Noteworthy effect of slight variation in aliphatic chain length of trisubstituted imidazole inhibitors against epidermal growth factor receptor L858R/T790M/C797S mutant in cancer therapy

11h is a very potent inhibitor against epidermal growth factor receptor triple mutation L858R/T790M/C797S (EGFR^TM) with 13‐fold stronger potency than the FDA‐approved osimertinib. Recently, two new EGFR^TM inhibitors, 11d and 11e , were reported which revealed 2.8‐ and 2.3‐fold stronger potency than 11h , respectively. 11h , 11d, and 11e have the same structures but differ only in their aliphatic chain length. However, the exact effects of differential aliphatic chain length on the inhibitory potencies of these compounds require further elaboration at the atomistic level, hence the objective of this report. Various computational tools were employed for this purpose. From our findings, it was revealed that van der Waals (vdW) interactions modulate the binding mechanisms of these inhibitors and play the most important role in the differential inhibitory activities of 11d , 11h, and 11e . The strong hydrogen bond formation between the aliphatic chain of 11d and key residue ARG841 was recognized as the reason for its higher activity and inhibitory potency relative to 11h and 11e . Moreover, the extension of the N‐terminal loop into the active site for vdW interaction with the phenyl group of 11e and carbon–hydrogen bond formed between the aliphatic chain of 11e and LEU718 engendered a higher activity of 11e than 11h .     

Posterolateral versus posterior interbody fusion in isthmic spondylolisthesis

Spondylolisthesis is a heterogeneous disorder characterized by subluxation of a vertebral body over another in the sagittal plane. Its most common form is isthmic spondylolisthesis (IS). This study aims to compare clinical outcomes of posterolateral fusion (PLF) with posterior lumbar interbody fusion (PLIF) with posterior instrumentation in the treatment of IS. We performed a randomized prospective study in which 80 patients out of a total of 85 patients with IS were randomly allocated to one of two groups: PLF with posterior instrumentation (group I) or PLIF with posterior instrumentation (group II). Posterior decompression was performed in the patients. The Oswestry low back pain disability (OLBP) scale and Visual Analogue Scale (VAS) were used to evaluate the quality of life (QoL) and pain, respectively. Fisher's exact test was used to evaluate fusion rate and the Mann-Whitney U test was used to compare categorical data. Fusion in group II was significantly better than in group I (p=0.012). Improvement in low back pain was statistically more significant in group I (p=0.001). The incidence of neurogenic claudication was significantly lower in group I than in group II (p=0.004). In group I, there was no significant correlation between slip Meyerding grade and disc space height, radicular pain, and low back pain. There was no significant difference in post-operative complications at 1-year follow-up. Our data showed that PLF with posterior instrumentation provides better clinical outcomes and more improvement in low back pain compared to PLIF with posterior instrumentation despite the low fusion rate.     

Duplication of male urethra

Male urethral duplication is an unusual anomaly with many variants including complete duplication from the bladder to the glans penis as well as incomplete and abortive forms. Two cases are presented of duplication of the male urethra of the epispadiac incomplete type. A chart has been constructed to facilitate categorization of the various forms of urethral duplication in the male.     

Serum paraoxonase and arylesterase activities in Iranian patients with nonalcoholic fatty liver disease

BackgroundThe aim of the study was to investigate paraoxonase-1 (PON1) and aryl esterase (ARE) activities in patients with nonalcoholic fatty liver disease (NAFLD).Materials and methodsThis case–control study was done on 83 subjects with confirmed NAFLD (50 male, 33 female, age; 40.46 ± 12.13 years) and 138 healthy individuals (75 male, 63 female; age; 40.94 ± 14.50 years). PON1, salt-stimulated PON1 and ARE activities were determined using paraoxon and phenyl acetate as substrate, respectively.ResultsThe levels of PON1 activities in NAFLD and healthy individuals were 90.83 ± 63.65 IU/L and 79.41 ± 68.14 IU/L, respectively. There was no significant differences regarding PON1 activity between NAFLD and healthy subjects (p = 0.229). While, ARE activity was significantly higher in NAFLD (83.34 ± 28.36 KU/L) than in normal subjects (64.06 ± 27.49 KU/L) (p < 0.001).ConclusionsOur results showed that PON1 activity is not a promising biomarker for the evaluation of NAFLD while arylesterase may have, but further studies in larger samples with different ethnic groups are required to validate our findings.     

Impact of HEC72702 chirality on the selective inhibition of hepatitis B virus capsid dimer: A dynamics–structure–energetics perspective

Chirality in drug design has been attracting wide interests and attention over the years based on its innate potentials of enhancing the selectivity and prowess of therapeutic molecules. This approach was fundamental to the recent design of two inhibitors, where (R,R)‐HEC72702 exhibited higher potency inhibition against hepatitis B virus capsid (HBVC) than (R,S)‐HEC72702. Nevertheless, the detailed molecular mechanism has remained unresolved. Here, we apply multiple computational approaches to explore, validate, and differentiate the binding modes of (R,R) and (R,S) ‐ HEC72702 and to explain the systematic roles mediated by chirality on the distinctive inhibition of HBVC dimer (HBVCd). Our findings revealed that chirality change from R,S to R,R engenders variations in the position of the propanoic acid group of HEC72702 toward the α5′ and C‐TER′ region of HBVCd chain B which could explain the higher inhibitory affinity of (R,R) ‐ HEC72702. Estimated binding free energies revealed a good correlation with bioactivity data. Moreover, analysis of energy decomposition revealed the prominent effects of van der Waals interactions in the binding process of both compounds to HBVCd. Furthermore, hierarchical clustering of residue‐based energetic contributions suggested two hot‐spot residues W125´ and F156´ play crucial roles in the systematic motions of the propanoic acid group toward chain B.     

Blood Levels of Methemoglobin in Patients with Aluminum Phosphide Poisoning and its Correlation with Patient’s Outcome

Although methemoglobinemia following aluminum phosphide (AlP) intoxication has been reported, probable effect of blood level of methemoglobin (Met-Hb) on outcome of AlP-poisoned patients has not yet been investigated. This study aimed to evaluate blood levels of methemoglobin in patients with AP intoxication and its correlation with patient’s outcome. This prospective study was carried out at the Loghman–Hakim poison hospital from April 2009 to August 2009. All patients aged >12 years who had ingested AlP and were admitted at the hospital were enrolled in the study. Using the co-oximetry, blood Met-Hb level was measured at the time of admission and 24 h later if the patient survived. Forty-eight patients with AlP intoxication including 24 males were evaluated. Mean age of the patients was 25.5 ± 9.5 years. There was significant association between blood level of Met-Hb at the time of admission and mortality (2.4% ± 7.1% in survivors versus 15.2% ± 13.5% in non-survivors, P < 0.001). The same association was found at the 2nd day of admission (2.9% ± 8.2% in survivors versus 26.5% ± 19.9% in non-survivors, P = 0.02). The present study found an association between blood level of Met-Hb and mortality in patients with AlP intoxication. Effect of administration of vitamin C and methylene blue on outcome of patients with AlP intoxication should be investigated in future studies.     

A comparative study of blood culture sampling from umbilical catheter line versus peripheral site

Neonatal sepsis is an important cause of death and morbidity in newborns and is diagnosed by isolation of organism in blood culture. In several reports,reliability of blood cultures were done from umbilical catheters,have been demonstrated. The objective of the present study was to determine, wether an indewelling umbilical catheter, could be an alternative site for blood culture. In a prospective study over 6 months during 2006, 141 paired blood cultures from 134 infant,were done simultaneously from peripheral site and umbilical catheter (mostly U. V. C),during the first four days of life. Majority of these infants were preterm and admitted to NICU for special care. these infants had indwelling umbilical line and had indication of sepsis workup. A total of 141 pairs of blood cultures were obtained from 134 infants. In 16 infants blood culture pairs were positive for one organism in both peripheral vein and umbilical site. 71. 6% of total cultures (n=11) pairs were negative in both sites. A total of 22 pairs were positive in one site only,with 5 positive from peripheral vein only and the other 17 from umbilical site. Two pairs were positive in both sites with two different organism. In over all 16 infant (11%) of blood were considered to be contaminated. Contamination rate were 2. 4% and 9. 2% for peripheral and umbilical catheter site. Contamination rate increased after 48 hours of age in umbilical catheter. The result showed that after 2 days contamination rate for blood culture taken from catheter line increased and specificity decreased. We recommended that blood culture via umbilical catheter in first 2 days in sick neonates with indwelling catheter can be a alternate site of blood culture sampling.