Somatic mosaicism in sperm is associated with intergenerational (CAG)n changes in Huntington disease

We have analysed the CAG repeat in the Huntington disease (HD)gene in sperm and blood from 20 unrelated HD patients. Althoughthe CAG repeat displayed significant mosaicism in sperm fromall individuals, there were marked differences in the degreeof repeat instability. Individuals who had either inheritedor transmitted an expanded CAG repeat displayed the highestlevels of repeat mosaicism, whereas individuals who had inheritedor transmitted a contracted repeat had very limited CAG mosaicismin sperm. A strong association between intergenerational changein CAG allele size and the level of sperm repeat mosaicism wasdetermined (P = 0.019). In contrast, neither blood CAG sizenor repeat mosaicism in blood, were significantly associatedwith intergenerational CAG changes. These data suggest the presenceof a c/s-acting factor, separate from CAG size, that stronglyinfluences the intergenerational behaviour of the CAG repeat.Additional studies are needed to determine whether analysisof CAG mosaicism in sperm is useful for assessing an individual'srisk for transmitting large expansions or contractions to hisoffspring.     

Strategies for preventing wheezing and asthma in small children

OBJECTIVE: To assess the effects of living in agreement with allergy preventive guidelines on wheezing and asthma at 2 years of age. DESIGN: Prospective birth cohort study (BAMSE). Questionnaires on heredity and environmental factors were answered when the child was 2 months, and detailed questionnaires on symptoms at 1 and 2 years of age. PARTICIPANTS: 4089 children, born during 1994-1996. SETTING: Child Health Centres in central and north-western parts of Stockholm, Sweden. MAIN OUTCOME MEASURES: Wheezing and asthma up to the age of 2. RESULTS: The effects of preventive guidelines regarding breastfeeding, maternal tobacco smoke and home dampness on wheezing and asthma were assessed in multiple logistic regression models. The cumulative incidence of recurrent wheezing at 2 years of age was 12.6% and of asthma 6.8% among those with a lifestyle in agreement with all guidelines and 24.1 and 17.9%, respectively, in families exposed to at least two of the three risk factors. Among children with no heredity, family lifestyle according to the guidelines gave a twofold reduction of asthma (5.3 vs. 10.5%), while the group with heredity had a threefold reduction (9.1 vs. 27.3%). The attributable fraction for asthma associated with the guidelines was 23% in total and 33% among those with heredity. CONCLUSION: In this observational study, family lifestyle according to preventive guidelines is associated with an important reduction of recurrent wheezing and asthma at 2 years of age, especially among children with allergic heredity. A follow-up will determine whether there still a risk reduction of both symptoms and disease.     

Four-year course of teacher-reported internalising,externalising and comorbid syndromes in preadolescent children

The aim of this study was to elucidate the nature of comorbidity between internalising and externalising syndromes and its meaning in the course of these syndromes from 8 to 12 years of age in a school setting. The children in the cohort (N=1320) were born in 1981. They were first surveyed in second grade (N=1284) and followed up in sixth grade (N=906). Teachers were the informants, and the study was carried out by means of a questionnaire. Data from both points of time were available on 861 subjects. The Rutter Teacher Questionnaire (RB2) measured behavioural and emotional symptoms at Time 1, and the Teacher Report Form (TRF) at Time 2. Comorbidity was more prevalent in boys than girls. Childhood comorbidity predicted externalising syndrome and comorbidity, but not internalising syndrome in early adolescence. It changed the course of boys’ internalising syndromes to an externalising direction over time. The data suggest a gender difference in the pattern of comorbidity. When comorbidity was partialled out, it was very rare for internalising and externalising syndromes to develop into contrasting syndromes over time. The recovery rate for childhood comorbidity was poor. Special attention should be paid to making schools recognise and help these children.     

Emotional and behavioural symptoms in 8–9-year-old children in relation to family structure

The association between family structure and behavioural and emotional symptoms in prepubertal children was studied in an epidemiological survey conducted in Finland. Five thousand eight hundred thirteen children aged 8 and 9 years were screened using the Rutter Parent Questionnaire (RA2) for parents and the Rutter Teacher Questionnaire (RB2) for teachers. Information concerning family type, birth order and sibship size were obtained from the parents. The majority of the children (84%) in the sample lived with both their biological parents, 10% with a single parent, and around 5% with a biological parent and a stepparent. Around 1% of the children lived outside their original home. The prevalence of behavioural and emotional symptoms was lowest in children living with both their biological parents and highest among children living outside their original home according to both parents’ and teachers’ reports. Children living with a parent and a stepparent had problems more often at home, but less often at school than children living with a single parent. Living with a single father was associated with having more externalising, school-related problems, while living with a stepfather was associated with having more internalising, home related problems. Having younger siblings seemed to be associated with fewer problems at school, and being the youngest child with having less problems both at home and at school.     

Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial.

OBJECTIVE: To assess the efficacy of lamotrigine, a novel antiepileptic drug that inhibits glutamate release, to retard disease progression in Huntington disease (HD). BACKGROUND: Excitatory amino acids may cause selective neuronal death in HD, and lamotrigine may inhibit glutamate release in vivo. METHODS: A double-blinded, placebo-controlled study was conducted of 64 patients with motor signs of less than 5 years' duration who were randomly assigned to either placebo or lamotrigine and assessed at 0 (baseline), 12, 24, and 30 months. The primary response variable was total functional capacity (TFC) score. Secondary response variables included the quantified neurological examination and a set of cognitive and motor tests. Repeated fluorodeoxyglucose measurements of regional cerebral metabolism using PET also were included. RESULTS: Fifty-five patients (28 on lamotrigine, 27 on placebo) completed the study. Neither the primary response variable nor any of the secondary response variables differed significantly between the treatment groups. Both the lamotrigine and the placebo group deteriorated significantly on the TFC, in the lamotrigine group by 1.89 and the placebo group by 2.11 points. No effect of CAG size on the rate of deterioration could be detected. CONCLUSIONS: There was no clear evidence that lamotrigine retarded the progression of early Huntington disease over a period of 30 months. However, more patients on lamotrigine reported symptomatic improvement (53.6 versus 14.8%; p = 0.006), and a trend toward decreased chorea was evident in the treated group (p = 0.08). The study also identified various indices of disease progression, including motor tests and PET studies, that were sensitive to deterioration over time.     

Familial Liability to Epilepsy and Attention-Deficit/Hyperactivity Disorder: A Nationwide Cohort Study

Background

Epilepsy and attention-deficit/hyperactivity disorder (ADHD) are strongly associated; however, the underlying factors contributing to their co-occurrence remain unclear. A shared genetic liability has been proposed as one possible mechanism. Therefore, our goal in this study was to investigate the familial coaggregation of epilepsy and ADHD and to estimate the contribution of genetic and environmental risk factors to their co-occurrence.

Transplantation of viable meniscal allograft. Survivorship analysis and clinical outcome of one hundred cases

BACKGROUND: Few medium-term or long-term reports on meniscal allograft transplantations are available. In this study, we present the results of a survival analysis of the clinical outcomes of our first 100 procedures involving transplantation of viable medial and lateral meniscal allografts performed in ninety-six patients. METHODS: Thirty-nine medial and sixty-one lateral meniscal allografts were evaluated after a mean of 7.2 years. Survival analysis was based on specific clinical end points, with failure of the allograft defined as moderate occasional or persistent pain or as poor function. An additional survival analysis was performed to assess the results of the sixty-nine procedures that involved isolated use of a viable allograft (twenty of the thirty-nine medial allograft procedures and forty-nine of the sixty-one lateral allograft procedures) and of the thirteen viable medial meniscal allografts that were implanted in combination with a high tibial osteotomy in patients with initial varus malalignment of the lower limb. RESULTS: Overall, eleven (28%) of the thirty-nine medial allografts and ten (16%) of the sixty-one lateral allografts failed. The mean cumulative survival time (11.6 years) was identical for the medial and lateral allografts. The cumulative survival rates for the medial and lateral allografts at ten years were 74.2% and 69.8%, respectively. The mean cumulative survival time and the cumulative survival rate for the medial allografts used in combination with a high tibial osteotomy were 13.0 years and 83.3% at ten years, respectively. CONCLUSIONS: Transplantation of a viable meniscal allograft can significantly relieve pain and improve function of the knee joint. Survival analysis showed that this beneficial effect remained in approximately 70% of the patients at ten years. This study identified the need for a prospective study comparing patients with similar symptoms and clinical findings treated with and without a meniscal allograft and followed for a longer period with use of clinical evaluation as well as more objective documentation tools regarding the actual fate of the allograft itself and the articular cartilage.     

Characterisation of human knee meniscus cell phenotype

OBJECTIVE: Studies on the biology of the human meniscus cell are scarce. The objective of our studies was to assess survival/proliferation of human meniscus cells in different culture conditions and to characterize the extracellular matrix (ECM) produced by these cells in these artificial environments. The composition of this ECM offers a variable to define the distinct meniscus cell phenotype. MATERIALS AND METHODS: Human meniscus cells were isolated enzymatically from visually intact lateral and medial knee menisci. Cells were cultured in monolayer conditions or in alginate gel. The composition of the cell-associated matrix (CAM) accumulated by the isolated cells during culture was investigated and compared to the CAM of articular chondrocytes cultured in alginate using flow cytometry with fluorescein isothiocyanate-conjugated monoclonal antibodies against type I collagen, type II collagen and aggrecan. Additional cell membrane markers analysis was performed to further identify the different meniscus cell populations in the alginate culture conditions and meniscus tissue sections. Proliferation was analyzed using the Hoechst 33258 dye method. In some experiments, the effect of TGFbeta1 on some of these variables was investigated. RESULTS: The CAM of monolayer cultured meniscus cells is composed of high amounts of type I and II collagen and low amounts of aggrecan. A major population of alginate cultured meniscus cells on the other hand synthesized a CAM containing high amounts of type I collagen, low amounts of type II collagen and high amounts of aggrecan. This population is CD44+CD105+CD34-CD31-. In contrast, a minor cell population in the alginate culture did not accumulate ECM and was mainly CD34+. The CAM of alginate cultured articular chondrocytes is composed of low amounts of type I collagen, high amounts of type II collagen and aggrecan. The expression of aggrecan and of type II collagen was increased by the addition of TGFbeta1 to the culture medium. The proliferation of meniscus cells is increased in the monolayer culture conditions. Cell numbers decrease slightly in the alginate culture, but can be increased after the addition of TGFbeta1. CONCLUSION: These results demonstrate that the human meniscus is populated by different cell types which can be identified by a distinct CAM composition and membrane marker expression. Unlike the monolayer culture conditions, the alginate culture conditions appear to favor a more fibrochondrocyte-like cell accumulating a CAM resembling the native tissue composition. This CAM composition is distinctly different from the CAM composition of phenotypically stable articular cartilage chondrocytes cultured in the same alginate matrix.     

Adherence to allergy prevention recommendations in children with a family history of asthma.

Allergen avoidance has been a major component of most programs for primary prevention of asthma and allergic diseases in childhood. As a part of the Childhood Asthma Prevention Study, families were provided with written and oral information on measures considered to be helpful in the primary prevention of allergic disease in high-risk infants. Dietary measures included advice to breastfeed for 6 months or longer, to delay the introduction of solid foods until after the infant turned 6 months of age, and to delay giving allergenic foods (egg and peanut butter) until after 12 months of age. In the active group of the randomized controlled trial aimed at reducing house dust mite (HDM) allergen levels, parents were advised to use an HDM-impermeable study mattress cover and an acaricide, to avoid sheep skins, and not to use a pillow before 12 months of age. Families received regular visits from the research nurses at 1, 3, 6, 9 and 12 months and phone calls every 6 wk. Only 43.4% of mothers were breastfeeding by 6 months and less than 20% by 12 months. The introduction of solid foods before 6 months was common, 26% by 3 months and 96% by 6 months. Adherence to infant-feeding recommendations was significantly greater in women over 30 yr of age, women who did not smoke during pregnancy, and women who had a tertiary education. Adherence to HDM reduction measures was greater than to those for infant feeding. The presence of symptoms in the form of an itchy rash by 4 wk did not significantly increase adherence. Complete adherence to infant-feeding recommendations in this intervention study of high-risk infants was low despite the provision of written information and reinforcement at home visits. In considering allergy prevention advice offered during clinical care, the likelihood of adherence is a factor which needs to be evaluated in assessing any potential benefits of allergy prevention regimens.