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 .     

Association Between Positive Affect and Attentional Shifting

This investigation tested the hypothesis that individuals low in positive affect are slower to shift attention from one focus to another. Ninety-six participants completed a self-report mood questionnaire and a standard attentional orienting task. Results indicated a significant correlation between cue validity effects and self-reported positive affect, such that individuals low in positive affect were relatively faster to respond to validly-cued targets and slower to respond to invalidly-cued targets, compared to individuals high in positive affect. Negative affect, psychometrically separated from positive affect by a principal components analysis, was unrelated to attentional orienting but was correlated with generalized alerting effects of cues. The main results are interpreted as supporting decreased cognitive flexibility in states of low positive affect.     

Use of epoetin alfa in critically ill patients

OBJECTIVE: To discuss the controversies regarding the use of epoetin alfa (EPO) for reducing red blood cell (RBC) transfusions in critically ill patients with anemia. DATA SOURCES: A MEDLINE search (1966-July 2003) was conducted using the search terms anemia; critical illness; erythropoietin; epoetin alfa; and erythropoietin, recombinant. References of selected articles were reviewed for studies that may have been missed by the computerized search. STUDY SELECTION AND DATA EXTRACTION: Studies pertaining to the use of EPO for anemia of critical illness with an emphasis on data obtained from controlled trials. DATA SYNTHESIS: Anemia is a common complication in patients admitted to the intensive care unit (ICU). Two prospective, randomized studies have demonstrated decreased transfusion requirements associated with EPO administration in medical/surgical patients who were in the ICU for at least 3 days and had hematocrit concentrations <38%. No differences were found in length of stay or mortality. A multicenter trial found that a restrictive strategy of RBC transfusion (hemoglobin goal 7-9 g/dL) was associated with in-hospital mortality lower than that with a more liberal approach, which calls into question the 38% hematocrit goal in the EPO trials. Furthermore, preliminary results from an economic analysis of EPO use in the ICU setting have demonstrated that EPO is not cost-effective. CONCLUSIONS: Given the controversies surrounding EPO administration in critically ill patients, institutions are encouraged to develop EPO guidelines to help ensure the most appropriate use of this expensive product. Additional studies regarding patients most likely to benefit from EPO therapy, the most effective dosing regimen, and use of adjunctive therapies are needed.     

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.     

A retrospective study of mushroom poisoning in Iran

The objective of this study was to describe the pattern of mushroom poisoning in adults admitted to the Loghman-Hakim Hospital Poison Center from 1992 to 2002. All patients > or = 12 years of age were included in the study. The frequency of mushroom poisoning with respect to age, sex, season, reason, place of residence, latent phase, clinical and laboratory findings, treatment, and outcome of patients was investigated. Of the 72421 poisoning cases admitted to Loghman-Hakim Hospital Poison Center from 1992 to 2002, only 37 were poisoned by consumption of toxic mushrooms. As some of the patients' files were incomplete, only 25 files were included in the study. Of this number, 68% were male. The patients' age ranged between 12 and 65 years, with a mean of 31 years of age. All cases were accidental and mostly from Tehran (36%) and the northern provinces (rainy woodlands) of Iran (32%). Autumn was the most common season for poisoning with a frequency of 80%. The latent phase of poisonings was between 0.5 and 12 hours. The most frequently reported symptoms were vomiting (84%), nausea (60%), abdominal pain (60%) and diarrhea (40%). Jaundice was observed in 44% of cases, with a 50% rate of hepatic encephalopathy. A total of 66% of patients were discharged and the duration range of hospitalization was 1-12 days. In conclusion, people should be more informed of the dangers posed by wild mushrooms. Training of physicians and nurses in the accurate diagnosis and management of patients poisoned with poisonous mushrooms would improve the rate of survival.     

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.