Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families

Within the past few years, there has been a significant change in identifying and characterizing the FMR1 premutation associated phenotypes. The premutation has been associated with elevated FMR1 mRNA levels and slight to moderate reductions in FMRP levels. Furthermore, it has been established that ∼20% of female premutation carriers present primary ovarian insufficiency (POI) and that fragile X-associated tremor/ataxia syndrome (FXTAS) occurs in one-third of all male premutation carriers older than 50 years. Besides POI and FXTAS, new disorders have recently been described among individuals (especially females) with the FMR1 premutation. Those pathologies include thyroid disease, hypertension, seizures, peripheral neuropathy, and fibromyalgia. However there are few reports related to FXTAS penetrance among female premutation carriers or regarding these disorders recently associated to the FMR1 premutation. Therefore, we have evaluated 398 fragile X syndrome (FXS) families in an attempt to provide an estimation of the premutation associated phenotypes penetrance. Our results show that signs of FXTAS are detected in 16.5% of female premutation carriers and in 45.5% of premutated males older than 50 years. Furthermore, among females with the FMR1 premutation, penetrance of POI, thyroid disease and chronic muscle pain is 18.6, 15.9 and 24.4%, respectively. The knowledge of this data might be useful for accurate genetic counselling as well as for a better characterization of the clinical phenotypes of FMR1 premutation carriers.     

Targeted deletion of Nm23/nucleoside diphosphate kinase A and B reveals their requirement for definitive erythropoiesis in the mouse embryo

The ubiquitously expressed nucleoside diphosphate kinases (Nm23/NDPK/Awd) are a large family of multifunctional enzymes implicated in nucleic acid metabolism and in normal and abnormal development. Here, we describe the generation and characterization of NDPK A‐ and B‐deficient (Nme1^?/?/Nme2^?/?) mice in which >95% of the enzyme activity is eliminated. These mice are undersized, die perinatally, and exhibit a spectrum of hematological phenotypes including severe anemia, impaired maturation of erythrocytes, and abnormal hematopoiesis in the liver and bone marrow. Flow cytometric analysis of developing Nme1^?/?/Nme2^?/? erythroid cells indicated that the major iron transport receptor molecule TfR1 is attenuated concomitant with a reduction of intracellular iron, suggesting that TfR1 is a downstream target of NDPKs and that reduced iron in Nme1^?/?/Nme2^?/? erythroblasts is inhibiting their development. We conclude that Nm23/NDPKs play critical roles in definitive erythroid development. Our novel mouse model also links erythropoiesis and nucleotide metabolism. Developmental Dynamics 238:775–787, 2009. © 2009 Wiley‐Liss, Inc.     

p.R254Q mutation in the aquaporin‐2 water channel causing dominant nephrogenic diabetes insipidus is due to a lack of arginine vasopressin‐induced phosphorylation

Vasopressin regulates human water homeostasis by re‐distributing homotetrameric aquaporin‐2 (AQP2) water channels from intracellular vesicles to the apical membrane of renal principal cells, a process in which phosphorylation of AQP2 at S256 by cAMP‐dependent protein kinase A (PKA) is thought to be essential. Dominant nephrogenic diabetes insipidus (NDI), a disease in which the kidney is unable to concentrate urine in response to vasopressin, is caused by AQP2 gene mutations. Here, we investigated a reported patient case of dominant NDI caused by a novel p.R254Q mutation. Expressed in oocytes, AQP2‐p.R254Q appeared to be a functional water channel, but was impaired in its transport to the cell surface to the same degree as AQP2‐p.S256A, which mimics non‐phosphorylated AQP2. In polarized MDCK cells, AQP2‐p.R254Q was retained and was distributed similarly to that of unstimulated wt‐AQP2 or AQP2‐p.S256A. Upon co‐expression, AQP2‐p.R254Q interacted with, and retained wt‐AQP2 in intracellular vesicles. In contrast to wild‐type AQP2, forskolin did not increase AQP2‐p.R254Q phosphorylation at S256 or its translocation to the apical membrane. Mimicking constitutive phosphorylation in AQP2‐p.R254Q with the p.S256D mutation, however, rescued its apical membrane expression. These date indicate that a lack of S256 phosphorylation is the sole cause of dominant NDI here, and thereby, p.R254Q is a loss of function instead of a gain of function mutation in dominant NDI. © 2009 Wiley‐Liss, Inc.     

Cross-Language Differential Item Functioning of the Job Content Questionnaire Among European Countries: The JACE Study

Background  Little is known about cross-language measurement equivalence of the job content questionnaire (JCQ) Purpose  The purposes of this study were to assess the extent of cross-language differential item functioning (DIF) of the 27 JCQ items in six languages (French, Dutch, Belgian-French, Belgian-Dutch (Flemish), Italian, and Swedish) from six European research centers and to test whether its effects on the scale-level mean comparisons among the centers were substantial or not. Method  A partial gamma coefficient method was used for statistical DIF analyses where the Flemish JCQ was the reference for other language versions. Additionally, equivalence between the Flemish and Dutch translations was subjected to a judgmental review. Results  On average, 36% to 39% of the total tested items appeared to be cross-language DIF items in the statistical analyses. The judgmental review indicated that half of the DIF items may be associated with translation difference. The impacts of the DIF items on the mean comparisons of the JCQ scales between the centers were non-trivial: underestimated skill discretion (Milan), underestimated decision authority (Leiden), underestimated psychological demands (Milan women), and incomparable coworker support (Gothenburg 95). Conclusion  Cross-language DIF of the JCQ among European countries should be considered in international comparative studies on psychosocial job hazards using JCQ scales.

Health-related quality of life 3 years after high-dose intensity-modulated radiotherapy with gold fiducial marker-based position verification

OBJECTIVE

To evaluate the change in quality of life (QoL) 3 years after high‐dose intensity‐modulated radiotherapy (IMRT) using gold fiducial marker‐based position verification in patients with locally advanced prostate cancer.

PATIENTS AND METHODS

Between October 2003 and November 2004, 95 patients with locally advanced prostate cancer were treated with 76 Gy IMRT with gold‐fiducial marker‐based position verification. Before treatment (baseline) and 1, 6 and 36 months after RT the QoL was measured using the RAND‐36, the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ‐C30(+3)) and the prostate tumour‐specific module (EORTC QLQ‐PR25). Changes in QoL with time of ≥10 points were considered clinically relevant.

RESULTS

After 3 years there was a statistically significant improvement in QoL for emotional role restriction and functioning, change in health, mental health and insomnia, compared with baseline. Emotional role restriction increased by >10 points and was therefore clinically relevant, while all other differences were of <10 points. There was a statistically significant deterioration of QoL after 3 years in physical and cognitive functioning, bowel symptoms/function and sexual activity. Only the sexual activity QoL score changed by 12 points and was therefore the only meaningful deterioration in QoL at 3 years after treatment.

CONCLUSION

IMRT and accurate position verification provide the possibility to deliver a high irradiation dose to the prostate without clinically relevant deterioration in long‐term QoL, except for a persistent decrease in sexual activity score.     

Associations evoked during memory encoding recruit the context-network

An extensive cortical network consisting of structures in the medial temporal lobe (hippocampus and parahippocampal cortex), lateral parietal cortex, retrosplenial cortex, and medial prefrontal cortex has recently attracted attention in cognitive neuroscience research, linking the network to both episodic memory and spatial processing. It has been suggested that its function may be best characterized as supporting the processing of contextual associations (context network). In this study, we explored whether the role of this network in contextual processing extends to associations that are evoked in a spontaneous manner. In a novel memory encoding task, participants indicated whether they encoded pictures (objects and novel faces) based on an evoked association or based on a perceptual feature. Memory encoding with subjective associations enhanced memory formation relative to feature-based encoding, and this effect was more pronounced for rapidly evoked associations. Functional magnetic resonance imaging during encoding yielded significant activations in all regions of the context network, i.e., medial prefrontal cortex, lateral parietal cortex, retrosplenial cortex, and posterior medial temporal lobe for the associative vs. feature-based comparisons. The low number of misses did not permit the analysis of a subsequent memory contrast. Our data suggest that the context network, which includes the posterior hippocampus and parahippocampal cortex, might support the linkage of external stimuli to long-term memory representations.     

Investigating the stabilising and mobilising features of footedness

This study investigated lower limb laterality for stabilising and mobilising actions in 10 right- and 10 mixed-footed participants by determining, via the Waterloo Footedness Questionnaire--Revised (WFQ-R), the preferred foot in carrying out a range of stabilising and mobilising activities and by recording foot performance on standing balance and ball juggling. The log odds ratio (lambda score) was used to quantify the degree of laterality in task performance. Differences between the stability and mobility scores and the two groups were analyzed using a 2 (Group) x 2 (Task) ANOVA model with repeated measures on Task. Right- and mixed-footed participants differed significantly in the stability but not in the mobility items of the WFQ-R. No significant between-group differences were noted in either ball-juggling or standing balance performance. Mixed-footed participants had a significant right-left foot difference in standing balance, whereas both groups had a significant right-left foot difference in ball juggling. It is concluded that preference is not a steady attribute across the mobility and stability items of the WFQ-R and appears to be dependent on the behavioural context of a particular task. Results further indicated a lack of concordance between questionnaire and performance-based measures suggesting that these two methods of measuring laterality may be indicators of different underlying factors.     

Dynamic changes of ictal high-frequency oscillations in neocortical epilepsy: using multiple band frequency analysis

PURPOSE: To characterize the spatial and temporal course of ictal high-frequency oscillations (HFOs) recorded by subdural EEG in children with intractable neocortical epilepsy. METHODS: We retrospectively studied nine children (four girls, five boys; 4-17 yr) who presented with intractable extrahippocampal localization-related epilepsy and who underwent extraoperative video subdural EEG (1000 Hz sampling rate) and cortical resection. We performed multiple band frequency analysis (MBFA) to evaluate the frequency, time course, and distribution of ictal HFOs. We compared ictal HFO changes before and after clinical onset and postsurgical seizure outcomes. RESULTS: Seventy-eight of 79 seizures showed HFOs. We observed wide-band HFOs ( approximately 250 Hz, approximately 120 electrodes) in six patients either with partial seizures alone (three patients) or with epileptic spasms (three patients). Three patients with partial seizures that secondarily generalized had wide-band HFOs ( approximately 170 Hz) before clinical onset and sustained narrow-band HFOs (60-164 Hz) with electrodecremental events after clinical onset ( approximately 28 electrodes). In four postoperatively seizure-free patients, more electrodes recorded higher-frequency HFOs inside the resection area than outside before and after clinical seizure onset. In five patients with residual seizures, electrodes recorded more HFOs that were of higher or equal frequency outside the surgical area than inside after clinical onset. CONCLUSION: For partial seizures alone and epileptic spasms, more electrodes recorded only wide-band HFOs; for partial seizures that secondarily generalized, fewer electrodes recorded wide-band HFOs, but in these seizures electrodes also recorded subsequent sustained narrow-band ictal HFOs. Resection of those brain regions having electrodes with ictal, higher HFOs resulted in postsurgical seizure-free outcomes.     

Clinical and MRI correlates of autoreactive antibodies in multiple sclerosis patients

BACKGROUND: Autoreactive antibodies (ARAB) occur more frequently in patients with multiple sclerosis (MS) than in general population and the presence of these antibodies often causes uncertainty regarding the disease course, response to therapy and the diagnosis of MS. METHODS: Retrospective analyses of the ARAB, clinical and MRI data of a consecutive patient cohort of MS and clinically isolated syndrome (CIS) patients were conducted. The patients were evaluated for an extensive panel that included various subtypes of antiphospholipid antibody (APLA) including anti-phosphatidylethanolamine (APE), anti-phosphatidylserine (APS), anti-beta-2-glycoprotein-1 (ABGP), anti-cardiolipin (ACA), and several other ARAB such as antinuclear antibody (ANA), anti-neutrophilic cytoplasmic antibodies (ANCA), anti-thyroid peroxidase antibodies (ATA), anti-SS-A, and anti-SS-B antibodies. Quantitative MRI analysis was performed in a subgroup of MS patients measuring T2-lesion volume (LV), T1 black hole LV and brain parenchymal fraction (BPF). RESULTS: A total of 137 patients (mean age 44.7, 84% female) with either MS (n=111; age: mean 46.5+/-S.D. 10.3 years; disease duration: mean 13.0+/-S.D. 10.4 years; EDSS: mean 3.2+/-S.D. 1.9) or CIS (n=26; age: mean 37.7+/-S.D. 7.8 years; disease duration: mean 1.3+/-S.D. 1.1 years; EDSS: mean 1.0+/-S.D. 0.7) were enrolled. Among MS patients, 82 were RRMS, 26 SPMS, and 3 had PPMS. Seventy-seven (69%) of MS patients showed presence of one or more ARAB. The proportion of MS patients with APLA was 55% (61 patients); IgM subtype was most frequent. Co-occurrence of ACA and APE was more frequent in SPMS as compared to RRMS (15.4% vs. 1.2%, p=0.012). The proportion of CIS patients with ARAB was 75% with IgM subtype being the most frequent. However, the ARAB in majority of CIS patients (9 out of 14, 64%) were transient on repeated testing. In a subgroup of 62 MS patients, quantitative MRI analysis showed significantly higher T2-LV in patients with positive APLA (15.1 ml for APLA positive vs. 6.75 ml for APLA negative) after correcting for the disease duration (p=0.048). The patients with ATA also had significantly higher T2-LV after correction for disease duration (19.0 ml vs.8.5, p=0.044). CONCLUSIONS: ARAB were present in more than two thirds of MS and CIS patients although most of APLA in CIS were transient. The presence of APLA in MS patients was associated with higher T2-LV.