Discovery of phthalimide derivatives as novel inhibitors of a soluble epoxide hydrolase

Soluble epoxide hydrolase (sEH) inhibitors are effective in reducing blood pressure, inflammation, and pain in a number of mammalian disease models. As most classical urea-based sEH inhibitors suffer from poor solubility and pharmacokinetic properties, the development of novel sEH inhibitors with an improved pharmacokinetic specification has received a great deal of attention. In this study, a series of amide-based sEH inhibitors bearing a phthalimide ring as the novel secondary pharmacophore (P₂) was designed, synthesized, and evaluated. Docking results illustrated that the amide group as the primary pharmacophore (P₁) was placed at a suitable distance from the three key amino acids (Tyr383, Tyr466, and Asp335) for an effective hydrogen bonding. In agreement with these findings, most of the newly synthesized compounds demonstrated moderate to high sEH inhibitory activities, relative to 12-(3-adamantan-1-yl-ureido)dodecanoic acid as the reference standard. Compound 12e with a 4-methoxybenzoyl substituent exhibited the highest sEH inhibitory activity, with an IC₅₀ value of 1.06 nM. Moreover, the ADME properties of the compounds were evaluated in silico, and the results revealed appropriate predictions.     

The effects of low-level laser irradiation on breast tumor in mice and the expression of Let-7a,miR-155, miR-21, miR125, and miR376b

Low-level laser therapy (LLLT) is a form of photon therapy which can be a non-invasive therapeutic procedure in cancer therapy using low-intensity light in the range of 450–800 nm. One of the main functional features of laser therapy is the photobiostimulation effects of low-level lasers on various biological systems including altering DNA synthesis and modifying gene expression, and stopping cellular proliferation. This study investigated the effects of LLLT on mice mammary tumor and the expression of Let-7a, miR155, miR21, miR125, and miR376b in the plasma and tumor samples. Sixteen mice were equally divided into four groups including control, and blue, green, and red lasers at wavelengths of 405, 532, and 632 nm, respectively. Weber Medical Applied Laser irradiation was carried out with a low power of 1–3 mW and a series of 10 treatments at three times a week after tumor establishment. Tumor volume was weekly measured by a digital vernier caliper, and qRT-PCR assays were performed to accomplish the study. Depending on the number of groups and the p value of the Kolmogorov-Smirnov test of normality, a t test, a one-way ANOVA, or a non-parametric test was used for data analyses, and p?<?0.05 was considered to be statistically significant. The average tumor volume was significantly less in the treated blue group than the control group on at days 21, 28, and 35 after cancerous cell injection. Our data also showed an increase of Let-7a and miR125a expression and a decrease of miR155, miR21, and miR376b expression after LLLT with the blue laser both the plasma and tumor samples compared to other groups. It seems that the non-invasive nature of laser bio-stimulation can make LLLT an attractive alternative therapeutic tool.     

Telephone and face-to-face consultation in breast cancer diagnosis: a comparative study

OBJECTIVE: This study compares telephone consultations with the results of clinical examinations to assess the value and accuracy of telephone consultations for the future planning in a breast cancer clinic in Tehran, Iran. METHODS: In 2500 telephone calls, 800 Symptomatic patients were identified and asked to visit the center for the further investigations by the specialists. The agreement between two observers data were compared by the kappa statistic. RESULTS: Totally 174 patients complied with the recommendation and included in the study. The most common chief complaints of visitors were: breast mass (42%) and breast pain (35%). Kappa statistic showed a very good agreement (K=0.62, P<0.001) between consultants' diagnosis and the specialists findings. This agreement for breast cancer diagnosis, although lower, was also good (K=0.55, P<0.001). CONCLUSION: The study findings indicate that consultants may diagnose and manage some common conditions via telephone, usually following the established protocols. More studies are needed to determine the economic and logistic advantages of telephone consultations. PRACTICE IMPLICATIONS: By assessment of strength and weakness of this service, it is possible to develop an easy to use information system for women who need breast care.     

Acceptance of evidence based medicine (EBM) databases by Iranian medical residents using unified theory of acceptance and use of technology (UTAUT)

Objective

Physicians often need uptodate, reliable and with easy access information for clinical decisions evidence based medicine (EBM) databases can be a suitable approach to meet this need. The aim of this study was to assess the knowledge, use and factors affecting the acceptance of EBM and its databases by Iranian medical residents using UTAUT model.

Effects of alpha lipoic acid supplementation on serum levels of IL-8 and TNF-α in patient with ESRD undergoing hemodialysis

Background

Chronic renal failure is a progressive and irreversible loss of kidney function, and the hemodialysis (HD) is one of the most common modalities in this regard. Oxidative stresses [like interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α)] and inflammation are the main risk factors associated with cardiovascular diseases and other complications in many organs in hemodialysis patients; meanwhile, antioxidants like alpha lipoic acid (ALA) may reduce the oxidative stress markers and the levels of inflammatory cytokines, so can improve of the patient’s quality of life.

Methods

In this randomized clinical trial study, 60 HD patients were randomly categorized in two case and control groups. Case group received a daily capsule of 600 mg of ALA supplementation for 8 weeks, and the control group received placebo capsules daily. The serum level of IL-8 and TNF-α was measured in both groups before and after the intervention.

Results

There were no significant differences in age, gender, duration of dialysis, and causative factor for dialysis between both groups (P > 0.05). The mean of IL-8 and TNF-α after the intervention in case group was 26.20 ± 15.34 and 21.25 ± 9.61, respectively; the difference between both groups was not statistically significant (P > 0.05).

Conclusion

Based on the better feeling and other beneficial effects of ALA were found in our study; we can conclude that it is a beneficial and recommended supplement, especially, for diabetic and dialysis patients.     

The effect of oxybutynin on cardiac autonomic modulation in healthy subjects

Purpose

The aim of this study was to assess the various doses of oral oxybutynin on cardiac autonomic modulation by measuring short-term heart rate variability (HRV) indexes during supine rest position.

Methods

Eight male healthy subjects (20–23 years) participated in the double-blind crossover randomized study. The single dose of oxybutynin (2.5, 5 and 10 mg) or placebo was given to the volunteers in four sessions within 5-day intervals. Before and minutes of 30, 60, 90 and 120 after administration, lead II electrocardiogram (ECG) was recorded for 5 min. ECG extracted RR intervals data became the base of the calculation of time domain and frequency domain HRV parameters, which indicate cardiac autonomic activity. Statistical analysis was done by using the nonparametric Wilcoxon and Kruskal–Wallis tests.

Results

The data analysis has revealed that MNN (P < 0.001), SDNN (P < 0.05), PNN50% (P < 0.01), RMSSD (P < 0.001), HFnu (P < 0.05) and LF/HF ratio (P < 0.05) values were significantly increased relative to baseline at various time points in all the groups except in placebo group. LFnu (P < 0.05) values were significantly increased relative to baseline at various time points in all the groups except in placebo group.

Conclusions

Our findings have revealed that acute consumption of 2.5, 5 and 10 mg oxybutynin (an anticholinergic compound) in the juvenile healthy male subjects produces a cholinergic effect according to time and frequency domain of HRV indexes.     

Renal Outcomes in Patients with Type 1 Diabetes and Macroalbuminuria

Macroalbuminuria, defined as urine albumin excretion rate (AER)≥300 mg/d, has long been considered a stage of irreversible kidney damage that leads reliably to GFR loss. We examined the long-term renal outcomes of persons with type 1 diabetes who developed incident macroalbuminuria during the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. One hundred fifty-nine participants developed incident macroalbuminuria and were subsequently followed for a median duration of 9 years (maximum of 25 years). At the time of macroalbuminuria diagnosis, mean (SD) age was 37 (9) years, mean (SD) duration of diabetes was 17 (5) years, median AER was 524 mg/d, and mean (SD) eGFR was 108 (20) ml/min per 1.73 m². Ten years after macroalbuminuria diagnosis, the cumulative incidence of a sustained reduction in AER to <300 mg/d was 52%, mostly but not entirely under treatment with renin-angiotensin system inhibitors. The cumulative incidence of impaired GFR (sustained eGFR<60 ml/min per 1.73 m²) 10 years after macroalbuminuria diagnosis was 32%, including 16% who developed ESRD. Lower hemoglobin A1c and BP and regression to AER<300 mg/d were associated with reduced risk of developing impaired GFR. In conclusion, people with type 1 diabetes who develop macroalbuminuria are at high risk of progressive kidney disease. However, through at least 10 years of follow-up, AER could often be controlled, and GFR frequently remained in the normal range.Macroalbuminuria, defined as urine albumin excretion rate (AER)≥300 mg/d, has long been considered a stage of irreversible kidney damage that leads reliably to GFR loss.¹ In early published type 1 diabetes cohorts, macroalbuminuria was associated with a 15-year cumulative incidence of ESRD as high as 75%.^2,3 However, contemporary long-term renal outcomes of macroalbuminuria have not been fully characterized.The Diabetes Control and Complications Trial (DCCT) and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, present a valuable opportunity to examine macroalbuminuria and its long-term clinical outcomes. In DCCT/EDIC, the onset of macroalbuminuria can be defined with confidence using frequent longitudinal measurements of AER, participants have been followed for up to 25 years after the diagnosis of macroalbuminuria, and outcomes were meticulously recorded using standardized methods. Previous work in this cohort has shown that most cases of impaired GFR are preceded by macroalbuminuria,⁴ which is associated with a 50-fold higher risk of developing impaired GFR (eGFR<60 ml/min per 1.73 m²).⁵ Here, we extend these studies by comprehensively evaluating the long-term renal outcomes of incident macroalbuminuria in the DCCT/EDIC cohort and examining the risk factors for its progression to impaired GFR.     

Water intake and risk of type 2 diabetes: A systematic review and meta-analysis of observational studies

Background and aimsThe association of water intake with type 2 diabetes mellitus (T2DM) is still unclear. Therefore, the aim of this systematic review and meta-analysis was to synthesize the knowledge about the relationship between water intake and the risk of T2DM.MethodsWe conducted a systematic search in PubMed and Scopus up to June 2018 for observational studies. Risk ratios (RR)s and 95% confidence intervals (95% CI)s were calculated and fixed effects models were used.ResultsOverall, 6 studies were included in the meta-analyses. There was an inverse relationship between water intake and risk of T2DM (RR: 0.94; 95% CI: 0.91–0.97, P < 0.001) with low heterogeneity (I2 = 24%, P = 0.24).ConclusionOur findings indicated that the intake of water was correlated with reduced risk of type 2 diabetes in women and men. These results support the current recommendations of water intake as an inseparable part of a diet with the lowest risk of diabetes mellitus.