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Aim: The aim of this study was to describe speech, expressive language, and verbal cognition of children with cerebral palsy (CP)., Method: A population study included 152 Icelandic children with congenital CP (74 males, 78 females; mean age 5y 5mo, range 4y-6y 6mo). Children who spoke in sentences, phrases, or one-word utterances were categorized as verbal. Speech was classified as normal, mild dysarthria, or severe dysarthria. Cognition was reported as IQ (Wechsler Preschool and Primary Scale of Intelligence - Revised) or developmental quotient (DQ)., Results: Most children (81%) had spastic CP and bilateral symptoms (76%); 74 (49%) were at Gross Motor Function Classification System (GMFCS) level I, 27% at levels II and III, and 24% at levels IV and V (p<0.001). One hundred and twenty-eight children (84%) communicated verbally whereas 24 were nonverbal. Nonverbal status and severe dysarthria were associated with greater motor impairment (GMFCS; p<0.001). Twenty-five children (16%) had severe dysarthria. Most (88%) of the nonverbal children had multiple disabilities compared with 18% of the verbal group (p<0.001). Median (interquartile range) verbal IQ was 93 (73-104) and performance IQ 77 (61-94; p<0.001). Sixty-eight children (45%) had normal verbal cognition and almost a quarter of the children with severe dysarthria had a full-scale IQ/DQ of 70., Interpretation: Most children with CP express sentences and almost half of them have normal verbal IQ. Nonverbal status frequently indicates multiple impairments whereas severe dysarthria may be associated with normal cognition., (© The Authors. Journal compilation © Mac Keith Press 2010.)

Objective: To estimate the incidence of olfactory dysfunction across traumatic brain injury (TBI) severity and decision-making deficits with regard to intracranial lesions' location and laterality., Method: A 1-year prospective study including 115 participants (16-55 years) with mild, moderate, and severe TBI. The Brief Smell Identification Test was used 3 months postinjury with a follow-up testing of olfactory dysfunction at 1 year. The Iowa Gambling Task (IGT) and 3 tasks of the Delis-Kaplan Executive Function System were administered 3-months postinjury. MRI was performed 1-year postinjury and TBI severity groups were then divided with respect to frontal, fronto-temporal, diffuse, and no lesions., Results: The incidence of olfactory dysfunction was estimated to be 22.3% at 3 months and 13.5% at 1 year. No significant differences were found on olfactory dysfunction across TBI severity at either check. Anosmia was identified in 10% with severe TBI and 3% with mild TBI. Olfactory dysfunction was associated with verbal fluency tasks. Repeated-measures analysis of variance revealed no significant effect over blocks on IGT, and no main group or interaction effects regarding TBI severity, lesions' location, or laterality. IGT performance at 3-months postinjury was deficient in 83% of persons with intracranial lesions and 71% of those without lesions., Conclusions: Olfactory dysfunction is independent of TBI severity, showing improvements in one third of cases from 3- to 12-months postinjury. However, anosmia was related to TBI severity. There is evidence for marked decision-making deficits after TBI, all subgroups performed similarly and failed to develop an advantageous strategy over time.

Background: The aims of this study were to describe the occurrence of substance use at the time of injury and pre-injury substance abuse in patients with moderate-to-severe traumatic brain injury (TBI). Effects of acute substance use and pre-injury substance abuse on TBI severity were also investigated., Methods: A prospective study of 111 patients, aged 16-55 years, injured from May 2005 to May 2007 and hospitalised at the Trauma Referral Centre in Eastern Norway with acute TBI (Glasgow Coma Scale 3-12). Based on structural brain damages shown on a computed tomography (CT) scan, TBI severity was defined by modified Marshall classification as less severe (score <3) and more severe (score >/=3). Clinical definition of substance use (alcohol and/or other psychoactive substances) was applied when hospital admission records reflected blood alcohol levels or a positive drug screen, or when a physician verified influence by examining the patient. Pre-injury substance abuse (alcohol and drug problems) was screened by using the CAGE questionnaire., Results: Forty-seven percent of patients were positive for substance use on admission to hospital. Significant pre-injury substance abuse was reported by 26% of patients. Substance use at the time of injury was more frequent in the less severe group (p = 0.01). The frequency of pre-injury substance abuse was higher in the more severe group (30% vs. 23%). In a logistic regression model, acute substance use at time of injury tended to decrease the probability of more severe intracranial injury, but the effect was not statistically significant after adjusting for age, gender, education, cause of injury and substance abuse, OR = 0.39; 95% CI 0.11-1.35, p = 0.14. Patients with positive screens for pre-injury substance abuse (CAGE >/=2) were more likely to have more severe TBI in the adjusted regression analyses, OR = 4.05; 95% CI 1.10-15.64, p = 0.04., Conclusions: Acute substance use was more frequent in patients with less severe TBI caused by low-energy events such as falls, violence and sport accidents. Pre-injury substance abuse increased the probability of more severe TBI caused by high-energy trauma such as motor vehicle accidents and falls from higher levels. Preventive efforts to reduce substance consumption and abuse in at-risk populations are needed.

Background and Purpose: The existence of a hypersensitive radiation response to doses below 0.5Gy is well established for many normal and tumour cell lines. There is also evidence for hypersensitive tissue responses in acute skin damage and kidney function in mice. Recently, we have identified that a hypersensitive gammaH2AX response exists in human epidermis. The aim of this study was to investigate the dose-response of basal clonogenic keratinocytes in normal skin to fractionated radiotherapy with low dose fractions., Materials: Skin punch biopsies were taken before and during radiotherapy from prostate cancer patients undergoing radiotherapy with a curative intent. Areas of epidermis receiving daily fractions of approximately 0.1, 0.2, 0.45 and 1.1Gy were biopsied on the same occasion to determine dose-response for each individual patient. In total, 89 cases were assessed either at 1, 2.5, 3, 4, 5 or 6.5 weeks in the treatment course. Biopsy sampling of another 25 patients was performed from areas receiving 0.45 and 1.1Gy per fraction at regular intervals throughout the 7-week treatment period. The number of basal keratinocytes per mm of the interfollicular epidermis was determined. The DNA damage response of the basal keratinocytes was investigated by immunohistochemical staining for molecular markers of growth arrest, mitosis and cell death, using p21, phospho-H3 and gammaH2AX, respectively. The number of stained keratinocytes in the basal layer was counted manually. The p21 staining was also quantified by digital image analysis., Results: The individual dose-response relationships revealed a low-dose hypersensitivity for reduction of basal keratinocytes throughout 7 weeks of radiotherapy (p<0.01). Growth arrest and cell proliferation assessed at 1 week and 6.5 weeks showed, in both cases, hypersensitive increase of p21 (p<0.01) and hypersensitive depression of mitosis (p<0.01). Manual counting and digital image analysis of p21 showed good agreement. Cell death was infrequent but increased significantly between 1 and 6.5 weeks and displayed a hypersensitive dose-response at the end of the treatment period., Conclusions: A low-dose hypersensitivity in basal skin keratinocyte reduction is present throughout 7 weeks of radiotherapy. A persistent hypersensitive growth arrest response and cell killing mediate this effect., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Outcome studies on traumatic brain injury (TBI) have shown that functional status can be predicted by demographic, injury severity, and trauma-related factors. Concurrent cognitive functions as one of the determinants of functional outcome is less documented. This study evaluated the effects of concurrent neuropsychological measures on functional outcome 1 year after injury. Neuropsychological data, employment status, self-reported fatigue, and the Glasgow Outcome Scale-Extended (GOSE) were collected from 115 persons with TBI (ranging from mild to severe) at 3 and 12 months postinjury. Principal components analysis was conducted with the neuropsychological measures and three components emerged. Multiple regression analysis, controlling for demographic and injury severity related factors, was used to test the effects of cognitive components at 12 months on functional outcome (GOSE). One year after injury, 64% were categorized as "good recovery" and 36% as "moderate disability" according to GOSE. Good functional recovery depended on shorter duration of posttraumatic amnesia, less fatigue, absence of intracranial pathology, higher education, and better performance on cognitive measures. The predictive values of Verbal/Reasoning and Visual/Perception components are supported; each added significantly and improved prediction of functional outcome. The Memory/Speed component showed a near-significant relationship to outcome.

Primary Objectives: To examine self-reported post-concussion symptoms from 3-12 months post-injury in adults with traumatic brain injury (TBI) and to identify predictors of these symptoms., Methods and Procedures: A 1-year prospective study in Eastern Norway including 115 persons (16-55 years), with mild, moderate and severe TBI. The Rivermead Post Concussion Symptoms Questionnaire (RPQ) and Hospital Anxiety and Depression Scale (HADS) were administered. Magnetic resonance imaging (MRI) was performed at 12 months., Results: In the whole sample of TBI, 27.8% of cases developed post-concussion syndrome (PCS) at 3 months and 23.6% at 12 months post-injury. The mild and moderate groups showed a decline of PCS symptoms over time, in contrast to the severe TBI group. Greater levels of somatic, cognitive and anxiety symptoms at 3 months, as well as shorter PTA duration, were found to be important predictors for the severity of PCS symptoms at 12 months. Intracranial pathology, Glasgow Coma Scale (GCS) and demographic variables were not related to the severity of PCS symptoms., Conclusions: PCS symptoms were reported to a greater degree in persons with mild TBI at 3 months post-injury. One year after injury, no differences were found between TBI groups on the presence of PCS.

We describe the cognitive profile in a complete national cohort of children with cerebral palsy (CP). One hundred and twenty-seven Icelandic children (67 females, 60 males) with CP, born between 1985 and 2000 and assessed between the ages of 4 and 6 years 6 months (mean age 5y 5mo, SD 6mo), were included in the study. IQ was measured using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) and developmental quotient (DQ) was obtained using various developmental scales. Physiological classification of CP in the children was: spasticity, n=104 (82%); dyskinesia, n=14 (11%); ataxia, n=six (4.7%), and unclassified CP, n=3 (2.3%). Spastic diplegia was the most prevalent subtype (35%) followed by hemiplegia and quadriplegia. Forty-five per cent of the group were at Level I of the Gross Motor Function Classification System, 32% were at Levels II and III, and 23% were at Levels IV and V. Sixty per cent of the children had an IQ or DQ >70. Median scores on the WPPSI were Full-scale IQ 84, Verbal IQ (VIQ) 92, and Performance IQ (PIQ) 77. Children with spastic diplegia and quadriplegia had a significantly lower PIQ than VIQ. Of the children who failed to complete the WPPSI, 20% had DQ >85. Thus, cognitive skills can be masked by limitations of movement and motor control in children with CP.

Grade II gliomas are morphologically and clinically heterogeneous tumors for which histopathological typing remains the major tool for clinical classification. To what extent the major histological subtypes - astrocytomas, oligodendrogliomas, and oligoastrocytomas - constitute true biological entities is largely unresolved. Furthermore, morphological classification is often ambiguous and would be facilitated by specific subtype markers. In this study, 23 grade II gliomas were expression-profiled and subjected to hierarchical clustering. All six oligodendrogliomas were grouped together in one of two major clusters; a significant correlation was thus observed between gene expression and histopathological subtype. Supervised analyses were performed to identify genes differentiating oligodendrogliomas from other grade II tumors. In a leave-one-out test using 10 features for classification, 20 out of 23 tumors were correctly classified. Among the most differentially expressed genes was rPTPbeta/zeta. The expression of the rPTP beta/zeta protein in oligodendrogliomas and astrocytomas was further validated by immunohistochemistry in an independent set of tumors. All 11 oligodendrogliomas of this set displayed strong staining. In contrast, neoplastic astrocytes were mostly negative for rPTPbeta/zeta staining. In summary, this study demonstrates a correlation between gene expression pattern and histological subtype in grade II gliomas. Furthermore, the results from the immunohistochemical analyses of rPTPbeta/zeta expression should prompt further evaluation of this protein as a novel oligodendroglioma marker.

Background: The aim of this prospective, population-based study is to present the incidence of hospital-treated traumatic brain injury (TBI) in Oslo, Norway, and to describe the severity of brain injuries and outcome of the patients' acute medical care., Methods: Data were obtained from hospital admission registers and medical records from May 2005 to May 2006. The initial severity of TBI was measured by the Glasgow Coma Scale. The region is urban with a population of 534,129., Results: The 445 patients identified represent an annual incidence of 83.3/100,000. The median age was 29 years. The male:female ratio was 1.8:1.0. The highest incidence of TBI hospitalizations was found in the elderly males and the youngest children. The most common causes of TBI were falls (51%) and transport accidents (29.7%). Intracranial lesions were found more often in the elderly. The case fatality rate was 2.0/100 hospitalized patients and was highest in the elderly., Conclusions: The incidence of hospital-treated TBI in this study is considerably lower than that found in previous studies from Norway and Scandinavia. Despite the apparent decline in TBI hospitalization rates, our findings should also draw attention to the need for more effective preventive programmes related to falls. Studies that assess long-term consequences of TBI in elderly patients are also needed., (2008 S. Karger AG, Basel)

Oligoastrocytomas are glial tumours consisting of a mixture of neoplastic astrocytic and oligodendroglial cells. Genetic alterations of oligoastrocytomas include loss of heterozygosity of chromosomes 1p and/or 19q (LOH 1p/19q), typically occurring in oligodendrogliomas, and mutations of TP53, frequently occurring in astrocytomas. To investigate whether these neoplastic cell types in oligoastrocytomas have different genetic profiles, we examined the two different components of oligoastrocytomas in comparison with the histological diagnosis of the specific tumour area for LOH 1p/19q and TP53 mutations by using microdissection technique. We found a variety of lost markers for 1p and 19q, and the presence of two different TP53 mutations in the tumour samples. In the majority of cases (9/11), the oligodendroglial and astrocytic components of an individual oligoastrocytoma displayed the same genotype. We present two cases of biphasic oligoastrocytomas with aberrant findings, suggesting the coexistence of genetically and morphologically distinct tumour cell clones in these tumours. In one case, the oligodendroglial part of the tumour showed LOH19q, whereas the astrocytic part showed TP53 mutation (codon 273). In another case, we found LOH 1p/19q in the oligodendroglial component, but two retained areas on chromosome 1p in the astrocytic component of the tumour. No evidence was found for the coexistence of tumour cells with the two genotypical changes within the same morphological region of one individual tumour. The two cases of biphasic oligoastrocytomas in our sample that display a different genotype in the astrocytic and oligodendroglial part of the tumour show that different components of an oligoastrocytoma may be derived from different cell clones during neoplastic transformation.

Intergenerational mixing of DNA through meiotic recombinations of homologous chromosomes during gametogenesis is a major event that generates diversity in the eukaryotic genome. We examined genome-wide microsatellite data for 23,066 individuals, providing information on recombination events of 14,140 maternal and paternal meioses each, and found a positive correlation between maternal recombination counts of an offspring and maternal age. We postulated that the recombination rate of eggs does not increase with maternal age, but that the apparent increase is the consequence of selection. Specifically, a high recombination count increased the chance of a gamete becoming a live birth, and this effect became more pronounced with advancing maternal age. Further support for this hypothesis came from our observation that mothers with high oocyte recombination rate tend to have more children. Hence, not only do recombinations have a role in evolution by yielding diverse combinations of gene variants for natural selection, but they are also under selection themselves.

Multiple sclerosis (MS) is a demyelinating disorder of the central nervous system (CNS) with a complex genetic background. Here we use a genome-wide association strategy with 4804 microsatellite markers successfully typed in separately pooled DNA from 200 patients and 200 controls. A total of 91 markers showed evidence of association. When compared to our in-house physical map of the genome, six 2-Mb regions containing at least two of these markers were detected. Of those, three regions have one or more markers among the 20 most strongly associated: chromosomes 3q25, 6p21.3 (the MHC region) and 19q13.

Immunization with a pneumococcal conjugate vaccine (PNC) containing serotype 19F induces cross-reactive antibodies to 19A in mice and human infants. Active immunization with PNC and passive immunization with serum samples from infants vaccinated with PNC containing serotype 19F, but not serotype 19A, protected against lung infection caused by both serotypes in a murine model.

In a collection of 173 cervical adenocarcinomas, the prevalence of HPV in relation to the age of women and the distribution of the various oncogenic types of HPV were evaluated. The tumour material was analysed by PCR of the HPV L1 gene followed by direct DNA sequencing and/or the polymerase chain reaction and single-strand conformation polymorphism (PCR-SSCP) technique for the identification and typing of HPV. In 68% (117/173) of the adenocarcinomas, HPV was present. A significant correlation was observed between the prevalence of HPV and age: in women younger than 40 years, HPV was present in 88%, whereas in women 60 years and older, it was found in only 39% (p<0.001). Among the HPV-positive tumours, type 18 predominated (52%) followed by type 16 (35%) and type 45 (7.7%) while other oncogenic types of HPV (31 and 59) were rarely found. HPV 16 was relatively more frequent in older women but this observation was not significant (p=0.06). HPV-typing by PCR and direct DNA sequence analysis is more specific than analysis by PCR-SSCP, especially among the less frequently occurring types of HPV. Our results further show that the prevalence of HPV in women with cervical adenocarcinomas is age-related and that the most frequently occurring types of HPV are 18, followed by 16 and 45. We have concluded that the oncogenic role of HPV in cervical squamous carcinomas and adenocarcinomas is, in some respects, discrepant.

Determination of recombination rates across the human genome has been constrained by the limited resolution and accuracy of existing genetic maps and the draft genome sequence. We have genotyped 5,136 microsatellite markers for 146 families, with a total of 1,257 meiotic events, to build a high-resolution genetic map meant to: (i) improve the genetic order of polymorphic markers; (ii) improve the precision of estimates of genetic distances; (iii) correct portions of the sequence assembly and SNP map of the human genome; and (iv) build a map of recombination rates. Recombination rates are significantly correlated with both cytogenetic structures (staining intensity of G bands) and sequence (GC content, CpG motifs and poly(A)/poly(T) stretches). Maternal and paternal chromosomes show many differences in locations of recombination maxima. We detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates.

Streptococcus pneumoniae serogroup 6 is an important cause of respiratory tract disease worldwide. Vaccination with 6B polysaccharide induces antibody response to the cross-reacting serotype 6A, but the protective capacity of 6A antibodies induced in infants remains unknown. In this study, passive immunization with serum samples obtained from infants vaccinated with an octavalent polysaccharide protein conjugate vaccine, PncT, protected mice against bacteremia and/or lung infection caused by intranasal challenge with serotypes 6B and 6A. Protective infant serum samples had significantly higher serotype-specific IgG levels and opsonic activity than did nonprotective serum samples. The protective level to either serotype was approximately 1 microg of specific IgG antibodies injected per mouse (corresponding to approximately 0.3 microg/mL). The protection was strongly related to opsonophagocytic antibody levels measured in vitro. These results demonstrate that PncT induces antibodies in infants that protect mice against invasive disease caused by the homologous serotype and by the cross-reacting serotype 6A.

The aim of this study was to evaluate normal tissue response by molecular markers to multifraction low doses of ionizing radiation, with the focus on changes in repopulation, estimated using Ki-67 as the proliferation marker, and on expressions of the p53 and p21 proteins, identified as key proteins in the DNA damage checkpoint. Repeated skin biopsies were taken from patients treated for prostate cancer with radiotherapy. The expressions of Ki-67, p53 and p21 of the keratinocytes in the basal cell layer of the epidermis were quantified immunohistochemically. The dose to the basal layer was 1.1 Gy per fraction, given five times per week for seven weeks. The indices of the three markers were determined over the whole period. A significant suppression of the Ki-67 index was observed during the first weeks, followed by a significant gradual increase in the Ki-67 index over the last weeks. The p53 and p21 protein levels were almost zero in the unirradiated skin. Upon irradiation, both the p53 and p21 index increased in a pattern very congruent to the Ki-67 index. In conclusion, daily fractions of about 1 Gy to the skin resulted in, for the keratinocytes in the basal layer, a cell growth arrest for a couple of weeks and a subsequent acceleration in repopulation during the following weeks of irradiation. The present findings also provided novel insights into the role of the p53/p21 pathway in the response of a normal epithelium to ionizing radiation as it is applied in radiotherapy.

Schimke immunoosseous dysplasia (SID) is a rare, pleiotropic disorder compromising spondyloepiphyseal dysplasia, nephrotic syndrome, defective T-cell-mediated immunity, and vascular changes which can lead to cerebral infarcts. The cause is unknown but an autosomal recessive inheritance pattern has been suggested. Understanding of the clinical phenotype is evolving; however, the neurologic spectrum is not well known. We report on a 17-year-old woman who presented with behavior changes, developmental regression, and partial complex seizures in early childhood. Computed tomographic scan of the brain was normal at that time. Short stature and cognitive deficits became evident several months later. At 4 1/2 years, she developed nephrotic syndrome and later malignant hypertension. Recent magnetic resonance imaging of the brain showed focal encephalomalacia in the parietal regions and a magnetic resonance angiography documented narrowing of the middle cerebral arteries. A skeletal survey showed evidence of spondyloepiphyseal dysplasia. We have not been able to identify an immune defect. To our knowledge this is the first reported patient with SID, profound mental retardation, and a seizure disorder. This case supports the theory that an intrinsic vascular defect may be more important in the pathogenesis of SID than a T-cell-mediated immune deficit.

Background: Streptococcus pneumoniae is a major cause of meningitis, bacteremia, pneumonia and otitis media. Pneumococcal polysaccharides are not immunogenic in infants, but improved immunogenicity of polysaccharide-protein conjugates has been demonstrated. Antibiotic-resistant pneumococci have increased the need for an effective vaccine., Objective: To study the safety and immunogenicity of a pneumococcal type 6B polysaccharidetetanus toxoid conjugate (Pn6B-TT) in infants and to assess the function of antibodies., Methods: Healthy infants were injected, Group A at 3, 4 and 6 months (n = 21) and Group B at 7 and 9 months (n = 19). Booster injection was given at 18 months. Antibodies were measured by enzyme-linked immunosorbent assay and radioimmunoassay, and functional activity was measured by opsonization of radiolabeled pneumococci. Nasopharyngeal cultures were obtained., Results: No significant adverse reactions were observed. Pn6B-IgG (enzyme-linked immunosorbent assay) increased to a geometric mean of 0.62 microgram/ml (P = 0.367, compared with prevaccination titers) in Group A at 7 months and 1.22 micrograms/ml (P < 0.001) in Group B at 10 months. Total Pn6B antibodies (radioimmunoassay) were 44 ng of antibody N/ml (P < 0.053) in Group A and 211 ng of antibody N/ml (P < 0.001) in Group B. A smaller increase in IgM and IgA anti-Pn6B was observed. Reinjection at 18 months elicited booster responses in total and IgG anti-Pn6B; 62% of those in Group A and 79% of those in Group B had > 300 ng of antibody N/ml. Opsonic activity, after initial and booster vaccinations, correlated with Pn6B-antibody titers. Three infants with nasopharyngeal cultures repeatedly positive for serogroup 6 had poor serum IgG responses., Conclusion: Our results demonstrate that Pn6B-TT is safe, elicits functional antibodies and memory responses in infants.

Class II genes of the bovine major histocompatibility complex (MHC) have been investigated by Southern blot analysis using human DNA probes. Previous studies revealed the presence of bovine DO beta, DQ alpha, DQ beta, DR alpha, and DR beta genes, and restriction fragment length polymorphisms for each of these genes were documented. In the present study, the presence of three additional class II genes, designated DZ alpha, DY alpha, and DY beta, are reported. DZ alpha was assumed to correspond to the human DZ alpha gene while the other two were designated DY because their relationship to human class II genes could not be firmly established. The linkage relationships among bovine class II genes and two additional loci, TCP1B and C4, were investigated by family segregation analysis and analysis of linkage disequilibrium. The results clearly indicated that all these loci belong to the same linkage group. This linkage group is divided into two subregions separated by a fairly high recombination frequency. One region includes the C4, DQ alpha, DQ beta, DR alpha, and DR beta loci and the other one is composed of the DO beta, DY alpha, DY beta, and TCP1B loci. No recombinant was observed within any of these subregions and there was a strong or fairly strong linkage disequilibrium between loci within groups. In contrast, as many as five recombinants among three different families were detected in the interval between these subregions giving a recombination frequency estimate of 0.17 +/- 0.07. The fairly high recombination frequency observed between class II genes in cattle is strikingly different from the corresponding recombination estimates in man and mouse. The finding implies either a much larger molecular distance between some of the bovine class II genes or alternatively the presence of a recombinational "hot spot" in the bovine class II region.