A novel N-hydroxy-N′-aminoguanidine derivative inhibits ribonucleotide reductase activity: Effects in human HL-60 promyelocytic leukemia cells and synergism with arabinofuranosylcytosine (Ara-C)

Ribonucleotide reductase (RR; EC 1.17.4.1) is responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are essential for DNA replication. RR is upregulated in tumor cells and therefore considered to be an excellent target for cancer chemotherapy.ABNM-13 (N-hydroxy-2-(anthracene-2-yl-methylene)-hydrazinecarboximidamide), a novel N-hydroxy-N′-aminoguanidine has been designed to inhibit RR activity using 3D molecular space modeling techniques. In this study, we evaluated its effect on human HL-60 promyelocytic leukemia cells. ABNM-13 proved to be a potent inhibitor of RR which was displayed by significant alterations of deoxyribonucleoside triphosphate (dNTP) pool balance and a highly significant decrease of incorporation of radiolabeled cytidine into DNA of HL-60 cells. Diminished RR activity caused replication stress which was consistent with activation of Chk1 and Chk2, resulting in downregulation/degradation of Cdc25A. In contrast, Cdc25B was upregulated, leading to dephosphorylation and activation of Cdk1. The combined disregulation of Cdc25A and Cdc25B was the most likely cause for ABNM-13 induced S-phase arrest. Finally, we combined ABNM-13 with the first-line antileukemic agent arabinofuranosylcytosine (Ara-C) and found that ABNM-13 synergistically potentiated the antineoplastic effects of Ara-C.Due to these promising results, ABNM-13 deserves further preclinical and in vivo testing.     

Senior triaging of ENT emergency clinic referrals alleviates pressures on the outpatient department

IntroductionThe ear, nose and throat (ENT) emergency clinic is managed by foundation year (FY) doctors from taking referrals to discharging patients, under the supervision of a registrar. FYs learn essential skills and knowledge on how to manage common ENT problems. The clinic is often overloaded because of a high patient demand, and this limits the opportunities for teaching. We hypothesised that the clinic bookings would be better managed if referrals from general practitioners (GPs) were triaged by registrars.MethodsTelephone referrals from GPs for the ENT emergency clinic were directed to the on-call ENT registrar, between 8am and 1pm from Monday to Friday, and to the FY outside of this period. Consecutive referrals to the emergency clinic were analysed in a baseline audit and a post-intervention cycle.ResultsA total of 646 and 611 patients were given clinic appointments in the first and second cycles, respectively. Clinic session overbookings decreased from 85% to 46.3%. Appointments for referrals that were deemed inappropriate had reduced from 22% to 12.1%.Discussion and ConclusionInvolvement of a registrar in taking referrals for the ENT emergency clinic was associated with a reduction in clinic overbookings. It is feasible and productive to involve a senior decision maker in the operational management of the emergency clinic, while preserving the delivery of this service by FYs for its training value.     

On the specific heat capacity of HITEC-salt nanocomposites for concentrated solar power applications

High specific heat capacity or C_P of molten salt is crucial for concentrated solar power plants as it will enhance the energy density of thermal energy storage. It can be achieved by doping nanoparticles into molten salts. However, reported results show inconsistency in C_P enhancement (positive and negative). Since the results are based on Differential Scanning Calorimeter (DSC) measurements of small batches (<10 mg), the average C_P obtained from these results may not represent the bulk-C_P of the nanocomposite, which is an important parameter from an application viewpoint. Moreover, the methods of salt-nanoparticle composite production lack industrial scalability. In this work, we examined a potentially scalable method based on mechanical shear mixing. The molten-salt of choice was HITEC due to its lower melting point, while inexpensive alumina and silica nanoparticles were used as dopants. To compare and contrast variability in C_P enhancement, the sample selection was made by random sampling; DSC measurement was performed on small-sized batches (<10 mg), and the T-history method was applied on large-sized batches (20 g). While DSC tests indicated a mean decrease in C_P for alumina (−43%) and an increase in C_P for silica nanocomposite (+15%), T-history tests indicated a mean decrement in the bulk-C_P for both alumina (−49%) and silica nanocomposites (−3%). This anomalous behavior in C_P values was further compared using a nonparametric statistical test, the Mann–Whitney U test, which revealed that the C_P of small-sized batches is statistically different from that of large-sized batches. Given their industrial scale of usage, the C_P of the nanocomposite must be measured using both DSC and T-history methods to ascertain the effect of nanoparticles.

The current study highlights the importance of testing the bulk-C_P and statistical inference for examining the specific heat capacity of nanoparticle-infused salt composites using DSC and T-history tests.     

APOE and LRPAP1 gene polymorphism and risk of Parkinson’s disease

Epidemiologic findings suggest that lipids and alteration in lipid metabolizing protein/gene may contribute to the development of neurodegenerative disorders. The aim of the current study was to determine the serum lipid levels and genetic variation in two lipid metabolizing genes, low-density lipoprotein receptor-related protein-associated protein (LRPAP1) and apolipoprotein E (APOE) gene in Parkinson’s disease (PD). Based on well-defined inclusion and exclusion criteria, this study included 70 patients with PD and 100 age-matched controls. LRPAP1 and APOE gene polymorphism were analyzed by polymerase chain reaction and restriction fragment length polymorphism, respectively. Fasting serum lipid levels were determined using an autoanalyser. The logistic regression analysis showed that high levels of serum cholesterol [odds ratio (OR) = 1.101, 95 % confidence interval (CI_95%) = 1.067–1.135], LRPAP1 I allelic variant alone (OR = 2.766, CI_95% = 1.137–6.752) and in combination with APOE ε4 allelic variant (OR = 4.187, CI_95% = 1.621–10.82) were significantly associated with increase in PD risk. Apart from that, the high levels of LDL cholesterol appears to have a protective role (OR = 0.931, CI_95% = 0.897–0.966) against PD. The LRPAP1 I allelic variant may be considered a candidate gene for PD, predominantly in patients having the APOE ε4 allelic variant.     

Psychiatric Morbidity,Social Support,and Coping in Wives of Alcohol and Opioid Dependent Men

The study aimed to ascertain the psychiatric morbidity in wives of substance dependent men and to assess social support and coping as its correlates. It was carried out at the Drug De-addiction and Treatment Centre of Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh. Two groups of substance dependent men (alcohol and opioid) and their wives were recruited (n = 50 in each group). The subjects were assessed for relevant socio-demographic and clinical variables, dependence severity measures, psychiatric morbidity (GHQ 12 and MINI), coping, and social support. Patients and spouses in the opioid dependent group were of younger age and had a lesser duration of marriage than those of alcohol dependent group. In both groups, more than 70 percent of the spouses had scores above the cutoff in GHQ-12. The psychiatric diagnosis was present in 16 percent and 20 percent of the wives in alcohol and opioid dependence groups, respectively, depression and dysthymia being the commonly encountered diagnoses. Social support was comparable across both groups. The most common coping mechanisms utilized were those of denial and internalization. On multivariate logistic regression, GHQ-12 scores were the predictors of MINI diagnosis. Psychological morbidity is common in wives of patients with substance use disorders. Attention to the mental health issues can relieve the distress in this vulnerable population.