Differences in peripheral myelin antigen-specific T cell responses and T memory subsets in atypical versus typical CIDP.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is presented by a large heterogeneity of clinical phenotypes. Around 50% of patients suffer from typical CIDP and show better therapy response than atypical variants. The goal of our study was to search for cellular immunological differences in typical versus atypical CIDP in comparison to controls. METHODS: We evaluated 26 (9 typical, 17 atypical) patients with mainly active-unstable CIDP using clinical and immunological examinations (enzyme-linked immunospot assay ELISPOT, fluorescence-activated cell sorting FACS) in comparison to 28 healthy, age-matched controls (HC). Typical or atypical CIDP measurements were compared with HC using Kruskal-Wallis test. RESULTS: Atypical CIDP patients showed increased frequencies of T cell subsets, especially CD4+ effector memory T cells (TEM) and CD4+ central memory T cells (TCM) as well as a tendency of higher T cell responses against the peripheral myelin antigens of PMP-22, P2, P0 and MBP peptides compared to typical CIDP. Searching for novel auto-antigens, we found that T cell responses against P0 180-199 as well as MBP 82-100 were significantly elevated in atypical CIDP patients vs. HC. CONCLUSIONS: Our results indicate differences in underlying T cell responses between atypical and typical CIDP characterized by a higher peripheral myelin antigen-specific T cell responses as well as a specific altered CD4+ memory compartment in atypical CIDP. Larger multi-center studies study are warranted in order to characterize T cell auto-reactivity in atypical CIDP subgroups in order to establish immunological markers as a diagnostic tool.

Refractory focal epilepsy in a patient with methylmalonic aciduria: case report on positive and long-lasting effect of rufinamide.

We report on a 5-year-old boy with methylmalonic aciduria, an autosomal recessive inborn error of metabolism leading to accumulation of methylmalonic-CoA and thereby causing intoxication with leading symptoms of hyperammonaemia and metabolic acidosis. Hyperammonemia itself causes brain oedema. In our patient, this led to a vast metabolic stroke of the left hemisphere and subsequent pharmacoresistant epilepsy. Guided by his main seizures--drop attacks--the orphan drug rufinamide (RUF) was introduced as "off-label use" and led to freedom of drop attacks and tonic-clonic seizures over a period of 14 months as well as normalisation of the electroencephalogramm. Only once during an episode of fever and diarrhoea with reduced level of RUF did some provoked seizures with focal complex semiology for the time period of infection occur. In the 16 months follow-up, the patient also improved in his development, showing a more stable gait with the hemiparesis and understanding more complex sentences.

Low long-term efficacy and tolerability of add-on rufinamide in patients with Dravet syndrome.

In this retrospective European multicenter study we evaluated the efficacy and tolerability of rufinamide in patients with Dravet syndrome and refractory seizures. Twenty patients were included; in 16 patients a SCN1A mutation was detected. The responder rate after 6 months was 20%, and after 34 months, 5%. The retention rate was 45% after 6 months and 5% after 34 months. Rufinamide treatment was stopped because of aggravation of seizures (30%), no effect (45%), and side effects (10%). The efficacy and long-term retention rate were low in our patients with Dravet syndrome and refractory seizures, far lower than in patients with Lennox-Gastaut syndrome; one-third of our patients experienced seizure aggravation. Therefore, rufinamide does not seem to be a suitable option for long-term treatment in patients with Dravet syndrome.

Determinants of survival in patients with brain metastases from cutaneous melanoma.

BACKGROUND: This retrospective study aimed to identify prognostic factors in patients with brain metastases from cutaneous melanoma. METHODS: In all, 265 patients under regular screening according to valid national surveillance guidelines were included in the study. Kaplan-Meier analyses were performed to estimate and to compare overall survival. Cox modeling was used to identify independent determinants of the overall survival, which were used in explorative classification and regression tree analysis to define meaningful prognostic groups. RESULTS: In total, 55.5% of our patients presented with two or less brain metastases, 82.6% had concurrent extracranial metastasis and 64% were asymptomatic and diagnosed during surveillance scans. In all, 36.7% were candidates for local treatment (neurosurgery or stereotactic radiosurgery (SRS)). The median overall survival of the entire collective was 5.0 months (95% confidence interval: 4.3-5.7). Favourable independent prognostic factors were: normal pre-treatment level of serum lactate dehydrogenase (P<0.001), administered therapy (neurosurgery or SRS vs other, P=0.002), number of brain metastases (single vs multiple, P=0.032) and presence of bone metastasis (false vs true, P=0.044). Three prognostic groups with significantly different overall survival were identified. Candidates for local treatment (group I) had the longer median survival (9 months). Remaining patients could be further classified in two groups on the basis of serum lactate dehydrogenase. CONCLUSION: Applied treatment and serum lactate dehydrogenase levels were independent predictors of survival of patients with brain metastases from cutaneous melanoma. Patients receiving local therapy have overall survival comparable with general stage IV melanoma patients.

The Rta/Orf50 transactivator proteins of the gamma-herpesviridae.

The replication and transcription activator protein, Rta, is encoded by Orf50 in Kaposi's sarcoma-associated herpesvirus (KSHV) and other known gammaherpesviruses including Epstein-Barr virus (EBV), rhesus rhadinovirus (RRV), herpesvirus saimiri (HVS), and murine herpesvirus 68 (MHV-68). Each Rta/Orf50 homologue of each gammaherpesvirus plays a pivotal role in the initiation of viral lytic gene expression and lytic reactivation from latency. Here we discuss the Rta/Orf50 of KSHV in comparison to the Rta/Orf50s of other gammaherpesviruses in an effort to identify structural motifs, mechanisms of action, and modulating host factors.

Do patients with congenital hemiparesis and ipsilateral corticospinal projections respond differently to constraint-induced movement therapy?

This study investigates whether the type of corticospinal reorganization (identified by transcranial magnetic stimulation) influences the efficacy of constraint-induced movement therapy (CIMT). Nine patients (five males, four females; mean age 16y [SD 6y 5mo], range 11-30y) controlling their paretic hand via ipsilateral corticospinal projections from the contralesional hemisphere and seven patients (three males, four females; mean age 17y [SD 7y], range 10-30y) with preserved crossed corticospinal projections from the affected hemisphere to the paretic hand underwent 12 consecutive days of CIMT. A Wolf motor function test applied before and after CIMT revealed a significant improvement in the quality of upper extremity movements in both groups. Only in patients with preserved crossed projections, however, was this amelioration accompanied by a significant gain in speed, whereas patients with ipsilateral projections tended to show speed reduction. These data, although preliminary, suggest that patients with congenital hemiparesis and ipsilateral corticospinal projections respond differently to CIMT.

MRI-imaging and clinical findings of eleven children with tick-borne encephalitis and review of the literature.

OBJECTIVES: The incidence of tick-borne encephalitis (TBE) is increasing in many countries. Magnetic resonance imaging (MRI) in the course of TBE is not regularly performed in children. The aim of our study was evaluating MRI-findings of children and adolescents with TBE. PATIENTS AND METHODS: Retrospective evaluation of the charts and MRIs of patients who had been treated for TBE in the four participating hospitals in the last twenty years. RESULTS: 11 patients (5 male; age at TBE 3 weeks-15 9/12 years; mean 104.9 months) were included. MRI (within the first week after admission) revealed symmetric or asymmetric T2-hyperintensities in both thalami in 7/11 patients with additional bilateral lesions in putamen and/or caudate nucleus in 3 patients, and additional cortical lesions in 2 patients. Our youngest patient presented with T2-hyperintensities affecting the whole left cerebral hemisphere including white and grey matter and both cerebellar hemispheres. One patient had a minimal reversible T2-hyperintensity in the splenium of the corpus callosum (RHSCC). 3/11 patients had a normal MRI. 4/11 patients showed complete neurological recovery (2/4 with a normal MRI, RHSCC patient). 6/11 children survived with significant sequelae: hemiparesis (n = 4); cognitive deficits (n = 4); pharmacoresistant epilepsy (n = 2). One patient died of a malignant brain edema. DISCUSSION: A spectrum of MRI findings can be found in children with TBE, often showing involvement of the subcortical deep grey matter structures. In children presenting with a meningoencephalitis and bilateral thalamic involvement TBE should be included in the differential diagnosis.

Early left periventricular brain lesions induce right hemispheric organization of speech.

Right-hemispheric organization of speech has been observed following early left-sided brain lesions involving the language cortex. The authors studied speech organization in hemiparetic patients with pre- and perinatally acquired lesions in the left periventricular white matter using fMRI, and found that right-hemisphere activation correlated with left facial motor tract involvement. This suggests that the impairment of speech motor output from the left hemisphere plays an important role in this alteration of language representation.

Exposure to Toxoplasma gondii and cat ownership in Nova Scotia.

In this survey, 998 children and adolescents between 7 months and 17 years of age who attended a hospital diagnostic center in the city of Halifax, Nova Scotia, for routine evaluation were tested for Toxoplasma gondii antibody. The 5.2% prevalence rate of antibody for children living in the outlying rural areas was significantly higher than the 1.1% rate among the urban children (P = .0006). Seroprevalence increased with age for both rural and urban children. Cat ownership was associated with antibodies to Toxoplasma among rural children but not urban children. Rural children who lived in a house with more than one cat were two times more likely to be infected than children who had one cat and three times more likely to be infected than children with no cats. The geometric mean titer was also significantly higher among the rural children with more than one cat, 1:152, than rural children with one or no cats, 1:63 (P = .02). In light of these findings for children and adolescents, the association of Toxoplasma infection with cat ownership needs to be thoroughly evaluated among pregnant women in rural areas.

Contribution of lateral substituents in heptane-bisammonium derivatives to the allosteric stabilization of antagonist binding to M2-receptors.

Phthalimide-containing heptane-bisammonium-type compounds retard the dissociation of the antagonist [3H]-N-methylscopolamine ([3H]NMS) from muscarinic M2-receptor allosterically with high potency. To study the contribution of the lateral substituents to this effect, a series of derivatives was synthesized in which the phthalimide moiety was truncated. The potency of the compounds to delay [3H]NMS dissociation was measured in porcine heart homogenates (50 mM Tris-HCl, 3 mM MgHPO4, pH 7.3, 37 degrees C). Potency declined with diminuition of the lateral substituents, e.g. loss of the aromatic ring of the phthalimide resulted in a 400fold reduction in potency. In the hexahydrophthalimide derivatives, the cis-stereoisomer was about fivefold more potent than the trans-isomer. In conclusion, almost flat hydrophobic lateral moieties appear to be pivotal for high allosteric potency, suggesting a hydrophobic interaction of these parts of the molecule with the [3H]NMS occupied receptor protein.

Probing the size of a hydrophobic binding pocket within the allosteric site of muscarinic acetylcholine M2-receptors.

Hexane-bisammonium-type compounds containing lateral phthalimide moieties are known to have a rather high affinity for the allosteric site of muscarinic M2 receptors. In order to get more insight into the contribution of the lateral substituents for alloster binding affinity, a series of compounds with unilaterally varying imide substituents were synthesized and tested for their ability to retard allosterically the dissociation of [3H]N-methylscopolamine from the receptor protein (control t1/2 = 2 min; 3 mM MgHCO4, 50 mM Tris, pH 7.3, 37 degrees C). Among the test compounds, the naphthalimide containing agent (half maximum effect at ECs5,diss = 60 nM) revealed the highest potency. Apparently, its affinity for the allosteric site in NMS-occupied receptors is 20fold higher compared with the phthalimide containing parent compound W 84. Analysis of quantitative structure-activity relationships yielded a parabolic correlation between the volume of the lateral substituents and the allosteric potency. The maximal volume was determined to be approximately 600 A3 suggesting that the allosteric binding site contains a binding pocket of a defined size for the imide moiety.

Effect of water stress on monoterpene emissions from young potted holm oak (Quercus ilex L.) trees.

We investigated the effects of a short period of water stress on monoterpene emissions from Quercus ilex, a common oak species of the Mediterranean vegetation and a strong emitter of monoterpenes. The experiment was carried out on two young saplings with a branch enclosure system under semi-controlled conditions. Under unstressed conditions, small qualitative (cis-ß-ocimene, trans-ß-ocimene, ß-caryophyllene and 1,8-cineol) and large quantitative (as much as 40% for the main compounds emitted) differences were observed between the two apparently similar trees. Nevertheless these differences did not affect the short-and long-term responses to temperature and water stress. Daily courses of emissions and gas exchanges were similar before and after the stress. During the most severe stress, emissions were reduced by a factor of two orders of magnitude and the log-linear relationship between emissions and temperature no longer existed. Photosynthesis and transpiration rates decreased as soon as the soil started to dry, whereas monoterpene emissions slightly increased for few days and then dropped when the daily CO2 balance approached zero. We concluded that under water stress monoterpene emissions were highly limited by monoterpene synthesis resulting from a lack of carbon substrate and/or ATP. After rewatering, both emissions and gas exchanges recovered immediately, but to a level lower than the pre-stress level. These results have many implications for monoterpene emission modelling in the Mediterranean area, since the dry period generally extends from May to August. If our results are confirmed by field experiments, water stress could lead to a large overestimation of the emissions under summer conditions, when the algorithms based on light and temperature would give high emission rates.

Effect of elevated CO2 on monoterpene emission of young Quercus ilex trees and its relation to structural and ecophysiological parameters.

We investigated growth, leaf monoterpene emission, gas exchange, leaf structure and leaf chemical composition of 1-year-old Quercus ilex L. seedlings grown in ambient (350 microl l(-1)) and elevated (700 microl l(-1)) CO2 concentrations ([CO2]). Monoterpene emission and gas exchange were determined at constant temperature and irradiance (25 degrees C and 1000 micromol m(-2) s(-1) of photosynthetically active radiation) at an assay [CO2] of 350 or 700 microl l(-1). Measurements were made on intact shoots after the end of the growing season between mid-October and mid-February. On average, plants grown in elevated [CO2] had significantly increased foliage biomass (about 50%). Leaves in the elevated [CO2] treatment were significantly thicker and had significantly higher concentrations of cellulose and lignin and significantly lower concentrations of nitrogen and minerals than leaves in the ambient [CO2] treatment. Leaf dry matter density and leaf concentrations of starch, soluble sugars, lipids and hemi-cellulose were not significantly affected by growth in elevated [CO2]. Monoterpene emissions of seedlings were significantly increased by elevated [CO2] but were insensitive to short-term changes in assay [CO2]. On average, plants grown in elevated [CO2] had 1.8-fold higher monoterpene emissions irrespective of the assay [CO2]. Conversely, assay [CO2] rapidly affected photosynthetic rate, but there was no apparent long-term acclimation of photosynthesis to growth in elevated [CO2]. Regardless of growth [CO2], photosynthetic rates of all plants almost doubled when the assay [CO2] was switched from 350 to 700 microl l(-1). At the same assay [CO2], mean photosynthetic rates of seedlings in the two growth CO2 treatments were similar. The percentage of assimilated carbon lost as monoterpenes was not significantly altered by CO2 enrichment. Leaf emission rates were correlated with leaf thickness, leaf concentrations of cellulose, lignin and nitrogen, and total plant leaf area. In all plants, monoterpene emissions strongly declined during the winter independently of CO2 treatment. The results are discussed in the context of the acquisition and allocation of resources by Q. ilex seedlings and evaluated in terms of emission predictions.

[Normal myelination in childhood brains using MRI--a meta analysis]. / Die normale Myelinisierung des kindlichen Gehirns in der MRT--eine Metaanalyse.

PURPOSE: To establish age limits for the assessment of normal myelination of the brain on T1-weighted (T1w) and T2-weighted (T2w) images. METHOD: Comparison of previous publications (Barkovich et al. 1988, Grodd 1993, Hayakawa et al. 1990, Hittmair et al. 1994, Martin et al. 1988/1990/1991, Nakagawa et al. 1998, Staudt et al. 1993/1994, Stricker et al. 1990). RESULTS: Despite technical and methodological differences, these studies principally agreed on the timing of myelination for most regions of the brain. Thus, a common time-table could be established: At 1 month, myelin is visible on both T1w and T2w in the medulla oblongata, tegmentum pontis, cerebellar peduncles and vermis, quadrigeminal plate, decussation of superior cerebellar peduncles, thalamus, posterior limb of internal capsule, optic radiation, corona radiata. Thereafter, the myelin-typical signal in the different regions of the brain should be present at the following ages (M = months): anterior limb of internal capsule (2 M: T1w; 7 M: T2w), splenium of corpus callosum (4 M: T1w; 6 M: T2w), genu of corpus callosum (6 M: T1w; 8 M: T2w), centrum semiovale (2 M: T1w; 7 M: T2w). Branching of myelin into the gyri of the telencephalon (= arborization) appears at the latest at: occipital lobe (5 M: T1w; 12 M: T2w) and frontal lobe (7 M: T1w; 14 M: T2w). CONCLUSION: These extracted age limits can be used for a more reliable assessment of myelination than the time-tables from a single study.

Barriers and facilitators to use of services following intensive family preservation services.

The primary caregivers of 101 families that used short-term, intensive home-based services were interviewed 2 months after the services to ascertain use of the recommended aftercare services, perceived barriers to service use, and perceived facilitators of service use. While 88% of the families accessed at least some of the recommended services, more than 50% failed to access all of the recommended aftercare services. The most often noted barriers to service use were enabling factors at the agency or community level. Yet, many of the services were used, and the respondents indicated that professionals played a role in helping them link to services. Researchers should continue to study the use of recommended aftercare services and the relationship between aftercare service use and clinical outcomes.

The role of family preservation therapists in facilitating use of aftercare services.

OBJECTIVE: The aims were to: (1) examine the process that family preservation therapists use when developing and implementing aftercare plans, and (2) examine how family preservation therapists perceive the availability and accessibility of community services that families need after short-term family preservation services. METHOD: Focus groups were conducted with therapists (n = 26) from five agencies that provide family preservation services in a large Midwest city. One agency was the local public child welfare agency, and the other four were nonprofit agencies with state contracts to provide family preservation services. RESULTS: Therapists viewed aftercare services as important and necessary, yet perceived barriers to families' use of aftercare services. Therapists undertook a number of activities to help families access and use services, though some therapists took a less active role than others did in helping families link to services. It was perceived that more follow-up was needed to ensure service use. Participants viewed certain services as especially difficult to access or unavailable, including services for men and adolescents. CONCLUSIONS: More explicit and focused attention to facilitating service use is needed. This can be accomplished by therapists focusing on service use during assessment and treatment planning. Regular follow-ups after short-term family preservation services for the purpose of helping families to productively use services may be needed. However, systemic changes are also needed to ensure that needed services are available and accessible.

Reporting and founding of child neglect in urban and rural communities.

The community context in which child abuse and neglect takes place may influence both reporting and outcomes of investigations into such incidents. This study examines and contrasts urban versus rural community perceptions of neglect by lay citizens and protective service workers.

First long-term experience with the orphan drug rufinamide in children with myoclonic-astatic epilepsy (Doose syndrome).

INTRODUCTION: We evaluated the long-term efficacy and tolerability of the orphan drug rufinamide (RUF) in children with pharmacoresistant myoclonic-astatic epilepsy (MAE, Doose syndrome). METHODS: This was a retrospective European multicenter study on eight patients who had started an intention-to-treat trial of RUF between July 2007 and June 2010. Clinical information was collected via questionnaire. Responder rate was defined as reduction of seizure frequency ≥50% in comparison to four weeks before starting RUF. Maximum follow-up was eighteen months. RESULTS: Responder rates were 7/8 patients after 3 months, 6/8 patients after 6 months and 5/8 patients after 12 months. RUF seemed particularly effective in the prevention of myoclonic-astatic seizures (comparable with drop attacks in Lennox-Gastaut-Syndrome, for which RUF is particularly effective). Some loss of efficacy was noticed in the long-term observation. Side-effects occurred in two patients. Seizure aggravation was not observed. CONCLUSION: RUF seems to be a promising therapeutic option in children with MAE. Further studies are warranted to confirm these first observations.