TNFRSF1A and MEFV mutations in childhood onset multiple sclerosis

To investigate frequency and phenotype of TNFRSF1A and MEFV mutations in childhood-onset multiple sclerosis (MS). Twenty-nine clinically well characterized patients were investigated for mutations in exons 2, 3, 4, and 6 of the TNFRSF1A gene and in exons 2, 3, 9, 10 of the MEFV gene. Standardized morbidity ratio (SMR) was used to assess whether the number of observed mutations was higher than expected. Eleven out of 29 patients tested positive for mutations. Heterozygosity for the TNFRSF1A R92Q (rs4149584) variant was found in 6/11 mutation-positive patients. The SMR for R92Q in our pediatric MS population was 4.6 (95% CI 1.7–10.0), 7.0 (95% CI 2.6–15.2), and 13.6 (95% CI 5.0–29.7), depending on reference population. Six patients carried at least one heterozygous MEFV mutation with SMRs of 21.4 (95% CI 7.9–46.6) and 14.6 (95% CI 5.4–31.9). Clinical characteristics of childhood MS patients with or without mutations did not differ significantly. Conclusion One third of our childhood MS patients had a heterozygous mutation in the TNFRSF1A and/or MEFV gene. This proportion by far exceeds the number of mutations expected and was higher than in adult MS patients, suggesting that these mutations might contribute to the pathogenesis of childhood MS.     

Flexibility of foveal attention during ocular pursuit

Smooth pursuit of natural objects requires flexible allocation of attention to inspect features. However, it has been reported that attention is focused at the fovea during pursuit. We ask here if foveal attention is obligatory during pursuit, or if it can be disengaged. Observers tracked a stimulus composed of a central dot surrounded by four others and identified one of the dots when it dimmed. Extinguishing the center dot before the dimming improved task performance, suggesting that attention was released from it. To determine if the center dot automatically usurped attention, we provided the pursuit system with an alternative sensory signal by adding peripheral motion that moved with the stimulus. This also improved identification performance, evidence that a central target does not necessarily require attention during pursuit. Identification performance at the central dot also improved, suggesting that the spatial extent of the background did not attract attention to the periphery; instead, peripheral motion freed pursuit attention from the central dot, affording better identification performance. The results show that attention can be flexibly allocated during pursuit and imply that attention resources for pursuit of small and large objects come from different sources.     

Botulinum toxin treatment of children with cerebral palsy — a short review of different injection techniques

The intramuscular application of botulinum toxin type A (BoNT/A) has emerged to be an established treatment option to reduce muscular hyperactivity due to spasticity in children with cerebral palsy. Accurate injection is a prerequisite for efficient and safe treatment with BoNT/A. So far, treatment procedures have not been standardized. This paper is a short review of different injection techniques, i.e., manual needle placement as well as guidance by electromyography, electrical stimulation, and ultrasound. Advantages and disadvantages of the different injection techniques are discussed with a focus on needle positioning within the targeted muscle, injection close to the neuromuscular junction and diffusion of BoNT/A within the target muscles and through fascia. The additional information gained by each injection technique is weighed in terms of the clinical impact for children with cerebral palsy.     

Treatment of adductor spasticity with BTX-A in children with CP: a randomized, double-blind, placebo-controlled study

Adductor spasticity in children with cerebral palsy (CP) impairs motor function and development. In a placebo-controlled, double-blind, randomized multicentre study, we evaluated the effects of botulinum toxin A(BTX-A) in 61 children (37 males, 24 females; mean age 6 years 1 month [SD 3y 1mo]) with CP (leg-dominated tetraparesis, n=39; tetraparesis, n=22; GMFCS level I, n=3; II, n=6; III, n=17; IV, n=29; V, n=6). Four weeks after treatment, a significant superiority of BTX-A was observed in the primary outcome measure (knee-knee distance 'fast catch', p=0.002), the Ashworth scale (p=0.001), and the Goal Attainment Scale (p=0.037).     

Alcohol consumption and risk of lymphoid and myeloid neoplasms: Results of the Netherlands cohort study

Results from epidemiological studies suggest that alcohol drinkers have a decreased risk of lymphoid neoplasms, whereas results for myeloid neoplasms are inconsistent. However, most of these studies have used retrospective data. We examined prospectively whether alcohol consumption decreases the risk of both lymphoid and myeloid neoplasms, including most common subtypes. Moreover, we investigated whether this decreased risk is due to ethanol or other contents of specific alcoholic beverages (i.e., beer, wine and liquor). The Netherlands cohort study consisted of 120,852 individuals who completed a baseline questionnaire in 1986. After 17.3 years of follow‐up, 1,375 cases of lymphoid and 245 cases of myeloid neoplasms with complete exposure information were available for analysis. Compared with abstinence, we observed for plasma cell neoplasms hazard rate ratios (HR) of 1.66 (95% confidence interval (CI), 1.21–2.29), 1.63 (95% CI, 1.17–2.27), 1.11 (95% CI, 0.75–1.64) and 0.85 (95% CI, 0.51–1.42) with daily ethanol consumption of 0.1–<5, 5–<15, 15–<30 and ≥30 g, respectively. A similar pattern was observed for chronic lymphocytic leukemia/small lymphocytic lymphoma. No associations were observed for other subtypes and for myeloid neoplasms. When results were analyzed by beverage type, no clear associations were observed. In conclusion, our study did not show an inverse association between alcohol consumption and lymphoid neoplasms. Also, no inverse association was observed with myeloid neoplasms. If any association between alcohol consumption and lymphoid neoplasms exists, our study suggests an increased risk rather than a decreased risk.     

Effects of a progestogen on normal human breast epithelial cell apoptosis in vitro and in vivo

Many investigators have reported cyclic proliferation of normal human breast epithelial cells. A delicate balance between proliferation and apoptosis (programmed cell death) ensures breast homeostasis. Both the follicular and luteal phases of the menstrual cycle are characterized by proliferation, whereas apoptosis occurs only at the end of the latter phase. In this study, we observed that the withdrawal of a synthetic progestin (nomegestrol acetate or NOMAC), but not continuous treatment with it, induced apoptosis of normal human breast epithelial cells in vitro and in women who applied NOMAC gel to their breasts. Furthermore, this apoptotic response was specific to normal breast cells, since withdrawal of NOMAC did not induce apoptosis of tumoral T47D cells in vitro or of fibroadenoma cells in women. These observations open up new perspectives in the prevention of hyperplasia and breast cancer.     

HNPCC mutations in hMSH2 result in reduced hMSH2-hMSH6 molecular switch functions

Mutations in the human mismatch repair (MMR) gene hMSH2 have been linked to approximately 40% of hereditary nonpolyposis colorectal cancers (HNPCC). While the consequences of deletion or truncating mutations of hMSH2 would appear clear, the detailed functional defects associated with missense alterations are unknown. We have examined the effect of seven single amino acid substitutions associated with HNPCC that cover the structural subdomains of the hMSH2 protein. We show that alterations which produced a known cancer-causing phenotype affected the mismatch-dependent molecular switch function of the biologically relevant hMSH2-hMSH6 heterodimer. Our observations demonstrate that amino acid substitutions within hMSH2 that are distant from known functional regions significantly alter biochemical activity and the ability of hMSH2-hMSH6 to form a sliding clamp.     

Komorbiditäten bei Zerebralparesen

Patients with cerebral palsy commonly suffer from epilepsy. Plenty of data exist regarding issues of treatment and prognosis of motor disturbances in this syndrome. However, few data are available on the epidemiology of epilepsy in patients with cerebral palsy. In the present article we summarize the findings of these studies with special respect to risk factors, treatment, and prognosis of epilepsy in children with cerebral palsy. Knowledge of these features might improve the counseling given these patients, their parents, and their caregivers in terms of treatment and prognosis.