• I can't get no satisfaction after my total knee replacement: rhymes and reasons.

      Dunbar, M J; Richardson, G; Robertsson, O; ] Dalhousie Univ, Halifax, NS B3H 3A7, Canada (British Editorial Soc Bone Joint Surgery, 2013-11)
      Satisfaction is increasingly employed as an outcome measure for a successful total knee replacement (TKR). Satisfaction as an outcome measure encompasses many different intrinsic and extrinsic factors related to a person's experience before and after TKR. The Swedish Knee Arthroplasty Registry has previously demonstrated on a large population study that 17% of TKR recipients are not satisfied with their TKR outcome. This finding has been replicated in other countries. Similar significant factors emerged from these registry studies that are related to satisfaction. It would appear that satisfaction is better after more chronic diseases and whether the TKR results in pain relief or improved function. Importantly, unmet pre-operative expectations are a significant predictor for dissatisfaction following a TKR. It may be possible to improve rates by addressing the issues surrounding pain, function and expectation before embarking on surgery.
    • Ibutilide for treatment of atrial fibrillation in the emergency department

      Viktorsdottir, O; Henriksdottir, A; Arnar, D O (BMJ Pub. Group, 2006-02-01)
      The purpose of this study was to assess the efficacy and safety of ibutilide, a class III antiarrhythmic drug, for acute treatment of atrial fibrillation (AF) in the emergency department (ED) setting. A retrospective analysis was done reviewing all patients with AF who received ibutilide in the ED in a university hospital setting. A total of 22 patients received ibutilide. Another 24 patients who received rate control drugs only served as a control group. Of the 22 patients who received ibutilide, 14 (64%) converted to sinus rhythm. The mean (SD) rate of AF was 137 (24) bpm and the mean QTc interval immediately after conversion to sinus rhythm was 420 (28) ms. There were no complications. In the rate control group 7 patients (29%) converted to sinus rhythm (p<0.05, compared with ibutilide). The mean rate of AF was 126 (26) bpm (p = ns, compared with ibutilide) and the mean QTc interval in those who converted was 377 (28) ms (p<0.05, compared with ibutilide). One patient developed severe bradycardia. Ibutilide is effective for conversion of recent onset AF in patients presenting to the ED and there is a low rate of complications from ibutilide in this setting.
    • IC31, a two-component novel adjuvant mixed with a conjugate vaccine enhances protective immunity against pneumococcal disease in neonatal mice.

      Olafsdottir, T A; Lingnau, K; Nagy, E; Jonsdottir, I; Department of Immunology, Landspitali University Hospital, Reykjavik, Iceland. (Blackwell Scientific Publications, 2009-03-01)
      IC31 is a novel adjuvant which combines the immunostimulatory effects of an 11-mer antibacterial peptide (KLKL(5)KLK) and a synthetic oligodeoxynucleotide (ODN1a) which is a Toll-like receptor 9 agonist without containing cytosine phosphate guanine (CpG) motifs. The effects of IC31 on neonatal immune response to vaccination have not been reported. Neonatal mice were immunized once or twice with a Streptococcus pneumoniae serotype 1 polysaccharide conjugate containing Tetanus Toxoid (Pnc1-TT) carrier protein, with or without IC31 or CpG-ODN. IC31 significantly enhanced IgG1, IgG2a and IgG2b antibodies (Ab) to the serotype 1 polysaccharide. One dose of Pnc1-TT and low dose IC31 elicited high Ab levels that protected the neonatal mice completely from bacteraemia and significantly reduced lung infection following i.n. challenge with serotype 1 pneumococcal strain. One-sixth of an adult murine dose of IC31 was sufficient and optimal for induction of protective immunity in neonatal mice. Two doses of Pnc1-TT with or without adjuvants protected the neonatal mice completely, but more rapid Ab response was observed when IC31 was given with the Pnc1-TT. IC31 is a promising new adjuvant for neonatal vaccinations, rapidly enhancing protective humoral responses when combined with Pnc1-TT.
    • The ice-water test in the diagnosis of detrusor-external sphincter dyssynergia

      Geirsson, G; Fall, M; Dept. of Urology, Reykjavik City Hospital, Iceland. (Taylor & Francis, 1995-12-01)
      The ice-water test (IWT) implies rapid intravesical infusion of 100 ml of sterile ice-water during continuous pressure measurement and registration of fluid leakage. In a typical positive test, there is fluid leakage around the catheter(s) during the peak of detrusor contraction elicited by cold stimulation. Seventy-six patients, the majority with different forms of spinal disorders and a clinical and urodynamically suspected detrusor-external sphincter dyssynergia, were subjected to cystometry, needle electromyography (EMG) and an ice-water test. Detrusor-external sphincter dyssynergia was found in 44 (59%) patients and 41 of them had a positive IWT. A positive test with a high detrusor pressure indicates detrusor-external sphincter dyssynergia whereas the contrary applies to the negative test. Eighteen patients who responded to cold stimulation with detrusor contraction but without fluid leakage, called positive non-leakage IWT, all presented detrusor-external sphincter dyssynergia according to EMG. In this situation, the cheap, non-invasive and simple IWT can replace a needle EMG study.
    • Iceland

      Jakobsson, Finnbogi; Olafsson, Elias (Blackwell Science, 2007-04-01)
      The question Icelandic neurologists get asked most frequently by colleagues visiting our island of 300 000 inhabitants in the North Atlantic is: "How many neurologists are practicing in Iceland?" The answer always raises an eyebrow. There are 13 more or less full-time neurologists, including 10 working at the only university hospital. This relative abundance of neurologists of one for every 25 000 contrasts with one for every 170 000 in the UK, for example.1 The principal hospital in Iceland, the Landspitali University Hospital in the capital Reykjavik, serves as the primary hospital for at least two thirds of the population and as the referral hospital for the rest of the population.
    • The Icelandic 16-electrode electrohysterogram database.

      Alexandersson, Asgeir; Steingrimsdottir, Thora; Terrien, Jeremy; Marque, Catherine; Karlsson, Brynjar; Reykjavik University, School of Science and Engineering , Reykjavik 101, Iceland. 2Landspitali University Hospital, Ob-Gyn department , Reykjavik 101, Iceland. 3Université de Technologie de Compiègne, Biomécanique et Bio-ingénierie , Compiègne 60203, France. (Nature Publishing Group, 2015)
      External recordings of the electrohysterogram (EHG) can provide new knowledge on uterine electrical activity associated with contractions. Better understanding of the mechanisms underlying labor can contribute to preventing preterm birth which is the main cause of mortality and morbidity in newborns. Promising results using the EHG for labor prediction and other uses in obstetric care are the drivers of this work. This paper presents a database of 122 4-by-4 electrode EHG recordings performed on 45 pregnant women using a standardized recording protocol and a placement guide system. The recordings were performed in Iceland between 2008 and 2010. Of the 45 participants, 32 were measured repeatedly during the same pregnancy and participated in two to seven recordings. Recordings were performed in the third trimester (112 recordings) and during labor (10 recordings). The database includes simultaneously recorded tocographs, annotations of events and obstetric information on participants. The publication of this database enables independent and novel analysis of multi-electrode EHG by the researchers in the field and hopefully development towards new life-saving technology.
    • Icelandic and United States families of adolescents with asthma: predictors of health-related quality of life from the parents' perspective.

      Svavarsdottir, Erla K; Burkhart, Patricia V; Rayens, Mary K; Orlygsdottir, Brynja; Oakley, Marsha G; Faculty of Nursing, University of Iceland, Reykjavik, Iceland. eks@hi.is (Wiley, 2011-01)
      AIMS: To evaluate cultural differences in sociodemographic factors, illness severity and parents' perception of their adolescent's quality of life for Icelandic and USA families of adolescents with asthma; and to determine predictors of parent-rated quality of life. BACKGROUND: Asthma is known to have an impact on the quality of life of affected adolescents and their families, but few studies have addressed parents' perception of their adolescent's health-related quality of life. DESIGN: Cross-sectional exploratory study. METHOD: The study involved families of adolescents with asthma included 15 from Iceland and 15 from USA, recruited from paediatric practices. Parent and adolescent participants completed questionnaires; this study is based on the parent responses. Data were collected from January-May 2006. FINDINGS: While parents from Iceland and USA were similar in demographic characteristics, parents from Iceland rated their children's health-related quality of life (PedsQL(TM) 3.0, Varni 1998) more positively than did USA parents, even though Icelandic parents were more likely than their USA counterparts to report that their adolescent's asthma is severe. Significant predictors of parent-rated quality of life included location (higher scores for Icelandic parents), gender (higher scores for parents of boys), exposure to second hand smoke in the home (higher scores for those not exposed) and frequency of troublesome wheezing (higher scores for lower frequency). CONCLUSION: Quality of life has been acknowledged as an essential health outcome measure. Even though gender difference was not found in asthma severity, parents of boys perceived their adolescent's quality of life as more positive compared with parents of girls. It might be helpful for Icelandic and USA families to integrate into care delivery models, cultural differences in parent-rated quality of life. RELEVANCE TO CLINICAL PRACTICE: Asthma management interventions may improve quality of life for adolescents with asthma by reducing symptoms. Interventions promoting smoke-free homes and enhanced self-monitoring to prevent exacerbations may improve quality of life.
    • The Icelandic child mental health study. An epidemiological study of Icelandic children 2–18 years of age using the child behavior checklist as a screening instrument

      Hannesdottir, Helga; Einarsdottir, Sif (Dr. Dietrich Steinkopff Verlag, 1995-10)
      The purpose of this study was to test the applicability of a standardised procedure for assessing Icelandic children's behaviour/emotional problems and competencies, and to identify differences related to demographic variables. This study focuses upon the method of using the Child Behavior Checklist (CBCL) by Achenbach to estimate the reported prevalence by parents and adolescents of emotional and behaviour problems in children from 2-16 years of age and self-reported prevalence of adolescents from 11-18 years, selected at random from the general population, both in urban and rural areas. The information was obtained by mailing checklists with a letter to parents of children 2-10 years of age. The checklists for adolescents 11-18 years of age were distributed by teachers in school. Those adolescents who were not in school received the checklists by mail at their homes. The Child Behavior Checklists used for analyses were completed by 109 parents of 2-3 year old children; 943 parents of 4-16 year old children, and 545 non-referred adolescents from the general population. The rate of response was lowest for the youngest age group, 47%, but increased to 62% with increasing age of the child. The response rate among the adolescents answering the Youth Self Report was 64%. Comparisons with the Child Behavior Checklist from this study are presented with Dutch, American, French, Canadian, German and Chilean samples and show striking similarities in four of these countries on the behaviour/emotional problems reported.
    • Icelandic families with autosomal dominant polycystic kidney disease: families unlinked to chromosome 16p13.3 revealed by linkage analysis

      Fossdal, R; Bodvarsson, M; Asmundsson, P; Ragnarsson, J; Peters, D; Breuning, M H; Jensson, O; Department of Medical Genetics, The Blood Bank, Reykjavík, Iceland. (Springer Verlag, 1993-07)
      We have mainly used 3 highly polymorphic DNA markers, 3'HVR (D16S85), 16AC2.5 (D16S291) and SM7 (D16S283), flanking the PKD1 region on chromosome 16p13.3 to establish linkage status in seven Icelandic families with autosomal dominant polycystic kidney disease (ADPKD). In four families, the disease locus is in the PKD1 region, and three families are "unlinked" to chromosome 16p13.3. In one of the "unlinked" families, the disease locus is excluded from a part of the long arm of chromosome 2, and we support a theory of more than 2 loci being responsible for ADPKD. Our data confirm the location of the locus YNH24 (D2S44) to chromosome 2q13-q24.
    • Icelandic nurses' beliefs, skills, and resources associated with evidence-based practice and related factors: a national survey.

      Thorsteinsson, Hrund S; Univ Hosp, Dept Nursing Profess Practice Dev, Fossvogur, Iceland Univ Iceland, Fac Nursing, Reykjavik, Iceland (Wiley-Blackwell, 2013-05)
      Evidence-based practice (EBP) is essential to the improvement of patient outcomes and the quality of care. Nurses' use of evidence in practice, however, remains limited. Assessing nurses' readiness for EBP where it is not as prominent as in countries leading EBP research was of particular interest.
    • Icelandic translation and reliability data on the DSM-5 version of the schedule for affective disorders and schizophrenia for school-aged children - present and lifetime version (K-SADS-PL).

      Þórðarson, Ólafur; Ævarsson, Friðrik Már; Helgadóttir, Sigríður; Lauth, Bertrand; Wessman, Inga; Sigurjónsdóttir, Steinunn Anna; Smárason, Orri; Harðardóttir, Harpa Hrönn; Skarphedinsson, Gudmundur; 1Reykjavík Municipal Service Centre for Breiðholt, Reykjavík, Iceland. 2Child and Adolescent Psychiatric Unit, Akureyri Hospital, Akureyri, Iceland. 3Department of School and Leisure, Reykjavík, Iceland. 4Reykjavík Municipal Service Centre for Laugadalur and Háaleiti, Reykjavík, Iceland. (Taylor & Francis, 2020-03-05)
      Background: The Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL) is a semi-structured interview based on the Diagnostic and Statistical Manual of Mental Disorders (DSM), and assesses past and present symptoms in children aged 6-18 years old. It has been translated into more than 20 languages and is widely used in clinical work. The K-SADS-PL has recently been revised by adopting new DSM-5 disorders and modifying probes accordingly. However, research on this revision is critically limited. The objective of this study was to examine the inter-rater reliability of the DSM-5 K-SADS-PL when administered by postgraduate students after receiving thorough training and supervision. Method: The DSM-5 K-SADS-PL was applied in a clinical sample of two outpatient units: The outpatient unit of the Department of Child and Adolescent Psychiatry at the Landspítali University Hospital in Reykjavík, Iceland and The Icelandic Anxiety Centre for Children, Adolescents and Young Adults. Results: Fourty-one (80%) consecutive patients aged 6-18 years consented and were included. Cohen's κ was calculated to estimate inter-rater reliability, with estimates ranging from fair to excellent (κ = 0.57-0.90), with most diagnoses in the excellent range (κ > 0.75). Conclusions: These results indicate that the Icelandic translation of the DSM-5 K-SADS-PL can be reliably administered by postgraduate students. Keywords: Inter-rater reliability; K-SADS-PL; clinical sample; paediatric.
    • An Icelandic Version of McMasters Family Assessment Device (FAD)

      Juliusdottir, G. M.; Olafsdottir, H.; 1 ] Landspitali Univ Hosp, Dept Child & Adolescent Psychiat, IS-105 Reykjavik, Iceland, Landspitali National University Hospital [ 2 ] Univ Iceland, Dept Social Work, Reykjavik, Iceland (SAGE Publications, 2014-07-01)
      Purpose: An analysis of the psychometric properties of an Icelandic version of McMasters Family Assessment Device (FAD) was conducted in this study. Method: Two groups, clinical and nonclinical, comprising of 529 parents answered the FAD. The study examined the internal reliability and discriminant validity of the instrument in addition to examining construct validity using exploratory factor analysis (EFA). Results: The theoretically based original FAD is reliable where the total scale had high a , .95. The factors found for the Icelandic FAD were not as reliable as the original FAD. The discriminant validity showed that the clinical group scored higher (more dysfunctional) than the nonclinical group in most dimensions of both original FAD and the Icelandic FAD. The eight factors extracted in an EFA were different from the original factors. Discussion: The Icelandic FAD possesses good psychometric properties, although its factor structure differs from the original FAD. The results are promising and merit continued application.
    • The Icelandic version of the dimensional obsessive compulsive scale (DOCS) and its relationship with obsessive beliefs

      Ólafsson, Ragnar P.; Arngrímsson, Jóhann B.; Árnason, Páll; Kolbeinsson, Þráinn; Emmelkamp, Paul M.G.; Kristjánsson, Árni; Ólason, Daníel Þ.; Department of Psychology, School of Health Sciences, University of Iceland, Iceland Division of Psychiatry, Landspítali-University Hospital, Iceland, Department of Clinical Psychology, University of Amsterdam, Netherlands King Abdulaziz University, Jeddah, Saudi Arabia, Institute of Cognitive Neuroscience, University College London, UK, (Elsevier, 2013)
      The Dimensional Obsessive Compulsive Scale (DOCS) is a self-report instrument to assess severity of OC symptoms along four thematically distinct symptom dimensions. This may carry benefits; both in assessment and for studying the link between OC related beliefs and symptoms. The validity and factor structure of the Icelandic version of the DOCS was investigated in a sample of 547 university students and the congruence between OC related beliefs and symptoms was also compared across different symptom measures (DOCS and OCI-R). Confirmatory factor analysis supported the proposed four-factor structure and a model with a higher-order general severity factor accounting for the inter-relations between the factors. Convergent validity of the scale was supported with moderate to strong correlations with the OCI-R and the Y-BOCS-Self Report version and its symptom checklist. Divergent validity was supported with low to moderate correlations with measures of general anxiety, depression and worry. Regression analyses partly replicated previous results regarding congruence between beliefs and DOCS symptom dimensions. Results did not depend on the symptom measure used. The DOCS has good psychometric properties and may be a useful assessment instrument in both research and clinical settings, although its advantages compared to other self-report measures are not clear.
    • An Icelandic version of the Kiddie-SADS-PL: translation, cross-cultural adaptation and inter-rater reliability

      Lauth, Bertrand; Magnusson, Pall; Ferrari, Pierre; Petursson, Hannes; Department of Child and Adolescent Psychiatry, University of Iceland, Landspitali University Hospital, Reykjavik, Iceland. bertrand@landspitali.is (Taylor & Francis Health Sciences, 2008-10-01)
      The development of structured diagnostic instruments has been an important step for research in child and adolescent psychiatry, but the adequacy of a diagnostic instrument in a given culture does not guarantee its reliability or validity in another population. The objective of the study was to describe the process of cross-cultural adaptation into Icelandic of the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (Kiddie-SADS-PL) and to test the inter-rater reliability of the adapted version. To attain cross-cultural equivalency, five important dimensions were addressed: semantic, technical, content, criterion and conceptual. The adapted Icelandic version was introduced into an inpatient clinical setting, and inter-rater reliability was estimated both at the symptom and diagnoses level, for the most frequent diagnostic categories in both international diagnostic classification systems (DSM-IV and ICD-10). The cross-cultural adaptation has provided an Icelandic version allowing similar understanding among different raters and has achieved acceptable cross-cultural equivalence. This initial study confirmed the quality of the translation and adaptation of Kiddie-SADS-PL and constitutes the first step of a larger validation study of the Icelandic version of the instrument.
    • Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

      Gaudet, Mia M; Kuchenbaecker, Karoline B; Vijai, Joseph; Klein, Robert J; Kirchhoff, Tomas; McGuffog, Lesley; Barrowdale, Daniel; Dunning, Alison M; Lee, Andrew; Dennis, Joe; et al. (Public Library Science, 2013)
      Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.
    • Identification of a breast tumor with microsatellite instability in a potential carrier of the hereditary non-polyposis colon cancer trait

      Bergthorsson, J T; Egilsson, V; Gudmundsson, J; Arason, A; Ingvarsson, S; Department of Pathology, National University Hospital, Reykjavík, Iceland. (Blackwell Publishing Inc, 1995-06)
      Allelic expansion at microsatellite loci in colorectal tumor DNA indicates a genomic instability caused by defects in DNA mismatch repair. This is observed in a high proportion of tumors from individuals affected by hereditary non-polyposis colorectal carcinoma, but to a lesser extent in sporadic colorectal tumors. In this study we screened 46 colorectal tumors for replication errors (RER). Tumors from six patients were found to be RER positive, two of which had a marked family history of colon cancer. In both cases the RER + phenotype was detected in colon tumors from other family members, suggesting a germline mutation in mismatch repair genes. Additionally, RER + phenotype, distinct from that of the colon and sporadic breast tumors, was found in malignant breast tissue from the mother of one proband.
    • Identification of a large set of rare complete human knockouts.

      Sulem, Patrick; Helgason, Hannes; Oddson, Asmundur; Stefansson, Hreinn; Gudjonsson, Sigurjon A; Zink, Florian; Hjartarson, Eirikur; Sigurdsson, Gunnar Th; Jonasdottir, Adalbjorg; Jonasdottir, Aslaug; et al. (Nature Publishing Group, 2015-05)
      Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10-261).
    • Identification of a novel neuregulin 1 at-risk haplotype in Han schizophrenia Chinese patients, but no association with the Icelandic/Scottish risk haplotype.

      Li, T; Stefansson, H; Gudfinnsson, E; Cai, G; Liu, X; Murray, R M; Steinthorsdottir, V; Januel, D; Gudnadottir, V G; Petursson, H; et al. (Nature Publishing Group Specialist Journals, 2004-07-01)
      To determine if neuregulin 1 (NRG1) is associated with schizophrenia in Asian populations, we investigated a Han Chinese population using both a family trio design and a case-control design. A total of 25 microsatellite markers and single nucleotide polymorphisms (SNPs) were genotyped spanning the 1.1 Mb NRG1 gene including markers of a seven-marker haplotype at the 5' end of the gene found to be in excess in Icelandic and Scottish schizophrenia patients. The alleles of the individual markers forming the seven marker at-risk haplotype are not likely to be causative as they are not in excess in patients in the Chinese population studied here. However using unrelated patients, we find a novel haplotype (HAP(China 1)), immediately upstream of the Icelandic haplotype, in excess in patients (11.9% in patients vs 4.2% in controls; P=0.0000065, risk ratio (rr) 3.1), which was not significant when parental controls were used. Another haplotype (HAP(China 2)) overlapping the Icelandic risk haplotype was found in excess in the Chinese (8.5% of patients vs 4.0% of unrelated controls; P=0.003, rr 2.2) and was also significant using parental controls only (P=0.0047, rr 2.1). A four-marker haplotype at the 3' end of the NRG1 gene, HAP(China 3), was found at a frequency of 23.8% in patients and 13.7% in nontransmitted parental haplotypes (P=0.000042, rr=2.0) but was not significant in the case-control comparison. We conclude that different haplotypes within the boundaries of the NRG1 gene may be associated with schizophrenia in the Han Chinese.
    • Identification of anticancer agents based on the thieno[2,3-b]pyridine and 1H-pyrazole molecular scaffolds.

      Eurtivong, Chatchakorn; Reynisdóttir, Inga; Kuczma, Stephanie; Furkert, Daniel P; Brimble, Margaret A; Reynisson, Jóhannes; 1School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. 2Cell Biology Unit, Department of Pathology, Landspítali University Hospital, Reykjavík, Iceland. 3School of Chemical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand. Electronic address: (Elsevier, 2016-08-15)
      Structural similarity search of commercially available analogues of thieno[2,3-b]pyridine and 1H-pyrazole derivatives, known anticancer agents, resulted in 717 hits. These were docked into the phosphoinositide specific-phospholipase C (PLC) binding pocket, the putative target of the compounds, to further focus the selection. Thirteen derivatives of the thieno[2,3-b]pyridines were identified and tested against the NCI60 panel of human tumour cell lines. The most active derivative 1 was most potent against the MDA-MB-435 melanoma cell line with GI50 at 30nM. Also, it was found that a piperidine moiety is tolerated on the thieno[2,3-b]pyridine scaffold with GI50=296nM (MDA-MB-435) for derivative 10 considerably expanding the structure activity relationship for the series. For the 1H-pyrazoles four derivatives were identified using the in silico approach and additionally ten were synthesised with various substituents on the phenyl moiety to extend the structural activity relationship but only modest anticancer activity was found.
    • Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility.

      Mbarek, Hamdi; Steinberg, Stacy; Nyholt, Dale R; Gordon, Scott D; Miller, Michael B; McRae, Allan F; Hottenga, Jouke Jan; Day, Felix R; Willemsen, Gonneke; de Geus, Eco J; et al. (Cell Press, 2016-05-05)
      Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10(-9), and rs17293443 in SMAD3, p = 1.57 × 10(-8)) and replicated (p = 3 × 10(-3) and p = 1.44 × 10(-4), respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.