Zebrafish screen identifies novel compound with selective toxicity against leukemia

To detect targeted antileukemia agents we have designed a novel, high-content in vivo screen using genetically engineered, T-cell reporting zebrafish. We exploited the developmental similarities between normal and malignant T lymphoblasts to screen a small molecule library for activity against immature T cells with a simple visual readout in zebrafish larvae. After screening 26 400 molecules, we identified Lenaldekar (LDK), a compound that eliminates immature T cells in developing zebrafish without affecting the cell cycle in other cell types. LDK is well tolerated in vertebrates and induces long-term remission in adult zebrafish with cMYC-induced T-cell acute lymphoblastic leukemia (T-ALL). LDK causes dephosphorylation of members of the PI3 kinase/AKT/mTOR pathway and delays sensitive cells in late mitosis. Among human cancers, LDK selectively affects survival of hematopoietic malignancy lines and primary leukemias, including therapy-refractory B-ALL and chronic myelogenous leukemia samples, and inhibits growth of human T-ALL xenografts. This work demonstrates the utility of our method using zebrafish for antineoplastic candidate drug identification and suggests a new approach for targeted leukemia therapy. Although our efforts focused on leukemia therapy, this screening approach has broad implications as it can be translated to other cancer types involving malignant degeneration of developmentally arrested cells.     

Antidiabetic and antioxidant potentials of spent turmeric oleoresin,a by-product from curcumin production industry

ObjectiveTo investigate the antidiabetic and antioxidant activity of spent turmeric oleoresin (STO).MethodsAntidiabetic activity of STO evaluated by α-amylase and α-glucosidase enzyme inhibition assays. The antioxidant capacity studied by DPPH., ABTS., superoxide radical scavenging and metal chelating activity methods.ResultsThe STO showed good antidiabetic activity by inhibiting key enzymes linked to type 2 diabetes, viz α-glucosidase and α-amylase with an IC50values of 0.71 and 0.16μg/mL respectively. The IC₅₀values for DPPH. and ABTS. assay were 58.1 and 33 μg/mL respectively. STO effectively scavenged the superoxide free radical with an IC50 value of 61.5μg/mL and showed a moderate iron chelation property.ConclusionsThe above study reveals that the spent turmeric oleoresin being wasted at present can be used as antioxidant and antidiabetic agent in food and neutraceutical products.     

The use of nuclear medicine techniques in the emergency department

Nuclear medicine techniques have received little attention in the practice of emergency medicine, yet radionuclide imaging can provide valuable and unique information in the management of acutely ill patients. In this review, emphasis is placed on the role of these techniques in patients with bone injuries, non-traumatic bone pain and in those with pleuritic chest pain. New developments such as single photon emission computed tomography (SPECT) in myocardial infarction are outlined and older techniques such as scrotal scintigraphy are reviewed. Radionuclide techniques are discussed in a clinical context and in relation to alternative imaging modalities or strategies that may be available to the emergency medicine physician. Aspects of a 24 hour nuclear medicine service are considered.     

Preparation and characterization of microencapsulated gelospheres for controlled oral theophylline delivery

Oil-containing polyterephthalamide microcapsules were synthesized by the interfacial polymerization of an oil-soluble monomer (terephthaloyl dichloride, TDC) and a mixture of two water-soluble monomers (diethylenetriamine, DETA, and 1,6-hexamethylenediamine, HMDA). The influence of several synthesis parameters (e.g. concentration ratio of the two amine monomers, stirring rate, concentration of the steric stabilizer PVA) on the size distribution, the membrane morphology and the electrokinetic properties of the microcapsules, was thoroughly investigated. Morphological analysis by electron microscopy showed a strong dependence of the membrane external morphology on the functionality of the water-soluble amine monomer. High stabilizer concentrations and agitation rates during emulsification favoured the production of smaller microcapsules with non-porous and rigid membranes. The electro-chemical interfacial properties of the microcapsules were investigated using a combination of potentiometric, conductimetric and electrokinetic measurements. The dependence of the mean surface charge density on pH revealed the presence of essentially two kinds of chemical groups (e.g. amino and carboxylic groups) on the microcapsule external surface. The total concentration of surface chemical groups and the isoelectric pH were measured as a function of the microcapsule synthesis conditions. Using the experimental data and an appropriate interfacial ionization model, the ratio of the surface groups densities, R = (S -COOH)/ (S -NH+ 3) , was evaluated and rational3 ized with respect to the microcapsules synthesis parameters.     

Awareness,knowledge and views of off‐label prescribing in children: a systematic review

AimThe aim of this review was to provide an updated overview of awareness, knowledge and views of off‐label prescribing in children.MethodA literature search using electronic databases including PubMed, Medline, Scopus, Science Direct, Springer Link, Proquest, Ebsco Host and Google Scholar was conducted. Additional articles were identified by reviewing the bibliography of retrieved articles. The articles were searched with any of the following medical subject headings (MeSH) terms in the title: attitude, awareness, knowledge, experience, view, off‐label, pediatric, paediatric and children. The inclusion criteria were full text articles published in English between January 2004 and February 2015 and reported outcome related to awareness, knowledge and views regarding off‐label prescribing in children. Editorials, reviews, notes, conference proceedings, letters and studies reporting prevalence of off‐label prescribing were excluded. The articles were scrutinized using thematic analysis.ResultsEleven studies conducted among doctors, community pharmacists, paediatric nurses, parents and children met the inclusion criteria. Nine themes were developed through document analysis which included main domains such as knowledge, awareness and views on off‐label drug use in children, choice of information sources, reasons and suggestions to reduce off‐label prescribing, concern regarding obtaining consent and participation in clinical trials.ConclusionThe studies reviewed reported that the majority of doctors and community pharmacists were familiar with the term off‐label prescribing but knowledge among parents was low. Awareness on off‐label prescribing in children remains low among all study participants. There is a mismatch between views on off‐label prescribing in children of study participants and the finding of previous studies.     

Knowledge-based approaches in the design and selection of compound libraries for drug discovery

In the past decade, the pharmaceutical industry has realized the increasing significance of impacting the early phase hit-to-lead development in the drug discovery process. In particular, knowledge-based approaches emerged and evolved to address a multitude of issues such as absorption, distribution, metabolism and excretion (ADME), potency, toxicity and overall drugability. Each of these approaches seeks to bring together all relevant pieces of information and create a knowledge-oriented process to deploy such information in drug discovery. This review focuses on work relating to drugability, which aims at obtaining hits (or leads) that have enhanced likelihoods of leading to successful clinical candidates by medicinal chemistry efforts. The period covered in this review is from 1997 (since the publication of Lipinski's rule of 5) to March 2002.     

Response of Fouling Brown Mussel, Perna perna (L.), to Chlorine

Perna perna (L.), the edible brown mussel, is very widely distributed in the tropical and subtropical regions and is commonly found in rocky shores. Apart from being a candidate for commercial cultivation, P. perna is also a common pest organism in cooling water systems of coastal power stations. Therefore, a lethal and sublethal response of this mussel to commonly used antifouling biocides is of considerable interest to the industry. Mortality pattern (LT₅₀ and LT₁₀₀) and physiological activities (oxygen consumption, filtration rate, foot activity index, and byssus thread production) of different size groups (9–34 mm shell lengths) of P. perna were studied in the laboratory under different residual chlorine concentrations (0.25, 0.50, 0.75, and 1.00 mg/L for sublethal responses and 1, 2, 3, and 5 mg/L for mortality). Results showed that exposure time for 100% mortality of mussels significantly decreased with increasing residual chlorine concentration. For example, mussels of 9 mm size group exposed to 1 mg/L chlorine residual took 384 h (16 days) to reach 100% mortality, whereas those exposed to 5 mg/L chlorine took 84 h (4 days). The effect of mussel size on mortality was significant between 1 mg/L and 5 mg/L residual chlorine, with larger mussels showing greater resistance than smaller ones. For example, at 2 mg/L residual chlorine, 9 mm and 34 mm size group mussels took 228 h (10 days) and 304 h (13 days), respectively, to achieve 100% mortality. All size groups of P. perna showed progressive reduction in physiological activities, when chlorine residuals were gradually increased from 0 to 1 mg/L. Reduction in physiological activities was strongly correlated with the residual level. A comparison of present data with data available for other common fouling organisms suggests that P. perna is relatively less tolerant to chlorine than Perna viridis (L.) and Brachidontes striatulus (Hanley), which also cause fouling problems in tropical coastal waters. Received: 2 May 2002/Accepted: 5 September 2002     

Increased Prevalence of Reduced Estimated Glomerular Filtration Rate in Chronic Hepatitis C Patients

Background  

To investigate the prevalence and severity of reduced estimated glomerular filtration rate (eGFR) in patients with chronic hepatitis C (CHC).     

Closing the Patient–Oncologist Communication Gap: A Review of Historic and Current Efforts

Effective communication is essential in developing any relationship—this is particularly true between oncologists and their patients. The patient–oncologist relationship is one of the most delicate in medicine, and given the strong emotions associated with cancer, successful communication plays a paramount role in the wellbeing of patients and oncologists. Significant advances to close the communication gap have occurred over the past several decades, largely by addressing deficiencies in the various stages of an oncologist's lengthy training: undergraduate medical education, residency and fellowship, and continuing medical education. Stemming from several milestones achieved by highly motivated groups of individuals, including the creation of consensus statements and guidelines by communication education experts, progress has been made to improve patient–oncologist communication. This progress is marked by the development of evidence-based communication skills training programs, such as Oncotalk and Comskil, in addition to the creation of distant-learning modalities, such as the Studying Communication in Oncologist-Patient Encounters trial. This review article outlines the history of communication education during medical education and training, and brings to light more recent efforts to promote competent, communication-minded physicians necessary for effective cancer care.     

Surface-engineered quantum dots for the labeling of hydrophobic microdomains in bacterial biofilms

Quantum dots (QDs) nanoprobes are emerging as alternatives to small-molecule fluorescent probes in biomedical technology. This paper reports an efficient and rapid method of producing highly dispersed and stable CdSe-core QDs with a hydrophobic gradient. Amphiphilic core/shell CdSe/ZnS QDs were prepared by ligand exchange at the surface of lipophilic CdSe/ZnS QDs using the dihydrolipoic acid (DHLA) dithiol ligand linked to leucine or phenylalanine amino acids. Contact angle relaxations on a hydrophobic surface and surface tension measurements indicated that aqueous dispersions of CdSe/ZnS@DHLA-Leu or CdSe/ZnS@DHLA-Phe QDs exhibit increased hydrophobicity compared to CdSe-core QDs capped by the hydrophilic 3-mercaptopropionic acid (MPA) ligand. We found that the surface functional groups and the ligand density at the periphery of these QDs significantly dictated their interactions with a complex biological matrix called biofilm. Using fluorescence confocal microscopy and an autocorrelation function (semi-variogram), we demonstrated that MPA-capped QDs were homogeneously associated to the biopolymers, while amphiphilic CdSe/ZnS@DHLA-Leu or CdSe/ZnS@DHLA-Phe QDs were specifically confined allowing identification of hydrophobic microdomains of the biofilms. Results obtained clearly point out that the final destination of QDs in biofilms can properly be controlled by an appropriate design of surface ligands.