lHuman cytotoxic T lymphocytes with reduced sensitivity to Fas-induced apoptosis

Effector-memory T cells expressing Fas (Apo-1/CD95) are switched to an apoptotic program by cross-linking with Fas-ligand (FasL). Consequently, tumors that express FasL can induce apoptosis of infiltrating Fas-positive T lymphocytes and subdue any antitumor host immune response. Since Epstein-Barr virus (EBV)-associated tumors such as Hodgkin lymphoma (HL) and nasopharyngeal carcinoma (NPC) express FasL, we determined whether EBV-specific cytotoxic T lymphocytes (EBV-CTLs) could be modified to resist this evasion strategy. We show that long-term down-modulation of Fas can be achieved in EBV-CTLs by transduction with small interfering RNA (siRNA) encoded in a retrovirus. Modified T cells resisted Fas/FasL-mediated apoptosis compared with control cells and showed minimal cleavage of the caspase3 substrate poly(ADP-ribose) polymerase (PARP) protein after Fas engagement. Prolonged Fas stimulation selected a uniformly Fas(low) and FasL resistant population. Removal of responsiveness to this single death signal had no other discernible effects on EBV-CTLs. In particular, it did not lead to their autonomous growth since the modified EBV-CTLs remained polyclonal, and their survival and proliferation retained dependence on antigen-specific stimulation and on the presence of other physiologic growth signals. EBV-CTLs with knocked down Fas should have a selective functional and survival advantage over unmodified EBV-CTLs in the presence of tumors expressing FasL and may be of value for adoptive cellular therapy. (c) 2005 by The American Society of Hematology

Typical general movements at 2 to 4 months:Movement complexity, fidgety movements, and their associations with risk factors and SINDA scores

Background: Movement complexity and the presence of fidgety movements (FMs) during general movements (GMs) both reflect aspects of neurological integrity in early infancy. Aim: To assess interrelations between the degree of movement complexity and characteristics of FMs during typical GMs and to investigate associations between mildly impaired GMs and risk factors and neurodevelopmental condition. Study design: Observational cohort study. Subjects: 283 infants (25 born preterm) at 2-4 months corrected age, representative of the general Dutch population. Outcome measures: GMs were classified in terms of GM-complexity (normal or mildly abnormal (MA)) and FMs (clearly present, sporadic, or exaggerated). Concurrent neurological, developmental and socio-emotional status were measured with the Standardized Infant NeuroDevelopmental Assessment (SINDA). Results: Infants with MA GM-complexity had a higher risk of having sporadic FMs and exaggerated FMs. Perinatal complications were not associated with mildly impaired GMs. MA GM-complexity was associated with advanced maternal age (adjusted OR = 2.29 [1.11, 4.76]) and having a non-native Dutch mother (adjusted OR = 2.93 [1.29, 6.64]). It was also associated with atypical neurological (OR = 7.62 [3.51, 16.54]) and developmental scores (OR = 2.38 [1.16, 4.88]). Sporadic and exaggerated FMs were associated with low-to-middle maternal education (adjusted OR = 2.88, [1.45, 5.72]) and having a non-native Dutch father (adjusted OR = 7.16 [1.41, 36.32]), respectively. However, neither sporadic nor exaggerated FMs were associated with the SINDA outcomes. Conclusions: GM-complexity and FMs are two interrelated but different aspects of GMs. Mild impairments in GM-complexity and FMs share a non-optimal socio-economic background as risk factor, but only MA GM-complexity is associated with a concurrent non-optimal neurodevelopmental condition

Atypical knee jerk responses in high-risk children:A longitudinal EMG-study

INTRODUCTION: We previously found that atypical responses to the knee jerk reflex, i.e., tonic responses (TRs), clonus and contralateral responses in very high-risk (VHR) infants were associated with cerebral palsy (CP) at 21 months. The current study aimed for a better understanding of pathophysiology of atypical knee jerk responses by evaluating whether infant atypical knee jerk responses are associated with CP and atypical knee jerk responses at school-age. METHODS: 31 VHR-children, who had also been assessed longitudinally during infancy, and 24 typically developing children, were assessed at 7-10 years (school-age). We continuously recorded surface EMG of thigh muscles during knee jerk responses longitudinally during infancy and once at school-age. Neurological condition was assessed with age-appropriate neurological examinations. It included the diagnosis of CP at 21 months corrected age and school-age. CP's type and severity (Gross Motor Function Classification System (GMFCS)) were reported. RESULTS: Persistent TRs in infancy were associated with CP at school-age. TR prevalence decreased from infancy to childhood. At school-age it was no longer associated with CP. Clonus prevalence in VHR-children did not change with increasing age; it was significantly higher in children without than those with CP. Reflex irradiation was common in all school-age children, and its prevalence in contralateral muscles in VHR-children decreased between infancy and childhood. CONCLUSIONS: In infancy, TRs indicated an increased risk of CP, but at school-age TRs were not associated with CP. In general, spinal hyperexcitability, expressed as reflex irradiation and TRs, decreased between infancy and school-age

Evaluating preclinical evidence for clinical translation in childhood brain tumours: Guidelines from the CONNECT, PNOC, and ITCC brain networks

Clinical outcomes for many childhood brain tumours remain poor, despite our increasing understanding of the underlying disease biology. Advances in molecular diagnostics have refined our ability to classify tumour types and subtypes, and efforts are underway across multiple international paediatric neuro-oncology consortia to take novel biological insights in the worst prognosis entities into innovative clinical trials. Whilst for the first time we are designing such studies on the basis of disease-specific biological data, the levels of preclincial evidence in appropriate model systems on which these trials are initiated is still widely variable. We have considered these issues between CONNECT, PNOC and ITCC-Brain, and developed a framework in which we can assess novel concepts being brought forward for possible clinical translation. Whilst not intended to be proscriptive for every possible circumstance, these criteria provide a basis for self-assessment of evidence by laboratory scientists, and a platform for discussion and rational decision-making prior to moving forward clinically

Optimalisatie van vraagarticulatie en kennisuitwisseling over de effecten van inundatie en waterberging (P2052) : eindrapport voor consortiumpartijen

Doel van dit project was om via een participatief proces de relevante kennisvragen te identificeren die in de praktijk spelen bij waterberging en deze te confronteren met specialistische kennis en met de praktijkervaring over bodem en water. Het proces werd uitgevoerd met partijen in een of meerdere stroomgebieden (Hoog-Nederland en Laag-Nederland) met alle betrokken partijen die met kennisvragen zitten t.a.v. inundatie-effecte

Infant motor behaviour and functional and cognitive outcome at school-age:A follow-up study in very high-risk children

BACKGROUND: The Infant Motor Profile (IMP) is an appropriate tool to assess and monitor infant motor behaviour over time. Infants at very high risk (VHR) due to a lesion of the brain generally show impaired motor development. They may grow into or out of their neurodevelopmental deficit. AIMS: Evaluate associations between IMP-trajectories, summarised by IMP-scores in early infancy and rates of change, and functional and cognitive outcome at school-age in VHR-children. STUDY DESIGN: Longitudinal study. SUBJECTS: 31 VHR-children, mainly due to a brain lesion, who had multiple IMP-assessments during infancy, were re-assessed at 7-10 years (school-age). OUTCOME MEASURES: Functional outcome was assessed with the Vineland-II, cognition with RAKIT 2. Associations between IMP-trajectories and outcome were tested by multivariable linear regression analyses. RESULTS: When corrected for sex, maternal education and follow-up age, initial scores of total IMP, variation and performance domains, as well as their rates of change were associated with better functional outcome (unstandardised coefficients [95% CI]): 36.44 [19.60-53.28], 33.46 [17.43-49.49], 16.52 [7.58-25.46], and 513.15 [262.51-763.79], 356.70 [148.24-565.15], and 269 [130.57-407.43], respectively. Positive rates of change in variation scores were associated with better cognition at school-age: 34.81 [16.58-53.03]. CONCLUSION: Our study indicated that in VHR-children IMP-trajectories were associated with functional outcome at school-age, and to a minor extent also with cognition. Initial IMP-scores presumably reflect the effect of an early brain lesion on brain functioning, whereas IMP rate of change reflects whether infants are able to grow into or out of their initial neurodevelopmental deficit

Development of muscle tone impairments in high-risk infants:Associations with cerebral palsy and cystic periventricular leukomalacia

AIM: To assess the prevalence and development of muscle tone impairments in infants at high risk of developmental disorders, and their associations with cerebral palsy (CP) and cystic periventricular leukomalacia (cPVL). METHOD: Longitudinal exploration of muscle tone in 39 infants at high risk of CP (LEARN2MOVE 0-2 project) mostly due to an early lesion of the brain. Muscle tone was assessed ≥4 times between 0 and 21 months corrected age (CA) with the Touwen Infant Neurological Examination. Diagnosis of CP was determined at 21 months CA. Neonatal neuro-imaging was available. Developmental trajectories were calculated using generalized linear mixed effect models. RESULTS: Infants showed atypical muscle tone in three or four body parts in 93% (172/185) of the assessments. The most prevalent muscle tone pattern was hypotonia of neck and trunk with hypertonia of the limbs (28%). From 7 months CA onwards hypertonia of the arms was associated with CP. Asymmetric arm tone during infancy was associated with unilateral CP. At 18-21 months CA ankle hypertonia was associated with CP at 21 months; leg hypertonia in infancy was not associated with CP. Leg hypertonia was associated with cPVL, regardless of age. INTERPRETATION: High-risk infants due to an early lesion of the brain often present with muscle tone impairment. In these infants, hypertonia and asymmetric muscle tone of the arms were from 7 months onwards associated with the diagnosis of CP at 21 months; hypertonia of the legs was not

Компьютерная томография и магнитно-резонансная томография в диагностике опухолей средостения

Резюме. Проанализированы результаты обследования 95 больных с опухолями средостения (ОС) с использованием рентгенологических методов: компьютерной томографии (КТ), магнитно-резонансной томографии (МРТ). Приведена КТ- и МРТ-семиотика ОС, оценена информативность результатов каждого метода в зависимости от локализации опухоли. На основании полученных данных обоснованы показания к применению и последовательность использования неинвазивных лучевых методов в целях диагностики ОС. В частности, МРТ наиболее показана при локализации опухоли в заднем и передневерхнем отделах средостения, тогда как КТ целесообразнее проводить, если опухоль располагается в переднесреднем, передненижнем или среднем отделах средостения. Ключевые слова: опухоли средостения, рентгенологическое исследование, компьютерная томография, магнитно-резонансная томография, диагностическая эффективность.Summary. The paper reports findings of examination of 95 patients with mediastinum tumors (MS) using the following roentgenologic methods: computed tomography (CT) and magnetic resonance tomography (MRT). CR and MRT semeiology of MS is described and the informative value of each method is assessed in dependence on tumor’s localization. Based on these findings, indications for application of non-invasive radiation methods in examination of mediastinum tumors are developed as well as the sequence of their using. In particular, MRT is especially promising in tumors localized in posterior and antero-superior portions of the mediastinum, while CT is more appropriate in tumors localized in antero-medial, antero-lower or medial portions of the mediastinum. Key Words: mediastinum tumors, roentgenologic examination, computed tomography, magnetic resonance tomography, diagnostic efficiency