Design, synthesis and SAR studies of 4-allyoxyaniline amides as potent 15-lipoxygensae inhibitors.

A group of 4-allyloxyaniline amides 5a-o were designed, synthesized and evaluated as potential inhibitors of soybean 15-lipoxygenase (SLO) on the basis of eugenol and esteragol structures. Compound 5e showed the best IC(50) in SLO inhibition (IC(50)=0.67+/-0.06 microM). All compounds were docked in SLO active site retrieved from RCSB Protein Data Bank (PDB entry: 1IK3) and showed that allyloxy group of compounds is oriented towards the Fe(3+)-OH moiety in the active site of enzyme and fixed by hydrogen bonding with two conserved His(513) and Gln(716). It is resulted that molecular volume of the amide moiety would be a major factor in inhibitory potency variation of the synthetic amides, where the hydrogen bonding of the amide group could also involve in the activity of the inhibitors.

Design and synthesis of 4-methoxyphenylacetic acid esters as 15-lipoxygenase inhibitors and SAR comparative studies of them.

A group of 4-methoxyphenylacetic acid esters were designed, synthesized and evaluated as potential inhibitors of soybean 15-lipoxygenase (SLO) on the basis of eugenol and esteragol structures. Compounds 7d-e showed the best IC(50) in SLO inhibition (IC(50)=3.8 and 1.9 microM, respectively). All compounds were docked in SLO active site and showed that carbonyl group of compounds is oriented toward the Fe(III)-OH moiety in the active site of enzyme and fixed by hydrogen bonding with hydroxyl group. It is assumed that lipophilic interaction of ligand-enzyme would be in charge of inhibiting the enzyme activity. The selectivity of the synthetic esters in inhibiting of 15-HLOb was also compared with 15-HLOa by molecular modeling and multiple alignment techniques.

Prevention and treatment of corneal neovascularization: comparison of different doses of subconjunctival bevacizumab with corticosteroid in experimental rats.

BACKGROUND: To evaluate and compare the effect of different doses of subconjunctival bevacizumab with betamethasone on the development of corneal major new vessels in a rat model of corneal chemical injury. METHODS: The right eyes of 100 male Sprague-Dawley rats were randomly divided into 10 experimental groups (n = 10 per group). Chemical cauterization of the cornea was performed by using silver nitrate/potassium nitrate sticks. Immediately following corneal cauterization, the animals in groups 1-5 received subconjunctival injections of 0.02 ml of normal saline (control A), betamethasone LA (6 mg/ml) and different doses of bevacizumab (1, 5 and 25 mg/ml), respectively. In another experiment, the animals in groups 6-10 received subconjunctival injections of 0.02 ml of normal saline (control B), betamethasone LA (6 mg/ml) and different doses of bevacizumab (1, 5 and 25 mg/ml), respectively, 7 days following corneal cauterization. The numbers of major thick-walled vessels originating from the limbus reaching the corneal scar were counted 7 days after corneal cauterization in groups 1-5 and 14 days after corneal cauterization in groups 6-10. RESULTS: The number of major vessels in groups 1-5 was 19.63 +/- 3.77, 17.25 +/- 5.33, 16.10 +/- 5.02, 12.89 +/- 2.70 and 12.36 +/- 4.45 when assessed 7 days after corneal cauterization, respectively. Administration of betamethasone in group 2 had no significant effect on the corneal major vessel count compared to control A. The number of major vessels in groups 4 and 5 (bevacizumab 5 and 25 mg/ml) was significantly lower than that of group 1 (p < 0.01, Student's t test). The number of vessels in groups 6-10 was 12.55 +/- 5.64, 11.30 +/- 9.33, 5.50 +/- 6.34, 2.73 +/- 4.73 and 2.67 +/- 3.77 when assessed 14 days after corneal cauterization, respectively. Subconjunctival administration of betamethasone 7 days after corneal cauterization did not reduce the amount of corneal major vessels compared to control B. Administration of 0.02 ml of bevacizumab in doses of 1, 5 and 25 mg/ml 7 days after corneal cauterization significantly reduced the amount of major vessels compared to group 6 (p = 0.01, p < 0.01 and p < 0.01, respectively). There was no significant difference in percent area of corneal scar between different groups. CONCLUSION: Single subconjunctival injection of bevacizumab is efficacious in the prevention of formation as well as regression of major vessels compared to betamethasone in this rat model of corneal neovascularization. Even lower doses of bevacizumab might be efficacious.

Factors associated with the metabolic syndrome in a national sample of youths: CASPIAN Study.

BACKGROUND AND AIM: To date, research on the influence of environmental factors on metabolic syndrome (MS) among youths is limited. This study was conducted to investigate for the first time the association of these factors with MS in a large national, representative sample of children from a non-Western population. METHODS AND RESULTS: The study population comprised of 4811 students (2248 boys and 2563 girls) aged 6-18 years, living in six different provinces in Iran. MS, defined based on criteria analogous to those of the Adult Treatment Panel III, was detected in 14.1% of participants. A birth weight of >4000 g in boys and <2500 g in girls increased the risk of having the MS [OR, 95% CI: 1.4 (1.007, 2.05) and 1.2 (1.1, 1.4), respectively]. Poorly educated parents and a positive parental history of chronic disease were other risks factors associated with MS. Low levels of physical activity significantly increased the risk of having MS [boys: 1.3 (1.1, 1.7); girls: 1.4 (1.2, 1.6)]. The risk of MS increased in-line with the consumption of solid hydrogenated fat [boys: 1.2 (1.07, 1.3); girls, 1.3 (1.1, 1.5)] and bread made with white flour [boys: 1.6 (1.3, 2.1); girls, 1.4 (1.1, 1.7)]. In contrast, an increased frequency of consumption of fruits and vegetable, as well as dairy products decreased the risk of having MS. CONCLUSION: Considering the effect of modifiable lifestyle habits and birth weight on MS in youths, urgent public health approaches should be directed towards primordial and primary prevention of this rapidly growing problem.

The impact of macular laser photocoagulation on contrast sensitivity function in patients with clinically significant macular edema.

BACKGROUND: Contrast sensitivity is an important aspect of visual function and is even more important for ordinary daily tasks than visual acuity. Contrast sensitivity function may be deteriorated to a significant level in diabetic retinopathy, especially in diabetic macular edema. The objective of this study was to determine the impact of macular laser photocoagulation-as the standard treatment of clinically significant macular edema-on contrast sensitivity function. METHODS: In a prospective noncomparative interventional case series, 17 patients with clinically significant bilateral macular edema and no history of prior macular laser photocoagulation were enrolled. Baseline visual acuity, contrast sensitivity function, and fluorescein angiography were obtained and reassessed three months after macular laser photocoagulation. RESULTS: Clinically significant macular edema resolved in 22 (65%) of 34 eyes, three months after their first session of macular laser photocoagulation. The mean pretreatment visual acuity was 24.5/40 (0.21 logMAR) +/-10.3/40. Three months after macular photocoagulation, visual acuity remained stable in 19 eyes, decreased in 12 eyes, and increased in three eyes. The mean post-treatment visual acuity was 24/40 (0.24 logMAR) +/-10.8/40. There was a statistically significant (P = 0.02) decrease in visual acuity following laser therapy. In subgroup analysis, this decrease in visual acuity was only observed in those with unresolved clinically significant macular edema. The mean contrast sensitivity threshold increased in all spatial frequencies by three months after macular photocoagulation. The maximum rise was observed in the frequency of 6.4 cycles per degree in the mid range of frequencies, with a pretreatment mean of 9.41 dB and a post-treatment mean of 11.50 dB (P<0.05). CONCLUSION: Contrast sensitivity function improved after macular laser photocoagulation in clinically significant macular edema patients.

Factor analysis of cardiovascular risk clustering in pediatric metabolic syndrome: CASPIAN study.

AIMS: To assess the results of factor analysis of coronary artery disease risk factors in a large national representative sample of children, and to compare its results on the variables measured between those with or without metabolic syndrome (MetS). METHODS: This cross-sectional multicenter population survey was conducted on 4,811 nationally representative school students aged 6-18 years. MetS was defined based on criteria analogous to the Adult Treatment Panel III. Factor analysis by principle components analysis and Varimax rotation was carried out to cluster risk factors. RESULTS: MetS was present in 14.1% of subjects (n = 678). From the nine variables assessed, factor analysis of the z scores of variables show that in all age groups, three similar factors were loaded: lipids, adiposity, and blood pressure, that accounted for 87.4-90.8% of the variance. Three factors were loaded in those with MetS (cholesterol/TG, metabolic/adiposity, and blood pressure) (65.9% of variance); and four factors (cholesterol, metabolic, adiposity, and blood pressure) were loaded among those without the MetS (75.6% of variance). We did not find a central feature that underlies all three factors among children with the MetS; however, waist circumference was the only variable that was loaded for two factors. CONCLUSION: These findings support a change in the concept of MetS from that of a single entity to one that represents several distinct but intercorrelated entities. An approach to assessing risk clustering from early life, and longitudinal studies that would elucidate how these various risk domains interact over time are needed.

Therapeutic effect of macular grid photocoagulation in treatment of nonexudative age-related macular degeneration.

BACKGROUND: To investigate the effect of prophylactic subthreshold laser macular grid photocoagulation on drusen area and to evaluate the visual outcome and incidence of choroidal neovascularization in patients with soft drusen maculopathy. METHODS: In a nonrandomized nonmasked clinical trial, 18 patients (36 eyes) with bilateral soft drusen maculopathy were studied. For each patient, one eye was treated with 48 subthreshold (invisible end-point) applications of 532-nm KTP-laser in a macular grid pattern and the fellow eye was observed. Soft drusen areas were calculated and compared between the two groups at baseline and follow-up visits at 3, 6, 12, and 30 months of therapy. Best corrected visual acuity was also compared in observed and laser-treated eyes. Reduction of drusen area, change in visual acuity, and rate of CNV were assessed in both groups. RESULTS: At baseline, there was no significant difference in the mean drusen surface area between the two groups (P = 0.90). The mean surface area of soft drusen in treated eyes was 6.51 mm(2) after 30 months and 7.58 mm(2) (P = 0.50) in the control eyes. There was a trend towards reduction in the mean soft drusen area after 30 months from baseline in laser-treated eyes (6.51 vs. 6.97 mm(2)). In treated eyes, there was no statistically significant difference between the mean best corrected visual acuity at the baseline (0.28 logMAR) and after 30 months (0.32 logMAR) (P = 0.40). CONCLUSION: Subthreshold macular grid photocoagulation with 532-nm KTP-laser did not seem to reduce drusen surface area significantly and did not improve best corrected visual acuity after 30 months. No exudative lesion developed in laser-treated eyes.

Ultrasound biomicroscopy study of vitreous incarceration subsequent to intravitreal injections.

OBJECTIVE: To study the existence of vitreous incarceration by ultrasound biomicroscopy (UBM) at the pars plana after direct intravitreal injection of triamcinolone acetonide ± bevacizumab without anterior chamber paracentesis. DESIGN: Interventional case series. PARTICIPANTS: Patients undergoing intravitreal injection of triamcinolone acetonide with or without intravitreal bevacizumab. METHODS: In 21 eyes, the existence of vitreous incarceration at the pars plana site of intravitreal injection of 0.05 mL of drug was studied by UBM (50 MHz probe of the VUmax, Sonomed, NY), the day after surgery, by 1 technician. The reason for injection was diabetic retinopathy in 12 (57.1%) eyes; age-related macular degeneration in 6 (28.6%) eyes; branch retinal vein occlusion in 2 (9.5%) eyes; and choroiditis in 1 eye (4.8%). In 1 eye, only triamcinolone acetonide was injected, and in the other eyes, bevacizumab mixed with triamcinolone acetonide was injected. RESULTS: We studied 21 eyes in 13 patients. Of the subjects, 61.5% were male. The mean age of the patients was 62.2 years. On the day after intravitreal injection of the drug, vitreous incarceration into the pars plana site was detected by UBM in 42.9% of the eyes. CONCLUSION: Vitreous incarceration exists after intravitreal injection of drug, but its clinical importance is still unknown. Further long-term prospective studies are recommended.

First reference curves of waist and hip circumferences in an Asian population of youths: CASPIAN study.

The Objective of the present study is to develop the first age- and gender-specific reference curves for waist and hip circumferences in an Asian population of youths. This cross-sectional population survey was conducted in 2003-04 on a nationally representative sample of 21111 school-students living in urban (84.6%) and rural (15.4%) areas of 23 provinces in Iran. After anthropometric measurements, smoothed reference curves for waist and hip circumference (WC, HiC) and waist-to-hip ratio (WHR) were developed by the LMS method. In both genders, WC and HiC percentile values increased with age. For girls, the 50th to 95th percentile curves for WC had a sharp increase between 8 and 13 years and 11-15 years, respectively, and began to plateau after this age, whereas for boys, these curves had a persistent and less sharp increase with age, until the age of 18 years. The WHR curves of girls decreased with age until 15 years and began to plateau thereafter, whereas for boys the 25th to 95th curves had a plateau pattern. Comparison of the current reference curves with the British ones showed that in boys, the 5th and 50th percentile curves were similar in both studies, but the 95th percentile curve of our study was higher than the British curves. For girls, the 5th percentile curves of both studies were similar, but the 50th and 95th percentile curves of our study were higher than the British ones. These curves represent the first childhood WC, HiC and WHR reference curves obtained in Asia. These curves can provide baseline data for analysis of time trends, as well as for international comparisons.

Association of physical activity and dietary behaviours in relation to the body mass index in a national sample of Iranian children and adolescents: CASPIAN Study.

OBJECTIVE: To examine the relation of dietary and physical activity (PA) patterns with the body mass index (BMI), and the associations between these patterns among children. METHODS: A representative sample of 21 111 school students aged 6-18 years was selected by multistage random cluster sampling from 23 provinces in the Islamic Republic of Iran. PA and dietary pattern were assessed by self-administered validated questionnaires. FINDINGS: Fruit and vegetables, dairy products and snacks (salty, fatty or sweet) had a similar consumption frequency of approximately twice a day. The type of fat most frequently consumed was hydrogenated solid fat (consumed by 73.8% of families). The PA level was significantly higher among boys than girls, in rural than in urban residents, and in intermediate students than high-school students. Among boys, the frequency of consumption of vegetables and plant proteins (R(2) = 0.46); and among girls, the frequency of consumption of dairy products and fruits, as well as high PA level had a significant inverse association with BMI (R(2) = 0.57). Among boys, the low frequency of consumption of fruits, the time spent on PA and the energy expenditure; and among girls, the time spent on PA and the energy expenditure, had significant relationships with overweight. When controlling for covariates, PA levels had significant relationships with the frequency of consumption of all food groups. CONCLUSION: Unhealthy lifestyles make Iranian young people prone to chronic diseases later in life. When examining their health benefits, the interrelationship of dietary and PA behaviours should be considered.

Association of anthropometric indices with cardiovascular disease risk factors among children and adolescents: CASPIAN Study.

BACKGROUND: For the first time in Iran, and to the best of our knowledge in Asia, we assessed the anthropometric indices most closely correlated to cardiovascular disease (CVD) risk factors in a large nationally representative sample of children and adolescents to be used as a simple tool for identifying those at risk. METHODS: This multi-center study was performed among a representative sample of 4811 school students (2248 boys and 2563 girls) aged 6-18 years, as part of the baseline survey of a national surveillance system. Anthropometric indices and CVD risk factors were measured using standard protocols, and their correlation was analyzed by using Receiver Operator Characteristic (ROC) curves and partial correlation. RESULTS: The most prevalent CVD risk factors were low HDL-C (28%), followed by hypertriglyceridemia (20.1%), and overweight (17%). The ROC analyses showed that among boys, all anthropometric indices had the same association with CVD risk factors in 6-9.9-year-age group, while in the 10-13.9 and 14-18-year-age groups, respectively waist circumference (WC) and body mass index (BMI) were the best in distinguishing CVD risk factors. Among girls, these indices were respectively BMI and waist to stature ratio (WSR); WC and WSR; and WC. In the partial correlation analysis, in boys, the highest coefficient was found for BMI; BMI and WC; and for WC and WSR; in girls, these indices were BMI; WC and WSR; and BMI respectively. CONCLUSIONS: In the present study, BMI, WC and WSR were the most appropriate in predicting CVD risk factors. It may be clinically useful in the pediatric population to routinely measure WC and WSR in addition to BMI as a screening tool to identify high-risk youth.