A novel <Emphasis Type="Italic">KCNA1</Emphasis> mutation in a family with episodic ataxia and malignant hyperthermia

Episodic ataxia type 1 (EA1) is an autosomal dominant channelopathy caused by mutations in KCNA1, which encodes the voltage-gated potassium channel, Kv1.1. Eleven members of an EA family were evaluated with molecular and functional studies. A novel c.746T>G (p.Phe249Cys) missense mutation of KCNA1 segregated in the family members with episodic ataxia, myokymia, and malignant hyperthermia susceptibility. No mutations were found in the known malignant hyperthermia genes RYR1 or CACNA1S. The Phe249Cys-Kv1.1 channels did not show any currents upon functional expression, confirming a pathogenic role of the mutation. Malignant hyperthermia may be a presentation of KCNA1 mutations, which has significant implications for the clinical care of these patients and illustrates the phenotypic heterogeneity of KCNA1 mutations.     

Evaluation of knowledge-based reconstruction for magnetic resonance volumetry of the right ventricle after arterial switch operation for dextro-transposition of the great arteries

Right ventricular (RV) volume and function evaluation is essential in the follow-up of patients after arterial switch operation (ASO) for dextro-transposition of the great arteries (d-TGA). Cardiac magnetic resonance (CMR) imaging using the Simpson’s method is the gold-standard for measuring these parameters. However, this method can be challenging and time-consuming, especially in congenital heart disease. Knowledge-based reconstruction (KBR) is an alternative method to derive volumes from CMR datasets. It is based on the identification of a finite number of anatomical RV landmarks in various planes, followed by computer-based reconstruction of the endocardial contours by matching these landmarks with a reference library of representative RV shapes. The purpose of this study was to evaluate the feasibility, accuracy, reproducibility and labor intensity of KBR for RV volumetry in patients after ASO for d-TGA. The CMR datasets of 17 children and adolescents (males 11, median age 15) were studied for RV volumetry using both KBR and Simpson’s method. The intraobserver, interobserver and intermethod variabilities were assessed using Bland–Altman analyses. Good correlation between KBR and Simpson’s method was noted. Intraobserver and interobserver variability for KBR showed excellent agreement. Volume and function assessment using KBR was faster when compared with the Simpson’s method (5.1?±?0.6 vs. 6.7?±?0.9 min, p?<?0.001). KBR is a feasible, accurate, reproducible and fast method for measuring RV volumes and function derived from CMR in patients after ASO for d-TGA.     

In Vitro Study on the Adhesive Performance of Some Resin-Based Materials Used to Restore Class II Cavities

The study aimed to evaluate the adhesive performances of two ormocer materials and two micro-hybrid composites placed to restore class II cavities. We tested the null hypothesis, which considered that the adhesive behaviors of tested materials did not differ. On each extracted tooth, two class II cavities were prepared having an enamel located cervical margin and a cementum located cervical margin, respectively, and were restored using two different restoration techniques. The teeth followed a tooth impregnating protocol and were sectioned and evaluated by optical microscopy to highlight the marginal microleakage around restorations. Cervical and occlusal microleakage as well as microleakage ratios were calculated. The microleakage test showed that all tested materials exhibited some degree of dentinal microleakage both on cervical and occlusal areas irrespective of the restoration technique. Some significant differences were recorded in adhesion performance of the materials. The cervical microleakage ratio was significantly increased for one of the micro-hybrid resin composites in comparison with one of the ormocer materials (p = 0.0159). Significantly differences were observed in occlusal microleakage ratios when the two micro-hybrid composites were compared (p = 0.047). The results failed to reject the null hypothesis. The present study could not demonstrate the superiority of ormocer-materials relative to conventional composites.     

The co-occurrence of multisensory facilitation and cross-modal conflict in the human brain

Perceptual objects often comprise a visual and auditory signature that arrives simultaneously through distinct sensory channels, and cross-modal features are linked by virtue of being attributed to a specific object. Continued exposure to cross-modal events sets up expectations about what a given object most likely "sounds" like, and vice versa, thereby facilitating object detection and recognition. The binding of familiar auditory and visual signatures is referred to as semantic, multisensory integration. Whereas integration of semantically related cross-modal features is behaviorally advantageous, situations of sensory dominance of one modality at the expense of another impair performance. In the present study, magnetoencephalography recordings of semantically related cross-modal and unimodal stimuli captured the spatiotemporal patterns underlying multisensory processing at multiple stages. At early stages, 100 ms after stimulus onset, posterior parietal brain regions responded preferentially to cross-modal stimuli irrespective of task instructions or the degree of semantic relatedness between the auditory and visual components. As participants were required to classify cross-modal stimuli into semantic categories, activity in superior temporal and posterior cingulate cortices increased between 200 and 400 ms. As task instructions changed to incorporate cross-modal conflict, a process whereby auditory and visual components of cross-modal stimuli were compared to estimate their degree of congruence, multisensory processes were captured in parahippocampal, dorsomedial, and orbitofrontal cortices 100 and 400 ms after stimulus onset. Our results suggest that multisensory facilitation is associated with posterior parietal activity as early as 100 ms after stimulus onset. However, as participants are required to evaluate cross-modal stimuli based on their semantic category or their degree of congruence, multisensory processes extend in cingulate, temporal, and prefrontal cortices.     

Clinical spectrum and medical treatment of children with electrical status epilepticus in sleep (ESES)

Purposes:   To describe the clinical spectrum and to evaluate the efficacy of different therapeutic agents in children with electrical status epilepticus in sleep (ESES).
Methods:   Clinical data of all patients with ESES (not including patients with Landau-Kleffner syndrome) in four pediatric neurology outpatient clinics were analyzed. Thirty patients with ESES had been treated between 1994 and 2007.
Results:   Eleven (37%) children had benign partial epilepsies of childhood, five (17%) had cerebral palsy, five (17%) had hydrocephalus, one (3%) had schizencephaly, one (3%) had prenatal parenchymal bleeding, and the etiology was unclear in seven (23%). The duration of ESES ranged between 2 and 60 months. The antiepileptic drugs that were found to be efficacious were: levetiracetam (41%), clobazam (31%), and sulthiame (17%). Valproic acid, lamotrigine, topiramate, and ethosuximide showed no efficacy. Steroids were efficacious in 65%; immunoglobulins were efficacious in 33%. High-dose diazepam was efficacious in 37%, but all the children had temporary response. Seventeen patients (57%) had cognitive deterioration, whereas the rest presented with regression in attention, speech, communication, and behavior. Fourteen children had permanent cognitive deficit. There was a significant correlation (p = 0.029) between the duration of ESES and residual intellectual deficit at follow-up.
Conclusions:   ESES reflects an evolution of benign partial epilepsy of childhood in more than one-third of the patients, whereas there is an underlying structural brain anomaly in another one-third. The most efficacious antiepileptic drugs (AEDs) are levetiracetam and clobazam. The duration of ESES correlated significantly with residual intellectual deficit at follow-up.     

Dihydrosphingosine 1‐phosphate has a potent antifibrotic effect in scleroderma fibroblasts via normalization of phosphatase and tensin homolog levels

Objective

Previous studies have revealed a phosphatase and tensin homolog (PTEN)–dependent interaction between the sphingolipid agonist dihydrosphingosine 1‐phosphate (dhS1P) and the transforming growth factor β/Smad3 signaling pathway. This study was undertaken to examine responses of systemic sclerosis (SSc) fibroblasts to sphingosine 1‐phosphate (S1P) and dhS1P and to gain further insight into the regulation of the S1P/dhS1P/PTEN pathway in SSc fibrosis.

Methods

Fibroblast cultures were established from skin biopsy samples obtained from patients with SSc and matched healthy controls. Western blotting and quantitative polymerase chain reaction were used to measure protein and messenger RNA levels, respectively. PTEN protein was examined in skin biopsy samples by immunohistochemistry.

Results

PTEN protein levels were low in SSc fibroblasts and correlated with elevated levels of collagen and phospho‐Smad3 and reduced levels of matrix metalloproteinase 1 (MMP‐1). Treatment with dhS1P restored PTEN levels and normalized collagen and MMP‐1 expression, as well as Smad3 phosphorylation status in SSc fibroblasts. S1P was strongly profibrotic in SSc and control fibroblasts. Distribution of S1P receptor isoforms was altered in SSc fibroblasts, which had reduced levels of S1P receptor 1 and S1P receptor 2 and elevated levels of S1P receptor 3. Only depletion of S1P receptor 1 abrogated the effects of dhS1P and S1P in control dermal fibroblasts. In contrast, depletion of either S1P receptor 1 or S1P receptor 2 prevented the effects of S1P and dhS1P in SSc fibroblasts.

Conclusion

Our findings demonstrate that PTEN deficiency is a critical determinant of the profibrotic phenotype of SSc fibroblasts. The antifibrotic effect of dhS1P is mediated through normalization of PTEN expression, suggesting that dhS1P or its derivatives may be effective as therapeutic antifibrotic agents. The distribution and function of S1P receptors differ in SSc and healthy fibroblasts, suggesting that alteration in the sphingolipid signaling pathway may contribute to SSc fibrosis.

     

Glycan profiling of anti–citrullinated protein antibodies isolated from human serum and synovial fluid

Objective

Anti–citrullinated protein antibodies (ACPA) exhibit unique specificity for rheumatoid arthritis. However, it is incompletely understood whether and how ACPA contribute to disease pathogenesis. The Fc part of human IgG carries 2 N‐linked glycan moieties that are crucial for the structural stability of the antibody and that modulate both its binding affinity to Fcγ receptors and its ability to activate complement. We undertook this study to analyze Fc glycosylation of IgG1 ACPA in serum and synovial fluid (SF) in order to further characterize the immune response to citrullinated antigens.

Methods

ACPA were isolated by affinity purification using cyclic citrullinated peptides as antigen. IgG1 Fc glycosylation was analyzed by mass spectrometry. ACPA IgG1 glycan profiles were compared with glycan profiles of total serum IgG1 obtained from 85 well‐characterized patients. Glycan profiles of paired SF and serum samples were available from 11 additional patients.

Results

Compared with the pool of serum IgG1, ACPA IgG1 lacked terminal sialic acid residues. In SF, ACPA were highly agalactosylated and lacked sialic acid residues, a feature that was not detected for total SF IgG1. Moreover, differential ACPA glycan profiles were detected in rheumatoid factor (RF)–positive and RF‐negative patients.

Conclusion

ACPA IgG1 exhibit a specific Fc‐linked glycan profile that is distinct from that of total serum IgG1. Moreover, Fc glycosylation of ACPA differs markedly between SF and serum. Since Fc glycosylation directly affects the recruitment of Fc‐mediated effector mechanisms, these data could further our understanding of the contribution of ACPA to disease pathogenesis.

     

Pay for performance: will dentistry follow?

Background  

"Pay for performance" is an incentive system that has been gaining acceptance in medicine and is currently being considered for implementation in dentistry. However, it remains unclear whether pay for performance can effect significant and lasting changes in provider behavior and quality of care. Provider acceptance will likely increase if pay for performance programs reward true quality. Therefore, we adopted a quality-oriented approach in reviewing those factors which could influence whether it will be embraced by the dental profession.