Frederic Acke

Mepolizumab, a humanized anti–IL-5 mAb, as a treatment option for severe nasal polyposis

BACKGROUND Approximately 85% of nasal polyps (NPs) in white subjects are characterized by prominent eosinophilia. IL-5 is the key driver of eosinophilic differentiation and survival. OBJECTIVE We sought to investigate the therapeutic potential of inhibiting IL-5 with a humanized mAb as treatment for severe nasal polyposis. METHODS Thirty patients with severe nasal polyposis (grade 3 or 4 or recurrent after surgery) refractory to corticosteroid therapy were randomized in a double-blind fashion to receive either 2 single intravenous injections (28 days apart) of 750 mg of mepolizumab (n = 20) or placebo (n = 10). Change from baseline in NP score was assessed monthly until 1 month after the last dose (week 8). Computed tomographic scans were also performed at week 8. RESULTS Twelve of 20 patients receiving mepolizumab had a significantly improved NP score and computed tomographic scan score compared with 1 of 10 patients receiving placebo at week 8 versus baseline. CONCLUSION Mepolizumab achieved a statistically significant reduction in NP size for at least 1 month after dosing in 12 of 20 patients. IL-5 inhibition is a potential novel therapeutic approach in patients with severe eosinophilic nasal polyposis.

Local receptor revision and class switching to IgE in chronic rhinosinusitis with nasal polyps

Chronic rhinosinusitis with nasal polyps (NP) and allergic rhinitis (AR) is characterized by local Th2 inflammation and up‐regulation of IgE; however, IgE in NP is ‘polyclonal’ and allergen specific, whereas IgE in AR is ‘oligoclonal’ and allergen specific. Germinal center (GC) reactions occur in AR, while only the formation of GC‐like structures in NP is described. The aim of this study was to investigate the involvement of local IgE production, class switch recombination, and receptor revision in NP.

Cerebral lateralization of praxis in right‐ and left‐handedness: Same pattern, different strength

We aimed to investigate the effect of hand effector and handedness on the cerebral lateralization of pantomiming learned movements. Fourteen right‐handed and 14 left‐handed volunteers performed unimanual and bimanual tool‐use pantomimes with their dominant or nondominant hand during fMRI. A left hemispheric lateralization was observed in the right‐ and left‐handed group regardless of which hand(s) performed the task. Asymmetry was most marked in the dorsolateral prefrontal cortex (DLPFC), premotor cortex (PMC), and superior and inferior parietal lobules (SPL and IPL). Unimanual pantomimes did not reveal any significant differences in asymmetric cerebral activation patterns between left‐ and right‐handers. Bimanual pantomimes showed increased left premotor and posterior parietal activation in left‐ and right‐handers. Lateralization indices (LI) of the 10% most active voxels in DLPFC, PMC, SPL, and IPL were calculated for each individual in a contrast that compared all tool versus all control conditions. Left‐handers showed a significantly reduced overall LI compared with right‐handers. This was mainly due to diminished asymmetry in the IPL and SPL. We conclude that the recollection and pantomiming of learned gestures recruits a similar left lateralized activation pattern in right and left‐handed individuals. Handedness only influences the strength (not the side) of the lateralization, with left‐handers showing a reduced degree of asymmetry that is most readily observed over the posterior parietal region. Together with similar findings in language and visual processing, these results point to a lesser hemispheric specialization in left‐handers that may be considered in the cost/benefit assessment to explain the disproportionate handedness polymorphism in humans. Hum Brain Mapp, 2012.

Prevalence of allergic sensitization versus allergic rhinitis symptoms in an unselected population

Background: Allergic rhinitis (AR) is the most common allergic disorder and its prevalence has significantly increased worldwide, nowadays affecting up to 40% of the population in young adults. The objective of the present survey was to evaluate the prevalence of allergic sensitization and the prevalence of clinically diagnosed AR in a sample of the Belgian population, and to estimate the effect of age and gender. Methods: We performed a cross-sectional population-based study at an annual public fair in Ghent. Participants underwent a skin prick test (SPT) to 3 aeroallergens: a mix of trees (hazel, alder, and birch), grass pollen, and house dust mite (HDM). The clinical relevance of sensitization was assessed by relating relevant symptoms of AR to the corresponding SPT. Results: A total of 2,320 participants (1,475 females, median age 44.7 years, range 3–86) were included in this study. The standardized prevalence rates of sensitization were 13.2% for tree mix, 25.9% for grass pollen, and 25.9% for HDM. Sensitization to at least one of the allergens was present in 40.3% of the subjects. Symptomatic sensitization related to trees was reported in 9.7% of cases, grass-related AR was 17.6%, and HDM-related AR was 17.1%. The overall prevalence of AR was 30.9%. Conclusion: In this study we demonstrated a 40.3% prevalence of a positive SPT to one or more common aeroallergens. A clinical diagnosis of AR was present in 30.9% of cases, peaking in the third and fourth decades of life. It is to be expected that in the next decades, when this generation grows older, the general AR prevalence will further increase.

Tool responsive regions in the posterior parietal cortex: Effect of differences in motor goal and target object during imagined transitive movements

Neuroanatomical and functional studies have proposed a functional segregation of the human dorsal stream into a dorso-dorsal pathway, believed to serve as an object-independent stream involved with on-line control of action, and a ventro-dorsal pathway that provides conceptual input guiding the functional manipulation of objects. We aim to evaluate whether the inferior parietal cortex deals specifically with action reliant on stored knowledge. Fifteen right-handed, normal volunteers varied the intention of their transitive movements by imagining their dominant arm and hand pointing to, grasping to move, grasping to use, or grasping and using three-dimensional representations of target objects depicting graspable neutral shapes, unfamiliar tools, and familiar tools. Imagined movements intended to make functional use of familiar objects revealed increased activation in the left inferior parietal lobule. Compared to gestures aimed at displacing an object, functional (use) intentions elicited activation in the anterior and middle portions of the lateral bank of the intraparietal sulcus, suggesting involvement in the higher order control of action. Compared to functionally unfamiliar objects, grasping movements aimed at familiar tools activated the convex portion of the inferior parietal lobule, suggesting a role for the ventro-dorsal stream in object-selectivity. These data confirm that stored knowledge for the skillful manipulation of familiar tools of right-handed volunteers is predominantly located in the left inferior parietal lobule, and further suggest that tool use-responsive regions and tool object-responsive regions are not identical, but may form a local network in which different nodes contribute differently to the representation of functional tool use in humans.

Hearing impairment in Stickler syndrome: a systematic review.

BackgroundStickler syndrome is a connective tissue disorder characterized by ocular, skeletal, orofacial and auditory defects. It is caused by mutations in different collagen genes, namely COL2A1, COL11A1 and COL11A2 (autosomal dominant inheritance), and COL9A1 and COL9A2 (autosomal recessive inheritance). The auditory phenotype in Stickler syndrome is inconsistently reported. Therefore we performed a systematic review of the literature to give an up-to-date overview of hearing loss in Stickler syndrome, and correlated it with the genotype.MethodsEnglish-language literature was reviewed through searches of PubMed and Web of Science, in order to find relevant articles describing auditory features in Stickler patients, along with genotype. Prevalences of hearing loss are calculated and correlated with the different affected genes and type of mutation.Results313 patients (102 families) individually described in 46 articles were included. Hearing loss was found in 62.9%, mostly mild to moderate when reported. Hearing impairment was predominantly sensorineural (67.8%). Conductive (14.1%) and mixed (18.1%) hearing loss was primarily found in young patients or patients with a palatal defect. Overall, mutations in COL11A1 (82.5%) and COL11A2 (94.1%) seem to be more frequently associated with hearing impairment than mutations in COL2A1 (52.2%).ConclusionsHearing impairment in patients with Stickler syndrome is common. Sensorineural hearing loss predominates, but also conductive hearing loss, especially in children and patients with a palatal defect, may occur. The distinct disease-causing collagen genes are associated with a different prevalence of hearing impairment, but still large phenotypic variation exists. Regular auditory follow-up is strongly advised, particularly because many Stickler patients are visually impaired.

Hearing loss in Waardenburg syndrome: a systematic review

Waardenburg syndrome (WS) is a rare genetic disorder characterized by hearing loss (HL) and pigment disturbances of hair, skin and iris. Classifications exist based on phenotype and genotype. The auditory phenotype is inconsistently reported among the different Waardenburg types and causal genes, urging the need for an up‐to‐date literature overview on this particular topic. We performed a systematic review in search for articles describing auditory features in WS patients along with the associated genotype. Prevalences of HL were calculated and correlated with the different types and genes of WS. Seventy‐three articles were included, describing 417 individual patients. HL was found in 71.0% and was predominantly bilateral and sensorineural. Prevalence of HL among the different clinical types significantly differed (WS1: 52.3%, WS2: 91.6%, WS3: 57.1%, WS4: 83.5%). Mutations in SOX10 (96.5%), MITF (89.6%) and SNAI2 (100%) are more frequently associated with hearing impairment than other mutations. Of interest, the distinct disease‐causing genes are able to better predict the auditory phenotype compared with different clinical types of WS. Consequently, it is important to confirm the clinical diagnosis of WS with molecular analysis in order to optimally inform patients about the risk of HL.

Novel pathogenic COL11A1/COL11A2 variants in Stickler syndrome detected by targeted NGS and exome sequencing

INTRODUCTION Stickler syndrome is caused by mutations in genes encoding type II and type XI collagens. About 85% of the pathogenic variants is found in COL2A1 (Stickler type 1), whereas a minority of mutations has been reported in COL11A1 (Stickler type 2) and COL11A2 (Stickler type 3). Beside the typical skeletal and orofacial manifestations, ocular anomalies are predominantly present in type 1 and type 2, while hearing loss is more pronounced in type 2 and type 3. METHODS We performed COL11A1 mutation analysis for 40 type 2 Stickler patients and COL11A2 mutation analysis for five type 3 Stickler patients, previously all COL2A1 mutation-negative, using targeted next-generation sequencing (NGS) whereas whole-exome sequencing (WES) was performed in parallel for two patients. Three patients were analyzed for both genes due to unclear ocular findings. RESULTS In total 14 COL11A1 and two COL11A2 mutations could be identified, seven of which are novel. Splice site alterations are the most frequent mutation type, followed by glycine substitutions. In addition, six variants of unknown significance (VUS) have been found. Identical mutations and variants were identified with both NGS techniques. CONCLUSION We expand the mutation spectrum of COL11A1 and COL11A2 in Stickler syndrome patients and show that targeted NGS is an efficient and cost-effective molecular tool in the genetic diagnosis of Stickler syndrome, whereas the more standardized WES might be an alternative approach.

Dissemination and implementation of the ARIA guidelines for allergic rhinitis in general practice.

Background: Allergic rhinitis (AR) is a prevalent problem in general practice. The first evidence-based guidelines for AR, the ARIA guidelines, were published and have been updated repeatedly since 2001 in order to improve the care of AR patients. Very limited information, however, is available on the impact of these guidelines on everyday clinical practice. The aim of this study was to evaluate the dissemination and implementation of the ARIA guidelines in general practice. Methods: Three hundred and fifty Flemish general practitioners (GPs) were recruited to complete a questionnaire covering their demographic and professional characteristics, awareness, perception and implementation of the ARIA guidelines. To assess compliance with the ARIA treatment recommendations, 4 fictitious case scenarios of AR were presented, in which the respondents were asked to select the treatment of choice. Results: Of the 350 GPs included, only 31% were aware of the ARIA guidelines and 10% stated that they implement them. For the diagnosis of AR, 71% of the GPs ask specific IgE tests or perform skin prick tests, whereas only 29% perform an anterior rhinoscopy. ARIA users are more likely to screen for concomitant asthma. In the clinical-case section, there was a large variability in proposed therapeutic strategies. Adherence to the evidence-based ARIA treatment guidelines was low, but recent graduation was a significant predictor of compliance with these recommendations. Conclusions: The ARIA guidelines remain relatively unknown among Flemish GPs and even those who are aware of them still tend to treat AR independently of the guideline recommendations.

Etiological approach in patients with unidentified hearing loss

OBJECTIVES Etiological diagnosis of hearing impairment is of great importance to ensure early and adequate management. Even after thorough history taking, clinical and audiometric evaluation, the cause of hearing loss remains unclear in a majority of patients. Further examinations can imply imaging, ophthalmologic investigations, laboratory tests, electrocardiography and genetic testing. Lately, the latter has taken an increasingly prominent place within this diagnostic work-up. However, clear guidelines about optimal implementation and sequence of these tests are required. METHODS Records of patients who visited the consultation for otogenetics at Ghent University Hospital (Belgium) during the period 2006-2012 were retrospectively reviewed. In order to optimize the etiological-diagnostic work-up of unidentified hearing loss, application patterns and results of various diagnostic tests, audiometric and etiological data of each patient were collected and analyzed. RESULTS Data of 191 patients were analyzed. In 81.2% of the patients, a cause of hearing loss could be determined or suspected. In total, 65.4% had a (presumably) genetic etiology, with connexin 26 (GJB2) mutations as the leading cause. Inquiry of risk factors, associated with congenital hearing loss, and pedigree analysis were found to have the highest diagnostic gain (61.3% and 41.8%). Connexin 26 gene mutations were only present in bilateral hearing impairment, whereas CT abnormalities were related to unilateral (P=0.003), profound (P<0.001) hearing loss. An enlarged vestibular aqueduct was present in 42.9% of all CT abnormalities. Ophthalmologic anomalies were detected in 35.7% of the studied patients. CONCLUSIONS A sequential approach for the etiological diagnosis of unidentified hearing loss could determine or suggest a cause in more than 80% of patients. The approach may vary based on the presenting phenotype.