Cerebral palsy (CP) affects around every one in 500 children born. It isn’t a particular illness or disease, but an umbrella term used to describe a physical condition that affects movement as a result of injury to the brain. There are several types of CP, the main ones being spastic, athetoid and ataxic. Despite medical advances, there is no cure for CP but there are ranges of treatments from drugs to Botulinum toxin type A injections, massage therapy to surgery. The aim of this study is to look at two of these treatments, namely Botulinum toxin type A injections and physiotherapy to treat spastic CP. Botulinum toxin is widely used to reduce muscle tone in the treatment of spasticity in children with cerebral palsy. The aim of the study is to compare the effects treatment with Botulinum toxin type A and Botulinum toxin type A with additional physical therapy in the management of a group of children with cerebral palsy. Experiments were done at The Prince Sultan Hospital and Al-Hada Armed Forces Hospital in Saudi Arabia. The local Ethics Committee approved the protocol. 47 children were recruited. All had cerebral palsy, diplegia, spasticity of the ankle planter flexors and significant gait abnormalities due to dynamic equinus foot deformity. They were divided into two groups. Both groups had their Gross Motor Function assessed one week before injection and at 4 and 6 weeks after injection. Additional measurements of range of movement and stiffness at the ankle and soleus electromyograms were recorded The soleus EMG was silent during ankle dorsiflexion in 20 children four weeks after injection of Botox. The EMG had returned six weeks after injection in every child. The Gross Motor Function Measurements were not significantly different in the two groups before the injection (p=0.23). The measurements improved significantly over the next six weeks in both groups (p<0.001). The magnitude of the improvement was greater in the group, which received Botulinum toxin type A and physical therapy (means 57.2 + 8.90 before, 64.9 + 9.78 after. Mean + SD) than in the group which received Botulinum toxin type A alone (59.5 + 11.0 before, 62.4 + 11.3 after Mean + SD). Conclusions 1. . The Treatment allocation provided groups, which were comparable pre-treatment in terms of baseline GMFM. 2. . Both treatments showed evidence of improvement in GMFM over the period of the study and particularly at 52 weeks. 3. . Treatment 2 showed a significant average advantage in GMFM over Treatment 1 at all times in the study. 4. . This advantage in average GMFM increased from 4 through to 52 weeks with a clear and significant difference between 4 and 52 weeks. 5. . This average advantage appeared to increase the higher the child’s baseline GMFM.

Since the introduction of glucocorticoids (GCs) in the treatment of rheumatoid arthritis in 1949, GC therapy has been associated with a number of adverse effects. Long-term use of GCs can result in growth retardation during childhood due to their actions on growth plate chondrocytes, although the exact mechanisms involved are unclear. The work of this thesis has investigated the cellular and molecular mechanisms involved in mediating GC effects at the growth plate. Affymetrix microarray has been used to identify and characterise the expression of lipocalin 2, a novel GC-responsive chondrocyte gene which may contribute to GC-induced growth retardation in the growth plate. In vitro and in vivo studies have also been used to examine the role of the cell cycle regulator, p21WAF1/CIP1 in GC-induced growth retardation. Finally, the growth plate sparing effects of a novel GC receptor modulator, AL-438, have also been identified. AL438, has reduced effects on bone growth compared to Dex, but maintains similar anti-inflammatory efficacy. This work has not only determined novel mechanisms of GC-induced growth retardation, but has also advanced the search for novel GC receptor modulators with reduced adverse effects.

Brain tissue, both grey and white matter from the cerebral parietal region and the cerebellum, was obtained from 66 infants dying of sudden infant death syndrome. The fatty acid composition was analysed in these tissues by gas liquid chromatography after extraction and derivatisation. The subjects were divided according to their dietary history, either breast or formula feeding. Formula-fed infants were further subdivided according to the content of -linolenic acid in the formula milk. At the time of this study no formula milks analysed contained long chain polyunsaturated fatty acids. Dietary related differences were found in the accretion of polyunsaturated fatty acids into neural membranes. Docosahexaenoic acid concentrations were higher and conversely n-6 series fatty acids lower in breast-fed than formula-fed infants. In cerebral white matter, nervonic acid, the long-chain fatty acid associated with myelination, appeared in breast-fed in advance of formula-fed infants. Similar dietary related differences in polyunsaturated fatty acid compositions were found in the cerebella cortex and the cerebellar white matter was associated with an earlier accretion of nervonic and lignoceric acids when compared to the cerebrum. Analysis of the phospholipid and glycolipid composition of the cerebral and cerebellar white matter tissues was achieved by means of separation by high performance thin layer chromatography followed by scanning densitometry. The results of this study support the need for breast feeding for a minimum of four months. Formulation of manufactured milks should include long chain polyunsaturated fatty acids and nervonic acid at concentrations similar to those of breast milk.

This thesis deals with the quantitative analysis of multiple drugs in the neonate, in blood and in meconium as an alternative biological specimen in forensic toxicology and is also concerned with the dangers of transmission of drugs used and abused by the mother to the foetus and neonate. The aims of the work were to investigate methods for performing a full drug screen on small amounts of biological specimen and to carry out a survey of illicit drug use during pregnancy in the Glasgow area. Following brief overviews of toxicology and the main problems facing the paediatric toxicologist, the development of analytical toxicology procedures to help to overcome them is summarised along with a more detailed examination of solid phase extraction (SPE) - theory, advantages and applications to biological samples. The initial experimental work established the feasibility of performing a full drug screen on small samples of blood such as those obtained from neonates, having a volume of 1-2ml. This used a single SPE cartridge for the extraction of a mixture of acidic and basic drugs followed by end-step analysis with enzyme immunoassay (ELA) and gas chromatography-mass spectrometry (GC/MS). Representative drugs from each group were selected for evaluation purposes: butobarbitone, amylobarbitone, methaqualone, primidone, and phenytoin drugs for the acidic drug group and cocaine, ecgonine methyl ester, morphine, diazepam, and desmethyldiazepam for the basic drug group. These were chosen as examples of drugs commonly used in the UK. Four analytes (morphine, methadone, cocaine and benzoylecgonine) were used to compare two different SPE cartridges, Bond Elut Certify® and Abselut®, which can be used to extract both acidic and basic drugs. The comparison involved four parameters: analyte recovery, lower limits of detection, presence of interferences in the extracts and analysis time required by each. Recoveries were in the range 60-100% and lower limits of detection were in the range 1-25 ng/ml and it was assessed that Bond Elut columns were better than Abselut columns.

This thesis consists of a series of studies utilising quantitative ultrasound (Sunlight Omnisense 7000P) to assess bone health of infants. Preterm infants are at risk of osteopenia of prematurity (OP) which can result in fractures in the short term and may have an impact on growth in infancy and childhood. OP has a multifactorial aetiology including factors such as poor mineral intake and immobility. There is an increasing number of ex-preterm survivors therefore morbidity becomes more important. There is also increasing evidence from epidemiological studies that growth in infancy can have an effect on adult diseases such as osteoporosis. The first study was a cross-sectional study of bone quantitative ultrasound measurements in 110 term and preterm infants shortly after birth. Speed of sound (SOS) was measured at the tibial and the radius. This validated the technique showing reproducible measurements with low inter and intra-observer error, and also showed no benefit to measuring multiple sites. Preterm infants were found to have a significantly lower SOS than term infants. There was a positive correlation between tibial SOS and gestation, with birthweight being a less significant factor than gestation. The second study followed 18 preterm infants longitudinally from birth to hospital discharge or term corrected gestational age (CGA). SOS fell significantly with time in all infants. The most preterm infants had the greatest fall in SOS. SOS at the end of the study period was negatively associated with peak serum alkaline phosphatase and severity of illness score. SOS was significantly lower in the infants who required total parenteral nutrition for longer than 3 weeks. These results show that the neonatal course has a significant impact on SOS trajectory. When preterm infants were followed up in the out-patient clinic over the first two years of life the SOS measurements taken as the next part of this study showed a catch up phenomenon. In the majority of infants, but not all infants, SOS moved into the normal range by 6 months CGA. In the subgroup of infants followed longitudinally those with the lowest SOS at hospital discharge/term corrected age had the greatest increase in SOS over time. An interventional study of passive exercise was performed to explore its role in influencing the bone health of preterm infants. Thirty one infants born at less than 33 weeks gestation were randomised to receive range of motion flexion and extension exercises once daily for 5 days each week starting ‘early’(n=15) or ‘late’ (when on 100kcal/kg/day enteral feeds, n=16) and continuing until term corrected gestational age (CGA) or discharge from hospital. Tibial SOS declined significantly from birth to end of physical activity in both ‘early’ and ‘late’ groups, and this was similar to the decrease seen in a group of historical controls from the earlier longitudinal study. Weight gain and head growth did not show a significant difference between groups or between study infants and controls. No infant was reported to have sustained a fracture, and length of hospital stay was not significantly different between groups. There was no significant increase in sepsis rate, retinopathy of prematurity or chronic lung disease in study infants but numbers were small. On longer term follow-up the intervention was not associated with any adverse effects. To investigate the possibility that the maternal environment plays an important role in influencing infants’ bone health we also studied SOS changes in 188 pregnant women and their offspring. Most women had SOS in the normal range antenatally, and there was no significant change in SOS across pregnancy in the group as a whole. There was a significant negative correlation with SOS SDS and BMI in early pregnancy. Women who smoked cigarettes had lower SOS throughout pregnancy and so did their infants. Serum bone biochemistry was measured in the women antenatally and after delivery, and umbilical cord blood was also taken where possible. Vitamin D deficiency was found to be common at the end of pregnancy. Women of Asian origin had significantly lower vitamin D levels at all stages of pregnancy. There was no significant relationship between maternal and infant SOS, or between maternal vitamin D status and infant SOS. The work of this thesis establishes quantitative ultrasound as a useful technique in the assessment of infant bone health. It is a radiation free tool which provides precise and reproducible measurements in both term and preterm infants. In agreement with a small number of other studies we found that preterm infants have a lower speed of sound at birth compared to term infants; speed of sound increases with increasing gestation while in utero. By including infants who were both appropriately grown and small for gestational age we found maturity to be a more important factor in bone strength than birthweight. Despite the apparent self limiting nature of osteopenia of prematurity an intervention to improve neonatal bone health is still desirable, to prevent fractures. Our results do not substantiate conclusions from previous studies that physical activity alone can improve neonatal bone health. .Findings are however limited by the small sample size. Further studies are needed which investigate alternative exercise regimens, taking into account mineral and nutrient supply. Vitamin D deficiency, smoking and obesity may adversely affect bone health of women and their offspring. In the west of Scotland vitamin D deficiency is common in pregnancy: women of south asian origin are at particularly high risk, and should be supplemented with Vitamin D.

The bacteria located within the human gastrointestinal tract (the gut microbiota) perform numerous protective, immunological and metabolic functions for the host. They are increasingly implicated in the pathogenesis of acquired inflammatory diseases of the gut in childhood, namely: necrotising enterocolitis (NEC) and inflammatory bowel disease (Crohn’s disease (CD) and ulcerative colitis (UC)). Study of the role that the microbiota may play in the development of such diseases may lead to new therapies to modulate or even cure them. However many current techniques depend on the ability to study such bacteria outwith their natural ecosystem. Although molecular techniques can identify species independent of standard cultures they can enlighten little on the metabolic activity of identified bacterial species, which may be important in the propagation of inflammatory responses. Little is known about the potential of novel therapeutic strategies, such as probiotics, to modulate diseases such as NEC. In addition inadequate scientific rigour has been applied to the science of probiotics. The aims of the study described in this dissertation were to test the following hypotheses. Hypotheses: 1. Probiotics prevent NEC in at risk infants of very low birth weight (VLBW). 2. The human gut microbiota can be labelled by stable isotope probing (SIP) to measure metabolic activity. 3. Quantitative measurement of the metabolic activity of the unculturable gut microbiota is a useful way of studying changes in the microbiota, compared with measures of bacterial diversity, and may enlighten our understanding of bacterially mediated inflammatory stimuli in inflammatory gut diseases of childhood.

This study aimed to investigate the effectiveness of Social Stories utilising either photograph or symbol illustrations to address the target behaviours of children with a diagnosis of Autism Spectrum Disorder (ASD). Multiple single-case experiments were conducted utilising an ABA design with 10 participants, all of whom were boys attending mainstream primary schools within a West Midlands Local Authority. The children ranged in age from 5-11 and all of them had a diagnosis and a primary need in relation to ASD. Personalised Social Stories were composed for each of the participants to address a specific target behaviour that had been identified by the child and members of teaching staff. The stories were written by the researcher alongside a member of staff from the Local Authority's Autism Outreach Service and all adhered to the criteria and guidelines for construction outlined by Carol Gray (2004). The format for each of the stories was identical but for the manipulation of the illustrations. The effectiveness of the intervention was monitored using a variety of measures including a Behaviour Log recording the frequency of the target behaviour across each of the experimental phases; the Strengths & Difficulties Questionnaire (Goodman, 1997); and a Teacher / Teaching Assistant Questionnaire that had been designed by the researcher and was based on items contained within the Behaviour Intervention Rating Scale (BIBS) (Elliot & Treuting, 1991). The data obtained from these measures was analysed through the visual inspection of graphical data and the calculation of effect sizes. Discussion is provided about the suitability, reliability and validity of each of the measures and the methods of data analysis. Overall the study provides evidence of the utility and effectiveness of Social Stories for addressing the target behaviours of children with a diagnosis of ASD. Furthermore it offers an original contribution to the existing literature by exploring the impact of different forms of illustration on story efficacy.

The selection of outcomes is a critically important decision when designing randomised controlled trials (RCTs). Informed clinical decisions can only be based on the results of RCTs that have measured outcomes of importance to both clinicians and patients. It can be difficult to know which outcomes should be measured in RCTs. Some groups advocate core outcome sets, which are a minimum set of outcomes that should be measured, and reported, in all clinical trials in a given condition. These increase the likelihood that important outcomes are measured, reduce nonuniformity between studies, and reduce the risk of outcome reporting bias. We systematically reviewed studies that determined which outcomes to measure in clinical trials in children, and found that such work had been conducted in only few conditions, and the quality of existing work was variable. Few studies used structured consensus techniques to reach agreement about which outcomes to measure in trials, and parents were seldom involved. No studies included children. One condition in which there were no robust recommendations about which outcomes to measurein RCTs was childhood asthma, which is a condition of considerable global importance. We subsequently aimed to assess whether the absence of a core outcome set for RCTs of children with asthma meant that certain outcome domains were measured less frequently than others, and whether there was nonuniformity between studies in terms of outcomes selected. We conducted a systematic review of RCTs of children with asthma, published between January 1988 and December 2007, and found that the included studies focussed on short-term disease activity, but quality of life, functional status, and long-term outcomes were infrequently measured. Certain outcomes were measured and reported in various ways. We recommended that a core outcome set should be developed for childhood asthma, using structured consensus techniques, such as the Delphi process. In order to aid the development of such a core set, we first systematically reviewed studies that used the Delphi process to determine which outcomes to measure in clinical trials. We observed variations in the methodology used, identified potential sources of bias, and provided recommendations about how such studies could be conducted and reported. In order to develop a core outcome set for childhood asthma, we used a Delphi process to ascertain the views of 46 clinicians, and around 100 parents and young people, about which outcomes are most important and relevant from their perspective, when making shared decisions about regular therapies which control asthma. The most important outcomes were symptoms, exacerbations, and quality of life. Although consensus still needs to be reached amongst other groups of individuals involved in clinical trials, we conclude that these outcomes should be measured, and reported, in all RCTs that aim to evaluate the effectiveness of regular therapies for children and young people with asthma.

Na região de São Fidélis, no Estado do Rio de Janeiro, ocorrem as unidades metaplutônicas Bela Joana e Angelim e as metassedimentares Catalunha, São Fidélis e Santo Eduardo, cujas idades prováveis são domédio ao final do Proterozóico. Todas as unidades estão estruturadas segundo um padrão de foliação SW-NE com mergulhos fortes. A associação charnockítica Bela Joana apresenta a configuração de um maciço lenticular e uma faixa estreita, separada do corpo principal por gnaisses migmatíticos. A unidade Bela Joana apresenta xenólitos de metamorfitos, representando restos de teto, e enclaves básicos, ambos relacionados à movimentação plutônica. Os eventos de deformação e metamorfismo que atuam posteriormente à formação das rochas das unidades Bela Joana e Angelim desenvolveram domínios deformacionais foliados e gnáissicos, relacionados às transformações metamórficas associadas a processos de cisalhamento dúctil. A foliação (\'S IND.C\') da unidade Bela Joana está presente também nos xenólitos de metamorfitos e nos enclaves básicos, podendo ser atribuída á fase de deformação \'S IND.n+1\' dos tipos litológicos gnáissico-migmatíticos encaixantes. As relações de contato entre as unidades Bela Joana e Catalunha situam a fase de colocação de associação charnockítica como anterior à intensa migmatização regional. A associação charnockítica abrange gabro-noritos, enderbitos, charno-enderbitos e charnockitos, com predominância dos termos intermediários; gabro-noritos e leuco-noritos também são encontrados sob a forma de enclaves. Como minerais primários tem-se plagioclásio, ortopiroxênio, clinopiroxênio, granada, quartzo e K-feldspato. Geoquimicamente, a unidade apresenta feições de uma seqüência cogenética de diferenciação magmática, com afinidade cálcico-alcalina, e com características de granitóide de arco magmático. A associação charnockítica é enriquecida em elementos terras raras, sobretudo em terras raras leves ) relativamente às terras raras pesadas, apresentando anomalias negativas de Eu bem definidas na maior parte das amostras. O granitóide Angelim ocorre paralelamente à foliação regional, encaixando entre as unidades Santo Eduardo e São Fidélis, sendo que as zonas cataclásticas cortam o ortognaisse ou indicam uma movimentação tectônica nas áreas de contato entre essas unidades. O Angelim é composto por rochas de composições tonalítica-granodioríticas com termos graníticos mais restritos. Os principais minerais fêmicos interpretados como magmáticos são a granada almandina e a hornblenda pargasítica; a biotita em grande parte é derivada das transformações desses minerais. Geoquimicamente, o Angelim apresenta afinidade cálcico-alcalina e enriquecimento em elementos incompatíveis, principalmente Rb e terras raras totais. As unidades gnáissico-migmatíticas Catalunha, São Fidélis e Santo Eduardo estão dispostas em faixas contínuas, onde a foliação principal (\'S IND.n+1\') está relacionada às faixas de cisalhamento dúctil desenvolvidas na região. As características petrográficas e geoquímicas sugerem que essas unidades representem a migmatização de seqüências supracrustais originalmente dominadas por grauvaca-pelitos com vulcânicas-vulcanoclásticas félsica-intermediárias associadas. As determinações geotermométricas e geobarométricas mostram que as fases minerais das unidades metaplutônicas e metassedimentares reequilibraram-se quimicamente sob condições de P-T em torno de 720 ° C e 6 Kb, expressando o pico do metamorfismo durante o Ciclo Brasiliano na região. Essas condições de P-T são consistentes com as fácies anfibolito alto e granulito, dependendo da abundância e composição das fases fluidas, particularmente das razões C\'O IND.2\'/\'H IND.2\'O nas rochas. / In the São Fidélis region occur the metaplutonic Bela Joana and Angelim and the metasedimentary Catalunha, São Fidelis and Santo Eduardo units of probable Mid-late Proterozoic age. All these lithologies presents a steep dipping SW-NE region al foliation related to ductile shear zones. Both the Bela Joana and Angelim units have massive, foliated and gneissic domains .The Bela Joana charnockitic sequence has metasedimentary xenoliths, as well as basic enclaves, and its contact relations with the Catalunha unit indicate that its emplacement preceded the intense regional migmatization. The Bela Joana have gabbro-norite-enderbite-charno-enderbite- charnockitic compositions with predominances of intermediate terms; enclaves of gabbro- norites and leuco - norites occur as well. The Bela Joana sequence have plagioclase, orthopyroxene, clinopyroxene, garnet, quartz and K-feldspars as primary minerals. Geochemically, it has characteristics of a calc-alkaline cogenetic magmatic differentiated sequence, similar to subduction-related magmatic-arc granitoids. Regarding the Rare Earth elements, it shows fractionated patterns with enrichment of LREE and conspicuous negative Eu anomalies.The Angelim unit have tonalitic-granodioritic com positions with subordinated granitic types, corresponding to garnet-bearing hornblende-biotite granitoids. It also have calc-alkaline affinities being slightly more enriched in incompatible elements than the Bela Joana rocks.The Catalunha, São Fidélis and Santo Eduardo gneissic-migmatitic units have mineralogical- chemical features which suggest that these lithologies correspond to the anatexis of supracrustal sequences, originally dominated by greywacke-pelites with subordinated felsic-intermediate volcanic-volcanic-lastic material. Geothermometric and geobarometric determinations indicate that all these metaplutonic and metasedimentary units re-equilibrated under similar P-T conditions of about 720 QC and 6 KB which indicate the peak of the late Proterozoic Brasiliano cYcle regional metamorphism in the region. These P-T conditions are consistent with the upper-amphibolite and granulite facies, depending on the abundance and composition of the fluid phases, particularly of the \'CO IND.2\' / \'H IND.2 O\' ratio.

Esta pesquisa se propôs a construir uma breve cronologia da evolução do desenho industrial no estado do Rio de Janeiro, tendo como fio condutor três linhas de atuação do design: prática profissional (profissionais, escritórios, empresas, produtos e projetos), ensino e promoção/divulgação (eventos, conferências, exposições, premiações e concursos). Estas informações hoje se encontram dispersas ou são de todo desconhecidas do grande público. A pesquisa então procurou levantar, organizar e analisar criticamente esse volume de dados e informações, de modo a documentar e resgatar o desenvolvimento do design industrial no Rio de Janeiro. Este trabalho concentrou o foco do estudo histórico no design de produto, visto que uma série de trabalhos recentemente publicados já iniciou o processo de prospecção histórica do design gráfico no Brasil. Em que pese, além disso, que um estudo regionalizado do design de produto, centrado no Rio de Janeiro, ser uma contribuição relevante à historiografia do design brasileiro. A pesquisa fez uso de técnicas qualitativas de obtenção e tratamento de dados, destacando-se a pesquisa bibliográfica (sempre que possível fazendo uso de fontes primárias); o contato (via cartas, entrevistas e/ou acesso a websites) com as personalidades envolvidas nos eventos citados no texto; e, finalmente, a consulta a arquivos (públicos e privados). Ao se concluir a pesquisa, foram organizadas três cronologias independentes relativas a cada um dos subproblemas propostos a partir da questão central. Essas cronologias identificaram e contextualizaram as diferentes áreas de atuação do design de produto, descreveram o processo de implantação e desenvolvimento do ensino do design e documentaram as iniciativas no âmbito da divulgação e promoção do design de produto no Rio de Janeiro. O capítulo cinco apresenta as conclusões da análise da pesquisa. / This research intends to build up a brief chronology of product design development process in the state of Rio de Janeiro, following its three main areas of influence: professional practice (designers, offices, companies, products and projects), design promotion (events, conferences, exhibitions, awards and competitions) and design tuition (the formative path of product design college education). As today this information is either dispersed or unknown to the public, this work intends to uncover, organize and eventually analyse this amount of data in order to provide documentation and also rescue the development of industrial design in Rio de Janeiro from its oblivion. This work focused on the historical development of product design, as long as previous works have already started out the research on the history of graphic design in Brazil. Qualitative techniques were mainly used to obtain and process data such as the search into the actual bibliography (recurring to primary sources whenever possible), the contact (by letter, interviews and/or access to websites) with professionals involved in the events mentioned in the text and the search into public or private files. The research outcome was organized into three independent chronologies which identified and related the different areas of influence of product design that were documentary in the design college tuition evolutionary process. This brought evidence to initiatives in the scope of design diffusion in Rio de Janeiro. The last chapter presents conclusions pertaining to the analysis of the main line of design evolutionary process. Being a regional oriented research, concentrated in Rio de Janeiro, it may turn out to be a relevant contribution to Brazilian design historiography.