivityThread.java:117)
E/AndroidRuntime(14530):    at android.app.ActivityThread$H.handleMessage(ActivityThread.java:935)
E/AndroidRuntime(14530):    at android.os.Handler.dispatchMessage(Handler.java:99)
E/AndroidRuntime(14530):    at android.os.Looper.loop(Looper.java:130)
E/AndroidRuntime(14530):    at android.app.ActivityThread.main(ActivityThread.java:3691)
E/AndroidRuntime(14530):    at java.lang.reflect.Method.invokeNative(Native Method)
E/AndroidRuntime(14530):    at java.lang.reflect.Method.invoke(Method.java:507)
E/AndroidRuntime(14530):    at com.android.internal.os.ZygoteInit$MethodAndArgsCaller.run(ZygoteInit.java:912)
E/AndroidRuntime(14530):    at com.android.internal.os.ZygoteInit.main(ZygoteInit.java:670)
E/AndroidRuntime(14530):    at dalvik.system.NativeStart.main(Native Method)
I/dalvikvm(14530): threadid=4: reacting to signal 3
I/dalvikvm(14530): Wrote stack traces to '/data/anr/traces.txt'

A: In your method com.owleyes.moustache.Viewer.basicInit you're referencing com.google.ads.AdView. You are probably missing a library in the libs folder.
Without posting more of your code no one is going to really be able to help you any more than that.

A: GoogleAdMobsAdsSDK is not attached to your project or it is attached in the wrong way. The easiest way to solve this problem is to copy the library to libs folder.
There is already topic on SO that concerns similar issue. Check this out for more info:
java.lang.NoClassDefFoundError: com.google.ads.AdView

A: In the Java Build Path, click the Export & Order tab to see if that jar file is checked. Make sure it is checked so the Admob jar file is packaged in the APK file.


text:
Lasciate fiorire i carciofi
Paola Ricci Taste Archaeologist©
Disegno poetico
Arte & Opere
Suono & Musica
Il doratore dell'isola
Archeologia dell'Ingrediente
Archeologia dell'alimento
Ricetta dello Chef
Arte di scrivere
Concept & Video
Scrittura, Viaggi
Published on 27 Marzo 2017
Il giorno più lungo / Arnie Hung II
written by Paola Ricci
I personaggi si dispongono lungo diverse traiettorie e si incrociano tra loro nella città che non si muove, ma aspetta che le persone nei diversi luoghi partano per andare, apparentemente, insieme.
Cosa è la solitudine ? Una dimensione mentale o una condizione fisica?
Queste persone parlano vivendo entrambe le dimensioni della solitudine, sia il corpo che si isola e poi anche la mente che si nega, quello che li unisce sono i dialoghi del silenzio, le pause che stanno in mezzo che danno il respiro e danno la motivazione del dubbio, di quello che stanno veramente vivendo è perchè lo vogliono o se lo sono imposto?
"But . . . ."
"OK then, I'll delay things with the owner, and you can think about it for a few days, OK?"
It was probably not something that could be fixed in a few days, but she was unable to admit to this. Mr. Ye was a conscientious intermediary, but now his diligence made her feel trapped and annoyed. If things went well, then it would be the next day. But if things were slower, then it needed several months, and she did not know how long. But when she saw the happy couple raising their heads to peer over at her and she caught their look, she immediately changed her mind and said, "OK, I'll think about it for a while."
Taipei, Arnie Hung©Photo
She hesitated. Basically, which one?
When she reached the cake shop, she stood bemused in front of all the cakes so beautifully decorated, uncertain which one was right. Was black forest gateau wrong? What about chiffon? Or cheesecake? Maybe tiramisu?
But who could decide who was right and who was not? In life, lots of things had no reason, and she had never been given any choice. From the fridge in the kitchen inside, the shop assistant brought out a cake that was already wrapped up. It had always been this flavor and this size, and they always had the same surprise party. It was just a formality, and nobody cared about it.
Soon it would be two o'clock. By now, the office must have noticed that she had gone out and not come back. The party was arranged for four o'clock, but she still could not face going back. In a spirit of rebelliousness, she carried the cake and strolled along the road.
She had tried several times to call the helpline, but it was always busy. She reckoned she must have remembered the number wrongly. But she did not want to go back to the office just yet, so she walked into the toy section of a nearby department store and chose the Dora doll that Xin-xin had always wanted. It was almost two thousand dollars, the amount the three of them spent on food over three days.
When she reached the nursery, the children were playing a game, and several chairs in the classroom were arranged in a circle. The children were singing along to some music while they walked around the chairs holding the shoulder of the person in front. The song was lively and cute, and they were singing happily, unable to predict when the music would stop. They were just singing.
She saw her daughter in their midst. But focused as she was on the game, Xin-xin didn't see her. She was truly moved by this scene. This nursery was the only place her daughter could make friends. She was just five. How could she leave her all day with her grandma, to do the grocery shopping and watch television?
Disegno di Arnie Hung©Photo
The game was still continuing. Several times the music suddenly stopped, and then one child who did not get a seat had to leave the group. The circle became smaller and smaller, but Xin-xin was still in the game. She was always good at sports, and even when there were just three chairs left, her movements continued to be agile.
Just as she was pondering over this, the teacher blew a whistle and the music stopped. Xin-xin ran to a chair and was about to sit down, but another child pushed her away and grabbed the seat, causing her to lose her balance and fall down on the soft mats. Then she knelt down in the middle of the classroom in front of everyone.
The teacher rushed forward and helped Xin-xin up, and another teacher came over to her mother and explained, "When the children are playing, you can't avoid a bit of pushing and shoving. But the covering on the floor is soft, so they don't get hurt. There's no need for you mothers to worry."
The game continued, and the sound of joy rose up. Just three children were left in the circle, none of whom she recognized. Only two chairs remained, and she suddenly felt that this game was actually rather cruel.
The teacher tried to lead Xin-xin over, but she pushed the teacher's hand away and angrily demanded, "Teacher, he pushed me. How come he can continue in the game?"
The teacher consoled her, saying, "Because you didn't sit down on the chair."
When her mother went over and took her hand, Xin-xin looked a bit surprised, but that did not stop her turning round and glaring at the teacher. Her mother also thought that the teacher had not been fair. But anyway, it was just a game. She tried to lead her daughter away, but Xin-xin truculuantly sat on the floor and would not move. She rarely behaved like this, and even when she saw some toy that she really wanted, she was not usually that stroppy. When her mother tried to take her hand, she looked back stubbornly, her cheeks puffed up in anger.
"What's the matter? Aren't you happy your mum has come to see you?"
"It's not fair!"
"It's just a game."
Xin-xin raised her head to look at her, and with a questioning look, she said, "Ma, aren't you always saying we must look after ourselves, and we should never let anyone push us around?"
Suddenly there was nothing she could say. Xin-xin picked herself up and went over to the circle. The music continued as she stood in front of the boy who had just pushed her over. The whole circle froze and everyone looked at her.
"Say you're sorry."
The happy music continued, but nobody was laughing any more. All the children were looking at the two of them. The teacher went over to get the boy to apologize, and in the end he lowered his head and said, "Sorry."
The game was over. She led Xin-xin out into the playground of the nursery. They sat down to have something to drink, and she took the opportunity to hand over the doll she had just bought.
"Wah! A Dora doll! Didn't you say we couldn't afford it?"
"Never mind. Don't you like it, Xin-xin?"
"Then you must be good. This evening, Mummy will come and collect you, and we'll go out for something good to eat."
She looked at her watch. It was ten past three.
"OK. I need to go back to work. Please don't fight with the other children."
Xin-xin nodded her head. "I wasn't fighting with them. I just thought I didn't do anything wrong."
I didn't do anything wrong! That's exactly what she herself wanted to shout out.
She needed to do everything really carefully to ensure nobody found out.
In a taxi, she brought back home three rather heavy cardboard boxes. Although her mother should be at home, she couldn't ask her to help. When she got them in, at first she left them by the door, while she planned how to move them one by one to the rooftop.
Xin-xin was about to finish at school, so she had to act quickly.
The setting sun was already too low to shine onto the stairs, so she turned on the lights. When she lifted the boxes, she wedged them against her stomach, and then one by one she carried them up to the rooftop on the fifth floor. Worried about making a noise, she moved slowly and carefully, like a snail, letting her sweat soak through her clothes. While she was doing this moving, one of her neighbors came out, and seeing how hard it was for her to lift the things, asked if she needed any help.
"There's no need. It's just a few household things I don't need."
"Oh! So you're taking them up to the rooftop?"
"Hmm. I'll put them there for the time being. In a couple of days, I'll get the junk collector to take them away."
"It's going to rain tomorrow. Don't let them get wet."
"I know. Thanks."
Taipei Arnie Hung©Photo
The neighbor went down, leaving her to deal with the heavy cardboard boxes on her own. After more than half an hour, she finally finished moving them all. The sky was already completely overcast. Her whole body was aching by the time she came downstairs and reached the door to her apartment. She wanted to go in, have a shower, and change into clean clothes, but remembering that her mother was at home, she held back.
Standing outside the door of the apartment, she called, telling her mother she would take Xin-xin out for a meal that evening so they wouldn't be back for dinner. Not caring about the smell from the sweat covering her body, she caught a bus. When she got off the bus, on the way to the nursery, she called the lifeline once more. It seemed she was unable to accept things like that and just give up. This time, unexpectedly she got through. She heard the welcome ringing sound, once, twice, but then in her shock she cut it off.
Wouldn't it be better if the line were always busy? That way, she could call again later, and maybe the next day as well. Or perhaps just today, her final day at work. It seemed like she preferred waiting for an answer but actually not getting one.
Her daughter was already waiting for her by the entrance to the nursery, and a teacher was with her.
"Sorry I'm late. I was held up at work."
"It doesn't matter. She was alone, so I stayed with her. I'll go now."
Xin-xin was holding the Dora doll tightly in her hand. Her mother asked her what she wanted to eat. She said anything would be fine. The two of them took a taxi to a department store. This was the third time she had taken a taxi that day, and she regretted that, but never mind, it was only for that day.
They walked into a western-style restaurant offering a buffet, the kind of place her daughter had never been to before. There was a whole spread of food on the table, including sumptuous vegetables and countless ice-creams and deserts, and next to it was a structure with a constant stream of chocolate emerging from the top, a sight that made Xin-xin gasp in delight.
"Mum, can we eat all these things?"
"Yes, as much as you want."
Xin-xin happily walked to and fro in front of the food, gazing at the steaks here and deserts there. In the past she would have stopped Xin-xin eating too much junk food, but today was different.
"Is today Mummy's birthday? Or . . . is it Children's Day? Hmm . . . maybe Christmas?"
"None of those."
"Mummy, why aren't you eating?"
Of course, she knew that this was a buffet and that she was paying for two people even if she did not eat. What's more, she had not eaten such splendid food for so many years. But she simply had no appetite.
She forced herself to go and get a cup of coffee, waiting for Xin-xin to try as much food as she wanted.
"Are you already full?"
"Delicious. It's a pity grandma couldn't come."
She laughed but did not answer. She did not know how to make it up to her mother. But if her mother had come this time, then she would have found out about everything.
Had anyone in the office noticed her absence?
When she reached her office building, still carrying the cake, she turned round and left, as she had thought of one place where she wouldn't be rejected.
The idea had suddenly come to her: in this world there was only one person who had never turned away from her – her ex-boyfriend. When they were together, no matter how silly the demand she made of him, he would always do it. In front of him, she had total authority, and it seemed there was nothing he would say no to. After three years together, she felt he was just too weak, never willing to say no to a woman, even though the person she was talking about was herself. Many times she felt it was not real love, as he was simply her slave. Especially when, as soon as he heard that she was pregnant, he suggested that, following the instruction of his mother, they should get married. She wanted to test his limits, just one time to see him get angry and shout at her, or look sad and cry out bitterly, or merely to show some bitterness and sigh with a groan, like the way she felt now. She just hoped he might express the usual range of emotions of a normal human being. But when she showed him her six month pregnant belly and deliberately provoked him by suggesting they should separate, after a slight suggestion of annoyance, he thought for a moment, then nodded and said, "Okay. I respect your decision."
She had no way out. Her partner collected his clothes and other things and left as if nothing had happened. It seemed like everything he had agreed to do was just out of obedience to her.
Five years. So many times she had woken up during the night, lonely and hopeless, wanting to telephone him. Maybe he would be willing to come and be with her, or at least listen to her. But she never did it, and she was worried that if he agreed, she would once again come to despise him.
But now it was herself she did not respect.
It was simply impossible for her to accept anything bad that happened to her, and as soon as something bad did occur, she would lean against her partner's chest so as not to be rejected. She wished someone would reassure her, "It'll all be fine."
Paola Ricci©Photo
The alternatives were to despise herself or to have nowhere to turn. She selected the first option.
Still clutching the cake, she caught a taxi. Seeing as she had decided to go ahead with it, she did not worry about saving money by taking a 15-NT dollar bus journey. She gave the address of his office, as she guessed he would still be working in the same place. She sat in the visitors' room. The receptionist asked what her purpose was, and she pointed to the cake and said the person had done her a favor and she was bringing a token of appreciation in the hope of directly expressing her gratitude.
Her emotions were turbulent. Had he changed after all those years? Did he still miss her? Was he now married?
Translated by David and Ellen DETERDING 戴德巍、陳艷玲
Taipei, Arnie Hung
Filed under: Scrittura, Viaggi
Tagged with: Body Frame, Cibo, Il viaggio della pantera, Senso, Silenzio
by Paola Ricci
"lasciate nel sole questo brillare di stelle, come libere parole donate la luce, accompagnatele dove loro vogliono andare / let the dazzling stars shine, like words, to accompany them wherever they choose to go"
Previous PostLa contemplazione / IV
Next PostIl collage scultoreo / Annette Messager
Ascoltare lo spazio Body Frame Cibo Colore Cucina Dondolandosi su fili di ragnatela Entropia Fluttuare Fotografia gusto Il doratore dell'isola Il mio letto è una nave Il viaggio della pantera Inspirazione Interior Place Intra-vedere Ispirazione L'ombra intatta Natura Senso Silenzio suono Take heart Trasparenza
Archeologia dell'alimento
Il doratore dell'isola
Copyright © 2020 Paola Ricci Taste Archaeologist©.
Theme: Zuki by Elmastudio.