Investigation on the interaction of the toxicant,gentian violet,with bovine hemoglobin

Gentian violet (GV) is a well-known triarylmethane dye that is used in aquacultural, industrial and medicinal fields. But concerns in growing number have been paid to its potential health problems to human beings and its hazardous effects to environment. Herein, the toxic interaction of GV with bovine hemoglobin (BHb) was investigated by a series of spectroscopic methods and molecular modeling method. The fluorescence emission profile exhibited a remarkable quenching upon addition of GV to the buffered aqueous solution of BHb and the analysis of results revealed the dominant role of static quenching mechanism in GV–BHb interaction. The negative ΔH and positive ΔS values demonstrated that the electrostatic interactions mainly stabilized this toxicantprotein complex. Synchronous fluorescence, UV–Vis absorption and CD spectroscopic studies proved that the conformational change of BHb was induced by GV’s combination. Molecular modeling studies exhibited the binding mode of GV–BHb complex and the detailed information of related driving forces. During the ¹H nuclear magnetic resonance spectra (¹H NMR) study, the chemical shift perturbation and spin–lattice relaxation times of different protons were further used to investigate the interaction of GV with BHb and the results indicated that GV bound orientationally to BHb.     

In-silico screening for DNA-dependent protein kinase (DNA-PK) inhibitors: Combined homology modeling,docking, molecular dynamic study followed by biological investigation

DNA-dependent protein kinase (DNA-PK) is a key enzyme in non-homologous DNA end joining (NHEJ) repair pathway. The targeted inhibition of such enzyme would furnish a valuable option for cancer treatment. In this study we report the development of validation of enzyme homology model, and the subsequent use of this model to perform docking-based virtual screening against a database of FDA-approved drugs. The nominated highest ranking hits (Praziquantel and Dutasteride) were subjected to biological investigation. Additionally, molecular dynamic study was carried-out for binding mode exploration. Results of the biological evaluation revealed that both compounds inhibit the DNA-PK enzymatic activity at relatively high concentration levels with an IC₅₀ of 17.3 μM for praziquantel and >20 μM for dutasteride. Furthermore, both agents enhanced the anti-proliferative effects of doxorubicin and cisplatin on breast cancer (MCF7) and lung cancer (A549) cell lines. This result indicates that these two hits are good candidate as DNA-PK inhibitors and worth further structural modifications to enhance their enzyme inhibitory effects.     

Pharmacokinetic/ pharmacodynamic evaluation of anti-infective agents

Pharmacokinetic/pharmacodynamic modeling has become an extremely important tool in evaluating and optimizing anti-infective therapy. By systematically linking the pharmacokinetic and pharmacodynamic properties of the anti-infective agent, it is possible to make educated decisions about the correct drug to be used, correct dosing regimen and to estimate the probability of success with the selected dose regimen. This article gives an overview of the current pharmacokinetic/pharmacodynamic approaches for anti-infective agents and discusses their use in optimizing drug therapy.     

Decisions About Marriage and Family Among Survivors of Childhood Cancer

Although the effects of treatment for childhood cancer on subsequent reproductive outcomes are unknown, they are often implicated as contributing to that outcome in a detrimental manner. In this study, 263 adult survivors of childhood cancer were compared with 369 adult sibling controls regarding their decisions to marry and have children. The survivors were more likely to report not marrying for health reasons. Although the long-term surivivors did not have significantly more documented or suspected infertility problems, they were less likely than controls to have been pregnant or involved with a pregnancy and were more likely to have been advised by a physician to avoid a pregnancy. However, when the frequency of birth defects among 253 offspring of the survivors was compared with the frequency of defents among 595 offspring of controls, the outcome of pregnancy among survivors and controls proved to equally favorable.     

In vitro modeling accurately predicts cardiac lead fracture at 10 years

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Inhibitors of Bacillus anthracis edema factor

Edema factor (EF) is a calmodulin (CaM)-activated adenylyl cyclase (AC) toxin from Bacillus anthracis that contributes to anthrax pathogenesis. Anthrax is an important medical problem, but treatment of B. anthracis infections is still unsatisfying. Thus, selective EF inhibitors could be valuable drugs in the treatment of anthrax infection, most importantly shock. The catalytic site of EF, the EF/CaM interaction site and allosteric sites constitute potential drug targets. To this end, most efforts have been directed towards targeting the catalytic site. A major challenge in the field is to obtain compounds with high selectivity for AC toxins relative to mammalian membranous ACs (mACs). 3′-(N-methyl)anthraniloyl-2′-deoxyadenosine-5′-triphosphate is the most potent EF inhibitor known so far (K_i, 10 nM), but selectivity relative to mACs needs to be improved (currently ~5–50-fold, depending on the specific mAC isoform considered). AC toxin inhibitors can be identified in virtual screening studies based on available EF crystal structures and examined in cellular test systems or at the level of purified toxin using classic radioisotopic or non-radioactive fluorescence assays. Binding of certain MANT-nucleotides to AC toxins elicits large direct fluorescence- or fluorescence resonance energy transfer signals upon interaction with CaM, and these signals can be used to identify toxin inhibitors in competition binding studies. Collectively, potent EF inhibitors are available, but before they can be used clinically, selectivity against mACs must be improved. However, several methodological approaches, complementing each other, are now available to direct the development of potent, selective, orally applicable and clinically useful EF inhibitors.     

Life Review in Family Psychotherapy

A number of theorists and clinicians have recognized the value of life review as a therapeutic tool in waking with the elderly. Few, however, have used review in marriage and family psychotherapy. This paper provides a brief overview of life review and explores possible ways of expanding its application in marriage and family work. in addition to summarizing the central characteristics of life review, this paper also identifies possible outcomes and limitations, and then, through case example, explores the relevance of life review for maniage and family psychotherapy.     

Substance abuse risk reduction: Verbal mediational training for children by parental and nonparental models

Little is known regarding the etiology and maintenance of substance abuse, especially factors which place children at higher risk for later drug use. The present study evaluated the impact of a 12‐week verbal mediational program (Think Aloud), which teaches children and parents cognitive and social problem‐solving skills and addresses early childhood risk factors related to the onset of drug use in adolescence. Fifty children and parents were included in the present study and were randomly divided into four groups: two groups received either a verbal mediation condition comprising the Think Aloud training or time to complete homework assignments. Each of the topic groups was subdivided into two groups, one in which the parents served as models and one in which the experimenter served as the model. Measures of family cohesion, expressiveness, and conflict, family organization and control, social skills, level of disruptiveness of the child's peer choice, academic competence, and the child's problem behaviors were administered to the parents and the teachers pre‐ and postinterventivefy. Children in the verbal mediation condition with parental models were expected to show the greatest reduction in risk factor scores, and children in the verbal mediation condition with the experimenter model were predicted to show the second greatest reduction in risk factor scores at posttest. Results of the study demonstrated partial support for experimental hypotheses in that the children involved in the Think Aloud program showed improvement on four of the six factors on posttest measures. The superiority of the parental model was not found.     

Differences in knee adduction moment between healthy subjects and patients with osteoarthritis depend on the knee axis definition

ObjectiveThis study, firstly, investigates the effect of using an anatomical versus a functional axis of rotation (FAR) on knee adduction moment (KAM) in healthy subjects and patients with knee osteoarthritis (KOA). Secondly, this study reports KAM for models with FAR calculated using weight-bearing and non-weight-bearing motion.DesignThree musculoskeletal models were created using OpenSim with different knee axis of rotation (AR): transepicondylar axis (TEA); FAR calculated based on SARA algorithm using a weight-bearing motion (wFAR) and a non-weight-bearing motion (nwFAR). KAM were calculated during gait in fifty-nine subjects (n = 20 healthy, n = 16 early OA, n = 23 established OA) for all models and groups.ResultsSignificant differences between the three groups in the first peak KAM were found when TEA was used (p = 0.038). However, these differences were no longer present when using FAR. In subjects with established OA, KAMs were significantly reduced when using nwFAR compared to TEA models but also compared to wFAR models.ConclusionThe presence of excessive KAM in subjects with established KOA showed to be dependent on the definition of the AR: anatomical versus functional. Therefore, caution should be accounted when comparing KAM in different studies on KOA patients. In patients with end-stage knee OA where increased passive knee laxity is likely to exist, the use of weight-bearing motions should be considered to avoid increased variability in the location and orientation of a FAR obtained from activities with only limited joint loading.