Advanced maternal age (AMA) is defined as childbearing in mothers ≥35 years of age and is becoming increasingly prevalent in high income countries. AMA has been associated with increased risk of adverse pregnancy outcomes, particularly stillbirth. Although AMA mothers have higher rates of chromosomal abnormalities and maternal co-morbidities, AMA remains an independent risk factor for stillbirth. Despite these findings, the etiology behind this increased risk is unknown. We hypothesise that an altered maternal environment, including increased oxidative stress and inflammation, due to ageing causes placental dysfunction which increases AMA mothers’ vulnerability to stillbirth. A holistic approach was applied to investigate placental dysfunction in AMA. Firstly, a systematic review and meta-analysis comprehensively reviewed existing data on AMA and associated adverse pregnancy outcomes. Secondly, Manchester Advanced Maternal Age Study (MAMAS), a multi-centre prospective observational cohort study, was conducted to investigate risk factors for composite adverse pregnancy outcome (CAPO) in AMA. MAMAS utilised both uni- and multivariate analysis on demographic and clinical data, and measuring biomarkers of ageing and placental dysfunction by ELISA in maternal circulation during the third trimester of pregnancy. Utero-placental dysfunction was directly investigated in uncomplicated AMA pregnancies by quantifying placental morphology, placental nutrient transport capabilities and both placental and maternal uterine vascular responses. Finally, a C57BL/6J murine model of AMA was developed and characterised to further investigate maternal age on pregnancy outcome and the role of the placenta. In the meta-analysis, maternal age was linearly associated with increased risk of stillbirth and other adverse outcomes strongly associated with placental dysfunction (fetal growth restriction, preeclampsia and placental abruption). In MAMAS, smoking status and primiparity were predictive of CAPO. After adjustment, AMA mothers had an odd ratio of 2.05-3.43 of CAPO compared to 20-30 year old mothers. AMA mothers showed evidence of increased oxidative stress and pro-inflammatory bias. AMA mothers who suffered CAPO showed reduced placental endocrine capacity seen in placental dysfunction. Placentas from uneventful AMA pregnancies showed evidence of accelerated ageing and placental adaptation with increased nutrient transport, increased placental weight but reduced efficiency, and altered vascular function. AMA mice showed many similar aspects to human AMA with increased fetal loss, fetal growth restriction and increased placental size. These studies provide robust evidence for increased incidence of adverse pregnancy outcome due to placental dysfunction in pregnancies of women of AMA. This finding requires the appropriate recognition in a clinical context, with a greater focus on personalised obstetric care in an attempt to reduce stillbirth rates in this high risk population. By optimising antenatal and obstetric care for AMA mothers, we could reduce stillbirth rates by 4.7% - the population attributable risk due to AMA. These studies highlight key areas of future research that will further understanding into stillbirth risk in AMA pregnancy, test predictive models and test therapies and clinical care interventions an ultimately improve pregnancy outcome in mothers of AMA.

We established that acute adrenergic receptor stimulation in β-cells suppresses oxidative metabolism. This effect provides the basis for understanding how CAs reduce cell proliferation. Furthermore, the effects of acute CA on Min6 cells were distinguished from chronic CA culture using proteomics. Together, the RNAseq, qPCR and proteomic studies support a role for adrenergic receptor signaling in the regulation of proliferaton in β-cells. This work describes the genetic and proteomic profile underlying chronic adrenergic signaling and identifies CA independent suppression of β-cell growth and metabolism. Through the use of multiple models and comparative bioinformatics, we refined the list of molecular dysfunctions associated with the IUGR pathology to a set of specific and testable adrenergic targets.

No description available.

Current research spans a wide range of objectives whose diversity includes the understanding of global epidemiology and the detailing of molecular interactions leading to specific pathologies. This work aligns more closely with the goal of mechanistic clarity by elucidating several aspects of signaling pathways involved in inflammatory and obstetric pathologies. Prior research has confirmed the role of Receptors for Advanced Glycation End-Products (RAGE) activation in signaling leading to chronic inflammation such as that observed in chronic obstructive pulmonary disease (COPD). RAGE activation has also been identified in other disease states including diabetes, Alzheimer’s disease, osteoarthritis, and cancers. We examined the role of RAGE in the obstetric complication intrauterine growth restriction (IUGR) wherein fetal development is delayed and infants are born at low birthweight. Exposure to tobacco smoke is known to activate RAGE, and smoke exposure also increases risk for IUGR. We confirm a role for RAGE signaling in development of IUGR. RAGE inhibition by semi-synthetic glycosaminoglycan ethers (SAGEs) significantly improved fetal and placental weights and reduced inflammatory signaling molecules. Interactions between RAGE and other signaling pathways have been noted in several research endeavors, and we sought to further understand signaling interactions specifically in obstetric pathologies by examining relationships between RAGE and Gas6/AXL signaling. We confirm that RAGE and Gas6/AXL signaling are not independent. Using tobacco smoke as a means of inducing RAGE, we determined that total AXL is inhibited when RAGE is active, but that phosphorylated AXL is increased. Inhibition of RAGE also increased Gas6 expression. These interactions require further clarification, but provide a foundation to expand upon. We further studied interactions within the Gas6/AXL pathway independent of RAGE. High levels of Gas6 have been noted in the serum of some women with preeclampsia, and early diagnosis and treatment of preeclampsia are currently limited. We demonstrate that, in a rat model, administration of Gas6 during pregnancy is sufficient to induce symptoms of preeclampsia including high blood pressure, increased proteinuria, and decreased trophoblast invasion. This provides a novel model which will further both diagnosis and treatment of preeclampsia. We also demonstrated that trophoblast invasion is influenced in a cell-type dependent manner by Gas6 and mTOR signaling, with decreased trophoblast invasion when Gas6 is high in trophoblast cells, but increased invasion with high Gas6 in a pulmonary adenocarcinoma cell type and in oral squamous cell carcinoma cells. Our work has clarified details of both RAGE and Gas6/AXL signaling that are crucial to further study of the pathways in which they are active, and the pathologies resulting from signaling misregulation.

OBJETIVOS: Descrever os resultados obstétricos e perinatais em três grupos de gestações gemelares monocoriônicas diamnióticas (MCDA) conduzidas de forma expectante: com diástole zero (DZ) e/ou reversa (DR) fixas na Dopplervelocimetria de artérias umbilicais (AU) e restrição de crescimento fetal seletiva (RCFs) (tipo II de Gratacós); com DZ e/ou DR intermitente e RCFs (tipo III de Gratacós) e com DZ e/ou DR intermitente sem RCFs (Sem RCFs). MÉTODOS: Estudo retrospectivo, realizado no período de abril de 2007 a abril de 2017. Foram incluídas todas as gestações MCDA no período com DZ e/ou DR no Doppler de AU com IG < 26 semanas e ausência de Síndrome de Transfusão feto-fetal (STFF) ou malformações fetais e das quais foi possível obtenção dos dados obstétricos, fetais e dos recém-nascidos (RNs) até a alta hospitalar. Todas as variáveis foram analisadas descritivamente. Além disso, para as variáveis qualitativas foram calculadas as frequências absolutas e relativas. RESULTADOS: 33 pacientes preencheram os critérios de inclusão; 6 no tipo II, 22 no tipo III e 5 no grupo Sem RCFs. A mediana da IG do diagnóstico foi semelhante em todos os grupos. As discordâncias entre os pesos dos fetos e RNs foram maiores no tipo II. Quando a DZ e/ou DR eram intermitentes (tipo III e Sem RCFs), a latência entre o diagnóstico e o óbito fetal (OF) foi superior. Quanto aos resultados obstétricos, a IG mediana do parto foi de 29; 32,71 e 30,78 semanas nos tipos II, III e Sem RCFs, respectivamente, e as indicações foram, em sua maioria, por deterioração dos parâmetros ultrassonográficos ou biofísicos fetais. A taxa de OF foi maior no tipo II (33,3%), ocorreu em 20% no Sem RCFs e 11,36% no tipo III. Em relação aos dados perinatais gerais, o pior resultado ocorreu no tipo II, em que nenhuma paciente levou 2 RNs vivos para casa, sendo que isso sucedeu em 72,7% no tipo III e 60% no Sem RCFs. No que concerne à morbidade neonatal, o peso de nascimento foi menor no tipo II. Já, a HIV mostrou-se mais comum no tipo III (30,3%), porém, no tipo II, a ocorrência foi similar (28,57%), não acometeu nenhum RN no grupo Sem RCFs. CONCLUSÃO: A prematuridade foi preponderante. O acompanhamento da vitalidade dos fetos é de suma importância, uma vez que a piora de seus parâmetros indica a resolução da gestação em considerável parcela desses casos. O tipo II foi o que apresentou os desfechos perinatais mais desfavoráveis, além da maior discordância de peso entre os fetos e os RNsAbsent and/or reversed end-diastolic flow in the umbilical arteries / OBJECTIVES: To describe obstetric and perinatal outcomes in three groups of monochorionic diamniotic (MCDA) twin pregnancies under expectant management: with absent and/or reversed end-diastolic Doppler flow (AREDF) in the umbilical arteries (UA) and selective intrauterine growth restriction (sIUGR) (Gratacós\' type II); with intermittent AREDF (iAREDF) and sIUGR (Gratacós\' type III) and with iAREDF without sIUGR (Without sIUGR). METHODS: This was a retrospective study, from April 2007 to April 2017. All the MCDA twin pregnancies presenting AREDF or iAREDF in the UA at less than 26 weeks of gestational age (GA), without signs of Twin to Twin Transfusion Syndrome (TTTS) or fetal anomalies and of whom it was possible to obtain obstetrical data and information of the fetuses and neonates until hospital discharge were included. All the variables were descriptively analysed. Furthermore, absolute and relative frequencies were calculated for the qualitative variables. RESULTS: 33 patients were included; 6 in type II, 22 in type III and 5 in the group Without sIUGR. Median GA at diagnosis was similar among the groups. Fetal and neonate\'s weight discordances were greater in type II. The groups with iAREDF (type III and Without sIUGR) had the longest latency between diagnosis and intrauterine fetal demise (IUFD). Regarding obstetric outcome, median GA at delivery were 29, 32.71 and 30.78 weeks for type II, III and Without sIUGR respectively and sonographic and biophysical parameters deterioration was the main reason to indicate deliveries. IUFD was also more frequent in type II (33,3%), occurred in 20% of type III and 11,36% in the group Without sIUGR. As far as general perinatal outcome is concerned, type II had the worst result, in which no patient took 2 neonates home; it happened in 72.7% in type III and 60% in the group Without sIUGR. In relation to perinatal morbidity, type II neonates presented the lowest weight at birth. Type III and II had the highest, but similar proportions of intraventricular hemorrhage (30.3% and 28.57% respectively), it didn\'t happen in the group Without sIUGR, though. CONCLUSION: Prematurity was preponderant. It is of the highest importance to monitor fetal wellbeing, since the great majority of deliveries were indicated by the deterioration of its parameters. Type II sIUGR showed the most unfavorable perinatal outcome and additionally, the greatest fetal and neonatal weight discordances

OBJETIVOS: Descrever os resultados obstétricos e perinatais em três grupos de gestações gemelares monocoriônicas diamnióticas (MCDA) conduzidas de forma expectante: com diástole zero (DZ) e/ou reversa (DR) fixas na Dopplervelocimetria de artérias umbilicais (AU) e restrição de crescimento fetal seletiva (RCFs) (tipo II de Gratacós); com DZ e/ou DR intermitente e RCFs (tipo III de Gratacós) e com DZ e/ou DR intermitente sem RCFs (Sem RCFs). MÉTODOS: Estudo retrospectivo, realizado no período de abril de 2007 a abril de 2017. Foram incluídas todas as gestações MCDA no período com DZ e/ou DR no Doppler de AU com IG < 26 semanas e ausência de Síndrome de Transfusão feto-fetal (STFF) ou malformações fetais e das quais foi possível obtenção dos dados obstétricos, fetais e dos recém-nascidos (RNs) até a alta hospitalar. Todas as variáveis foram analisadas descritivamente. Além disso, para as variáveis qualitativas foram calculadas as frequências absolutas e relativas. RESULTADOS: 33 pacientes preencheram os critérios de inclusão; 6 no tipo II, 22 no tipo III e 5 no grupo Sem RCFs. A mediana da IG do diagnóstico foi semelhante em todos os grupos. As discordâncias entre os pesos dos fetos e RNs foram maiores no tipo II. Quando a DZ e/ou DR eram intermitentes (tipo III e Sem RCFs), a latência entre o diagnóstico e o óbito fetal (OF) foi superior. Quanto aos resultados obstétricos, a IG mediana do parto foi de 29; 32,71 e 30,78 semanas nos tipos II, III e Sem RCFs, respectivamente, e as indicações foram, em sua maioria, por deterioração dos parâmetros ultrassonográficos ou biofísicos fetais. A taxa de OF foi maior no tipo II (33,3%), ocorreu em 20% no Sem RCFs e 11,36% no tipo III. Em relação aos dados perinatais gerais, o pior resultado ocorreu no tipo II, em que nenhuma paciente levou 2 RNs vivos para casa, sendo que isso sucedeu em 72,7% no tipo III e 60% no Sem RCFs. No que concerne à morbidade neonatal, o peso de nascimento foi menor no tipo II. Já, a HIV mostrou-se mais comum no tipo III (30,3%), porém, no tipo II, a ocorrência foi similar (28,57%), não acometeu nenhum RN no grupo Sem RCFs. CONCLUSÃO: A prematuridade foi preponderante. O acompanhamento da vitalidade dos fetos é de suma importância, uma vez que a piora de seus parâmetros indica a resolução da gestação em considerável parcela desses casos. O tipo II foi o que apresentou os desfechos perinatais mais desfavoráveis, além da maior discordância de peso entre os fetos e os RNsAbsent and/or reversed end-diastolic flow in the umbilical arteries / OBJECTIVES: To describe obstetric and perinatal outcomes in three groups of monochorionic diamniotic (MCDA) twin pregnancies under expectant management: with absent and/or reversed end-diastolic Doppler flow (AREDF) in the umbilical arteries (UA) and selective intrauterine growth restriction (sIUGR) (Gratacós\' type II); with intermittent AREDF (iAREDF) and sIUGR (Gratacós\' type III) and with iAREDF without sIUGR (Without sIUGR). METHODS: This was a retrospective study, from April 2007 to April 2017. All the MCDA twin pregnancies presenting AREDF or iAREDF in the UA at less than 26 weeks of gestational age (GA), without signs of Twin to Twin Transfusion Syndrome (TTTS) or fetal anomalies and of whom it was possible to obtain obstetrical data and information of the fetuses and neonates until hospital discharge were included. All the variables were descriptively analysed. Furthermore, absolute and relative frequencies were calculated for the qualitative variables. RESULTS: 33 patients were included; 6 in type II, 22 in type III and 5 in the group Without sIUGR. Median GA at diagnosis was similar among the groups. Fetal and neonate\'s weight discordances were greater in type II. The groups with iAREDF (type III and Without sIUGR) had the longest latency between diagnosis and intrauterine fetal demise (IUFD). Regarding obstetric outcome, median GA at delivery were 29, 32.71 and 30.78 weeks for type II, III and Without sIUGR respectively and sonographic and biophysical parameters deterioration was the main reason to indicate deliveries. IUFD was also more frequent in type II (33,3%), occurred in 20% of type III and 11,36% in the group Without sIUGR. As far as general perinatal outcome is concerned, type II had the worst result, in which no patient took 2 neonates home; it happened in 72.7% in type III and 60% in the group Without sIUGR. In relation to perinatal morbidity, type II neonates presented the lowest weight at birth. Type III and II had the highest, but similar proportions of intraventricular hemorrhage (30.3% and 28.57% respectively), it didn\'t happen in the group Without sIUGR, though. CONCLUSION: Prematurity was preponderant. It is of the highest importance to monitor fetal wellbeing, since the great majority of deliveries were indicated by the deterioration of its parameters. Type II sIUGR showed the most unfavorable perinatal outcome and additionally, the greatest fetal and neonatal weight discordances

Magnesium alloys have been extensively used for structural and functional applications due to their low densities. In order to improve the mechanical properties, grain refinement of the microstructures of magnesium alloys has been studied for many years. However, an effective and efficient grain refiner or refinement technique hasn’t been achieved yet, especially for those with aluminium contained. In this study, solution for this problem has been discovered through further understanding of the solidification process, including the potency and the efficiency of nucleation particles, the role of solute, and the role of casting conditions. First of all, the study suggested that MgO particles can act as nuclei in magnesium alloys by measuring and analyzing the differences in cooling curves with various amount of endogenous MgO particles. The differences indicated that the number density of MgO particles has a huge influence on the microstructure. This idea has been fatherly proved by the inoculation of MgO particles in magnesium alloys because the microstructures have been significantly refined after the inoculation. A new kind of refiner (AZ91D-5wt%MgO) has been developed based on such understandings. Secondly, the study discovered that the role of solute has much smaller effect on the grain size than it was suggested in traditional understandings. The inverse-proportional relationship between the grain size and the solute is highly suspected and the major role of solute is to cause columnar- equiaxed transition. The role of casting conditions has also been studied in order to provide experimental evidence for the existence of melt quenching effect in magnesium alloys. It is shown that various casting conditions, such as pouring temperatures and mould temperatures, have large influence on the critical heat balance temperature after rapid pouring. In this study, a theoretical model based on the analysis of cooling curves is presented for grain size prediction. An analytical model of the advance of equiaxed solidification front is developed based on the understanding of the role of casting conditions. Eventually, all these understandings have been applied to magnesium direct-chill (DC) casting. The refined microstructure of DC cast ingots can further assist in understanding the mechanism of advanced shearing achieved by MCAST unit. The comparison of the ingots with and without melt shearing indicated that the advance shearing device can disperse MgO film into individual particles.

Early pregnancy is characterized by complex interactions between blood vessels, leukocytes, and conceptus-derived trophoblasts within the gestational uterus. Uterine Natural Killer (uNK) cells become the most abundant leukocyte during decidualization and produce a wide array of angiogenic factors, yet little is known regarding their early pregnancy functions. To characterize the role(s) of uNK cells, whole mount in situ immunohistochemistry of live early implant sites was performed. A timecourse examination of murine early pregnancy (virgin, and gd4.5-9.5) implantation sites was performed. Comparison of Gd6.5, 8.5 and 9.5 implant sites from BALB/c+/+ controls (BALB/c) and BALB/c-Rag2-/-Il2rg-/- (alymphoid) identified anomalies that result from the absence of lymphocytes. In alymphoid decidua basalis, mesometrial angiogenesis was widespread but pruning of nascent vessels within alymphoid decidua basalis was deficient. As early gestation progressed, vessels of alymphoid decidua basalis showed no evidence for remodeling. Alymphoid implantation sites showed ~24h delay in uterine lumen closure and embryonic development. To determine if uNK cells would normalize the anomalies observed in alymphoid implantation sites, adoptive cell transfer of NK+ B- T- marrow to alymphoid mice was performed. All of the above anomalies were reversed by adoptive transfer of NK+B-T- marrow. My results suggest that uNK cells support vascular growth and development which ensures the decidua can support the growing conceptus early in pregnancy prior to formation and function of the placenta. Human decidual NK cells may fill similar roles and be important targets for strategies designed to correct intra-uterine growth restriction. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2013-08-02 08:42:06.487

Submitted by Rosivalda Pereira (mrs.pereira@ufma.br) on 2017-08-21T18:59:25Z No. of bitstreams: 1 SilviaSousa.pdf: 2280503 bytes, checksum: a06b53b8d68a96973316e3b881bd15d6 (MD5) / Made available in DSpace on 2017-08-21T18:59:25Z (GMT). No. of bitstreams: 1 SilviaSousa.pdf: 2280503 bytes, checksum: a06b53b8d68a96973316e3b881bd15d6 (MD5) Previous issue date: 2017-02-22 / Introduction: Intrauterine growth restriction (IUGR) and preterm birth (PT) are considered to be public health problems in developing countries. The occurrence of catch-up favors the ability of these infants to obtain equivalent growth to that of infants born without IUGR and at term. Objective: To assess the influence of IUGR and of PT on the occurrence of catch-up in weight and BMI in schoolchildren from two birth cohorts from cities with contrasting socioeconomic conditions in the Northeast and Southeast of Brazil. Method: A total of 1,463 children were studied, from whom information was collected at birth and at school age in 1994 and 2004/2005 in Ribeirão Preto, SP (RP) and in 1997/1998 and 2005/2006 in São Luís, MA (SL). The response variable was defined as the difference in weight and BMI between the Z-score of the schoolchild and the Z-score at birth. A change in Z-score ≥ 0.67 was considered to be catch-up. The explanatory variable was divided into four categories: without IUGR and at term (NIUGR-T), only IUGR (IUGR-T), only PT (NIUGR-PT), and PT plus IUGR (IUGR-PT). Estimates of the relative risk for catch-up in weight were obtained by logistic regression in separate models for each city. Results: RP children had a greater proportion of both catch-up than SL children. In RP, 90.8% of IUGR-PT and 70.8% of NIUGR-PT (it was more frequent in pre-terms, restricted or not) caught up in weight at school age. In SL, the NIUGR-PT and IUGR-T caught up in a similar way. There was no difference between genders. Regarding marital status, in RP, no difference was found, however, in SL, the odds of catching up at 7 years old was 65% lower for those schoolchildren whose mothers did not have a partner. Having only one child, both in RP and in SL, increased almost twofold (OR=1.89 in RP and 1.83 in SL) the odds of the schoolchild catching up; and receiving up to 5 times the monthly minimum wage decreased by 50% the odds of catching up in SL, although no difference was found in RP. The head of the family’s occupation being unqualified manual labor or unemployed decreased by half the odds of catching up in both cities. Maternal age and education level were not associated to catchup in school age. Conclusion: In both cities, children born preterm with/without IUGR had a greater proportion of catch-up in weight and without IUGR and at term in BMI. / Introdução: A restrição de crescimento intrauterino (RCIU) e o nascimento pré-termo (PT) são considerados problemas de saúde pública nos países em desenvolvimento. A ocorrência de catch-up propicia que estes consigam equiparar seu crescimento ao das crianças nascidas sadias. Objetivo: Avaliar a influência da RCIU e do PT na ocorrência de catch-up de peso e IMC em escolares de duas coortes de nascimentos de cidades com condições socioeconômicas contrastantes. Método: Foram estudadas 1.463 crianças, cujas informações foram coletadas ao nascer e na idade escolar em 1994 e 2005/06 em Ribeirão Preto, SP (RP) e em 1997/98 e 2005/06 em São Luís, MA (SL). A variável resposta foi definida pela diferença entre o escore z do escolar e escore z ao nascimento do peso e IMC. Considerou-se como catch-up uma mudança de escore z de ≥ 0,67. A variável explanatória foi dividida em quatro categorias: sem RCIU e a termo (TNR), só RCIU (TR), só PT (PTNR) e PT com RCIU (PTR). Estimativas do risco relativo para catch-up de peso foram obtidas por regressão logística em modelos separados por cidade. Resultados: O fenômeno “catch-up” tanto de peso quanto de IMC foi mais evidente em RP para todas as categorias das chamadas condições de nascimento. Para ambas as cidades a maior incidência de catch-up de peso se deu para os PT e/ou com RCIU, já o de IMC para os TNR. Não houve diferença entre os sexos. Ter somente 1 filho, maior renda familiar e escolaridade materna além da ocupação do chefe mais qualificada aumentou a frequência do catch-up de peso e IMC em ambas as cidades. Conclusão: Não só condições biológicas ao nascer mas também as condições de vida, tais como, acesso aos serviços de saúde e melhor oferta de alimentos nas idades mais precoces da criança influenciam na ocorrência de catch-up de peso e IMC nas duas cidades estudadas.

β-grain size is an influential microstructural parameter on the properties of titanium components. A reduction of β-grain size is generally associated with improvements to ductility, strength, corrosion and fatigue resistance of many α, α/β and β titanium alloys. During production of wrought titanium components, the β-grain size is carefully controlled during thermomechanical processing but there is currently no control of the β-grain size during solidification of cast components. As such, this inability to control the β-grain structure during solidification may limit the applications for solidification based technologies including casting, welding and direct metal deposition. Due to the limited knowledge of grain refinement practices and the lack of commercial grain refiners for the titanium system, this thesis investigates the mechanisms of β-grain refinement during solidification of cast titanium alloys. In this thesis, generalized theories for grain refinement that have been developed from research into other metallic systems are applied to the titanium system. Similar to the findings from aluminium and magnesium research, it is shown that grain refinement of cast titanium alloys requires the addition of growth restricting solutes which provide constitutional undercooling as well as the presence of potent nucleant particles. It is demonstrated that commercially pure titanium contains a natural distribution of nuclei particles which may originate from the mould wall and when powerful growth restricting solutes are introduced, significant prior-β grain refinement is achievable. All solutes investigated do not interact or poison the naturally occurring nucleants enabling the grain size of the titanium alloys to be predicted by an empirically determined relationship based on the growth restriction factor. A full list of growth restriction factors for various elements in titanium is determined and it is proven that growth restriction theory is valid in the titanium system. A further reduction in β-grain size is achievable by introducing additional nucleant particles to titanium castings in conjunction with growth-restricting solutes. Using a novel technique, titanium powder was introduced to the melt stream prior to solidification and was mixed throughout the liquid. The powder particles partially melted and the oxide surface layer dissolved allowing intimate substrate-liquid contact, enabling the titanium substrates to act as sites for heterogeneous nucleation. Using this technique, it was possible to grain refine commercially pure titanium without foreign elemental addition and when growth restricting solutes were present it was possible to obtain approximately an order of magnitude grain size reduction. The results and concepts developed from this work may aid the future development of a commercial grain refiner for titanium. If a grain refiner is developed, its application will not just be limited to the titanium casting industry but may also benefit other solidification based technologies such as welding, direct metal deposition and wrought billet production.