Juvenile neuronal ceroid lipofuscinosis; psychiatric symptoms, GAD-autoantibodies, and response to medication

Juvenile neuronal ceroid lipofuscinosis (JNCL) is one of the most common neurodegenerative diseases in childhood. Its clinical onset, with visual failure as the first sign, is between the ages of 4 to 8 years. During the disease progress, epilepsy, motor symptoms, cognitive decline, and psychiatric symptoms become apparent. It leads to premature death between ages 15 and 30. Treatment consists of symptomatic drug administration and various forms of rehabilitation, but to date, no curative treatment exists. To gain a more comprehensive picture of psychiatric problems, symptoms were evaluated by the Child Behavior Checklist, the Teacher Report Form, and the Children s Depression Inventory. The JNCL patients had a great number of severe psychiatric symptoms, with wide inter-individual variability. The most common symptoms were social, thought, attention, and sleep problems, somatic complaints, and aggressive behaviour. Patients with psychotropic treatment had more problems than did those without psychotropic treatment, and female patients had more problems than did males. Between 10 and 20% of the patients reported depressive symptoms. In a 5-year follow-up, [123I]β-CIT SPECT and MRI revealed a tendency of decreasing serotonin transporter (SERT) availability and progressive brain atrophy. The correlation between changes in midbrain SERT and total brain volume was positive; no correlation appeared between SERT or brain atrophy and depressive symptoms. Thus, it seems likely that the low SERT availability is associated with progressive brain atrophy; it may also predispose towards depression, however. An open survey of psychotropic drugs and their efficacy was performed on JNCL patients in Finland. The most commonly used psychotropic drugs were the antidepressant citalopram and the antipsychotic risperidone. Their efficacy was good or satisfactory in the majority of cases and they seemed well tolerated. Quetiapine had a marked effect on one patient with a history of severe psychotic symptoms. Glutamate decarboxylase 65 autoantibodies (GAD65ab), found in JNCL patients, indicate that an immunomediated reaction against GAD or GABAergic neurons may play a part in the underlying pathogenetic mechanism. GAD65ab s also appeared in the serum of all eight JNCL patients included and intermittent corticosteroid therapy was initiated in all cases. After one year, the GAD65ab s had disappeared in the two oldest patients, who experienced an improvement in motor symptoms and alertness associated with their prednisolone therapy. Two younger patients experienced a significant IQ increase, but no change in GADab s. A randomized study with longer follow-up time is needed, however, to clarify the effect of prednisolone on disease progression.

Karyotype instability in the ponerine ant genus Diacamma

The queenless ponerine ant Diacamma ceylonense and a population of Diacamma from the Nilgiri hills which we refer to as `nilgiri', exhibit interesting similarities as well as dissimilarities. Molecular phylogenetic study of these morphologically almost similar taxa has shown that D ceylonense is closely related to `nilgiri' and indicates that `nilgiri' is a recent diversion in the Diacamma phylogenetic tree. However, there is a striking behavioural difference in the way reproductive monopoly is maintained by the respective gamergates (mated egg laying workers), and there is evidence that they are genetically differentiated, suggesting a lack of gene flow To develop a better understanding of the mechanism involved in speciation of Diacamma, we have analysed karyotypes of D. ceylonense and `nilgiri' In both, we found surprising inter-individual and intra-individual karyotypic mosaicism. The observed numerical variability, both at intra-individual and inter-individual levels, does not appear to have hampered the sustainability of the chromosomal diversity in each population under study Since the related D. indicum, displays no such intra-individual or inter-Individual variability whatsoever under identical experimental conditions, these results are unlikely to he artifacts. Although no known mechanisms can account for the observed karyotypic variability of this nature, we believe that the present findings on the ants under study would provide opportunities for exciting new discoveries concerning the origin, maintenance and significance of intra-individual and inter-individual karyotypic mosaicism.

Avaliação da estabilidade da cirurgia de avanço mandibular através da superposição de modelos tridimensionais

Embora a cirurgia de avanço mandibular seja considerada um procedimento altamente estável, existem algumas preocupações clínicas em relação a mudanças nos côndilos e nos segmentos proximais, que podem levar a recidiva sagital e abertura de mordida. A avaliação dos resultados da cirurgia através de ferramentas de geração e superposição de modelos virtuais tridimensionais (3D) permite a identificação e quantificação dos deslocamentos e remodelação óssea que podem ajudar a explicar as interações entre os componentes dentários, esqueléticos e de tecido mole que estão relacionados a resposta ao tratamento. Este estudo observacional prospectivo avaliou, através de tomografia computadorizada de feixe cônico (CBCT), mudanças na posição/remodelação 3D dos ramos mandibulares, côndilos e mento. Assim, exames CBCT de 27 pacientes foram adquiridos antes da cirurgia (T1), imediatamente após a cirurgia(T2), e 1 ano após a cirurgia(T3). Uma técnica automática de superposição na base do crânio foi utilizada para permitir a avaliação das mudanças ocorridas nas regiões anatômicas de interesse (RAI). Os deslocamentos foram visualizados e quantificados em mapas coloridos 3D através da ferramenta de linha de contorno (ISOLINE). Pelo teste t pareado compararam-se as mudanças entre T1-T2 e T2-T3. O coeficiente de correlação de Pearson verificou se os deslocamentos ocorridos nas RAI foram correlacionados entre si e entre os tempos de avaliação. O nível de significância foi determinado em 0,05. O avanço mandibular médio foi de 6,813,2mm em T2 e 6,363,41mm em T3 (p=0,13). Entre T2 e T3, a posição do mento variou positivamente (≥2mm) em 5 pacientes negativamente em 7. 12% dos pacientes sofreram recidivas ≥4mm. Para todas as outras RAI avaliadas, apenas a porção inferior dos ramos (lado direito - 2,342,35mm e lado esquerdo 2,972,71mm) sofreram deslocamentos médios >2mm com a cirurgia. No acompanhamento em longo prazo, esse deslocamento lateral da porção inferior dos ramos foi mantido (lado direito - 2,102,15mm, p=0,26; e lado esquerdo -2,762,80, p=0,46), bem como todos os outros deslocamentos observados (p>0,05). As mudanças na posição do mento foram correlacionadas a adaptações pós-cirúrgicas nos bordos posteriores dos ramos (esquerdo r=-0,73 e direito r=-0,68) e côndilos (esquerdo r=-0,53 e direito r=-0,46). Os deslocamentos médios sofridos pelas estruturas do lado esquerdo foram suavemente maiores do que no direito. Correlações dos deslocamentos ocorridos entre T1-T2 e T2-T3 mostraram que: os deslocamentos dos côndilos esquerdos com a cirurgia foram negativamente correlacionados às adaptações pós-cirúrgicas destes (r=-0,51); e que o deslocamento da porção superior do ramo esquerdo com a cirurgia foi correlacionado à adaptação pós-cirúrgica ocorrida nos bordos posteriores (r=0,39) e côndilos do mesmo lado (r=0,39). Pode-se concluir que: (1) os deslocamentos causados pela cirurgia foram de modo geral estáveis no acompanhamento de 1 ano, mas identificou-se uma considerável variação individual; (2) as mudanças pós-cirúrgicas na posição do mento foram correlacionadas a adaptações sofridas pelos côndilos e bordos posteriores dos ramos; e que (3) deslocamentos suavemente maiores causados pela cirurgia nas estruturas do lado esquerdo levaram a maiores adaptações pós-cirúrgicas no segmento proximal deste lado.

Growth of Skipjack tuna (Katsuwonus pelamis) in the eastern Pacific Ocean as estimated from tagging data

English: Data obtained from tagging experiments initiated during 1953-1958 and 1969-1981 for skipjack tuna from the coastal eastern Pacific Ocean (EPO) are reanalyzed, using the Schnute generalized growth model. The objective is to provide information that can be used to generate a growth transition matrix for use in a length-structured population dynamics model. The analysis includes statistical approaches to include individual variability in growth as a function of length at release and time at liberty, measurement error, and transcription error. The tagging data are divided into northern and southern regions, and the results suggest that growth rates differ between the two regions. The Schnute model provides a significantly better fit to the data than the von Bertalanffy model, a sub-model of the Schnute model, for the northern region, but not for the southern region. Individual variation in growth is best described as a function of time at liberty and as a function of growth increment for the northern and southern regions, respectively. Measurement error is a significant part of the total variation, but the results suggest that there is no bias caused by the measurement error. Additional information, particularly for small and large fish, is needed to produce an adequate growth transition matrix that can be used in a length-structured population dynamics model for skipjack tuna in the EPO. Spanish: Los datos obtenidos de los experimentos de marcado iniciados durante los períodos de 1953- 1958 y de 1969-1981 para el atún barrilete en las costas del Océano Pacífico Oriental (OPO) fueron analizados nuevamente, utilizando el modelo de crecimiento generalizado de Schnute. El objetivo es brindar información que sea útil para producir una matriz sobre la tran-sición de crecimiento que pueda utilizarse en un modelo de dinámica poblacional estructurado por talla. El análisis usa enfoques estadísticos para poder incluir la variabilidad individual del crecimiento como función de la talla de liberación y tiempo en libertad, el error de medición, y el error de transcripción. Los datos de marcado son divididos en regiones norte y sur, y los resultados sugieren que las tasas de crecimiento en las dos regiones son diferentes. En la región norte, pero no en la región sur, el modelo de Schnute se ajusta significativamente mejor a los datos que el modelo von Bertalanffy, un sub-modelo del modelo de Schnute. La mejor descripción de la variación individual en el crecimiento es como una función del tiempo en libertad y como una función del incremento de crecimiento para las regiones norte y sur, respectivamente. El error de medición es una parte significativa de la variación total, pero los resultados sugieren que no existe un sesgo causado por el error de medición. Se necesita información adicional, particularmente para peces pequeños y grandes, para poder producir una matriz de transición de crecimiento adecuada que pueda utilizarse en el modelo de dinámica poblacional estructurado por tallas para el atún barrilete en el OPO.

A emergência da competência oral como sistema dinâmico, adaptativo e complexo no ensino-aprendizagem de inglês como língua adicional para iniciantes

No âmbito do ensino-aprendizagem de línguas adicionais, pesquisas acerca do desenvolvimento da oralidade têm demonstrado que se trata de um fenômeno multidimensional. Nakatani (2010) mostrou que o domínio de estratégias comunicacionais são indicadores de desempenho linguístico e se relacionam com a proficiência do aprendiz; Kang, Rubin e Pickering (2010) observaram que os traços fonológicos afetam a percepção sobre inteligibilidade e proficiência; Hewitt e Stephenson (2011), e Ahmadian (2012) indicaram que as condições psicológicas individuais interferem na qualidade da produção oral. Escribano (2004) sugeriu que a referência contextual é essencial na construção de sentido; Gao (2011) apontou os benefícios do ensino baseado na construção do sentido, a partir de metáforas conceptuais (LAKOFF e JOHNSON, 1980), codificação dupla (CLARK e PAIVIO, 1991) e esquemas imagéticos (LAKOFF, 1987); e Ellis e Ferreira-Junior (2009) demonstraram que as construções exibem efeitos de recência e priming, afetando o uso da linguagem dos parceiros interacionais. Tais estudos apontam para a natureza complexa da aquisição de L2, mas o fazem dentro do paradigma experimental da psicolinguística. Já Larsen-Freeman (2006), demonstra que a fluência, a precisão e a complexidade desenvolvem-se com o tempo, com alto grau de variabilidade, dentro do paradigma da Teoria da Complexidade. Em viés semelhante, Paiva (2011) observa que os sistemas de Aquisição de Segunda Língua (ASL) são auto-organizáveis. Esses trabalhos, no entanto, não abordaram aprendizes de L2 com proficiência inicial, como pretendo fazer aqui. Tendo como referenciais teóricos a Teoria da Complexidade e a Linguística Cognitiva, o presente trabalho apresenta um estudo de caso, qualitativo-interpretativista, com nuances quantitativos, que discute os processos de adaptação que emergiram na expressão oral de um grupo de aprendizes iniciantes de inglês como língua adicional no contexto vocacional. Parte do entendimento de que na sala de aula vários (sub)sistemas complexos coocorrem, covariando e coadaptando-se em diferentes níveis. A investigação contou com dados transcritos de três avaliações coletados ao longo de 28 horas de aula, no domínio ENTREVISTA DE EMPREGO. Após observar a produção oral das aprendizes, criei uma taxonomia para categorizar as adaptações que ocorreram na sintaxe, semântica, fonologia e pragmática da língua-alvo. Posteriormente organizei as categorias em níveis de prototipicidade (ROSCH et al, 1976) de acordo com as adaptações mais frequentes. Finalmente, avaliei a inteligibilidade de cada elocução, classificando-as em três níveis. A partir desses dados, descrevi como a prática oral dessas participantes emergiu e se desenvolveu ao longo das 28 horas. Os achados comprovam uma das premissas da Linguística Cognitiva ao mostrarem que os níveis de descrição linguística funcionam conjuntamente em prol do sucesso comunicacional. Além disso, demonstram que a função do professor, como discutem LARSEN-FREEMAN e CAMERON (2008), não é gerar uniformidade, mas sim oportunizar vivências que estabeleçam continuidade entre o mundo, o corpo e a mente

Ecologia funcional de duas comunidades de peixes de riacho: a importância da variação intraespecífica e interespecífica em diferentes atributos ecológicos

A compreensão sobre a estrutura e funcionamento das comunidades biológicas é uma das principais questões das teorias ecológicas e principalmente no contexto de diversidade funcional, já que os atributos das espécies influenciam fortemente a distribuição e o papel que os organismos desempenham nos ecossistemas. Neste trabalho, tivemos como objetivo avaliar a variabilidade intraespecífica e interespecífica dos atributos ecológicos em duas assembleias de peixes localizadas em riachos sujeitos a diferentes condições físicas. A variação na utilização dos recursos, seja entre indivíduos e/ou entre espécies pode nos ajudar a compreender as interações bióticas e a estrutura das populações e comunidades de peixes. Os atributos referentes a morfologia, dieta, uso do habitat e alguns aspectos comportamentais foram avaliados e suas variações foram testadas a partir dos valores individuais. As coletas foram realizadas em dois riachos tropicais, sendo um localizado no ambiente da Mata Atlântica e o outro, no ambiente do semiárido brasileiro. Além das análises empíricas, uma revisão bibliográfica sobre o tema e uma possível composição funcional dos grupos de peixes de riacho foram descritas no capítulo 1 da presente tese. Nos capítulos 2 e 3, foram testadas as hipóteses de que existe alta variabilidade intraespecífica em relação aos atributos ecológicos dos peixes e que esta variabilidade é influenciada pela alta disponibilidade de recursos, enquanto no capítulo 4, a variação entre os indivíduos foi testada em relação a aspectos comportamentais. Nossos resultados revelaram que, de fato, a variação intraespecífica foi alta em ambas as assembleias, porém na assembleia do semiárido, esta variabilidade foi maior. Este resultado pode estar relacionado a alta disponibilidade de recursos espaciais encontrada nesta localidade. A morfologia e a dieta apresentaram correlação significativa, porém foi fraca em ambas as assembleias, demonstrando assim a importância de mensurar esses dois aspectos da biodiversidade dos peixes. Os resultados relacionados ao uso do habitat também apresentaram alta variabilidade entre os indivíduos e entre as espécies nos dois riachos em estudo. A assembleia do semiárido apresentou maior variabilidade física com potenciais microambientes formados por bancos de macrófitas a serem explorados pelos organismos, permitindo assim, o uso diferenciado e a escolha individual por diferentes recursos espaciais. A variabilidade individual também foi encontrada no comportamento social de duas espécies desta assembleia, onde houve formação de cardumes compostos por indivíduos maiores nas extremidades com maior capacidade de fuga na relação presa-predador. Neste sentido, a alta variação intraespecífica para diversos aspectos funcionais avaliados neste trabalho evidencia ainda mais a importância de mensurar as características ecológicas dos peixes a partir de valores individuais. Adicionalmente, a partir desta ferramenta, podemos compreender melhor a complementaridade da especialização e originalidade ecológica dos indivíduos e finalmente, sugerir de que forma os atributos funcionais dos organismos influenciam a estrutura das populações e comunidades de peixes de riachos tropicais

Genes and the ageing muscle: a review on genetic association studies

Western populations are living longer. Ageing decline in muscle mass and strength (i.e. sarcopenia) is becoming a growing public health problem, as it contributes to the decreased capacity for independent living. It is thus important to determine those genetic factors that interact with ageing and thus modulate functional capacity and skeletal muscle phenotypes in older people. It would be also clinically relevant to identify 'unfavourable' genotypes associated with accelerated sarcopenia. In this review, we summarized published information on the potential associations between some genetic polymorphisms and muscle phenotypes in older people. A special emphasis was placed on those candidate polymorphisms that have been more extensively studied, i.e. angiotensin-converting enzyme (ACE) gene I/D, α-actinin-3 (ACTN3) R577X, and myostatin (MSTN) K153R, among others. Although previous heritability studies have indicated that there is an important genetic contribution to individual variability in muscle phenotypes among old people, published data on specific gene variants are controversial. The ACTN3 R577X polymorphism could influence muscle function in old women, yet there is controversy with regards to which allele (R or X) might play a 'favourable' role. Though more research is needed, up-to-date MSTN genotype is possibly the strongest candidate to explain variance among muscle phenotypes in the elderly. Future studies should take into account the association between muscle phenotypes in this population and complex gene-gene and gene-environment interactions.

Host genetics and HIV-1: the final phase?

This is a crucial transition time for human genetics in general, and for HIV host genetics in particular. After years of equivocal results from candidate gene analyses, several genome-wide association studies have been published that looked at plasma viral load or disease progression. Results from other studies that used various large-scale approaches (siRNA screens, transcriptome or proteome analysis, comparative genomics) have also shed new light on retroviral pathogenesis. However, most of the inter-individual variability in response to HIV-1 infection remains to be explained: genome resequencing and systems biology approaches are now required to progress toward a better understanding of the complex interactions between HIV-1 and its human host.

Mapping the structure of perceptual and visual-motor abilities in healthy young adults.

The ability to quickly detect and respond to visual stimuli in the environment is critical to many human activities. While such perceptual and visual-motor skills are important in a myriad of contexts, considerable variability exists between individuals in these abilities. To better understand the sources of this variability, we assessed perceptual and visual-motor skills in a large sample of 230 healthy individuals via the Nike SPARQ Sensory Station, and compared variability in their behavioral performance to demographic, state, sleep and consumption characteristics. Dimension reduction and regression analyses indicated three underlying factors: Visual-Motor Control, Visual Sensitivity, and Eye Quickness, which accounted for roughly half of the overall population variance in performance on this battery. Inter-individual variability in Visual-Motor Control was correlated with gender and circadian patters such that performance on this factor was better for males and for those who had been awake for a longer period of time before assessment. The current findings indicate that abilities involving coordinated hand movements in response to stimuli are subject to greater individual variability, while visual sensitivity and occulomotor control are largely stable across individuals.

Sex differences in fetal habituation

There is some evidence for sex differences in habituation in the human fetus, but it is unknown whether this is due to differences in central processing (habituation) or in more peripheral processes, sensory or motor, involved in the response. This study examined whether the sex of the fetus influenced auditory habituation at 33weeks of gestation, and whether this was due to differences in habituation or in the sensory or motor components using a set of four experiments. The first experiment found that female fetuses required significantly fewer stimulus presentations to habituate than males. The second experiment revealed no difference in the spontaneous motor behaviour of male and female fetuses. The third experiment examined auditory intensity thresholds for the stimuli used to habituate the fetus. No differences in thresholds were found between males and females, although there was inter-individual variability in thresholds. A final experiment, using stimuli individualized for that particular fetus' auditory intensity threshold, found that female fetuses habituated faster than males. In combination, the studies reveal that habituation in the human fetus is affected by sex and this is due to a difference in central 'information processing' of the stimuli rather than peripheral aspects of the response. It is argued that male and female fetuses present different neurobehavioural developmental trajectories, with females more advanced at 33weeks than males. This study suggests that research examining prenatal behaviour should consider the factor of fetal sex. This may be particularly pertinent where there is an intention to use the results diagnostically. © 2012 Blackwell Publishing Ltd.

Population pharmacokinetic and pharmacogenetic analysis of tacrolimus in paediatric liver transplant patients

Aims: To build a population pharmacokinetic model that describes the apparent clearance of tacrolimus and the potential demographic, clinical and genetically controlled factors that could lead to inter-patient pharmacokinetic variability within children following liver transplantation.

Methods: The present study retrospectively examined tacrolimus whole blood pre-dose concentrations (n = 628) of 43 children during their first year post-liver transplantation. Population pharmacokinetic analysis was performed using the non-linear mixed effects modelling program (nonmem) to determine the population mean parameter estimate of clearance and influential covariates.

Results: The final model identified time post-transplantation and CYP3A5*1 allele as influential covariates on tacrolimus apparent clearance according to the following equation:

TVCL=12.9×(Weight /13.2)^0.75×EXP(-0.00158×TPT)×EXP(0.428×CYP3A5)

where TVCL is the typical value for apparent clearance, TPT is time post-transplantation in days and the CYP3A5 is 1 where*1 allele is present and 0 otherwise. The population estimate and inter-individual variability (%CV) of tacrolimus apparent clearance were found to be 0.977 l h kg (95% CI 0.958, 0.996) and 40.0%, respectively, while the residual variability between the observed and predicted concentrations was 35.4%.

Conclusion: Tacrolimus apparent clearance was influenced by time post-transplantation and CYP3A5 genotypes. The results of this study, once confirmed by a large scale prospective study, can be used in conjunction with therapeutic drug monitoring to recommend tacrolimus dose adjustments that take into account not only body weight but also genetic and time-related changes in tacrolimus clearance. © 2013 The British Pharmacological Society.

Comparison of Microbiomes from Different Niches of Upper and Lower Airways in Children and Adolescents with Cystic Fibrosis

Changes in the airway microbiome may be important in the pathophysiology of chronic lung disease in patients with cystic fibrosis. However, little is known about the microbiome in early cystic fibrosis lung disease and the relationship between the microbiomes from different niches in the upper and lower airways. Therefore, in this cross-sectional study, we examined the relationship between the microbiome in the upper (nose and throat) and lower (sputum) airways from children with cystic fibrosis using next generation sequencing. Our results demonstrate a significant difference in both α and β-diversity between the nose and the two other sampling sites. The nasal microbiome was characterized by a polymicrobial community while the throat and sputum communities were less diverse and dominated by a few operational taxonomic units. Moreover, sputum and throat microbiomes were closely related especially in patients with clinically stable lung disease. There was a high inter-individual variability in sputum samples primarily due to a decrease in evenness linked to increased abundance of potential respiratory pathogens such as Pseudomonas aeruginosa. Patients with chronic Pseudomonas aeruginosa infection exhibited a less diverse sputum microbiome. A high concordance was found between pediatric and adult sputum microbiomes except that Burkholderia was only observed in the adult cohort. These results indicate that an adult-like lower airways microbiome is established early in life and that throat swabs may be a good surrogate in clinically stable children with cystic fibrosis without chronic Pseudomonas aeruginosa infection in whom sputum sampling is often not feasible.

Determining the optimal current direction of transcranial magnetic stimulation to induce motor responses in the tongue: A preliminary study of neurologically healthy individuals

Objective
To determine the optimal transcranial magnetic stimulation (TMS) coil direction for inducing motor responses in the tongue in a group of non-neurologically impaired participants.
Methods
Single-pulse TMS was delivered using a figure-of-eight Magstim 2002 TMS coil. Study 1 investigated the effect of eight different TMS coil directions on the motor-evoked potentials elicited in the tongue in eight adults. Study 2 examined active motor threshold levels at optimal TMS coil direction compared to a customarily-used ventral-caudal direction. Study 3 repeated the procedure of Study 1 at five different sites across the tongue motor cortex in one adult.
Results
Inter-individual variability in optimal direction was observed, with an optimal range of directions determined for the group. Active motor threshold was reduced when a participant's own optimal TMS coil direction was used compared to the ventral-caudal direction. A restricted range of optimal directions was identified across the five cortical positions tested.
Conclusions
There is a need to identify each individual's own optimal TMS coil direction in investigating tongue motor cortex function. A recommended procedure for determining optimal coil direction is described.
Significance
Optimized TMS procedures are needed so that TMS can be utilized in determining the underlying neurophysiological basis of various motor speech disorders.

Is the raised volume rapid thoracic compression technique ready for use in clinical trials in infants with cystic fibrosis?

The European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) has established a Standardization Committee to undertake a rigorous evaluation of promising outcome measures with regard to use in multicentre clinical trials in cystic fibrosis (CF). The aim of this article is to present a review of literature on clinimetric properties of the infant raised-volume rapid thoracic compression (RVRTC) technique in the context of CF, to summarise the consensus amongst the group on feasibility and answer key questions regarding the promotion of this technique to surrogate endpoint status.

METHODS: A literature search (from 1985 onwards) identified 20 papers that met inclusion criteria of RVRTC use in infants with CF. Data were extracted and tabulated regarding repeatability, validity, correlation with other outcome measures, responsiveness and reference values. A working group discussed the tables and answered 4 key questions.

RESULTS: Overall, RVRTC in particular forced expiratory volume in 0.5s, showed good clinimetric properties despite presence of individual variability. Few studies showed a relationship between RVRTC and inflammation and infection, and to date, data remains limited regarding the responsiveness of RVRTC after an intervention. Concerns were raised regarding feasibility in multi-centre studies and availability of reference values.

CONCLUSION: The ECFS-CTN Working Group considers that RVRTC cannot be used as a primary outcome in clinical trials in infants with CF before universal standardization of this measurement is achieved and implementation of inter-institutional networking is in place. We advise its use currently in phase I/II trials and as a secondary endpoint in phase III studies. We emphasise the need for (1) more short-term variability and longitudinal 'natural history' studies, and (2) robust reference values for commercially available devices.

Serum Cytokines and Adipokines in Periodontitis

Objective: To investigate whether there was an association between serum levels of pro-inflammatory cytokines, adipokines and periodontitis in 60-70 year-old men in Northern Ireland. Methods: Test subjects (n=61) with established periodontitis, categorised by loss of periodontal attachment (PAL) and pocketing of at least 5mm, were matched for age, smoking and BMI with controls (n=60) who were periodontitis resistant (no PAL or pocketing over 3mm). Serum levels of IL 1 alpha, TNF alpha, IL 6, adiponectin, resistin, leptin and C-reactive protein (CRP) were measured from serum using a multiplex array (Randox, UK). Mann Whitney analysis was used with the level of significance set at p<0.05. Results: There was considerable inter-individual variability in all the analytes measured. There was a significantly higher level of IL 6 in men with periodontitis (3.25 pg/ml, SD 2.29) than in those with no periodontitis (2.38 pg/ml, SD1.62), p=0.0041 (after Bonferroni correction for multiple testing p=0.029). Serum IL 6 was strongly correlated with CRP: r=0.52 (95% CI 0.38-0.64), p<0.0001. There was a lower serum level of adiponectin in men with periodontitis (3662.1 ng/ml, SD 2383.4) compared with those who were periodontitis resistant (4265.9 ng/ml, SD 2266.0), which just escaped statistical significance at p=0.068. There were no significant differences in the serum levels of any of the other analytes measured in relation to periodontal status. Conclusions: There was evidence in the 60-70 year-old male population investigated that periodontitis was associated with an increased serum level of IL 6.