Pyrrolizine-5-carboxamides: Exploring the impact of various substituents on the anti-inflammatory and anticancer activities

Towards optimization of the pyrrolizine-5-carboxamide scaffold, a novel series of six derivatives (4a-c and 5a-c) was prepared and evaluated for their anti-inflammatory, analgesic and anticancer activities. The (EZ)-7-cyano-6-((4-hydroxybenzylidene)amino)-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (4b) and (EZ)-6-((4-chlorobenzylidene)-amino)-7-cyano-N-(p-tolyl)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (5b) bearing the electron donating methyl group showed the highest anti-inflammatory activity while (EZ)-6-((4-chlorobenzylidene)amino)-7-cyano-N-phenyl-2,3-dihydro-1H-pyrrolizine-5-carboxamide (5a) was the most active analgesic agent. Cytotoxicity of the new compounds was evaluated against the MCF-7, A2780 and HT29 cancer cell lines using the MTT assay. Compounds 4b and 5b displayed high anticancer activity with IC50 in the range of 0.30–0.92 µmol L–1 against the three cell lines, while compound (EZ)-N-(4-chlorophenyl)-7-cyano-6-((4-hydroxybenzylidene)-amino)-2,3-dihydro-1H-pyrrolizine-5-carboxamide (4c) was the most active against MCF-7 cells (IC50 = 0.08 µmol L–1). Both the anti-inflammatory and anticancer activities of the new compounds were dependent on the type of substituent on the phenyl rings. Substituents with opposite electronic effects on the two phenyl rings are preferable for high cytotoxicity against the MCF-7 and A2780 cells. COX inhibition was suggested as the molecular mechanism of the anti-inflammatory activity of the new compounds while no clear relationship could be observed between COX inhibition and anticancer activity. Compound 5b, the most active against the three cell lines, induced dose-dependent early apoptosis with 0.1–0.2 % necrosis in MCF-7 cells. New compounds showed promising drug-likeness scores while the docking study revealed high binding affinity to COX-2. Taken together, this study highlighted the significant impact of the substituents on the anti-inflammatory and anticancer activity of pyrrolizine-5-carboxamides, which could help in further optimization to discover good leads for the treatment of cancer and inflammation

The value of computed tomography-urography in predicting the postoperative outcome of antenatally diagnosed pelviureteric junction obstruction

Background The natural course of pelviureteric junction (PUJ) obstruction is  variable. Of those who require surgical intervention, there is no definite reliable  preoperative predictor of the likely postoperative outcome. We evaluated the value of preoperative computed tomography (CT)-urography in predicting the  postoperative outcome.Patients and methods Ten newborns with antenatally diagnosed PUJ obstruction  were evaluated after delivery with an abdominal ultrasound, and those with a renal pelvis measuring more than 3 cm in diameter were subjected to preoperative CT-urography. The kidney size, renal pelvis size, and renal parenchyma thickness were measured and documented. All underwent open surgical Anderson-Hynes dismembered pyeloplasty. The outcome was correlated to the preoperative renal parenchymal thickness as measured by means of preoperative CT-urography.Results Ten newborns (seven male and three female) with PUJ obstruction were  operated on. Their ages at surgery ranged from 8 days to 4 months (mean= 1.75 months). Eight had PUJ obstruction on the right side and two had PUJ obstruction on the left side. The mean renal pelvis size on the affected side was 4.9 cm (3.6–6.3 cm). The mean renal parenchymal thickness was 0.57cm (0.25–1.3 cm). Four patients had a renal parenchymal thickness less than 0.5 cm, and these patients showed poor results on followup isotope scan compared with those who had a renalparenchymal thickness of more than 0.5 cm [mean= 14.9% (12–19.6%)] compared with a mean of 44.2% (33–54%).Conclusion This is a preliminary report and the number of patients in our study is small to make definite conclusions, and further studies in this regard are important. We believe that renal parenchymal thickness as measured by means of preoperative CT-urography is an important predictor of the final outcome in patients with  antenatally diagnosed hydronephrosis. Those who had a renal parenchymal thickness of 0.5 cm or less showed poor results on followup isotope scan compared with those who had a renal parenchymal thickness of more than 0.5 cm.Keywords: outcome, pelviureteric junction obstruction, pyeloplast

10 A noninvasive approach for the early detection of diabetic retinopathy

This chapter introduces one of the most critical problems in ophthalmology, specifically the diagnosis and detection of diabetic retinopathy (DR). Developing a fast, accurate, and reliable method for the early detection of DR is of great clinical importance to prevent blindness in patients. For this reason, various methods for early detection of DR have been investigated and used such as a dilated eye examination, tonometry, fluorescein angiography, optical coherence tomography, and ultrawide-field retinal imaging. With the increased popularity of machine learning, researchers have formulated their own algorithms and methods to detect DR with various rates of success. This chapter overviews past and current diagnostic methods that have been developed for DR. In addition, this chapter addresses new methodologies being developed/researched and some challenges that researchers face in developing fast, accurate, and reliable diagnosis

Oxidative Stress and Anti-Oxidant Markers in Premature Infants with Respiratory Distress Syndrome

BACKGROUND: Neonatal respiratory distress syndrome (RDS) caused by decreased surfactant and structural lung immaturity. The imbalance between oxidative status and antioxidant defence system was suggested to be an important trigger for lung affection with RDS. AIM: The goal of the current research was to elucidate the significance of the oxidant/ antioxidant status in the pathogenesis of RDS in preterm infants. PATIENTS AND METHODS: This controlled study included 31 preterm neonates with RDS and 36 healthy preterm neonates. Quantification level of oxidative stress biomarkers; malondialdehyde (MDA) & hydrogen peroxide (H2O2) along with antioxidant enzymes activity; catalase (CAT) & superoxide dismutase (SOD) in plasma of healthy premature neonates compared with those with RDS. RESULTS: status of oxidative stress markers (MDA & H2O2) showed a significant increase with decreased levels of antioxidant enzymes activity (CAT & SOD) in neonates with RDS when compared to healthy prematures. CONCLUSION: The results obtained in this study indicate that the increased oxidative stress accompanied by reduced antioxidant defences may play a significant role in the pathogenesis of respiratory distress in preterm newborns

Repeating adrenal vein sampling when neither aldosterone/cortisol ratio exceeds peripheral yields a high incidence of aldosterone-producing adenoma

Objectives:In primary aldosteronism, adrenal vein sampling (AVS) suggests unilateral aldosterone-producing adenoma (APA) when the aldosterone/cortisol (A/F) ratio is less than or equal to peripheral on one side and at least two times peripheral on the other. When A/F ratios are lower bilaterally than peripheral despite adequate samples (adrenal venous cortisol 3 times peripheral), we recommend repeat AVS. This study aimed to determine the frequency of this occurrence and outcomes in such cases.Methods:We performed a retrospective observational study of all cases of primary aldosteronism undergoing initial AVS over a 34-year period.Results:Initial AVS in 1397 patients returned satisfactory and discriminatory results in 1066 (76.3%) but 37 patients (2.6%) had adequate samples but bilateral A/F ratios no higher than peripheral. Of the 22 of these 37 who agreed to repeat AVS, 10 demonstrated unilateral aldosterone production, and eight of these had unilateral adrenalectomy disclosing APAs and resulting in cure (3) or improvement (5) in hypertension. Eight had bilateral aldosterone production. Four studies were inconclusive. Patients with initial unsatisfactory AVS because of bilaterally low A/F ratios had significantly (P=0.023) more unilateral disease [10 of 18 satisfactory repeat studies (55.6%) vs. 326 of 1066 satisfactory initial studies (30.6%)] and a significantly higher (67.6 vs. 49.9%, P=0.034) percentage of males.Conclusion:As the incidence of APAs was high in a subgroup with low A/F bilaterally on initial AVS, these patients should be offered repeat AVS. This might reflect both a greater dependence of aldosterone production on adrenocorticotrophic hormone (ACTH) in APAs and the pulsatile nature of ACTH secretion

Two-temperature dual-phase-lags theory in a thermoelastic solid half-space due to an inclined load

This article addresses the thermoelastic interaction due to inclined load on a homogeneous isotropic half-space in context of two-temperature generalized theory of thermoelasticity with dual-phase-lags. It is assumed that the inclined load is a linear combination of both normal and tangential loads. The governing equations are solved by using the normal mode analysis. The variations of the displacement, stress, conductive temperature, and thermodynamic temperature distributions with the horizontal distance have been shown graphically. Results of some earlier workers have also been deduced from the present investigation as special cases. Some comparisons are graphically presented to estimate the effects of the two-temperature parameter, the dual-phase-lags parameters and the inclination angle. It is noticed that there is a significant difference in the values of the studied fields for different value of the angle of inclination. The method presented here maybe applicable to a wide range of problems in thermodynamics and thermoelasticity

L-isoleucine-supplemented Oral Rehydration Solution in the Treatment of Acute Diarrhoea in Children: A Randomized Controlled Trial

Antimicrobial peptides represent an important component of the innate immune defenses of living organisms, including humans. They are broad-spectrum surface-acting agents secreted by the epithelial cells of the body in response to infection. Recently, L-isoleucine and its analogues have been found to induce antimicrobial peptides. The objectives of the study were to examine if addition of L-isoleucine to oral rehydration salts (ORS) solution would reduce stool output and/or duration of acute diarrhoea in children and induce antimicrobial peptides in intestine. This double-blind randomized controlled trial was conducted at the Dhaka Hospital of ICDDR,B. Fifty male children, aged 6-36 months, with acute diarrhoea and some dehydration, attending the hospital, were included in the study. Twenty-five children received L-isoleucine (2 g/L)-added ORS (study), and 25 received ORS without L-isoleucine (control). Stool weight, ORS intake, and duration of diarrhoea were the primary outcomes. There was a trend in reduction in mean±standard deviation (SD) daily stool output (g) of children in the L-isoleucine group from day 2 but it was significant on day 3 (388±261 vs 653±446; the difference between mean [95% confidence interval (CI) (-)265 (−509, −20); p=0.035]. Although the cumulative stool output from day 1 to day 3 reduced by 26% in the isoleucine group, it was not significant. Also, there was a trend in reduction in the mean±SD intake of ORS solution (mL) in the L-isoleucine group but it was significant only on day 1 (410±169 vs 564±301), the difference between mean (95% CI) (-)154 (-288, −18); p=0.04. The duration (hours) of diarrhoea was similar in both the groups. A gradual increase in stool concentrations of ß-defensin 2 and 3 was noted but they were not significantly different between the groups. L-isoleucine-supplemented ORS might be beneficial in reducing stool output and ORS intake in children with acute watery diarrhoea. A further study is warranted to substantiate the therapeutic effect of L-isoleucine

A Follow-up Experience of 6 months after Treatment of Children with Severe Acute Malnutrition in Dhaka, Bangladesh

Aim: As there is lack of information about what happens to children after recovery from severe acute malnutrition (SAM), we report their relapse, morbidity, mortality and referral during follow-up period. Methods: From February 2001 to November 2003, 180 children completing acute and nutrition rehabilitation (NR) phases of protocolized management were advised for 6-months follow-up. The mean (SD) age was 12 (5) months, 55% were infants, 53% were male and 68% were breast-fed. Results: The follow-up compliance rate dropped from 91% at first to 49% at tenth visit. The common morbidities following discharge included fever (26%), cough (24%) and diarrhoea (20%). Successful follow-up done in 124 children [68.9% (95% CI 61.8-75.2%)], partial follow-up in 45 [25% (95% CI 19.2-31.8%)], relapse in 32 [17.8% (95% CI 12.9-24%)] and 5 [2.8% (95% CI 1.2-6.3%)] died. Conclusion: Our findings highlight need for follow-up as part of overall management of SAM and recommend an effective community follow-u

5-Methoxybenzothiophene-2-Carboxamides as Inhibitors of Clk1/4: Optimization of Selectivity and Cellular Potency

Clks have been shown by recent studies to be promising targets for cancer therapy, as they are considered key regulators in the process of pre-mRNA splicing, which in turn affects every aspect of tumor biology. In particular, Clk1 and -4 are overexpressed in several human tumors. Most of the potent Clk1 inhibitors reported in the literature are non-selective, mainly showing off-target activity towards Clk2, Dyrk1A and Dyrk1B. Herein, we present new 5-methoxybenzothiophene2-carboxamide derivatives with unprecedented selectivity. In particular, the introduction of a 3,5- difluoro benzyl extension to the methylated amide led to the discovery of compound 10b (cell-free IC50 = 12.7 nM), which was four times more selective for Clk1 over Clk2 than the previously published flagship compound 1b. Moreover, 10b showed an improved growth inhibitory activity with T24 cells (GI50 = 0.43 µM). Furthermore, a new binding model in the ATP pocket of Clk1 was developed based on the structure-activity relationships derived from new rigidified analogues