Responsivity to dyslexia training indexed by the N170 amplitude of the brain potential elicited by word reading.

The present study examined training effects in dyslexic children on reading fluency and the amplitude of N170, a negative brain-potential component elicited by letter and symbol strings. A group of 18 children with dyslexia in 3rd grade (9.05±0.46years old) was tested before and after following a letter-speech sound mapping training. A group of 20 third-grade typical readers (8.78±0.35years old) performed a single time on the same brain potential task. The training was differentially effective in speeding up reading fluency in the dyslexic children. In some children, training had a beneficial effect on reading fluency ('improvers') while a training effect was absent in others ('non-improvers'). Improvers at pre-training showed larger N170 amplitude to words compared to non-improvers. N170 amplitude decreased following training in improvers but not in non-improvers. But the N170 amplitude pattern in improvers continued to differ from the N170 amplitude pattern across hemispheres seen in typical readers. Finally, we observed a positive relation between the decrease in N170 amplitude and gains in reading fluency. Collectively, the results that emerged from the present study indicate the sensitivity of N170 amplitude to reading fluency and its potential as a predictor of reading fluency acquisition.

Mortality in out-of-hospital cardiac arrest patients has decreased in the era of therapeutic hypothermia.

BACKGROUND: Mild therapeutic hypothermia (TH) improves survival after out-of-hospital cardiac arrest (OHCA). This treatment was implemented in most Finnish intensive care units (ICUs) in 2003. The aim of this study was to find out whether hospital mortality of ICU-treated OHCA patients has changed in the era of TH. METHODS: This was a retrospective study of data collected prospectively into the database of the Finnish Intensive Care Consortium during the years 2000-2008. The study population consisted of 3958 patients for whom cardiac arrest was registered as the reason for ICU admission and who were transferred to the ICU from the emergency department. We divided the patients into those treated in the pre-hypothermia era (2000-2002) and those treated in the hypothermia era (2003-2008). We investigated whether the treatment period had any impact on hospital mortality. RESULTS: There were no differences between the periods regarding the age or initial Glasgow Coma Scores of the patients. Mean severity of illness was higher in the latter period. Despite this, mortality decreased: the hospital mortality rate was 57.9% in 2000-2002 and 51.1% in 2003-2008, P < 0.001. In a multivariate logistic regression analysis, treatment in 2003-2008 was associated with a reduced risk of in-hospital death (adjusted odds ratio 0.54, 95% confidence interval 0.45-0.64 and P < 0.001). Survival improved markedly between the years 2002 and 2003. This improvement has persisted, but there has been no further improvement. CONCLUSION: Concurrently with the implementation of TH, hospital mortality of OHCA patients treated in Finnish ICUs decreased.

Infant brain responses associated with reading-related skills before school and at school age.

INTRODUCTION: In Jyväskylä Longitudinal Study of Dyslexia, we have investigated neurocognitive processes related to phonology and other risk factors of later reading problems. Here we review studies in which we have investigated whether dyslexic children with familial risk background would show atypical auditory/speech processing at birth, at six months and later before school and at school age as measured by brain event-related potentials (ERPs), and how infant ERPs are related to later pre-reading cognitive skills and literacy outcome. PATIENTS AND METHODS: One half of the children came from families with at least one dyslexic parent (the at-risk group), while the other half belonged to the control group without any familial background of dyslexia. RESULTS: Early ERPs were correlated to kindergarten age phonological processing and letter-naming skills as well as phoneme duration perception, reading and writing skills at school age. The correlations were, in general, more consistent among at-risk children. Those at-risk children who became poor readers also differed from typical readers in the infant ERP measures at the group level. ERPs measured before school and at the 3rd grade also differed between dyslexic and typical readers. Further, speech perception at behavioural level differed between dyslexic and typical readers, but not in all dyslexic readers. CONCLUSIONS: These findings suggest persisting developmental differences in the organization of the neural networks sub-serving auditory and speech perception, with cascading effects on later reading related skills, in children with familial background for dyslexia. However, atypical auditory/speech processing is not likely a sufficient reason by itself for dyslexia but rather one endophenotype or risk factor.

Event-related potentials to pitch and rise time change in children with reading disabilities and typically reading children.

OBJECTIVE: The purpose of the present study was to investigate whether children with reading disabilities (RD) process rise time and pitch changes differently to control children as a function of the interval between two tones. METHODS: Children participated in passive oddball event-related potential (ERP) measurements using paired stimuli. Mismatch negativity (MMN), P3a and late discriminative negativity (LDN) responses to rise time and pitch changes were examined. RESULTS: Control children produced larger responses than children with RD to pitch change in the P3a component but only when the sounds in the pair were close to each other. Compared to children with RD, MMN was smaller and LDN larger in control children in response to rise time change when the sounds in the pair were further apart. The non-overlap in ERP measures between the groups was 40-50%. CONCLUSIONS: Problems in rapid processing of pitch change were reflected in a component associated with attention switching while amplitude envelope processing problems were reflected in components associated with stimulus detection or discrimination. SIGNIFICANCE: Children with RD process both rise time and pitch changes differently from control children thus providing evidence for the nature of amplitude envelope processing and rapid auditory processing deficits in dyslexia.

N1 and P2 components of auditory event-related potentials in children with and without reading disabilities.

OBJECTIVE: The effects of within stimulus presentation rate and rise time on basic auditory processing were investigated in children with reading disabilities and typically reading children. METHODS: Children with reading disabilities (RD; N=19) and control children (N=20) were studied using event-related potentials (ERPs). Paired stimuli were used with two different within-pair-intervals (WPI; 10 and 255 ms) and two different rise times (10 and 130 ms). Each stimulus was presented with equal probability and long between-pair inter-stimulus intervals (1-5s). The study focused on N1 and P2 components. RESULTS: The P2 responses to the first tone in the pair showed differences between children with RD and control children. Also, children with RD had larger N1 response than control children to stimuli with short WPI and long rise time. CONCLUSIONS: These results provide evidence for basic auditory processing abnormalities in children with RD. This processing difference could be related to extraction of stimulus features from sounds or to attentional mechanisms. SIGNIFICANCE: Our results show support for behavioral findings that children with RD and control children process rise times differently. More than half of children with RD showed atypical auditory processing.

Detection of sound rise time by adults with dyslexia.

Low sensitivity to amplitude modulated (AM) sounds is reported to be associated with dyslexia. An important aspect of amplitude modulation cycles are the rise and fall times within the sound. In this study, simplified stimuli equivalent to just one cycle were used and sensitivity to varying rise times was explored. Adult participants with dyslexia or compensated dyslexia and a control group performed a detection task with sound pairs of different rise times. Results showed that the participants with dyslexia differed from the control group in rise time detection and a correlation was found between rise time detection and reading and phonological skills. A subgroup of participants with lower sensitivity to rise time detection characterized by low accuracy in syllable-level phonological skills was found within the dyslexic group. Short stimuli containing only one rise time produced associations with phonological skills and reading, even in a language where the perception of rise time contrasts are not crucial for the signaling of phonemic contrast.

Prevalence of spinal cord injury in Helsinki.

STUDY DESIGN: Retrospective register-based epidemiological study. OBJECTIVE: To estimate the prevalence rate of persons with spinal cord injury (SCI) with special reference to ASIA Impairment Grade A-D. SETTING: Helsinki, Finland. METHODS: Cases were identified using the registers of the Kapyla Rehabilitation Centre, Helsinki University Central Hospital and the local organization for the disabled. Local health centres were informed about the study, residential service houses were contacted, and announcements were published in patient magazines. RESULTS: A regional population was found to have a prevalence rate of 28/100,000 inhabitants with SCI (ASIA Impairment Scale A-D). CONCLUSION: The prevalence rate in this study is consistent with the data published in other Nordic countries. SPONSORSHIP: The Finnish Cultural Foundation.

Early development of children at familial risk for dyslexia--follow-up from birth to school age.

We review the main findings of the Jyväskylä Longitudinal study of Dyslexia (JLD) which follows the development of children at familial risk for dyslexia (N = 107) and their controls (N = 93). We will illustrate the development of these two groups of children at ages from birth to school entry in the skill domains that have been connected to reading and reading disability in the prior literature. At school entry, the highest score on the decoding task among the poorer half (median) of the at risk children--i.e. of those presumably being most likely genetically affected--is 1 SD below the mean of the control group. Thus, the familial risk for dyslexia shows expected consequences. Among the earliest measures in which group differences as well as significant predictive associations with the first steps in reading have emerged, are indices of speech processing in infancy. Likewise, various measures of early language including pronunciation accuracy, phonological, and morphological skills (but not performance IQ) show both group differences and predictive correlations, the majority of which become stronger as the reliability of the measures increases by age. Predictive relationships tend to be strong in general but higher in the at risk group because of its larger variance in both the predictor variables and in the dependent measures, such as early acquisition of reading. The results are thus promising in increasing our understanding needed for early identification and prevention of dyslexia.

Auditory evoked magnetic fields to speech stimuli in newborns--effect of sleep stages.

The aim of the study was to examine whether a newborn can detect changes in a speech stimulus consisting of a fricative followed by a vowel /su/. In addition, we studied possible effect of the two sleep stages (active and quiet sleep) on the evoked magnetic responses. In young children (6 years), the same stimulus evokes a prominent deflection, consisting of two peaks. The first one (P1m) is evoked by the beginning of the fricative consonant and has a latency of about 145 ms. The second peak (P2m) with a latency of 340 ms, is evoked by the switch to the vowel. In newborns (n = 10), the waveform resembled that of the older children but latencies of the corresponding peaks were longer, 190 and 435 ms, correspondingly. The results suggest that already the newborn brain detects the change inside the auditory speech stimulus, namely the fricative sound changing into a vowel. However, the immaturity of the brain is reflected in the prolonged latencies. In addition, the responses were higher in amplitude in quiet sleep than in active sleep (F (1.9) = 36.5; p < 0.0002). This is in line with the enhanced somatosensory magnetic fields to tactile stimulation in quiet compared to active sleep in newborns.

Event-related potentials in newborns with and without familial risk for dyslexia: principal component analysis reveals differences between the groups.

Differences revealed by factor scores extracted by principal component analysis (PCA) from event-related potential (ERP) data of newborns with and without familial risk for dyslexia were examined and compared to results obtained by using original averaged ERPs. ERPs to consonant-vowel syllables (synthetic /ba/, /da/, /ga/; and natural /paa/, /taa/, /kaa/) were recorded from 26 at-risk and 23 control 1-7 day-old infants. The stimuli were presented equiprobably and with interstimulus intervals varying at random from 3,910 to 7,285 ms. Statistically significant between-group differences were found to be relatively similar irrespective of the methods of analysis (original ERPs vs. factor scores from PCA). Responses to /ga/ differed from those to /ba/ and /da/ between the groups in the right hemisphere at the latencies of 50-170 ms (Factor 4) and 540-630 ms (Factor 3). The groups differed also in their responses to /da/ in the posterior electrode sites at 740-940 ms (Factor 2). There were no group differences in the natural stimulus set. These results demonstrate that brain activation differences may be implicated in risk for dyslexia immediately after birth. The results also show that the PCA-ANOVA procedure is an effective way of identifying the group-related variance in the ERP-data when the component structure, such as those of infants, is not well-known in advance.

EC-SOD gene therapy reduces paracetamol-induced liver damage in mice.

BACKGROUND: Paracetamol overdose causes acute liver damage which leads to severe centrilobular hepatic necrosis. The hepatotoxic effect is caused by reactive metabolites and oxidative stress. Since extracellular superoxide dismutase (EC-SOD) protects tissues against the harmful effects of superoxide anion, the hypothesis that systemic adenovirus-mediated EC-SOD gene transfer could reduce liver damage was tested. METHODS: Mice were given paracetamol (600 mg/kg) enterally 2 days after adenovirus-mediated gene transfer of EC-SOD (2 x 10(9) pfu). Five days after gene transfer, plasma and tissue samples were collected for clinical chemistry analyses and tissue pathology evaluation. RESULTS: EC-SOD was expressed in a dose-dependent manner with the highest enzyme activity occurring 3 days after the gene transfer. Clinical chemistry and tissue pathology analyses showed that adenoviral EC-SOD gene transfer significantly attenuated release of liver enzymes and inhibited necrosis and apoptosis caused by paracetamol overdose. CONCLUSION: The results indicate the involvement of superoxide anion in paracetamol-mediated liver damage and suggest a possible protective role for EC-SOD gene transfer in paracetamol-induced liver damage.

Gene transfer of extracellular superoxide dismutase to atherosclerotic mice.

Clinical and epidemiological studies have provided circumstantial evidence that oxidized low-density lipoprotein (LDL) and antioxidants are involved in the pathogenesis of atherosclerosis. Superoxide dismutases (SODs) have been shown in vitro to protect LDL from deleterious effects of superoxide anions. In the present study, we have used adenoviral gene transfer to determine effect of extracellular SOD (EC-SOD) on atherogenesis in LDL receptor -/- mice. Intravenous administration of EC-SOD adenovirus (2 x 10(9) plaque forming units) into tail vein targeted transgene mainly to liver and induced a 3.5- to sevenfold increase in plasma total SOD activity. EC-SOD was secreted into circulation for 2-3 weeks mostly in a truncated B-form, suggesting that endogenous proteolytic mechanisms control the level and distribution of the enzyme. Therapeutic potential was determined by measuring plasma resistance against copper oxidation and analyzing atherosclerotic lesion areas in aortas of LDL receptor -/- mice. Mice were kept on a cholesterol diet for 10 weeks before gene transfer and 3 or 6 weeks after the gene transfer. Results showed a tendency for a reduction in the overall lesion area after EC-SOD gene transfer as compared with LacZ transduced control mice, but the difference did not reach statistical significance. It is concluded that short-term overexpression of EC-SOD in vivo does not affect atherogenesis in LDL receptor -/- mice.

Optimized in situ PCR method for the detection of gene transfer vector in histological sections.

BACKGROUND: Detection of transferred genes in histological sections has been problematic due to low transfection efficiency and copy number achieved with current vectors. In situ polymerase chain reaction (in situ PCR) is a new method for the detection of low-abundance nucleic acid targets in tissue sections. METHODS: We have adapted in situ PCR method for the detection and histological localization of transgene DNA after in vivo and ex vivo retroviral gene transfer by using mild fixation and permeabilization methods. We used 4% paraformaldehyde/15% sucrose fixation combined with proteinase K permeabilization and microwave treatment. PCR signal was detected with non-radioactive digoxigenin-dUTP tailed oligonucleotide sense-probe. RESULTS: The method was applicable for both paraffin-embedded and frozen tissue sections and reached the sensitivity to detect a few copies of target DNA sequence per cell. CONCLUSIONS: In situ PCR is a sensitive method to localize integrated gene transfer vectors and to analyze the relationship between expression of the treatment gene and biological effects in the transfected tissues.

Event-related potentials and consonant differentiation in newborns with familial risk for dyslexia.

We measured event-related potentials (ERPs) to synthetic consonant-vowel syllables (/ba/, /da/, /ga/) from 26 newborns with familial risk for dyslexia and 23 control infants participating in the Jyväskylä Longitudinal Study of Dyslexia. The syllables were presented with equal probability and with interstimulus intervals ranging from 3,010 to 7,285 ms. Analyses of averaged ERPs from the latencies identified on the basis of principal component analysis (PCA) revealed significant group differences in stop-consonant processing in several latency ranges. At the latencies of 50-170 ms and 540-630 ms, the responses to /ga/ were larger and more positive than those to /ba/ and /da/ in the right hemisphere in the at-risk group. Between 740 and 940 ms, the responses to /ba/ and /da/ differed between anterior and posterior electrode sites in the control group. These results indicate that the cortical electric activation evoked by speech elements differs between children with and without risk for dyslexia even immediately after birth. Group-related effects at early and late latency ranges of ERPs suggest differences both in the early sound processing based on activation of afferent elements and in later phases of syllable encoding.

Developmental pathways of children with and without familial risk for dyslexia during the first years of life.

Comparisons of the developmental pathways of the first 5 years of life for children with (N = 107) and without (N = 93) familial risk for dyslexia observed in the Jyväskylä Longitudinal study of Dyslexia are reviewed. The earliest differences between groups were found at the ages of a few days and at 6 months in brain event-related potential responses to speech sounds and in head-turn responses (at 6 months), conditioned to reflect categorical perception of speech stimuli. The development of vocalization and motor behavior, based on parental report of the time of reaching significant milestones, or the growth of vocabulary (using the MacArthur Communicative Development Inventories) failed to reveal differences before age 2. Similarly, no group differences were found in cognitive and language development assessed by the Bayley Scales of Infant Development and the Reynell Developmental Language Scales before age 2.5. The earliest language measure that showed lower scores among the at-risk group was maximum sentence length at age 2. Early gross motor development had higher correlation to later language skills among the at-risk group rather than the control children. The most consistent predictor of differential development between groups was the onset of talking. Children who were identified as late talkers at age 2 were still delayed at the age 3.5 in most features of language-related skills-but only if they belonged to the group at familial risk for dyslexia. Several phonological and naming measures known to correlate with reading from preschool age differentiated the groups consistently from age 3.5. Our findings imply that a marked proportion of children at familial risk for dyslexia follow atypical neurodevelopmental paths. The signs listed previously comprise a pool of candidates for early predictors and precursors of dyslexia, which await validation.

Mismatch negativity (MMN) as a tool for investigating auditory discrimination and sensory memory in infants and children.

For decades behavioral methods, such as the head-turning or sucking paradigms, have been the primary methods to investigate auditory discrimination, learning and the function of sensory memory in infancy and early childhood. During recent years, however, a new method for investigating these issues in children has emerged. This method makes use of the mismatch negativity (MMN), the brain's automatic change-detection response, which has been used intensively in both basic and clinical studies in adults for twenty years. This review demonstrates that, unlike many other components of event-related potentials, the MMN is developmentally quite stable and can be obtained even from pre-term infants. Further, MMN amplitude is only slightly smaller in infants than is usually reported in school-age children and it does not seem to differ much from that obtained in adults. MMN latency has been reported to be slightly longer in infants than in adults but reaches adult values by the early school-age years. Child MMN does not seem to be analogous to adult MMN, however. For example, contrary to the results of adult studies, a prominent MMN can be obtained from in all waking- and sleep states in infants. Moreover, MMN scalp distribution seems to be broader and more central in children than in adults.

Improved gene transfer efficiency in liver with vesicular stomatitis virus G-protein pseudotyped retrovirus after partial liver resection and thymidine kinase-ganciclovir pre-treatment.

Liver-directed gene therapy is a promising alternative for the treatment of various liver diseases. Pseudotyped (VSV-G) retroviruses can be produced in high titres which is essential to overcome the problem of low gene transfer efficiency detected previously with first generation Moloney murine (MMLV) retroviruses and plasmid vectors. We compared the lacZ gene transfer efficiency of MMLV retroviruses and VSV-G retroviruses in Watanabe heritable hyperlipidaemic rabbit liver using an intraportal administration route. Hepatocyte proliferation was stimulated by a partial (10%) liver resection and a thymidine kinase-ganciclovir treatment. We also studied the safety of the gene transfer by clinical chemistry, tissue pathology and PCR analysis of lung, kidney, spleen and gonads. Gene transfer efficiency with the VSV-G retrovirus was significantly higher than with the traditional MMLV-based retrovirus (9.5+/-5.26 vs 0.21+/-0.10 positive hepatocytes mm(-2), P<0.05). After a 12-month follow-up period no lacZ expression was detected in liver samples. No transgene was detected in plasma or in lung, kidney, spleen and gonads by PCR analysis 7 days after gene transfer. Transient increases were found in plasma c-reactive protein, aspartyl aminotransferase and alanine aminotransferase levels shortly after the operation with both types of retroviruses. VSV-G retrovirus was well tolerated and may become an efficient new tool in liver gene therapy. The absence of transgene in systemic circulation or in extrahepatic tissues including gonads is an important safety feature required for in vivo gene therapy.

Enhanced plasma cholesterol lowering effect of retrovirus-mediated LDL receptor gene transfer to WHHL rabbit liver after improved surgical technique and stimulation of hepatocyte proliferation by combined partial liver resection and thymidine kinase--ganciclovir treatment.

In this study we report an improved method for in vivo gene transfer to liver. Repeated injections of Moloney murine leukemia virus-derived retroviruses containing LDL receptor cDNA were given to the portal vein in combination with a 10% partial liver resection and stimulation of hepatocyte proliferation by plasmid/liposome-mediated thymidine kinase gene transfer and ganciclovir treatment. The method was used for the treatment of LDL receptor deficiency in Watanabe heritable hyperlipidemic rabbits. We demonstrate an increase in hepatocyte proliferation index by thymidine kinase and ganciclovir treatment from 0.9 to 1.35% and a maximum of 35% decrease in total plasma cholesterol level 2-3 months after the gene transfer. A 20% decline was still present after a 52-week follow-up period. A 50% decrease was also observed in plasma triglycerides. Liver function tests indicated a transient increase in plasma alkaline phosphatase level up to 12 weeks after the gene transfer. In situ PCR and RT-PCR analyses indicated that the transgene was present in periportal areas and was transcribed to mRNA 1 week after the gene transfer. Because of the relatively simple and controllable technique we suggest that repeated retrovirus injections via a portal vein catheter together with the limited partial liver resection and plasmid/liposome-mediated thymidine kinase gene transfer-ganciclovir treatment may be used to improve the results of retrovirus-mediated liver gene therapy.

Cortical responses of infants with and without a genetic risk for dyslexia: I. Age effects.

We studied auditory event-related potentials (ERP) in newborns and 6-month-old infants, about half of whom had a familial risk for dyslexia. Syllables varying in vowel duration were presented in an oddball paradigm, in which ERPs to deviating stimuli are assumed to reflect automatic change detection in the brain. The ERPs of newborns had slow positive deflections typical of their age, but significant stimulus and group effects were found only by the age of 6 months. In both groups, the responses to the deviant /ka/ were more positive than those to the standard /kaa/ stimuli, contrary to the findings of adult ERPs to duration changes. The results also suggested differences in brain activation pattern between the groups.