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1. Metabolic health and obesity: early determinants, trajectories and causal analysis:the Northern Finland Birth Cohort 1966 and 1986 studies

Author: Järvelin, M. (Marjo-Riitta), Miettunen, J. (Jouko), Ruddock, M. (Minna), Nedelec, R. (Rozenn), Järvelin, M. (Marjo-Riitta), Miettunen, J. (Jouko), Ruddock, M. (Minna), and Nedelec, R. (Rozenn)
Abstract: The obesity epidemic has grown over the last four decades in most European countries including Finland where 21.5% of women and 20% of men are now living with obesity. There is a large body of evidence establishing that the first years of life, including the foetal period, are critical for obesity and general health later in life. However, a better understanding of the link between early life determinants and the life-course trajectory of obesity is needed. In this thesis, associations between early life determinants and cardio-metabolically healthy obesity, defined as obesity in the absence of any cardiometabolic disorders, were investigated. The relationships between early life determinants and developmental body mass index (BMI) trajectories were explored. Finally, the associations between temperament traits and cardiovascular health and whether eating behaviours and fitness mediated the associations were examined. The research was conducted on data from the prospective Northern Finland Birth Cohorts 1966 (NFBC1966) and 1986 (NFBC1986) using association analyses, latent trajectory modelling and causal mediation analysis. The first study suggested that early life determinants such as age at adiposity rebound were associated with cardio-metabolically healthy obesity and that the association differed between males and females. In the second study, developmental BMI trajectories were modelled from NFBC1966 and NFBC1986. Adverse maternal factors were associated with unfavourable BMI trajectories. A different pattern of association between age at adiposity peak and BMI trajectories was found between the different cohorts, uncovering secular trends. The third study provided evidence that associations between temperament traits, established early in life, and cardiovascular health measures could be sex-specific. Furthermore, eating behaviours and mediators involved in the associations seemed to be associated with sex. The research undertaken in this thesis provi, Tiivistelmä Lihavuus on yleistynyt viimeisen neljän vuosikymmenen aikana useimmissa Euroopan maissa, myös Suomessa. Suomessa naisista 21,5 % ja miehistä 20 % on ylipainoisia. Aiempien tutkimusten mukaan ensimmäiset elinvuodet, sikiökausi mukaan luettuna, ovat tärkeitä myöhemmän lihavuuden ja yleisen terveyden kannalta. Tieto elämän varhaisvaiheisiin liittyvien tekijöiden ja lihavuuden kehityksen välisestä yhteydestä on kuitenkin puutteellista. Tämän väitöskirjan ensimmäisessä osatyössä tutkittiin elämän varhaisvaiheiden tekijöiden yhteyttä kardiometabolisesti terveeseen lihavuuteen, joka määritellään lihavuudeksi ilman verenkiertoelimistön sairauksia tai niiden tunnettuja riskitekijöitä. Toisessa osatyössä tutkittiin elämän varhaisvaiheiden tekijöiden ja painoindeksin kehityskaarten välisiä suhteita. Viimeisessä osatyössä tutkittiin temperamentin ja metabolisen terveyden, veren rasva-arvojen, välisiä yhteyksiä sekä näiden yhteyksien välittymistä syömiskäyttäytymisen ja fyysisen kunnon kautta. Tutkimus tehtiin Pohjois-Suomen syntymäkohorteissa 1966 (NFBC1966) ja 1986 (NFBC1986) käyttäen assosiaatioanalyysejä, latenttikasvukäyrämallinnusta sekä kausaalisuhdeanalyysejä. Ensimmäisessä osatyössä havaittiin, että elämän varhaisvaiheiden tekijät vaikuttivat kardiometabolisesti terveeseen lihavuuteen. Tällainen tekijä oli esimerkiksi ikä, jossa leikki-ikäisen lapsen painoindeksi on pienin ennen kuin se alkaa jälleen kasvaa (engl. adiposity rebound). Vaikutus oli kuitenkin erilainen miehillä ja naisilla. Toisessa tutkimuksessa painoindeksin kehityskaaret mallinnettiin NFBC1966 ja NFBC1986 -kohorteissa. Äidin tupakointi ja raskautta edeltänyt korkeampi painoindeksi olivat yhteydessä lapsen epäsuotuisaan painoindeksin kehityskaareen. Yhteys imeväisiän painoindeksin kasvukäyrän huipun ajoittumisen ja mallinnetun painoindeksin kehityskaaren välillä oli kohorteissa erilainen, mikä viittaa aikakaudellisiin ympäristön vaikutuksiin. Kolmannessa työssä tutkittiin erilaisia temperamen
Published: 2023

2. Well-being needs of elite sports coaches

Author: Ruddock, M. and Donaldson, A.
Published: 2024
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3. Improving sleep in a population at high risk of trauma: A pilot study examining self-reported sleep, psychological symptomology and actigraphy measured night-time sleep

Author: Maguire, D., primary, Armour, C., additional, Lagdon, S., additional, Ruddock, M., additional, Moore, T., additional, and Milanak, M., additional
Published: 2022
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4. Royal academy of medicine in Ireland section of biomedical sciences: Proceedings of winter meeting held in Trinity College Dublin, 1996

Author: Sharma, S., Sharma, S. C., Byrne, P. D., Lyons, J. B., Boylan, J. F., McShane, A. J., Galligan, E. S., Sweetman, S. F., Clements, B. A., Lowe, A. S., McCormack, K. J. M., Walsh, D. M., Baxter, G. D., Allen, J. M., Kelleher, S., Keenan, A. K., Burns, D. M., Brown, J. C. W., Ruddock, M. W., Kennovin, G. D., Dykes, E. L., Flitney, F. W., Hirst, D. G., Winter, D. C., Cuffe, J., O’Sullivan, G. C., Harvey, B. J., Thompson, G. H., Murray, J. M., Brehony, F., Kelly, J. P., Leonard, B. E., Cotton, K. D., Hollywood, M. A., McHale, N. G., Thornbury, K. D., Stapleton, M. T., Allshire, A. P., Freeburn, J. C., Wallace, J. M. W., Sinnamon, D., Craig, B., Strain, J. J., Gilmore, W. S., Lyons, J. D. M, Murray, J., Trinick, T., Fee, J. P. H., Hennessy, L., Watson, A. W. S., Halley, W. L., Weir, M. A., Friery, O. P., Hejmadi, M. V., McIntyre, I. A., McALeer, J. J. A., Patterson, L. H., McKeown, S. R., Leckey, J. L., Nevin, G. B., Soppitt, D. S., Harkin, A. J., Wrynn, A. S., Earley, B., Dineen, T. M., Powell, R., Houghton, J. A., Cantillon, D., McDaid, J., O’Halloran, K. D., Bradford, A., Curran, A. K., Harmon, D., Sweeney, M., McLoughlin, P., O’Leary, D., O’Connor, J. J., Broderick, A. M., Keon, N., and Martin, F.
Published: 1996
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5. Whole exome sequencing in identifying genetic factors in musculoskeletal diseases

Author: Ruddock, M. (Minna), Skarp, S. (Sini), Ruddock, M. (Minna), and Skarp, S. (Sini)
Abstract: Musculoskeletal diseases, such as osteoarthritis (OA), lumbar disc degeneration (LDD) and osteoporosis (OP), are common complex disorders affected by both environmental and genetic factors. OA and LDD are degenerative diseases affecting joints and spine and Modic changes (MC) are a specific phenotype of LDD. OP is a disorder causing bone fragility. There are families with a history of early onset cartilage degradation, disc disorders and bone fragility as well as rare, more severe disorders with these traits as part of the phenotype. The aim of this study was to identify predisposing genetic factors in Finnish families with three different musculoskeletal phenotypes and to investigate the use of whole exome sequencing (WES) as a tool. Six families were studied here, three diagnosed with hip and knee OA, two with MC and one with primary OP. Using WES together with in silico and in vitro analyses we identified new candidate genes. In the two OA families we identified family specific variants, c.-127G>T in the 5’UTR of FIP1L1 and p.Arg210Gly in OLIG3. We observed expression of these genes in human bone and cartilage. Both FIP1L1 and OLIG3 participate in the regulation of transcription. Family specific variants were also found in both families with MC: p.Gln1611fs in HSPG2 and p.Glu553Lys in MAML1. HSPG2 encodes for an important structural protein in the disc and MAML1 is a transcription factor. The family with primary OP had previously been reported to carry a heterozygous COL1A2 deletion leading to nonsense-mediated mRNA decay. In the WES we identified an additional change that may contribute to the phenotype: p.Arg428* in ZNF528. We showed experimentally that the variant leads to expression of a truncated form of ZNF528 in the nucleus. ZNF528 binding sites are located near genes associated with bone phenotypes. We identified twelve potential target genes for ZNF528 that were differentially expressed in patients’ cells compared to controls. Altogether, we ide, Tiivistelmä Tuki- ja liikuntaelinsairaudet, kuten nivelrikko, välilevyrappeuma ja osteoporoosi, ovat yleisiä, monitekijäisiä sairauksia. Nivelrikko ja välilevynrappeuma ovat eteneviä nivelten ja selkärangan sairauksia. Modic muutokset ovat välilevyn ja nikaman välisten päätelevyjen muutoksia. Osteoporoosi on luuta haurastuttava sairaus. Varhaisessa iässä ilmenevää ruston haurastumista, välilevyn sairauksia tai luun haurautta tavataan myös suvuittain esiintyvinä sairauksina tai vakavien harvinaisten sairauksien oireina. Tutkimuksen tarkoitus oli tunnistaa altistavia geneettisiä tekijöitä kolmelle tuki- ja liikuntaelimistön sairaudelle suomalaisissa perheissä käyttäen eksomisekvensointi-menetelmää. Aineisto koostui kuudesta perheestä: kolmessa oli diagnosoitu lonkan ja polven nivelrikko, kahdessa selän välilevyjen Modic muutoksia ja yhdessä primaarinen vaikea selän osteoporoosi. Tunnistimme uusia ehdokasgeenejä käyttäen eksomisekvensointi-menetelmää sekä in silico ja in vitro analyysejä. Kahdessa nivelrikkoperheessä tunnistimme perhekohtaiset variantit kahdessa geenissä: c.-127G>T variantin FIP1L1 geenin säätelyalueella ja p.Arg210Gly variantin OLIG3 geenissä. Osoitimme, että nämä traskription säätelyyn osallistuvat geenit ilmenevät ihmisen luu- ja rustokudoksessa. Perhekohtaiset variantit havaittiin myös perheissä, joilla oli todettu Modic muutoksia: p.Gln1611fs HSPG2 -geenissä ja p.Glu553Lys MAML1 -geenissä. HSPG2 koodaa välilevylle tärkeää rakenneproteiinia ja MAML1 on transkriptiota säätelevä tekijä. Primaarista osteoporoosia sairastavalla perheellä oli aiemmin havaittu heterotsygootti, geenituotteen hajottamiseen johtava deleetio, COL1A2 -geenissä. Eksomisekvensoinnlla havaitsimme mahdollisesti taudin ilmiasuun lisäksi vaikuttavan muutoksen ZNF528 -geenissä. Osoitimme kokeellisesti, että havaittu variantti johtaa lyhentyneen proteiinin tuottoon solussa. ZNF528 on transkriptiotekijä, jolle tunnistimme kaksitoista mahdollista kohdegeeniä ja havaitsimme että niiden
Published: 2019

6. Risk factors for sciatica

Author: Karppinen, J. (Jaro), Heliövaara, M. (Markku), Ruddock, M. (Minna), Euro, U. (Ulla), Karppinen, J. (Jaro), Heliövaara, M. (Markku), Ruddock, M. (Minna), and Euro, U. (Ulla)
Abstract: Sciatica is a common musculoskeletal disorder, especially among the working-age population. It causes huge costs to society through work absenteeism and hospital treatments. The common cause of sciatica is the herniated lumbar disc compressing the nerve root. The neurological deficit resulting from this compression can be either sensory or motor-related. Earlier studies have shown both genetic and environmental factors to exist in the aetiology of sciatica. The aim of this study was to investigate how individual, physical and work-related risk factors associate with sciatica, and to determine the prevalence of sciatic pain among Finnish adolescents. The data used in this study were from large, population-based Finnish surveys: the Northern-Finland Birth Cohort 1986, the Mobile Clinic Health Examination Survey, the Mini-Finland Health Survey, Health 2000, the Young Finns Study, and the Helsinki Health Studies. The results of this study showed that sciatic symptoms are already common among adolescents. Young women in particular reported sciatic pain more often than men. Low back pain at the age of 16 predicted sciatic pain at the age of 18. Physically demanding work, smoking and obesity were found to predict an increased risk of hospitalization for sciatica. In the Mobile Clinic Health Examination Survey, leisure-time physical activity protected men from hospitalization for sciatica, whereas among women obesity increased this risk. Occupation also modified the effects of various risk factors. In the Mini-Finland Health Survey, overweight and obese participants who had been exposed to whole body vibration in their work were at a higher risk of hospitalization due to sciatica. In addition, lifting and carrying heavy objects at work, or sedentary work involving the handling of heavy objects predicted an increased risk of hospitalization for sciatica. Heavy or very heavy work protected against hospitalization for sciatica. A meta-analysis of four prospective coho, Tiivistelmä Iskias on etenkin työikäisten keskuudessa yleinen sairaus, joka aiheuttaa paljon työkyvyttömyyttä ja sairaalahoitoja ja siten kustannuksia yhteiskunnalle. Iskiaksen taustalla on yleensä välilevyn pullistuma, joka painaa hermojuuria. Hermojuuren puristuksesta aiheutuva neurologinen puutosoire voi olla joko sensorinen tai motorinen. Aiemmat tutkimukset ovat osoittaneet iskiaksen taustalla olevan sekä geneettisiä että ympäristötekijöitä. Tämän tutkimuksen tavoitteena oli selvittää yksilöllisten, fyysisten ja työhön liittyvien riskitekijöiden yhteyttä iskiakseen sekä tutkia iskiaskivun yleisyyttä suomalaisilla nuorilla aikuisilla. Aineistoina tutkimuksessa käytettiin laajoja väestöpohjaisia suomalaisia aineistoja: Pohjois-Suomen syntymäkohorttia 1986, Autoklinikka- ja Mini-Suomi-aineistoja sekä Terveys 2000-, Young Finns- ja Helsinki Health Study -tutkimuksia. Tutkimuksessa selvisi, että iskiasoireet ovat yleisiä jo nuorilla aikuisilla ja etenkin naiset raportoivat iskiaskipua useammin miehiin verrattuna. 16-vuotiaana ilmennyt alaselkäkipu oli myös yhteydessä iskiasoireisiin 18 vuoden iässä. Työn fyysisen rasittavuuden, tupakoinnin ja lihavuuden todettiin lisäävän sairaalahoitoon johtaneen iskiaksen riskiä. Autoklinikka-aineistossa vapaa-ajan fyysinen aktiivisuus suojasi miehiä sairaalahoitoon johtaneelta iskiakselta, naisilla taas ylipaino lisäsi iskiaksen riskiä. Lisäksi ammatti näytti muokkaavan riskitekijöiden assosiaatioita. Mini-Suomi-aineistossa ylipainoiset ja lihavat henkilöt, jotka olivat altistuneet työssään koko kehon tärinälle, olivat korkeammassa riskissä sairaalahoitoon johtaneen iskiaksen suhteen. Töissä raskaiden esineiden nostaminen tai kantaminen tai painavien esineiden käsittelyä sisältävä istumatyö lisäsivät myös iskiaksen riskiä. Raskas tai erittäin raskas fyysinen työ taas näytti suojaavan sairaalahoitoon johtaneelta iskiakselta. Neljän prospektiivisen kohorttitutkimuksen meta-analyysissä selvisi, että työmatkapyöräily tai -kävely vähe
Published: 2019

7. Genetics and molecular epidemiology of metabolic syndrome-related traits:focus on metabolic profiling of lipid-lowering therapies and fatty liver, and the role of genetic factors in inflammatory load

Author: Ruddock, M. (Minna), Sebert, S. (Sylvain), Kettunen, J. (Johannes), Sliz, E. (Eeva), Ruddock, M. (Minna), Sebert, S. (Sylvain), Kettunen, J. (Johannes), and Sliz, E. (Eeva)
Abstract: Metabolic syndrome is a constellation of metabolic abnormalities predisposing to cardiovascular diseases (CVD), type 2 diabetes, and increased mortality. Due to the high prevalence and severe co-morbidities, metabolic syndrome constitutes a major burden for both public health and the global economy. Improved understanding of the detailed molecular mechanisms could provide novel strategies for the treatment and preferably prevention of the metabolic syndrome-related health issues. Recent advancements in ‘omics’ technologies have facilitated the development of novel tools to examine the links between genetic variation and human health. The new techniques allow determination of millions of genotypes or quantification of hundreds of metabolic measures from a single blood sample. In this thesis, genomics and metabolomics approaches are coupled to improve our understanding of the metabolic syndrome-related health issues. More precisely, my projects evaluate the metabolic effects of two lipid-lowering therapies and non-alcoholic fatty liver, as well as assess genetic determinants of chronic inflammation. The present results indicate generally consistent metabolic effects of statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) genetic inhibition. The subtle discrepancies observed could potentially contribute to differences in the efficacy to lower CVD risk between statins and PCSK9 inhibitors. The dissimilar metabolic effects of the four genetic variants that increase the risk of non-alcoholic fatty liver disease (NAFLD) highlight the heterogeneity of the molecular mechanisms involved in NAFLD pathogenesis. The results further suggest that fatty liver by itself might not promote unfavourable metabolic aberrations associated with fatty liver on a population level. The newly identified loci associating with inflammatory phenotypes elucidate the genetic mechanisms contributing to the inflammatory load. In particular, the present results suggest the import, Tiivistelmä Metabolinen oireyhtymä on tila, jossa useiden aineenvaihdunnallisten riskitekijöiden kasautuminen suurentaa riskiä sairastua tyypin 2 diabetekseen ja sydän- ja verisuonitauteihin sekä lisää kokonaiskuolleisuutta. Vakavista liitännäissairauksista ja suuresta esiintyvyydestä johtuen metabolinen oireyhtymä kuormittaa merkittävästi sekä terveydenhuoltoa että kansantaloutta. Jotta metabolisen oireyhtymän hoitoon ja ennaltaehkäisyyn voitaisiin kehittää uusia keinoja, on tärkeää ymmärtää paremmin oireyhtymän syntyyn vaikuttavat täsmälliset molekyylimekanismit. Niin sanottujen ’omiikka-tekniikoiden’ viimeaikainen kehitys tarjoaa uusia mahdollisuuksia tutkia geenimuutosten vaikutuksia terveyteen. Uusien tekniikoiden avulla voidaan määrittää miljoonia genotyyppejä tai satoja aineenvaihdunnan merkkiaineita yhdestä verinäytteestä. Tässä väitöskirjatyössä yhdistetään genomiikan ja metabolomiikan menetelmiä metaboliseen oireyhtymään liittyvien terveysongelmien tutkimiseksi. Väitöskirjani osatöissä arvioin kahden lipidilääkkeen sekä ei-alkoholiperäisen rasvamaksan aineenvaihdunnallisia vaikutuksia sekä pyrin tunnistamaan krooniseen tulehdukseen vaikuttavia geneettisiä tekijöitä. Tulosten mukaan statiinien ja PCSK9:n (engl. proprotein convertase subtilisin/kexin type 9) geneettisen eston aineenvaihduntavaikutukset ovat hyvin samankaltaiset. Kuitenkin havaitut pienet poikkeavuudet tietyissä merkkiaineissa voivat vaikuttaa eroavaisuuksiin siinä, kuinka tehokkaasti lääkeaineet alentavat sydäntautiriskiä. Suuret erot rasvamaksan riskiä lisäävien geenimuutosten vaikutuksissa aineenvaihduntaan korostavat rasvamaksaan liittyvien molekyylimekanismien monimuotoisuutta. Tulosten perusteella vaikuttaa siltä, että rasvan kertyminen maksaan ei luultavasti itsessään aiheuta suuria muutoksia verenkierron aineenvaihduntatuotteiden pitoisuuksiin. Tulehdusmerkkiaineisiin assosioituvat uudet geenialueet täydentävät tulehduksen molekyylimekanismeihin liittyvää tietoa. Tulokset korostavat A
Published: 2019

8. A comparison of the clinical effectiveness and cost of specialised individually delivered parent training for preschool attention-deficit/hyperactivity disorder and a generic, group-based programme: a multi-centre, randomised controlled trial of the New Forest Parenting Programme versus Incredible Years

Author: Sonuga-Barke, EJS, Barton, J, Daley, D, Hutchings, J, Maishman, T, Raftery, J, Stanton, L, Laver-Bradbury, C, Chorozoglou, M, Coghill, D, Little, L, Ruddock, M, Radford, M, Yao, GL, Lee, L, Gould, L, Shipway, L, Markomichali, P, McGuirk, J, Lowe, M, Perez, E, Lockwood, J, Thompson, MJJ, Sonuga-Barke, EJS, Barton, J, Daley, D, Hutchings, J, Maishman, T, Raftery, J, Stanton, L, Laver-Bradbury, C, Chorozoglou, M, Coghill, D, Little, L, Ruddock, M, Radford, M, Yao, GL, Lee, L, Gould, L, Shipway, L, Markomichali, P, McGuirk, J, Lowe, M, Perez, E, Lockwood, J, and Thompson, MJJ
Abstract: The objective of this study is to compare the efficacy and cost of specialised individually delivered parent training (PT) for preschool children with attention-deficit/hyperactivity disorder (ADHD) against generic group-based PT and treatment as usual (TAU). This is a multi-centre three-arm, parallel group randomised controlled trial conducted in National Health Service Trusts. The participants included in this study were preschool children (33-54 months) fulfilling ADHD research diagnostic criteria. New Forest Parenting Programme (NFPP)-12-week individual, home-delivered ADHD PT programme; Incredible Years (IY)-12-week group-based, PT programme initially designed for children with behaviour problems were the interventions. Primary outcome-Parent ratings of child's ADHD symptoms (Swanson, Nolan & Pelham Questionnaire-SNAP-IV). Secondary outcomes-teacher ratings (SNAP-IV) and direct observations of ADHD symptoms and parent/teacher ratings of conduct problems. NFPP, IY and TAU outcomes were measured at baseline (T1) and post treatment (T2). NFPP and IY outcomes only were measured 6 months post treatment (T3). Researchers, but not therapists or parents, were blind to treatment allocation. Analysis employed mixed effect regression models (multiple imputations). Intervention and other costs were estimated using standardized approaches. NFPP and IY did not differ on parent-rated SNAP-IV, ADHD combined symptoms [mean difference - 0.009 95% CI (- 0.191, 0.173), p = 0.921] or any other measure. Small, non-significant, benefits of NFPP over TAU were seen for parent-rated SNAP-IV, ADHD combined symptoms [- 0.189 95% CI (- 0.380, 0.003), p = 0.053]. NFPP significantly reduced parent-rated conduct problems compared to TAU across scales (p values < 0.05). No significant benefits of IY over TAU were seen for parent-rated SNAP, ADHD symptoms [- 0.16 95% CI (- 0.37, 0.04), p = 0.121] or parent-rated conduct problems (p > 0.05). The cost per family of providing NFPP in the trial was
Published: 2018

9. The heritability and genetic risk factors of Modic changes

Author: Ruddock, M. (Minna), Karppinen, J. (Jaro), Kraatari, M. (Minna), Ruddock, M. (Minna), Karppinen, J. (Jaro), and Kraatari, M. (Minna)
Abstract: Low back pain (LBP) is a highly prevalent musculoskeletal condition and the leading cause for workplace absenteeism. Lumbar disc degeneration (DD) is considered as a contributing factor to LBP. The role of genetic factors in the development of lumbar DD has been demonstrated to be significant, with heritability estimates ranging from 64% to 81%. Modic change (MC), a distinct phenotype of lumbar DD, is a subchondral and vertebral bone marrow change revealed only by magnetic resonance imaging (MRI). MC has been associated with LBP in both clinical samples and the general population. The genetic background of MC is largely unknown, and the heritability of MC has not previously been assessed. The aim of this study was to assess the heritability of MC using a twin study, identify predisposing genetic factors for MC in a family-based design using whole-exome sequencing and to identify genetic loci associated with MC using genome-wide association study (GWAS) meta-analysis. An additional aim was to study the prevalence, incidence and morphology of MC. The data consisted of two general population samples, the Northern Finland Birth Cohort 1966 (NFBC1966) and TwinsUK from the United Kingdom, as well as two Finnish families from the Oulu region. MC was found to be partly heritable with a heritability estimate of 30%. Two novel candidate genes, HSPG2 and MAML1, were found co-segregating with MC in two Finnish families. Both genes are important in the growth and differentiation of chondrocytes. Finally, a genetic locus on chromosome 9 was found to be significantly associated with MC using genome-wide meta-analysis of NFBC1966 and TwinsUK. These results showed that genetic factors play a role in the development of MC. In conclusion, this thesis increased the knowledge on the genetics of MC. However, the specific roles of these genes need to be studied further., Tiivistelmä Alaselkäkivun kansaterveydellinen merkitys on suuri, sillä jopa 84% aikuisista kärsii siitä elämänsä aikana. Selkäkivun vuoksi Suomessa kertyy yli 2 miljoona sairauslomapäivää vuodessa. Välilevyrappeumaa pidetään merkittävänä tekijänä alaselkäkivun synnyssä ja perinnölliset tekijät selittävät välilevyrappeuman synnystä jopa 74%. Modic-muutokset ovat selkärangan välilevyjen päätelevyjen ja subkondraalisen luun muutoksia, jotka voidaan havaita ainoastaan magneettikuvauksella. Niitä pidetään välilevyrappeuman alatyyppinä. Modic-muutosten on osoitettu olevan yhteydessä alaselkäkipuun, mutta etiologia tunnetaan huonosti. Perinnöllisyyden osuutta Modic-muutoksien synnyssä ei ole aiemmin tutkittu ja niiden taustalla vaikuttavat geneettiset tekijät ovat pääasiassa tuntemattomia. Tämän tutkimuksen tavoitteena oli arvioida perinnöllisyyden osuutta Modic-muutoksissa kaksoisaineistossa, tunnistaa Modic-muutoksille altistavia geneettisiä muutoksia perheaineistossa käyttäen eksomisekvensointia ja tunnistaa genomin alueita, jotka assosioituvat Modic-muutoksiin. Tutkimus perustui kahteen väestöperäiseen aineistoon: Pohjois-Suomen Syntymäkohorttiin 1966 ja TwinsUK-kaksosaineistoon Yhdistyneistä kuningaskunnista sekä kahteen pohjois-suomalaiseen perheeseen. Tutkimuksessa osoitettiin, että Modic-muutokset ovat perinnöllisiä ja, että perinnölliset tekijät selittävät noin 30% niiden ilmenemisestä. Lisäksi tutkimuksessa tunnistettiin kaksi uutta alttiusgeeniä; HSPG2- ja MAML1-geenit. Molemmilla geeneillä on tärkeä rooli rustosolujen kasvamisessa ja erilaistumisessa. Tutkimuksessa myös tunnistettiin kromosomista 9 genomin alue, joka assosioituu Modic-muutoksiin. Väitöskirjassani osoitettiin, että perinnöllisillä tekijöillä on merkitystä Modic-muutosten synnyssä. Kokonaisuudessaan tämä väitöskirja kasvattaa ymmärrystä Modic-muutoksista, mutta lisätutkimusta aiheesta tarvitaan.
Published: 2018

10. The breeding population of Peregrine Falcon Falco peregrinus in the United Kingdom, Isle of Man and Channel Islands in 2014

Author: Wilson, M. W., primary, Balmer, D. E., additional, Jones, K., additional, King, V. A., additional, Raw, D., additional, Rollie, C. J., additional, Rooney, E., additional, Ruddock, M., additional, Smith, G. D., additional, Stevenson, A., additional, Stirling-Aird, P. K., additional, Wernham, C. V., additional, Weston, J. M., additional, and Noble, D. G., additional
Published: 2018
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11. The breeding population of Peregrine Falcon <italic>Falco peregrinus</italic> in the United Kingdom, Isle of Man and Channel Islands in 2014.

Author: Wilson, M. W., Balmer, D. E., Jones, K., King, V. A., Raw, D., Rollie, C. J., Rooney, E., Ruddock, M., Smith, G. D., Stevenson, A., Stirling-Aird, P. K., Wernham, C. V., Weston, J. M., and Noble, D. G.
Abstract: Capsule: Overall numbers of Peregrines are higher than previously recorded, due primarily to the growth of lowland populations, despite declines in many upland areas. Aims: To estimate the breeding population of Peregrines, and changes in this population over time, as well as to relate variation in trends and observed breeding success to variation in region, breeding site type and other ecological influences. Methods: Two types of survey methods were used. Site-based visits focussed on locations where Peregrines were known to have bred previously, while area-based searches aimed to find all Peregrines breeding in randomly chosen 5 km × 5 km squares. Findings from each method were used to estimate population size in different parts of the survey area. Breeding outcome and site type were assessed for most of the pairs found during either survey. Results: In 2014, the breeding population of Peregrines in the UK, Isle of Man and Channel Islands was estimated at 1769 pairs. This is 22% larger than the population estimate from the previous survey in 2002. Most of this increase is accounted for by increases in lowland England. Populations in some upland areas have declined. Conclusions: The gap between the fortunes of lowland and upland Peregrines has continued to grow, along with the overall UK population. Likely reasons for the continued success of Peregrines in the lowlands include increasing uptake of breeding sites on human structures, abundant availability of prey in many lowland situations and, in many areas, a relative lack of conflict with humans. Factors likely to be limiting upland Peregrine populations vary between different regions, and include ongoing illegal killing and deliberate disturbance, and food supply. [ABSTRACT FROM AUTHOR]
Published: 2018
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12. Biomarkers That Differentiate Benign Prostatic Hyperplasia from Prostate Cancer: A Literature Review

Author: McNally CJ, Ruddock MW, Moore T, and McKenna DJ
Subjects: prostate cancer, benign prostatic hyperplasia, biomarkers, differentiation, trans-rectal ultrasound guided biopsy, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: Christopher J McNally,1,2 Mark W Ruddock,1 Tara Moore,2 Declan J McKenna2 1Randox Laboratories Ltd, Crumlin, Co. Antrim BT29 4QY, Northern Ireland; 2Biomedical Sciences Research Institute, Ulster University, Coleraine BT52 1SA, Northern IrelandCorrespondence: Declan J McKenna Tel +44 2870124356Email dj.mckenna@ulster.ac.ukAbstract: Prediction of prostate cancer in primary care is typically based upon serum total prostate-specific antigen (tPSA) and digital rectal examination results. However, these tests lack sensitivity and specificity, leading to over-diagnosis of disease and unnecessary, invasive biopsies. Therefore, there is a clinical need for diagnostic tests that can differentiate between benign conditions and early-stage malignant disease in the prostate. In this review, we evaluate research papers published from 2009 to 2019 reporting biomarkers that identified or differentiated benign prostatic hyperplasia (BPH) from prostate cancer. Our review identifies hundreds of potential biomarkers in urine, serum, tissue, and semen proposed as useful targets for differentiating between prostate cancer and BPH patients. However, it is still not apparent which of these candidate biomarkers are most useful, and many will not progress beyond the discovery stage unless they are properly validated for clinical practice. We conclude that this validation will come through the use of multivariate panels which can assess the value of biomarker candidates in combination with clinical parameters as part of a risk prediction calculator. Implementation of such a model will help clinicians stratify patients with prostate cancer symptoms in primary care, with tangible benefits for both the patient and the health service.Keywords: prostate cancer, benign prostatic hyperplasia, biomarkers, differentiation, transrectal ultrasound-guided biopsy
Published: 2020

13. Thrombomodulin Expression in Bladder Cancer Tissue and Its Association with Prognosis and Patient Survival

Author: Watt J, Maguire DG, Reid CN, Lamont JV, Fitzgerald SP, and Ruddock MW
Subjects: transitional urothelial carcinoma, tissue microarrays, immunohistochemistry, bladder cancer., Diseases of the genitourinary system. Urology, RC870-923
Abstract: Joanne Watt, Daniel G Maguire, Cherith N Reid, John V Lamont, Stephen P Fitzgerald, Mark W Ruddock Randox Laboratories Ltd, Molecular Biology, Crumlin, County Antrim BT29 4QY, Northern Ireland, UKCorrespondence: Mark W RuddockRandox Laboratories Ltd, Molecular Biology, 55 Diamond Road, Crumlin, County Antrim BT29 4QY, Northern Ireland, United KingdomTel +44 28 9442 2413Fax +44 28 9445 2912Email Mark.Ruddock@randox.comBackground: Decreased expression of thrombomodulin (TM) in bladder cancer tissue has been shown to be associated with cell proliferation, increased malignancy and a poor prognosis. The aim of this study was to investigate the immunoexpression of TM in bladder tissue cores by immunohistochemistry (IHC) and the relationship between TM score and patient survival for the following pathologies: transitional cell papillary carcinoma (TCPC), transitional cell carcinoma (non-papillary) (TCC), squamous cell carcinoma (SCC), adenocarcinoma, and sarcoma. TM immunoexpression was also evaluated in normal adjacent bladder tissue cores.Methods: TM immunoexpression was assessed in n=185 formalin-fixed paraffin-embedded (FFPE) bladder tissue cores from n=98 patients by IHC. Tissue cores included TCPC (n=29), TCC (n=85), SCC (n=21), adenocarcinoma (n=12), sarcoma (n=4), and normal tissue cores (n=34).Results: TM immunoexpression scores are stronger in TCPC, TCC and SCC bladder cancer tissue cores with respect to adenocarcinoma and sarcoma (mean TM immunoexpression scores: 3.04, 2.57, 2.55, 1.55 and 1.19, respectively) (Kruskal–Wallis p< 0.001). TM immunoexpression scores significantly decreased in bladder cancer tissue cores across both stage (p< 0.001) and grade (p< 0.001) (Kruskal–Wallis). Survival data were available for n=45 bladder cancer patients (mean follow-up of 34 months). Applying a TM immunoexpression cut-off score of 3.0 demonstrated that patients with bladder cancer who had a TM immunoexpression score < 3.0 had lower survival rates (median survival 23.5 months). In contrast, patients with TM immunoexpression scores ≥ 3.0 had longer survival rates (median survival 40 months) (log-rank; p=0.045).Conclusion: TM immunoexpression in bladder cancer tissue may be a clinically relevant predictor of tumor progression and survival. Low expression of TM in bladder cancer biopsies or in recurrent bladder cancer may be indicative of a poor prognosis. TM immunoexpression could be used to guide clinical decision making.Keywords: transitional urothelial carcinoma, tissue microarrays, immunohistochemistry, bladder cancer
Published: 2020

14. Urinary Biomarkers in Bladder Cancer

Author: O'Kane, H.F., primary, Abogunrin, F., additional, Duggan, B., additional, Ruddock, M., additional, O'Rourke, D., additional, and Williamson, K., additional
Published: 2009
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15. 48LBA Algorithmic classifiers to diagnose bladder cancer

Author: Williamson, K., primary, Abogunrin, F., additional, Stevenson, M., additional, O'Sullivan, J., additional, Duggan, B., additional, Anderson, N., additional, O'Rourke, D., additional, O'Kane, H., additional, Ruddock, M., additional, and Lamont, J., additional
Published: 2009
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16. Saturated Fatty Acids Inhibit Hepatic Insulin Action by Modulating Insulin Receptor Expression and Post-receptor Signalling

Author: Ruddock, M. W., primary, Stein, A., additional, Landaker, E., additional, Park, J., additional, Cooksey, R. C., additional, McClain, D., additional, and Patti, M.-E., additional
Published: 2008
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17. Urinary biomarkers in bladder cancer

Author: O’Kane, H.F., Abogunrin, F., Duggan, B., Ruddock, M., O’Rourke, D., and Williamson, K.
Published: 2009
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18. The effect of nicotinamide on spontaneous and induced activity in smooth and skeletal muscle

Author: Ruddock, M. W., Burns, D. M., Murphy, L. E., O'Rourke, M. G., and Hirst, D. G.
Published: 2000
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19. Contractile properties of human renal cell carcinoma recruited arteries and their response to nicotinamide

Author: Ruddock, M. W., Burns, D. M., McKeown, S. R., Murphy, L., Walsh, I. K., Keane, P. F., and Hirst, D. G.
Published: 2000
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20. Collectives of diagnostic biomarkers identify high-risk subpopulations of hematuria patients: exploiting heterogeneity in large-scale biomarker data

Author: Emmert-Streib Frank, Abogunrin Funso, de Matos Simoes Ricardo, Duggan Brian, Ruddock Mark W, Reid Cherith N, Roddy Owen, White Lisa, O'Kane Hugh F, O'Rourke Declan, Anderson Neil H, Nambirajan Thiagarajan, and Williamson Kate E
Subjects: hematuria, biomarker, risk stratification, Random Forests Classifier, hierarchical clustering, feature selection, urothelial cancer, proteinuria, Medicine
Abstract: Abstract Background Ineffective risk stratification can delay diagnosis of serious disease in patients with hematuria. We applied a systems biology approach to analyze clinical, demographic and biomarker measurements (n = 29) collected from 157 hematuric patients: 80 urothelial cancer (UC) and 77 controls with confounding pathologies. Methods On the basis of biomarkers, we conducted agglomerative hierarchical clustering to identify patient and biomarker clusters. We then explored the relationship between the patient clusters and clinical characteristics using Chi-square analyses. We determined classification errors and areas under the receiver operating curve of Random Forest Classifiers (RFC) for patient subpopulations using the biomarker clusters to reduce the dimensionality of the data. Results Agglomerative clustering identified five patient clusters and seven biomarker clusters. Final diagnoses categories were non-randomly distributed across the five patient clusters. In addition, two of the patient clusters were enriched with patients with 'low cancer-risk' characteristics. The biomarkers which contributed to the diagnostic classifiers for these two patient clusters were similar. In contrast, three of the patient clusters were significantly enriched with patients harboring 'high cancer-risk" characteristics including proteinuria, aggressive pathological stage and grade, and malignant cytology. Patients in these three clusters included controls, that is, patients with other serious disease and patients with cancers other than UC. Biomarkers which contributed to the diagnostic classifiers for the largest 'high cancer- risk' cluster were different than those contributing to the classifiers for the 'low cancer-risk' clusters. Biomarkers which contributed to subpopulations that were split according to smoking status, gender and medication were different. Conclusions The systems biology approach applied in this study allowed the hematuric patients to cluster naturally on the basis of the heterogeneity within their biomarker data, into five distinct risk subpopulations. Our findings highlight an approach with the promise to unlock the potential of biomarkers. This will be especially valuable in the field of diagnostic bladder cancer where biomarkers are urgently required. Clinicians could interpret risk classification scores in the context of clinical parameters at the time of triage. This could reduce cystoscopies and enable priority diagnosis of aggressive diseases, leading to improved patient outcomes at reduced costs.
Published: 2013
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21. Urinary Biomarkers in Bladder Cancer

Author: O'Kane, H.F., Abogunrin, F., Duggan, B., Ruddock, M., O'Rourke, D., and Williamson, K.
Published: 2009
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22. Metabolic health and obesity: early determinants, trajectories and causal analysis:the Northern Finland Birth Cohort 1966 and 1986 studies

Author: Nedelec, R. (Rozenn), Järvelin, M. (Marjo-Riitta), Miettunen, J. (Jouko), and Ruddock, M. (Minna)
Subjects: obesity, eating behaviours, child adiposity, temperament, maternal BMI, early life determinants, kasvun kehityskaaret, elämän varhaisvaiheiden tekijät, temperamentti, syömiskäyttäytyminen, growth trajectories, kausaliteetti, lihavuus, lapsen lihavuus, causal mediation, äidin painoindeksi
Abstract: The obesity epidemic has grown over the last four decades in most European countries including Finland where 21.5% of women and 20% of men are now living with obesity. There is a large body of evidence establishing that the first years of life, including the foetal period, are critical for obesity and general health later in life. However, a better understanding of the link between early life determinants and the life-course trajectory of obesity is needed. In this thesis, associations between early life determinants and cardio-metabolically healthy obesity, defined as obesity in the absence of any cardiometabolic disorders, were investigated. The relationships between early life determinants and developmental body mass index (BMI) trajectories were explored. Finally, the associations between temperament traits and cardiovascular health and whether eating behaviours and fitness mediated the associations were examined. The research was conducted on data from the prospective Northern Finland Birth Cohorts 1966 (NFBC1966) and 1986 (NFBC1986) using association analyses, latent trajectory modelling and causal mediation analysis. The first study suggested that early life determinants such as age at adiposity rebound were associated with cardio-metabolically healthy obesity and that the association differed between males and females. In the second study, developmental BMI trajectories were modelled from NFBC1966 and NFBC1986. Adverse maternal factors were associated with unfavourable BMI trajectories. A different pattern of association between age at adiposity peak and BMI trajectories was found between the different cohorts, uncovering secular trends. The third study provided evidence that associations between temperament traits, established early in life, and cardiovascular health measures could be sex-specific. Furthermore, eating behaviours and mediators involved in the associations seemed to be associated with sex. The research undertaken in this thesis provides evidence to support the effect of early life determinants on life-course metabolic health and highlights the role of sex in these pathways. In addition, this work further advances the importance of psychological factors in relation to metabolic health with a specific focus on sex-specific temperament and behavioural mediators. Tiivistelmä Lihavuus on yleistynyt viimeisen neljän vuosikymmenen aikana useimmissa Euroopan maissa, myös Suomessa. Suomessa naisista 21,5 % ja miehistä 20 % on ylipainoisia. Aiempien tutkimusten mukaan ensimmäiset elinvuodet, sikiökausi mukaan luettuna, ovat tärkeitä myöhemmän lihavuuden ja yleisen terveyden kannalta. Tieto elämän varhaisvaiheisiin liittyvien tekijöiden ja lihavuuden kehityksen välisestä yhteydestä on kuitenkin puutteellista. Tämän väitöskirjan ensimmäisessä osatyössä tutkittiin elämän varhaisvaiheiden tekijöiden yhteyttä kardiometabolisesti terveeseen lihavuuteen, joka määritellään lihavuudeksi ilman verenkiertoelimistön sairauksia tai niiden tunnettuja riskitekijöitä. Toisessa osatyössä tutkittiin elämän varhaisvaiheiden tekijöiden ja painoindeksin kehityskaarten välisiä suhteita. Viimeisessä osatyössä tutkittiin temperamentin ja metabolisen terveyden, veren rasva-arvojen, välisiä yhteyksiä sekä näiden yhteyksien välittymistä syömiskäyttäytymisen ja fyysisen kunnon kautta. Tutkimus tehtiin Pohjois-Suomen syntymäkohorteissa 1966 (NFBC1966) ja 1986 (NFBC1986) käyttäen assosiaatioanalyysejä, latenttikasvukäyrämallinnusta sekä kausaalisuhdeanalyysejä. Ensimmäisessä osatyössä havaittiin, että elämän varhaisvaiheiden tekijät vaikuttivat kardiometabolisesti terveeseen lihavuuteen. Tällainen tekijä oli esimerkiksi ikä, jossa leikki-ikäisen lapsen painoindeksi on pienin ennen kuin se alkaa jälleen kasvaa (engl. adiposity rebound). Vaikutus oli kuitenkin erilainen miehillä ja naisilla. Toisessa tutkimuksessa painoindeksin kehityskaaret mallinnettiin NFBC1966 ja NFBC1986 -kohorteissa. Äidin tupakointi ja raskautta edeltänyt korkeampi painoindeksi olivat yhteydessä lapsen epäsuotuisaan painoindeksin kehityskaareen. Yhteys imeväisiän painoindeksin kasvukäyrän huipun ajoittumisen ja mallinnetun painoindeksin kehityskaaren välillä oli kohorteissa erilainen, mikä viittaa aikakaudellisiin ympäristön vaikutuksiin. Kolmannessa työssä tutkittiin erilaisia temperamenttipiirteitä, jotka myös ilmenivät varhaisella iällä. Työ osoitti, että temperamentti on yhteydessä veren rasva-arvoihin, mutta osin eri tavoin eri sukupuolilla. Lisäksi havaittiin miesten ja naisten välisiä eroja siinä, miten elintavat välittivät temperamenttipiirteiden ja veren rasva-arvojen välisiä yhteyksiä. Tämän väitöskirjan tulokset tarjoavat lisänäyttöä elämän varhaisvaiheen tekijöiden yhteyksistä metaboliseen terveyteen läpi elämän ja korostavat sukupuolten välisiä eroja. Tulokset vahvistavat käsitystä metaboliseen terveyteen vaikuttavien tekijöiden monimuotoisuudesta temperamentista terveyskäyttäytymiseen läpi elämän.
Published: 2023

23. Whole exome sequencing in identifying genetic factors in musculoskeletal diseases

Author: Skarp, S. (Sini) and Ruddock, M. (Minna)
Subjects: eksomisekvensointi, osteoarthritis, nivelrikko, genetiikka, osteoporoosi, disc degeneration, genetics, välilevyn rappeuma, osteoporosis, whole exome sequencing
Abstract: Musculoskeletal diseases, such as osteoarthritis (OA), lumbar disc degeneration (LDD) and osteoporosis (OP), are common complex disorders affected by both environmental and genetic factors. OA and LDD are degenerative diseases affecting joints and spine and Modic changes (MC) are a specific phenotype of LDD. OP is a disorder causing bone fragility. There are families with a history of early onset cartilage degradation, disc disorders and bone fragility as well as rare, more severe disorders with these traits as part of the phenotype. The aim of this study was to identify predisposing genetic factors in Finnish families with three different musculoskeletal phenotypes and to investigate the use of whole exome sequencing (WES) as a tool. Six families were studied here, three diagnosed with hip and knee OA, two with MC and one with primary OP. Using WES together with in silico and in vitro analyses we identified new candidate genes. In the two OA families we identified family specific variants, c.-127G>T in the 5’UTR of FIP1L1 and p.Arg210Gly in OLIG3. We observed expression of these genes in human bone and cartilage. Both FIP1L1 and OLIG3 participate in the regulation of transcription. Family specific variants were also found in both families with MC: p.Gln1611fs in HSPG2 and p.Glu553Lys in MAML1. HSPG2 encodes for an important structural protein in the disc and MAML1 is a transcription factor. The family with primary OP had previously been reported to carry a heterozygous COL1A2 deletion leading to nonsense-mediated mRNA decay. In the WES we identified an additional change that may contribute to the phenotype: p.Arg428* in ZNF528. We showed experimentally that the variant leads to expression of a truncated form of ZNF528 in the nucleus. ZNF528 binding sites are located near genes associated with bone phenotypes. We identified twelve potential target genes for ZNF528 that were differentially expressed in patients’ cells compared to controls. Altogether, we identified five new candidate genes for the studied phenotypes demonstrating that WES can be used as a tool in studying complex musculoskeletal phenotypes in families. One of the identified candidate genes, HSPG2, encodes a structural protein, whereas, OLIG3, FIP1L1, MAML1 and ZNF528, participate in the regulation of transcription supporting the importance of regulatory mechanisms in the pathogenesis of musculoskeletal diseases. Tiivistelmä Tuki- ja liikuntaelinsairaudet, kuten nivelrikko, välilevyrappeuma ja osteoporoosi, ovat yleisiä, monitekijäisiä sairauksia. Nivelrikko ja välilevynrappeuma ovat eteneviä nivelten ja selkärangan sairauksia. Modic muutokset ovat välilevyn ja nikaman välisten päätelevyjen muutoksia. Osteoporoosi on luuta haurastuttava sairaus. Varhaisessa iässä ilmenevää ruston haurastumista, välilevyn sairauksia tai luun haurautta tavataan myös suvuittain esiintyvinä sairauksina tai vakavien harvinaisten sairauksien oireina. Tutkimuksen tarkoitus oli tunnistaa altistavia geneettisiä tekijöitä kolmelle tuki- ja liikuntaelimistön sairaudelle suomalaisissa perheissä käyttäen eksomisekvensointi-menetelmää. Aineisto koostui kuudesta perheestä: kolmessa oli diagnosoitu lonkan ja polven nivelrikko, kahdessa selän välilevyjen Modic muutoksia ja yhdessä primaarinen vaikea selän osteoporoosi. Tunnistimme uusia ehdokasgeenejä käyttäen eksomisekvensointi-menetelmää sekä in silico ja in vitro analyysejä. Kahdessa nivelrikkoperheessä tunnistimme perhekohtaiset variantit kahdessa geenissä: c.-127G>T variantin FIP1L1 geenin säätelyalueella ja p.Arg210Gly variantin OLIG3 geenissä. Osoitimme, että nämä traskription säätelyyn osallistuvat geenit ilmenevät ihmisen luu- ja rustokudoksessa. Perhekohtaiset variantit havaittiin myös perheissä, joilla oli todettu Modic muutoksia: p.Gln1611fs HSPG2 -geenissä ja p.Glu553Lys MAML1 -geenissä. HSPG2 koodaa välilevylle tärkeää rakenneproteiinia ja MAML1 on transkriptiota säätelevä tekijä. Primaarista osteoporoosia sairastavalla perheellä oli aiemmin havaittu heterotsygootti, geenituotteen hajottamiseen johtava deleetio, COL1A2 -geenissä. Eksomisekvensoinnlla havaitsimme mahdollisesti taudin ilmiasuun lisäksi vaikuttavan muutoksen ZNF528 -geenissä. Osoitimme kokeellisesti, että havaittu variantti johtaa lyhentyneen proteiinin tuottoon solussa. ZNF528 on transkriptiotekijä, jolle tunnistimme kaksitoista mahdollista kohdegeeniä ja havaitsimme että niiden tuotto oli muuttunut potilaiden soluissa kontrollisoluihin verrattuna. Tunnistimme viisi uutta ehdokasgeeniä kolmessa eri sairaudessa eksomisekvensointi-menetelmän avulla. Yksi tunnistetuista geeneistä, HSPG2, koodaa rakenneproteiinia, ja muut osallistuvat transkription säätelyyn. Tämä tukee käsitystä säätelytekijöiden tärkeydestä TULE sairauksien synnyssä.
Published: 2019

24. Risk factors for sciatica

Author: Euro, U. (Ulla), Karppinen, J. (Jaro), Heliövaara, M. (Markku), and Ruddock, M. (Minna)
Subjects: population-based data, occupation, risk factors, sairaalahoito, iskias, riskitekijät, väestöaineisto, ammatti, hospitalization, sciatica
Abstract: Sciatica is a common musculoskeletal disorder, especially among the working-age population. It causes huge costs to society through work absenteeism and hospital treatments. The common cause of sciatica is the herniated lumbar disc compressing the nerve root. The neurological deficit resulting from this compression can be either sensory or motor-related. Earlier studies have shown both genetic and environmental factors to exist in the aetiology of sciatica. The aim of this study was to investigate how individual, physical and work-related risk factors associate with sciatica, and to determine the prevalence of sciatic pain among Finnish adolescents. The data used in this study were from large, population-based Finnish surveys: the Northern-Finland Birth Cohort 1986, the Mobile Clinic Health Examination Survey, the Mini-Finland Health Survey, Health 2000, the Young Finns Study, and the Helsinki Health Studies. The results of this study showed that sciatic symptoms are already common among adolescents. Young women in particular reported sciatic pain more often than men. Low back pain at the age of 16 predicted sciatic pain at the age of 18. Physically demanding work, smoking and obesity were found to predict an increased risk of hospitalization for sciatica. In the Mobile Clinic Health Examination Survey, leisure-time physical activity protected men from hospitalization for sciatica, whereas among women obesity increased this risk. Occupation also modified the effects of various risk factors. In the Mini-Finland Health Survey, overweight and obese participants who had been exposed to whole body vibration in their work were at a higher risk of hospitalization due to sciatica. In addition, lifting and carrying heavy objects at work, or sedentary work involving the handling of heavy objects predicted an increased risk of hospitalization for sciatica. Heavy or very heavy work protected against hospitalization for sciatica. A meta-analysis of four prospective cohort studies showed that walking and cycling to work reduced the risk of hospitalization for sciatica. This thesis extends our knowledge regarding the risk factors for sciatica. Its results show that these risk factors are complex and can modify each other’s effects. Thus, further research on the interactions of the various risk factors is needed. Tiivistelmä Iskias on etenkin työikäisten keskuudessa yleinen sairaus, joka aiheuttaa paljon työkyvyttömyyttä ja sairaalahoitoja ja siten kustannuksia yhteiskunnalle. Iskiaksen taustalla on yleensä välilevyn pullistuma, joka painaa hermojuuria. Hermojuuren puristuksesta aiheutuva neurologinen puutosoire voi olla joko sensorinen tai motorinen. Aiemmat tutkimukset ovat osoittaneet iskiaksen taustalla olevan sekä geneettisiä että ympäristötekijöitä. Tämän tutkimuksen tavoitteena oli selvittää yksilöllisten, fyysisten ja työhön liittyvien riskitekijöiden yhteyttä iskiakseen sekä tutkia iskiaskivun yleisyyttä suomalaisilla nuorilla aikuisilla. Aineistoina tutkimuksessa käytettiin laajoja väestöpohjaisia suomalaisia aineistoja: Pohjois-Suomen syntymäkohorttia 1986, Autoklinikka- ja Mini-Suomi-aineistoja sekä Terveys 2000-, Young Finns- ja Helsinki Health Study -tutkimuksia. Tutkimuksessa selvisi, että iskiasoireet ovat yleisiä jo nuorilla aikuisilla ja etenkin naiset raportoivat iskiaskipua useammin miehiin verrattuna. 16-vuotiaana ilmennyt alaselkäkipu oli myös yhteydessä iskiasoireisiin 18 vuoden iässä. Työn fyysisen rasittavuuden, tupakoinnin ja lihavuuden todettiin lisäävän sairaalahoitoon johtaneen iskiaksen riskiä. Autoklinikka-aineistossa vapaa-ajan fyysinen aktiivisuus suojasi miehiä sairaalahoitoon johtaneelta iskiakselta, naisilla taas ylipaino lisäsi iskiaksen riskiä. Lisäksi ammatti näytti muokkaavan riskitekijöiden assosiaatioita. Mini-Suomi-aineistossa ylipainoiset ja lihavat henkilöt, jotka olivat altistuneet työssään koko kehon tärinälle, olivat korkeammassa riskissä sairaalahoitoon johtaneen iskiaksen suhteen. Töissä raskaiden esineiden nostaminen tai kantaminen tai painavien esineiden käsittelyä sisältävä istumatyö lisäsivät myös iskiaksen riskiä. Raskas tai erittäin raskas fyysinen työ taas näytti suojaavan sairaalahoitoon johtaneelta iskiakselta. Neljän prospektiivisen kohorttitutkimuksen meta-analyysissä selvisi, että työmatkapyöräily tai -kävely vähensivät sairaalahoitoon johtaneen iskiaksen riskiä. Tämä väitöstutkimus kasvattaa ymmärtämystä iskiaksen taustalla olevista riskitekijöistä. Tulokset osoittavat, että iskiaksen riskitekijät ovat moniulotteisia ja voivat muokata toistensa vaikutuksia, joten lisätutkimusta eri riskitekijöiden välisistä interaktioista tarvitaan.
Published: 2019

25. Genetics and molecular epidemiology of metabolic syndrome-related traits:focus on metabolic profiling of lipid-lowering therapies and fatty liver, and the role of genetic factors in inflammatory load

Author: Sliz, E. (Eeva), Ruddock, M. (Minna), Sebert, S. (Sylvain), and Kettunen, J. (Johannes)
Subjects: chronic inflammation, perinnöllisyystiede, rasvamaksa, biomarkers, Mendeliaaninen satunnaistaminen, metabolomics, molecular epidemiology, metabolic syndrome, PCSK9, ei-alkoholiperäinen rasvamaksa, cardiovascular disease, markkerit, krooninen tulehdus, lipidilääkkeet, Mendelian randomization, sydän- ja verisuonitaudit, GWAS, genetics, non-alcoholic fatty liver, type 2 diabetes, metabolomiikka, aikuistyypin diabetes, metabolinen oireyhtymä, lipid-lowering medication, molekyyliepidemiologia
Abstract: Metabolic syndrome is a constellation of metabolic abnormalities predisposing to cardiovascular diseases (CVD), type 2 diabetes, and increased mortality. Due to the high prevalence and severe co-morbidities, metabolic syndrome constitutes a major burden for both public health and the global economy. Improved understanding of the detailed molecular mechanisms could provide novel strategies for the treatment and preferably prevention of the metabolic syndrome-related health issues. Recent advancements in ‘omics’ technologies have facilitated the development of novel tools to examine the links between genetic variation and human health. The new techniques allow determination of millions of genotypes or quantification of hundreds of metabolic measures from a single blood sample. In this thesis, genomics and metabolomics approaches are coupled to improve our understanding of the metabolic syndrome-related health issues. More precisely, my projects evaluate the metabolic effects of two lipid-lowering therapies and non-alcoholic fatty liver, as well as assess genetic determinants of chronic inflammation. The present results indicate generally consistent metabolic effects of statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) genetic inhibition. The subtle discrepancies observed could potentially contribute to differences in the efficacy to lower CVD risk between statins and PCSK9 inhibitors. The dissimilar metabolic effects of the four genetic variants that increase the risk of non-alcoholic fatty liver disease (NAFLD) highlight the heterogeneity of the molecular mechanisms involved in NAFLD pathogenesis. The results further suggest that fatty liver by itself might not promote unfavourable metabolic aberrations associated with fatty liver on a population level. The newly identified loci associating with inflammatory phenotypes elucidate the genetic mechanisms contributing to the inflammatory load. In particular, the present results suggest the important role of the locus determining the ABO blood types in the regulation of the soluble adhesion molecule levels. To conclude, this thesis successfully complements the knowledge of the molecular mechanisms involved in metabolic syndrome-related traits and provides examples of how to couple omics technologies in the study of complex traits or in the evaluation of drug effects. Tiivistelmä Metabolinen oireyhtymä on tila, jossa useiden aineenvaihdunnallisten riskitekijöiden kasautuminen suurentaa riskiä sairastua tyypin 2 diabetekseen ja sydän- ja verisuonitauteihin sekä lisää kokonaiskuolleisuutta. Vakavista liitännäissairauksista ja suuresta esiintyvyydestä johtuen metabolinen oireyhtymä kuormittaa merkittävästi sekä terveydenhuoltoa että kansantaloutta. Jotta metabolisen oireyhtymän hoitoon ja ennaltaehkäisyyn voitaisiin kehittää uusia keinoja, on tärkeää ymmärtää paremmin oireyhtymän syntyyn vaikuttavat täsmälliset molekyylimekanismit. Niin sanottujen ’omiikka-tekniikoiden’ viimeaikainen kehitys tarjoaa uusia mahdollisuuksia tutkia geenimuutosten vaikutuksia terveyteen. Uusien tekniikoiden avulla voidaan määrittää miljoonia genotyyppejä tai satoja aineenvaihdunnan merkkiaineita yhdestä verinäytteestä. Tässä väitöskirjatyössä yhdistetään genomiikan ja metabolomiikan menetelmiä metaboliseen oireyhtymään liittyvien terveysongelmien tutkimiseksi. Väitöskirjani osatöissä arvioin kahden lipidilääkkeen sekä ei-alkoholiperäisen rasvamaksan aineenvaihdunnallisia vaikutuksia sekä pyrin tunnistamaan krooniseen tulehdukseen vaikuttavia geneettisiä tekijöitä. Tulosten mukaan statiinien ja PCSK9:n (engl. proprotein convertase subtilisin/kexin type 9) geneettisen eston aineenvaihduntavaikutukset ovat hyvin samankaltaiset. Kuitenkin havaitut pienet poikkeavuudet tietyissä merkkiaineissa voivat vaikuttaa eroavaisuuksiin siinä, kuinka tehokkaasti lääkeaineet alentavat sydäntautiriskiä. Suuret erot rasvamaksan riskiä lisäävien geenimuutosten vaikutuksissa aineenvaihduntaan korostavat rasvamaksaan liittyvien molekyylimekanismien monimuotoisuutta. Tulosten perusteella vaikuttaa siltä, että rasvan kertyminen maksaan ei luultavasti itsessään aiheuta suuria muutoksia verenkierron aineenvaihduntatuotteiden pitoisuuksiin. Tulehdusmerkkiaineisiin assosioituvat uudet geenialueet täydentävät tulehduksen molekyylimekanismeihin liittyvää tietoa. Tulokset korostavat ABO-veriryhmän määräävän geenin vaikutusta liukoisten adheesiomolekyylien pitoisuuksiin. Kaiken kaikkiaan väitöskirjan osatyöt tuovat uutta tietoa metaboliseen oireyhtymään liittyvien terveysongelmien molekyylimekanismeihin. Projektit havainnollistavat, miten omiikka-tekniikoita voidaan hyödyntää monitekijäisten fenotyyppien tutkimuksessa sekä lääkeaineiden aineenvaihduntavaikutusten arvioinnissa.
Published: 2019

26. The heritability and genetic risk factors of Modic changes

Author: Kraatari, M. (Minna), Ruddock, M. (Minna), and Karppinen, J. (Jaro)
Subjects: kaksostutkimus, genetiikka, Modic-muutos, välilevyrappeuma, koko genomin laajuinen assosiaatioanalyysi, modic change, heritability, eksomisekvensointi, alaselkäkipu, disc degeneration, genome wide association study (GWAS), genetics, twin study, exome sequencing, low back pain, perinnöllisyys
Abstract: Low back pain (LBP) is a highly prevalent musculoskeletal condition and the leading cause for workplace absenteeism. Lumbar disc degeneration (DD) is considered as a contributing factor to LBP. The role of genetic factors in the development of lumbar DD has been demonstrated to be significant, with heritability estimates ranging from 64% to 81%. Modic change (MC), a distinct phenotype of lumbar DD, is a subchondral and vertebral bone marrow change revealed only by magnetic resonance imaging (MRI). MC has been associated with LBP in both clinical samples and the general population. The genetic background of MC is largely unknown, and the heritability of MC has not previously been assessed. The aim of this study was to assess the heritability of MC using a twin study, identify predisposing genetic factors for MC in a family-based design using whole-exome sequencing and to identify genetic loci associated with MC using genome-wide association study (GWAS) meta-analysis. An additional aim was to study the prevalence, incidence and morphology of MC. The data consisted of two general population samples, the Northern Finland Birth Cohort 1966 (NFBC1966) and TwinsUK from the United Kingdom, as well as two Finnish families from the Oulu region. MC was found to be partly heritable with a heritability estimate of 30%. Two novel candidate genes, HSPG2 and MAML1, were found co-segregating with MC in two Finnish families. Both genes are important in the growth and differentiation of chondrocytes. Finally, a genetic locus on chromosome 9 was found to be significantly associated with MC using genome-wide meta-analysis of NFBC1966 and TwinsUK. These results showed that genetic factors play a role in the development of MC. In conclusion, this thesis increased the knowledge on the genetics of MC. However, the specific roles of these genes need to be studied further. Tiivistelmä Alaselkäkivun kansaterveydellinen merkitys on suuri, sillä jopa 84% aikuisista kärsii siitä elämänsä aikana. Selkäkivun vuoksi Suomessa kertyy yli 2 miljoona sairauslomapäivää vuodessa. Välilevyrappeumaa pidetään merkittävänä tekijänä alaselkäkivun synnyssä ja perinnölliset tekijät selittävät välilevyrappeuman synnystä jopa 74%. Modic-muutokset ovat selkärangan välilevyjen päätelevyjen ja subkondraalisen luun muutoksia, jotka voidaan havaita ainoastaan magneettikuvauksella. Niitä pidetään välilevyrappeuman alatyyppinä. Modic-muutosten on osoitettu olevan yhteydessä alaselkäkipuun, mutta etiologia tunnetaan huonosti. Perinnöllisyyden osuutta Modic-muutoksien synnyssä ei ole aiemmin tutkittu ja niiden taustalla vaikuttavat geneettiset tekijät ovat pääasiassa tuntemattomia. Tämän tutkimuksen tavoitteena oli arvioida perinnöllisyyden osuutta Modic-muutoksissa kaksoisaineistossa, tunnistaa Modic-muutoksille altistavia geneettisiä muutoksia perheaineistossa käyttäen eksomisekvensointia ja tunnistaa genomin alueita, jotka assosioituvat Modic-muutoksiin. Tutkimus perustui kahteen väestöperäiseen aineistoon: Pohjois-Suomen Syntymäkohorttiin 1966 ja TwinsUK-kaksosaineistoon Yhdistyneistä kuningaskunnista sekä kahteen pohjois-suomalaiseen perheeseen. Tutkimuksessa osoitettiin, että Modic-muutokset ovat perinnöllisiä ja, että perinnölliset tekijät selittävät noin 30% niiden ilmenemisestä. Lisäksi tutkimuksessa tunnistettiin kaksi uutta alttiusgeeniä; HSPG2- ja MAML1-geenit. Molemmilla geeneillä on tärkeä rooli rustosolujen kasvamisessa ja erilaistumisessa. Tutkimuksessa myös tunnistettiin kromosomista 9 genomin alue, joka assosioituu Modic-muutoksiin. Väitöskirjassani osoitettiin, että perinnöllisillä tekijöillä on merkitystä Modic-muutosten synnyssä. Kokonaisuudessaan tämä väitöskirja kasvattaa ymmärrystä Modic-muutoksista, mutta lisätutkimusta aiheesta tarvitaan.
Published: 2018

27. Feto-maternal indicators of cardiac dysfunction as a justification for the cardiac origins for pre-eclampsia.

Author: Reilly KM, Watson C, Ruddock M, Watt J, Kurth MJ, Fitzgerald P, Breathnach F, and Mone F
Subjects: Humans, Female, Pregnancy, Heart Diseases etiology, Pre-Eclampsia physiopathology, Biomarkers blood
Abstract: While the pathophysiology of pre-eclampsia has been postulated as being secondary to placental dysfunction, a cardiac origin has more recently been proposed. Although an association between fetal congenital cardiovascular disease and pre-eclampsia has been demonstrated, no precise pathophysiologic mechanism for this association has been described. This review highlights the current biophysical (including echocardiography and Doppler indices) and biochemical (including proteomic, metabolomic and genetic/transcriptomic) markers of cardiac dysfunction that have been investigated in maternal and fetal cardiac disease and their overlap with predictors of pre-eclampsia. Common pathways of inflammatory and anti-angiogenesis imbalance, endothelial damage, and oxidative stress have been demonstrated in both cardiovascular disease and pre-eclampsia and further investigation into these pathways could help to elucidate the common pathophysiologic mechanisms linking these disorders., (© 2024 The Author(s). International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)
Published: 2024
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28. A 6-Week Mindfulness-Acceptance-Commitment Intervention to Improve Professional Ballet Dancers' Psychological States Around Performance.

Author: Harrison C, Ruddock S, Mayes S, Cook J, O'Halloran P, Ferrar K, Li X, and Ruddock M
Abstract: Background: Mindfulness and acceptance-based approaches have been trialled in professional sport. The present pilot study was a randomized controlled trial with professional ballet dancers investigating the effectiveness of the Mindfulness-Acceptance-Commitment (MAC) approach, developed for athletes, compared to an education program which included topics relevant to ballet and performance. Methods: Participants included 16 professional ballet dancers (2 men and 14 women) who were randomly assigned into either the MAC or education group for 1 session per week, for 6 weeks. Participants were assessed pre-and post-intervention using the Mindfulness Inventory for Sport (MIS) and the Acceptance Action Questionnaire (AAQ-II). Within 2 weeks of the final mindfulness session, all participants completed a semi-structured interview. Results: No differences were found when comparing the questionnaire responses between pre- and post- intervention, nor between the MAC group and the control group at post intervention for all subscales. Although dancers reported in the interviews that the sessions were valuable, they advised their ability to dedicate time to mindfulness ongoing would be challenging. Conclusions: Mindfulness interventions, as explored in this study, show promise to promote the well-being of professional ballet dancers. For consistent and ongoing mindfulness practice, future designs should seek to embed mindfulness practice into dancer and company schedules., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Published: 2024
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29. Spatial localization of β-unsaturated aldehyde markers in murine diabetic kidney tissue by mass spectrometry imaging.

Author: Harkin C, Smith KW, MacKay CL, Moore T, Brockbank S, Ruddock M, and Cobice DF
Subjects: Aldehydes, Animals, Biomarkers, Mice, Mice, Inbred ICR, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization methods, Diabetes Mellitus, Diabetic Nephropathies
Abstract: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Limitations in current diagnosis and screening methods have sparked a search for more specific and conclusive biomarkers. Hyperglycemic conditions generate a plethora of harmful molecules in circulation and within tissues. Oxidative stress generates reactive α-dicarbonyls and β-unsaturated hydroxyhexenals, which react with proteins to form advanced glycation end products. Mass spectrometry imaging (MSI) enables the detection and spatial localization of molecules in biological tissue sections. Here, for the first time, the localization and semiquantitative analysis of "reactive aldehydes" (RAs) 4-hydroxyhexenal (4-HHE), 4-hydroxynonenal (4-HNE), and 4-oxo-2-nonenal (4-ONE) in the kidney tissues of a diabetic mouse model is presented. Ionization efficiency was enhanced through on-tissue chemical derivatization (OTCD) using Girard's reagent T (GT), forming positively charged hydrazone derivatives. MSI analysis was performed using matrix-assisted laser desorption ionization (MALDI) coupled with Fourier-transform ion cyclotron resonance mass spectrometry (FT-ICR). RA levels were elevated in diabetic kidney tissues compared to lean controls and localized throughout the kidney sections at a spatial resolution of 100 µm. This was confirmed by liquid extraction surface analysis-MSI (LESA-MSI) and liquid chromatography-mass spectrometry (LC-MS). This method identified β-unsaturated aldehydes as "potential" biomarkers of DN and demonstrated the capability of OTCD-MSI for detection and localization of poorly ionizable molecules by adapting existing chemical derivatization methods. Untargeted exploratory distribution analysis of some precursor lipids was also assessed using MALDI-FT-ICR-MSI., (© 2022. The Author(s).)
Published: 2022
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30. INTERSTAARS: Attention training for infants with elevated likelihood of developing ADHD: A proof-of-concept randomised controlled trial.

Author: Goodwin A, Jones EJH, Salomone S, Mason L, Holman R, Begum-Ali J, Hunt A, Ruddock M, Vamvakas G, Robinson E, Holden CJ, Taylor C, Smith TJ, Sonuga-Barke E, Bolton P, Charman T, Pickles A, Wass S, and Johnson MH
Subjects: Attention, Child, Humans, Infant, Treatment Outcome, Attention Deficit Disorder with Hyperactivity therapy
Abstract: Attention-deficit/hyperactivity disorder (ADHD) is first diagnosed during middle childhood, when patterns of difficulty are often established. Pre-emptive approaches that strengthen developing cognitive systems could offer an alternative to post-diagnostic interventions. This proof-of-concept randomised controlled trial (RCT) tested whether computerised gaze-based attention training is feasible and improves attention in infants liable to develop ADHD. Forty-three 9- to 16-month-old infants with a first-degree relative with ADHD were recruited (11/2015-11/2018) at two UK sites and randomised with minimisation by site and sex to receive 9 weekly sessions of either (a) gaze-contingent attention training (intervention; n = 20); or (b) infant-friendly passive viewing of videos (control, n = 23). Sessions were delivered at home with blinded outcome assessments. The primary outcome was a composite of attention measures jointly analysed via a multivariate ANCOVA with a combined effect size (ES) from coefficients at baseline, midpoint and endpoint (Registration: ISRCTN37683928 ). Uptake and compliance was good but intention-to-treat analysis showed no significant differences between 20 intervention and 23 control infants on primary (ES -0.4, 95% CI -0.9 to 0.2; Complier-Average-Causal Effect ES -0.6, 95% CI -1.6 to 0.5) or secondary outcomes (behavioural attention). There were no adverse effects on sleep but a small increase in post-intervention session fussiness. Although feasible, there was no support for short-term effects of gaze-based attention training on attention skills in early ADHD. Longer-term outcomes remain to be assessed. The study highlights challenges and opportunities for pre-emptive intervention approaches to the management of ADHD., (© 2021. The Author(s).)
Published: 2021
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31. A comparison of the clinical effectiveness and cost of specialised individually delivered parent training for preschool attention-deficit/hyperactivity disorder and a generic, group-based programme: a multi-centre, randomised controlled trial of the New Forest Parenting Programme versus Incredible Years.

Author: Sonuga-Barke EJS, Barton J, Daley D, Hutchings J, Maishman T, Raftery J, Stanton L, Laver-Bradbury C, Chorozoglou M, Coghill D, Little L, Ruddock M, Radford M, Yao GL, Lee L, Gould L, Shipway L, Markomichali P, McGuirk J, Lowe M, Perez E, Lockwood J, and Thompson MJJ
Subjects: Attention Deficit Disorder with Hyperactivity diagnosis, Child, Child, Preschool, Female, Humans, Male, Parents psychology, Problem Behavior, Surveys and Questionnaires, Treatment Outcome, Attention Deficit Disorder with Hyperactivity therapy, Family Therapy methods, Parenting, Parents education
Abstract: The objective of this study is to compare the efficacy and cost of specialised individually delivered parent training (PT) for preschool children with attention-deficit/hyperactivity disorder (ADHD) against generic group-based PT and treatment as usual (TAU). This is a multi-centre three-arm, parallel group randomised controlled trial conducted in National Health Service Trusts. The participants included in this study were preschool children (33-54 months) fulfilling ADHD research diagnostic criteria. New Forest Parenting Programme (NFPP)-12-week individual, home-delivered ADHD PT programme; Incredible Years (IY)-12-week group-based, PT programme initially designed for children with behaviour problems were the interventions. Primary outcome-Parent ratings of child's ADHD symptoms (Swanson, Nolan & Pelham Questionnaire-SNAP-IV). Secondary outcomes-teacher ratings (SNAP-IV) and direct observations of ADHD symptoms and parent/teacher ratings of conduct problems. NFPP, IY and TAU outcomes were measured at baseline (T1) and post treatment (T2). NFPP and IY outcomes only were measured 6 months post treatment (T3). Researchers, but not therapists or parents, were blind to treatment allocation. Analysis employed mixed effect regression models (multiple imputations). Intervention and other costs were estimated using standardized approaches. NFPP and IY did not differ on parent-rated SNAP-IV, ADHD combined symptoms [mean difference - 0.009 95% CI (- 0.191, 0.173), p = 0.921] or any other measure. Small, non-significant, benefits of NFPP over TAU were seen for parent-rated SNAP-IV, ADHD combined symptoms [- 0.189 95% CI (- 0.380, 0.003), p = 0.053]. NFPP significantly reduced parent-rated conduct problems compared to TAU across scales (p values < 0.05). No significant benefits of IY over TAU were seen for parent-rated SNAP, ADHD symptoms [- 0.16 95% CI (- 0.37, 0.04), p = 0.121] or parent-rated conduct problems (p > 0.05). The cost per family of providing NFPP in the trial was significantly lower than IY (£1591 versus £2103). Although, there were no differences between NFPP and IY with regards clinical effectiveness, individually delivered NFPP cost less. However, this difference may be reduced when implemented in routine clinical practice. Clinical decisions should take into account parental preferences between delivery approaches.
Published: 2018
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32. Investigation and verification of a bioluminescent biosensor for the quantitation of ara-CTP generation: a biomarker for cytosine arabinoside sensitivity in acute myeloid leukaemia.

Author: Anderson E, Conway M, Alloush H, O'Malley K, Smith MA, Martin A, Ruddock M, Reid C, Lamont J, Fitzgerald SP, Smith JG, Mehta P, and Salisbury V
Subjects: Arabinofuranosylcytosine Triphosphate blood, Biomarkers, Tumor blood, Humans, Leukemia, Myeloid, Acute pathology, Limit of Detection, Luminescent Measurements, Arabinofuranosylcytosine Triphosphate isolation & purification, Biosensing Techniques, Cytarabine isolation & purification, Leukemia, Myeloid, Acute blood
Abstract: A novel whole cell bacterial biosensor, which emits light in response to the active metabolite of cytosine arabinoside (ara-C, cytarabine), ara-CTP, has been investigated and verified. The biosensor has been formulated as an ex vivo assay, designed for peripheral blood or bone marrow cells, which can produce a clinical result within a working day. The nucleoside analogue ara-C is a key agent for treatment of acute myeloid leukaemia (AML); treatment decisions are made rapidly with AML, patients often receiving same-day commencement of chemotherapy. Currently no rapid predictive test is available to select appropriate therapy for patients prior to treatment. Experiments were designed to determine optimal assay conditions using leukaemic cell lines. We observed a significant increase (~15 fold) in bioluminescence signal compared to control after 8-h incubation of the biosensor with ara-C. This corresponded to a >2-log increase in light output per bacterial cell. Interestingly, bioluminescence conferred a survival advantage to the bacteria following ara-C treatment. The assay is sensitive (lower limit of quantitation of 0.05 µM), selective, accurate (≤ 15% RE) and precise (≤ 15% coefficient of variation) over a linear concentration range of ara-CTP (0.05-0.5 µM), and detection is independent of reaction volume. Recovery of added standard was tested using ex vivo patient leukaemic cells (n=5). Stability studies on lyophilized bacterial biosensor were performed to ensure maintenance of performance over 12 months. The biosensor assay could be invaluable to the clinician, assisting with treatment selection, and potentially mitigating the risks of resistance and toxicity observed with this drug., (© 2013 Elsevier B.V. All rights reserved.)
Published: 2014
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33. A novel bioluminescent bacterial biosensor for measurement of Ara-CTP and cytarabine potentiation by fludarabine in seven leukaemic cell lines.

Author: Anderson E, Smith MA, Martin A, Ruddock M, Lamont J, Alloush H, Conway M, Mehta P, Smith JG, and Salisbury V
Subjects: Apoptosis drug effects, Bacterial Proteins analysis, Cell Line, Tumor, HL-60 Cells, Humans, K562 Cells, Leukemia diagnosis, Leukemia drug therapy, Luminescent Measurements methods, Luminescent Proteins analysis, Treatment Outcome, Vidarabine pharmacology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Arabinofuranosylcytosine Triphosphate analysis, Biosensing Techniques methods, Cytarabine pharmacology, Leukemia pathology, Vidarabine analogs & derivatives
Abstract: This study evaluates an in vitro biosensor assay capable of detecting the intracellular levels of the tri-phosphorylated form of cytarabine (Ara-CTP) within one working day. The biosensor predicted the response of seven leukaemic cell lines with varying known sensitivities to cytarabine alone and in combination with fludarabine. High-performance liquid chromatography (HPLC), 3-day assessment of cellular viable mass, and flow cytometric assessment of apoptosis were used to validate biosensor performance. A correlation between the biosensor results and Ara-CTP quantitation by HPLC was confirmed (R=0.972). The biosensor was also capable of detecting enhanced accumulation of Ara-CTP following sequential pre-treatment of leukaemic cells with cytarabine ± fludarabine., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
Published: 2013
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34. Greater arousal and less attentiveness to face/voice stimuli by neonates of depressed mothers on the Brazelton Neonatal Behavioral Assessment Scale.

Author: Hernandez-Reif M, Field T, Diego M, and Ruddock M
Subjects: Acoustic Stimulation methods, Adult, Arousal physiology, Depressive Disorder epidemiology, Female, Humans, Infant Behavior physiology, Infant, Newborn, Male, Maternal Behavior physiology, Maternal Behavior psychology, Photic Stimulation methods, Attention physiology, Depressive Disorder psychology, Face, Infant Behavior psychology, Psychiatric Status Rating Scales, Voice
Abstract: Neonates born to depressed (n=44) versus non-depressed (n=43) mothers were compared on individual items of the Brazelton Neonatal Behavioral Assessment Scale (NBAS). The neonates of depressed mothers received lower scores on orienting to the live face/voice stimulus and on the alertness items, suggesting they were less attentive. They also scored less optimally on the cuddliness and hand-to-mouth activity items, suggesting they were more aroused. These data lend support to the model that infants of depressed mothers are more aroused and less attentive.
Published: 2006
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35. Nicotinamide-inhibited vasoconstriction: lack of dependence on agonist signalling pathways.

Author: Burns DM, Ruddock MW, Walker MD, Allen JM, Kennovin GD, and Hirst DG
Subjects: Animals, Arginine Vasopressin pharmacology, Calcium Signaling physiology, Drug Interactions, In Vitro Techniques, Male, Perfusion, Phenylephrine pharmacology, Rats, Rats, Wistar, Vasoconstrictor Agents pharmacology, Endothelium metabolism, Muscle Contraction drug effects, Muscle, Smooth, Vascular drug effects, Niacinamide pharmacology, Vasoconstriction drug effects
Abstract: Previously, we have shown that nicotinamide inhibits both high [K+]- and phenylephrine-induced constrictions in a dose-dependent manner in rat tail arteries. We have now investigated the effect of nicotinamide on intracellular signalling pathways in vascular smooth muscle. Nicotinamide (8.2 mM) reduced the response to phenylephrine- and [Arg8]vasopressin-induced constrictions by means of 72.9+/-6.9 and 51.8+/-5.7%, respectively. It also blocked phenylephrine-induced constrictions in the absence of a functional endothelium (P < 0.0136). In addition, pre-treatment of the artery with nifedipine (10 mM) also failed to inhibit nicotinamide's activity (P < 0.0178). Moreover, nicotinamide significantly reduced the sensitivity to phenylephrine in Ca2+-free Krebs' solution (P < 0.0152). Continuous perfusion of maximal concentrations of ryanodine or thapsigargin significantly inhibited the response to phenylephrine; the addition of nicotinamide (8.2 mM) caused a significant additional inhibition when compared to the effect of ryanodine (P < 0.0006) or thapsigargin (P<0.037) alone. In addition, beta-escin (0.02%) permeabilisation and Ca2+ (2.5 mM)-mediated constriction was also significantly attenuated by nicotinamide (P < 0.0001). However, phorbol ester-induced constriction was not attenuated by nicotinamide. This would suggest that nicotinamide directly inhibits vascular smooth muscle cell contraction and is unlikely to act via blockage of external Ca2+ entry or release of Ca2+ from intracellular stores.
Published: 1999
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36. The effect of the vasodilator nicotinamide on cyclic nucleotide pathways in vascular smooth muscle.

Author: Burns DM, Ruddock MW, Brown JC, Kennovin GD, Dykes EL, Flitney FW, and Hirst DG
Subjects: 1-Methyl-3-isobutylxanthine pharmacology, Animals, Arteries, Enzyme Inhibitors pharmacology, In Vitro Techniques, Muscle, Smooth, Vascular drug effects, Phenylephrine pharmacology, Phosphoric Diester Hydrolases metabolism, Rats, Rats, Wistar, Second Messenger Systems, Vasodilation drug effects, Cyclic AMP metabolism, Cyclic GMP metabolism, Imines pharmacology, Muscle, Smooth, Vascular physiology, Niacinamide pharmacology, Oxadiazoles pharmacology, Quinoxalines pharmacology, Vasodilator Agents pharmacology
Published: 1997
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36 results on '"Ruddock M"'

1. Metabolic health and obesity: early determinants, trajectories and causal analysis:the Northern Finland Birth Cohort 1966 and 1986 studies

2. Well-being needs of elite sports coaches

3. Improving sleep in a population at high risk of trauma: A pilot study examining self-reported sleep, psychological symptomology and actigraphy measured night-time sleep

4. Royal academy of medicine in Ireland section of biomedical sciences: Proceedings of winter meeting held in Trinity College Dublin, 1996

5. Whole exome sequencing in identifying genetic factors in musculoskeletal diseases

6. Risk factors for sciatica

7. Genetics and molecular epidemiology of metabolic syndrome-related traits:focus on metabolic profiling of lipid-lowering therapies and fatty liver, and the role of genetic factors in inflammatory load

9. The heritability and genetic risk factors of Modic changes

10. The breeding population of Peregrine Falcon Falco peregrinus in the United Kingdom, Isle of Man and Channel Islands in 2014

11. The breeding population of Peregrine Falcon <italic>Falco peregrinus</italic> in the United Kingdom, Isle of Man and Channel Islands in 2014.

12. Biomarkers That Differentiate Benign Prostatic Hyperplasia from Prostate Cancer: A Literature Review

13. Thrombomodulin Expression in Bladder Cancer Tissue and Its Association with Prognosis and Patient Survival

14. Urinary Biomarkers in Bladder Cancer

15. 48LBA Algorithmic classifiers to diagnose bladder cancer

16. Saturated Fatty Acids Inhibit Hepatic Insulin Action by Modulating Insulin Receptor Expression and Post-receptor Signalling

17. Urinary biomarkers in bladder cancer

18. The effect of nicotinamide on spontaneous and induced activity in smooth and skeletal muscle

19. Contractile properties of human renal cell carcinoma recruited arteries and their response to nicotinamide

20. Collectives of diagnostic biomarkers identify high-risk subpopulations of hematuria patients: exploiting heterogeneity in large-scale biomarker data

21. Urinary Biomarkers in Bladder Cancer

22. Metabolic health and obesity: early determinants, trajectories and causal analysis:the Northern Finland Birth Cohort 1966 and 1986 studies

23. Whole exome sequencing in identifying genetic factors in musculoskeletal diseases

24. Risk factors for sciatica

25. Genetics and molecular epidemiology of metabolic syndrome-related traits:focus on metabolic profiling of lipid-lowering therapies and fatty liver, and the role of genetic factors in inflammatory load

26. The heritability and genetic risk factors of Modic changes

27. Feto-maternal indicators of cardiac dysfunction as a justification for the cardiac origins for pre-eclampsia.

28. A 6-Week Mindfulness-Acceptance-Commitment Intervention to Improve Professional Ballet Dancers' Psychological States Around Performance.

29. Spatial localization of β-unsaturated aldehyde markers in murine diabetic kidney tissue by mass spectrometry imaging.

30. INTERSTAARS: Attention training for infants with elevated likelihood of developing ADHD: A proof-of-concept randomised controlled trial.

32. Investigation and verification of a bioluminescent biosensor for the quantitation of ara-CTP generation: a biomarker for cytosine arabinoside sensitivity in acute myeloid leukaemia.

33. A novel bioluminescent bacterial biosensor for measurement of Ara-CTP and cytarabine potentiation by fludarabine in seven leukaemic cell lines.

34. Greater arousal and less attentiveness to face/voice stimuli by neonates of depressed mothers on the Brazelton Neonatal Behavioral Assessment Scale.

35. Nicotinamide-inhibited vasoconstriction: lack of dependence on agonist signalling pathways.

36. The effect of the vasodilator nicotinamide on cyclic nucleotide pathways in vascular smooth muscle.

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