Synthesis and biological activities of aminopyrimidyl-indoles structurally related to meridianins

International audienceThe synthesis of new meridianin derivatives substituted at the C-5 position of the 2-aminopyrimidine ring by various aryl groups and substituted or not by a methyl group on the indole nitrogen is described. These compounds were tested for their kinase inhibitory potencies toward five kinases (CDK5/p25, CK1δ/ε, GSK-3α/β, Dyrk1A and Erk2) as well as their in vitro antiproliferative activities toward a human fibroblast primary culture and two human solid cancer cell lines (MCF-7 and PA 1

Feasibility study of determing a risk assessment model for obstructive sleep apnea in children based on local findings and clinical indicators

Objective: To test a feasible and reliable model for diagnosing obstructive sleep apnea (OSA) in children, based on clinically relevant parameters, in comparison to a polysomnography. Methods: A total of 94 children with the suspected underlying OSA were included in the analyses. An association between clinical parameters (modified Mallampati score, tonsil size, adenoid size, age, gender, and body mass index) and apnea-hypopnea index (AHI) obtained following an overnight polysomnography was assessed, and significant variables were incorporated in the logistic regression model. Also, the sensitivity and specificity calculations of the model with the inclusion of ROC curve analysis were performed. Results: All three local clinical parameters were significantly associated with AHI (p<0.001). The most significant correlation with AHI was shown with the modified Mallampati score (r=0.723), following with tonsil size (r=0.673), and adenoid size (r=0.502). The sensitivity of the tested model was 84%, and specificity was 74%. Conclusion: This study derived a model based on the local clinical findings that significantly overlapped with the results of an overnight polysomnography, in diagnosing OSA in children

Organellar inheritance in the green lineage: insights from Ostreococcus tauri

Along the green lineage (Chlorophyta and Streptophyta), mitochondria and chloroplast are mainly uniparentally transmitted and their evolution is thus clonal. The mode of organellar inheritance in their ancestor is less certain. The inability to make clear phylogenetic inference is partly due to a lack of information for deep branching organisms in this lineage. Here, we investigate organellar evolution in the early branching green alga Ostreococcus tauri using population genomics data from the complete mitochondrial and chloroplast genomes. The haplotype structure is consistent with clonal evolution in mitochondria, while we find evidence for recombination in the chloroplast genome. The number of recombination events in the genealogy of the chloroplast suggests that recombination, and thus biparental inheritance, is not rare. Consistent with the evidence of recombination, we find that the ratio of the number of nonsynonymous to the synonymous polymorphisms per site is lower in chloroplast than in the mitochondria genome. We also find evidence for the segregation of two selfish genetic elements in the chloroplast. These results shed light on the role of recombination and the evolutionary history of organellar inheritance in the green lineage

Spontaneous mutation rate in the smallest photosynthetic eukaryotes

Mutation is the ultimate source of genetic variation, and knowledge of mutation rates is fundamental for our understanding of all evolutionary processes. High throughput sequencing of mutation accumulation lines has provided genome wide spontaneous mutation rates in a dozen model species, but estimates from nonmodel organisms from much of the diversity of life are very limited. Here, we report mutation rates in four haploid marine bacterial-sized photosynthetic eukaryotic algae; Bathycoccus prasinos, Ostreococcus tauri, Ostreococcus mediterraneus, and Micromonas pusilla. The spontaneous mutation rate between species varies from μ = 4.4 × 10−10 to 9.8 × 10−10 mutations per nucleotide per generation. Within genomes, there is a two-fold increase of the mutation rate in intergenic regions, consistent with an optimization of mismatch and transcription-coupled DNA repair in coding sequences. Additionally, we show that deviation from the equilibrium GC content increases the mutation rate by ∼2% to ∼12% because of a GC bias in coding sequences. More generally, the difference between the observed and equilibrium GC content of genomes explains some of the inter-specific variation in mutation rates

Population genomics of picophytoplankton unveils novel chromosome hypervariability

Tiny photosynthetic microorganisms that form the picoplankton (between 0.3 and 3 mm in diameter) are at the base of the food web in many marine ecosystems, and their adaptability to environmental change hinges on standing genetic variation. Although the genomic and phenotypic diversity of the bacterial component of the oceans has been intensively studied, little is known about the genomic and phenotypic diversity within each of the diverse eukaryotic species present. We report the level of genomic diversity in a natural population of Ostreococcus tauri (Chlorophyta, Mamiellophyceae), the smallest photosynthetic eukaryote. Contrary to the expec- tations of clonal evolution or cryptic species, the spectrum of genomic polymorphism observed suggests a large panmictic population (an effective population size of 1.2 × 107) with pervasive evidence of sexual reproduction. De novo assemblies of low-coverage chromosomes reveal two large candidate mating-type loci with suppressed recom- bination, whose origin may pre-date the speciation events in the class Mamiellophyceae. This high genetic diversity is associated with large phenotypic differences between strains. Strikingly, resistance of isolates to large double- stranded DNA viruses, which abound in their natural environment, is positively correlated with the size of a single hypervariable chromosome, which contains 44 to 156 kb of strain-specific sequences. Our findings highlight the role of viruses in shaping genome diversity in marine picoeukaryotes

Orbitalno-kranijska penetrirajuća ozljeda

A case of a 37-year-old female patient is presented. The patient was admitted to the Surgical Emergency Unit after accidental fall on a metal rod when she had sustained stab injury of the right orbit with penetration into the right frontal brain lobe. Multi-slice computed tomography (MSCT) showed penetrating injury and fracture of the right orbital roof without eyeball damage and endocranial impressed bone fragments into the right frontal brain lobe. Urgent surgical intervention was performed by a maxillofacial surgeon and neurosurgeon, including reposition of bone fragments of the orbital roof and cranioplasty. Reconstruction of Tenon’s capsule of the right eyeball was performed by an ophthalmologist. From the intraoperative wound swab of the orbit, Bacillus cereus was isolated, therefore the patient was administered ciprofloxacin and rifampicin as recommended by an infectious disease (ID) specialist. Follow up brain MSCT at 15 days and magnetic resonance imaging of the brain at 25 days showed brain edema in the right frontal area and signs of local brain abscess. Intravenous administration of the ciprofloxacin and metronidazole antibiotics with corticosteroids for edema suppression were ordered by the ID physician. Fourteen weeks after this therapy, brain MSCT showed complete abscess regression and no neurologic deficit with only mild psychomotor changes.Prikazujemo slučaj 37-godišnje bolesnice primljene na hitni kirurški prijam nakon slučajnog pada na metalnu šipku i posljedične ubodne ozljede desne orbite s probojem u desni frontalni režanj mozga. Svijest nije gubila. MSCT je pokazao penetrirajuću ozljedu i frakturu krova desne orbite bez oštećenja očnog bulbusa i endokranijskim imprimatom fragmenata u desni frontalni režanj mozga. Nije bilo znakova edema mozga, ali je bila prisutna proptoza, ptoza i curenje cerebrospinalnog likvora iz lezije konjunktive. Hitan operativni zahvat su izveli maksilofacijalni kirurg i neurokirurg; učinjena je repozicija koštanih fragmenata krova orbite i kranioplastika. Oftalmolog je izveo rekonstrukciju Tenonove kapsule desnog očnog bulbusa. Iz intraoperacijskog obriska rane orbite izoliran je Bacillus cereus te su prema preporuci infektologa ordinirani antibiotici ciprofloksacin i rifampicin. Kontrolni MSCT mozga nakon 15 dana i MRI mozga nakon 25 dana su pokazali edem mozga desne frontalne regije i znakove lokalnog apscesa mozga. Infektolog je ordinirao intravensku primjenu antibiotika ciprofloksacin i metronidazol s kortikosteroidima radi suzbijanja edema. Nakon 14 tjedana antibiotske terapije MSCT mozga je pokazao potpunu regresiju apscesa bez okolnog edema, a bolesnica je bila bez neurološkog deficita s blagim psihomotornim promjenama

An evaluation of indirubin analogues as phosphorylase kinase inhibitors

Phosphorylase kinase (PhK) has been linked with a number of conditions such as glycogen storage diseases, psoriasis, type 2 diabetes and more recently, cancer (Camus S. et al., Oncogene 2012, 31, 4333). However, with few reported structural studies on PhK inhibitors, this hinders a structure based drug design approach. In this study, the inhibitory potential of 38 indirubin analogues have been investigated. 11 of these ligands had IC50 values in the range 0.170 – 0.360 µM, with indirubin-3’-acetoxime (1c) the most potent. 7-bromoindirubin-3’-oxime (13b), an antitumor compound which induces caspase-independent cell-death (Ribas J. et al., Oncogene, 2006, 25, 6304) is revealed as a specific inhibitor of PhK (IC50 = 1.8 µM). Binding assay experiments performed using both PhK-holo and PhK-γtrnc confirmed the inhibitory effects to arise from binding at the kinase domain (γ subunit). High level computations using QM/MM-PBSA binding free energy calculations were in good agreement with experimental binding data, as determined using statistical analysis, and support binding at the ATP-binding site. The value of a QM description for the binding of halogenated ligands exhibiting -hole effects is highlighted. A new statistical metric, the ‘sum of the modified logarithm of ranks’ (SMLR), has been defined which measures performance of a model for both the “early recognition” (ranking earlier/higher) of active compounds and their relative ordering by potency. Through a detailed structure activity relationship analysis considering other kinases (CDK2, CDK5 and GSK-3α/β), 6’(Z) and 7(L) indirubin substitutions have been identified to achieve selective PhK inhibition. The key PhK binding site residues involved can also be targeted using other ligand scaffolds in future work

Ethical issues in healthcare

Sestrinstvo se percipira kao etička struka od samih početaka. Tijekom vremena je neminovno došlo do promjene percepcije etike i etičnosti. Danas se sestra smatra zagovornicom pacijenta (engl. patient advocate) koja pomaže pacijentima kod donošenja kompleksnih odluka. Medicinska sestra i sama nastoji etički postupati u svakodnevnim kliničkim situacijama. Napredak dijagnostike i terapije u medicini je omogućio bolji i kvalitetniji oporavak pacijenata i produljenje životnoga vijeka. Posljedično svekolikom napretku medicine dolazi i do sve učestalijih moralnih i etičkih dvojbi vezanih za pacijentov integritet, boljitak, kvalitetu i cijenu zdravstvene skrbi. Iako se uglavnom općenito zna ili nagađa o postojanju etičke problematike ista nije sistematski istražena i to prvenstveno u smislu vrste i učestalosti. Glavni cilj ovog rada je utvrditi vrstu i pojavnost etičkih problema medicinskih sestara/tehničara te korelirati povezanost etičkih problema s godinama staža u struci, vrstom struke i spolom. U KBCu Split je provedeno presječno istraživanje (engl. cross-sectional study) koje je uključivalo medicinske sestre i tehničare zaposlene u KBC-u a koji su bili voljni sudjelovati u istraživanju i ispuniti upitnik etičkih dvojbi. U istraživanju je korišten obrazac za upis demografskih podataka i upitnik Skala etičkih problema(dvojbi) (engl. Ethical Issues Scale). U ovom istraživanju je potvrđeno postojanje etičkih problema ispitanika. Najčešći etički problemi su iz domene ljudskih prava. Rezultati ovog istraživanja su u suglasju sa rezultatima etičkih istraživanja iz razvijenih država. Nije potvrđena korelacija rezultata s trajanjem radnog staža, dobi i spolom ispitanika. Iako se općenito zna o postojanju etičkih problema sestara isti nisu sistematski istraženi kako u našoj državi tako i u svijetu. Identifikacija etičkih problema je put ka efikasnom rješavanju istih jer neriješeni etički problemi negativno utječu na produktivnost. Etički problemi ovise o individualnom, ali i o organizacijskom aspektu zdravstvenog radnika i zdravstvene ustanove. Najčešći etički problemi medicinskih sestara i tehničara koji su sudjelovali u ovom istraživanju su iz domene problematike u svezi s ljudskim pravima. Takvi rezultati su u suglasju s publiciranim istraživanjima razvijenih država. Temeljem ovih rezultata postoji konkretna osnova za rješavanje tj. ublažavanje etičke problematike.Nursing has been perceived as an ethical profession since its inception. Over time, the perception of ethics inevitably changed. Today, a nurse is considered a patient advocate who helps patients make complex decisions. Nurse tries to act ethically in everyday clinical situations. Advances in diagnostics and therapy in medicine have enabled better recovery of patients and prolongation of life expectancy. As a result, with the progress of medicine, there are much more moral and ethical doubts related to the patient's integrity, well-being, quality and cost of health care, etc. Although it is generally known about the existence of ethical problems it has not been systematically investigated, primarily in terms of type and frequency. The main goal of this work is to determine the type and occurrence of ethical problems of nurses/technicians. Also we wanted to correlate the relationship between ethical problems and years of experience in the profession, type of profession and gender. A cross-sectional study was conducted at University hospital Split, which included nurses and technicians employed at KBC who were willing to participate in the research and fill the Ethical Issues Scale questionnaire. The research used a form for entering demographic data and the Ethical Issues Scale questionnaire. In this research, the existence of ethical problems of the nurses was confirmed. The most common ethical problems are from the domain of human rights. The results of this research are in agreement with the results of ethical research from developed countries. The correlation of the results with the length of service, age and gender of the respondents was not confirmed. Although it is generally known about the existence of ethical problems of nurses, they have not been systematically investigated both in our country and in the world. Identification of ethical problems is the way to their efficient solution. Ethical problems depend on the individual but also on the organizational aspect of the health worker and the health institution. The most common ethical problems of nurses and technicians who participated in this research are from the domain of issues related to human rights. Such results are in agreement with published studies of developed countries. Based on these results, there is a concrete basis for solving, i.e. mitigating, ethical issues