METHODS: Mice were initiated with single dose of 7,12-dimethylbenz[α]anthracene (DMBA) (390 nmol/100 μL) followed by, in subsequent week, repeated promotion (twice weekly; 22 weeks) with 12-O-tetradecanoylphorbol-13-acetate (TPA) (1.7 nmol/100 μL). Annonacin (85 nM) and curcumin (10 mg/kg; reference) were, respectively, applied topically to DMBA/TPA-induced mice 30 min before each TPA application for 22 weeks. Upon termination, histopathological examination of skin, liver and kidney as well as genes and proteins expression analysis were conducted to elucidate the potential mechanism of annonacin.
RESULTS: With comparison to the carcinogen control, Annonacin significantly increased the tumor latency period and reduced the tumor incidence, tumor burden and tumor volume, respectively. In addition, it also suppressed tumorigenesis manifested by significant reduction of hyperkeratosis, dermal papillae and number of keratin pearls on skin tissues. Annonacin also appeared to be non-toxic to liver and kidney. Significant modulation of both AKT, ERK, mTOR, p38, PTEN and Src genes and proteins were also observed in annonacin-targeted signaling pathway(s) against tumorigenesis.
CONCLUSIONS: Collectively, results of this study indicate that annonacin is a potential therapeutic compound targeting tumor promoting stage in skin tumorigenesis by modulating multiple gene and protein in cancer signaling pathways without apparent toxicity.
METHODS: A retrospective review of all paediatric systemic lupus erythematosus patients with at least 6 months follow-up at Selayang Hospital from 2004 to 2016. Epidemiological, clinical and outcome data were collected and analysed.
RESULTS: A total of 141 paediatric systemic lupus erythematosus patients, 87.9% females, were followed up for a median 6.3 years (interquartile range 3.6-9.0). The median age at diagnosis was 10.8 years (interquartile range 9.0-12.0 years), positive family history of systemic lupus erythematosus was present in 12.1% and the majority (61.7%) were of Malay ethnicity. Common presentations included fever (87.2%), vasculitic rash (72.3%) and lethargy (69.5%). At diagnosis, leukopenia (51.1%), thrombocytopenia (41.8%) and cutaneous lupus (56%) predominate with significant renal involvement (39.7%). Renal (45.4%), liver (26%) and the central nervous system (17%) were important major organs involved during the course of the disease. At diagnosis, almost all (99.3%) patients had high disease activity (mean Systemic Lupus Erythematosus Disease Activity Index score 20.1 ± 9.6). The majority (62.4%) achieved remission or low disease activity after 6 months, maintained over the next 10 years. Damage occurred early (39.1% at 1 year) and increased with time. Ocular damage was the most common side effect (29%) and was predominantly corticosteroid related (93%). Growth retardation was significant (38.2%) with no gonadal failure or secondary malignancies. End-stage renal disease occurred in 3.1% patients whereas 53.1% had sustained renal remission. Overall mortality was 1.4%.
CONCLUSION: Despite high disease activity at diagnosis, the majority had good sustained response to treatment with low overall mortality. However, there was progressive accrual of organ damage, highlighting the need for further research and refinements into therapies for paediatric systemic lupus erythematosus.
METHODS: This study was a quasi-experimental with posttestonly control group design. Twenty-five adult male Swiss Webster mice were randomly divided into five groups: shamoperated group (SO), UUO-control day-7 (U7), UUO-control day-14 (U14), UUO-chlorogenic acid day-7 (UC7), and UUOchlorogenic acid day 14 (UC14). Myofibroblasts were identified by immunohistochemical staining of alphasmooth muscle actin (α-SMA) while collagen fibers were identified by Sirius Red staining. Both data were presented as area fraction. BMP-7 and HGF mRNA expressions were assessed by reverse transcription PCR (RT-PCR). Data were quantified using ImageJ software.
RESULTS: UUO-control groups (U7 and U14) showed higher α- SMA-immunopositive (6.52±1.33, 18.24±1.39 vs. 0.22±0.01; p<0.05) and Sirius Red-positive area fractions (6.61±0.8, 12.98±2.31 vs. 0.62±0.10; p<0.05), lower BMP-7 (1.02±0.47, 1.18±0.65 vs. 2.09±0.87; p<0.05) and HGF mRNA expressions (1.06±0.31, 0.89±0.14 vs. 1.88±0.81; p<0.05) compared to SO group. UUO-chlorogenic acid groups (UC7 and UC14) showed lower α-SMA-immunopositive (1.24±0.37, 4.58±0.61; p<0.05) and Sirius Red-positive area fractions (4.76±1.03, 3.72±0.54; p<0.05), higher BMP-7 (1.84±0.49, 2.19±0.43; p<0.05) and HGF (1.58±0.38; p>0.05, 1.84±0.42; p<0.05) mRNA expressions compared to UUO-control groups. UUOchlorogenic acid groups showed BMP-7 and HGF mRNA expressions that were not significantly different from the SO group.
CONCLUSION: Chlorogenic acid administration prevents kidney fibrosis in UUO mice model through modulating antifibrotic pathway.
METHODS: This retrospective study was performed on all KTRs ≥18 years of age at our center from January 1, 2006 to December 31, 2015, who were prescribed diltiazem as tacrolimus-sparing agent. Blood tacrolimus trough level (TacC0) and other relevant clinical data for 70 eligible KTRs were reviewed.
RESULTS: The dose of 1 mg tacrolimus resulted in a median TacC0 of 0.83 ± 0.52 ng/mL. With the introduction of a 90-mg/d dose diltiazem, there was a significant TacC0 increase to 1.39 ± 1.31 ng/mL/mg tacrolimus (P < .01). A further 90-mg increase in diltiazem to 180 mg/d resulted in a further increase of TacC0 to 1.66 ± 2.58 ng/mL/mg tacrolimus (P = .01). After this, despite a progressive increment of every 90-mg/d dose diltiazem to 270 mg/d and 360 mg/d, there was no further increment in TacC0 (1.44 ± 1.15 ng/mL/mg tacrolimus and 1.24 ± 0.94 ng/mL/mg tacrolimus, respectively [P < .01]). Addition of 180 mg/d diltiazem reduced the required tacrolimus dose to 4 mg/d, resulting in a cost-savings of USD 2045.92 per year (per patient) at our center. Adverse effects reported within 3 months of diltiazem introduction were bradycardia (1.4%) and postural hypotension (1.4%), which resolved after diltiazem dose reduction.
CONCLUSION: Coadministration of tacrolimus and diltiazem in KTRs appeared to be safe and resulted in a TacC0 increment until reaching a 180-mg/d total diltiazem dose, at which point it began to decrease. This approach will result in a marked savings in immunosuppression costs among KTRs in Malaysia.
Objective: To examine the long-term effects of lipid-lowering therapy on all-cause mortality, cardiovascular morbidity, CKD progression, and socioeconomic well-being in Australian, New Zealand, and Malaysian SHARP (Study of Heart and Renal Protection) trial participants-a randomized controlled trial of a combination of simvastatin and ezetimibe, compared with placebo, for the reduction of cardiovascular events in moderate to severe CKD.
Design: Protocol for an extended prospective observational follow-up.
Setting: Australian, New Zealand, and Malaysian participating centers in patients with advanced CKD.
Patients: All SHARP trial participants alive at the final study visit.
Measurements: Primary outcomes were measured by participant self-report and verified by hospital administrative data. In addition, secondary outcomes were measured using a validated study questionnaire of health-related quality of life, a 56-item economic survey.
Methods: Participants were followed up with alternating face-to-face visits and telephone calls on a 6-monthly basis until 5 years following their final SHARP Study visit. In addition, there were 6-monthly follow-up telephone calls in between these visits. Data linkage to health registries in Australia, New Zealand, and Malaysia was also performed.
Results: The SHARP-Extended Review (SHARP-ER) cohort comprised 1136 SHARP participants with a median of 4.6 years of follow-up. Compared with all SHARP participants who originally participated in the Australian, New Zealand, and Malaysian regions, the SHARP-ER participants were younger (57.2 [48.3-66.4] vs 60.5 [50.3-70.7] years) with a lower proportion of men (61.5% vs 62.8%). There were a lower proportion of participants with hypertension (83.7% vs 85.0%) and diabetes (20.0% vs 23.5%).
Limitations: As a long-term follow-up study, the surviving cohort of SHARP-ER is a selected group of the original study participants, which may limit the generalizability of the findings.
Conclusion: The SHARP-ER study will contribute important evidence on the long-term outcomes of cholesterol-lowering therapy in patients with advanced CKD with a total of 10 years of follow-up. Novel analyses of the socioeconomic impact of CKD over time will guide resource allocation.
Trial Registration: The SHARP trial was registered at ClinicalTrials.gov NCT00125593 and ISRCTN 54137607.
METHODS: This study was performed using data from a large multinational prospective cohort. Active lupus nephritis at any visit was defined by the presence of urinary casts, proteinuria, haematuria or pyuria, as indicated by the cut-offs in the SLE Disease Activity Index (SLEDAI)-2K, collected at each visit. Organ damage accrual was defined as a change of SLICC-ACR Damage Index (SDI) score >0 units between baseline and final annual visits. Renal damage accrual was defined if there was new damage recorded in renal SDI domains (estimated glomerular filtration rate <50%/proteinuria >3.5 g per 24 h/end-stage kidney disease). Time-dependent hazard regression analyses were used to examine the associations between active lupus nephritis and damage accrual.
RESULTS: Patients (N = 1735) were studied during 12,717 visits for a median (inter-quartile range) follow-up period of 795 (532, 1087) days. Forty per cent of patients had evidence of active lupus nephritis at least once during the study period, and active lupus nephritis was observed in 3030 (24%) visits. Forty-eight per cent of patients had organ damage at baseline and 14% accrued organ damage. Patients with active lupus nephritis were 52% more likely to accrue any organ damage compared with those without active lupus nephritis (adjusted hazard ratio = 1.52 (95% confidence interval (CI): 1.16, 1.97), p
METHODS: In 567 adult participants planned for AVF creation, all were randomised to fish oil (4g/d) or placebo, and 406 to aspirin (100mg/d) or placebo, starting one day pre-surgery and continued for three months. Outcomes evaluated within 12 months included AVF intervention rates, CVC exposure, late dialysis suitability failure, and times to primary patency loss, abandonment and successful cannulation.
RESULTS: Final analyses included 536 participants randomised to fish oil or placebo (mean age 55 years, 64% male, 45% diabetic) and 388 randomised to aspirin or placebo. Compared with placebo, fish oil reduced intervention rates (0.82 vs 1.14/1000 patient-days, incidence rate ratio [IRR] 0.72, 95% confidence interval [CI] 0.54-0.97), particularly interventions for acute thrombosis (0.09 vs 0.17/1000 patient-days, IRR 0.53, 95% CI 0.34-0.84). Aspirin significantly reduced rescue intervention rates (IRR 0.45, 95% CI 0.27-0.78). Neither agent significantly affected CVC exposure, late dialysis suitability failure or time to primary patency loss, AVF abandonment or successful cannulation.
CONCLUSION: Although fish oil and low-dose aspirin given for 3 months reduced intervention rates in newly created AVF, they had no significant effects on CVC exposure, AVF usability and time to primary patency loss or access abandonment. Reduction in access interventions benefits patients, reduces costs and warrants further study.
METHODS AND ANALYSIS: The study is an open-label randomised controlled trial. A total of 434 patients with end-stage renal disease undergoing CAPD will be enrolled and randomised to either the intervention group, Stay Safe Link, or the control group, Stay Safe. All study subjects will be followed up and monitored for 1 year. The primary safety outcome is the rate of peritonitis while the primary efficacy outcomes are the delivered dialysis dose and ultrafiltration volume.
ETHICS AND DISSEMINATION: The study was approved by the Medical Research Ethics Committee, National Institute of Health Malaysia. A written informed consent will be obtained from all participating subjects prior to any trial-related procedure and the study conduct will adhere strictly to Good Clinical Practice. The findings will be disseminated in a peer-reviewed journal.
TRIAL REGISTRATION NUMBER: NCT03177031; Pre-results.
METHODS: Pressurized hot water extraction P. tenellus was carried out and standardized to 7.9% hydrosable tannins. In vitro toxicity of the extract was tested on NIH 3 T3 cell by MTT assay. The cellular antioxidant level was quantified by measuring cellular level of glutathione. Oral sub-chronic toxicity (200, 1000 and 3000 mg/kg body weight) of P. tenellus extract were evaluated on healthy mice. Liver and kidney antioxidant level was quantified by measuring levels of Ferric Reducing Antioxidant Potential (FRAP), superoxide dismutase, glutathione.
RESULTS: The P. tenellus extract did not induce cytotoxicity on murine NIH 3 T3 cells up to 200 μg/mL for 48 h. Besides, level of glutathione was higher in the extract treated NIH 3 T3 cells. P. tenellus extract did not cause mortality at all tested concentration. When treated with 1000 mg/kg of the extract, serum liver enzymes (ALP and ALT) and LDH were lower than normal control and mice treated with 200 mg/kg of extract. Moreover, SOD, FRAP and glutathione levels of liver of the mice treated with 200 and 1000 mg/kg of extract were higher than the normal control mice. On the other hand, when treated with 3000 mg/kg of extract, serum liver enzymes (ALP and ALT) and LDH were higher than normal mice without changing the liver SOD and glutathione level, which may contribute to the histological sign of ballooning hepatocyte.
CONCLUSION: P. tenellus extract standardized with 7.9% hydrosable tannins and their catabolites increased the antioxidant levels while reducing the nitric oxide levels in both liver and kidney without causing any acute and sub-chronic toxicity in the mice.