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Abstract. Over the years, projective tests lost their power and became the target of criticism. The methods were old, not supported by any powerful evidence, and were ridiculed in cartoons, movies, and popular media. It is difficult for clinicians to deal with these criticisms. A difficulty often heard among clinicians who are proficient in personality assessment is how to cope with skepticism and preconceptions in the use of projective methods. Working in a forensic setting and a residential setting for people with severe personality disorders challenged us on how to implement the Rorschach in our daily work as assessors, teachers, and supervisors. In this article we describe our journey in trying to work collaboratively with our clients, management staff, colleagues, and students in the use of projective methods. Although research overall shows that multimethod assessment is the gold standard, daily practice shows differently. The use of semi-structured self-report methods seems to be more popular, and these are perceived as more evidence-based. We compare the implementation of the Rorschach in an evidence-based setting with the implementation of a new therapeutic model from a heuristic point of view ( Hutsebaut et al., 2012 ).

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): 1.Flanders Research Foundation- FWO (doctoral research grant) 2.UZA Foundation-Wolvenbos Grant 2019 Background Anthracycline chemotherapy is a cornerstone in the treatment of several malignancies. However, it causes substantial toxicity, of which cardiotoxicity is the most frequent and most severe (1). Ideally, patients at risk for cardiotoxicity are identified prior to treatment, however, traditional patient- and treatment-related factors fail to fully predict the individual risk at the moment. Improved risk stratification for ANT-induced cardiotoxicity could possibly be reached by taking genetic risk factors into account. Purpose We assessed the prevalence of variants in genes encoding for cardiac proteins in the development of anthracycline-induced cardiotoxicity. Methods Patients presenting with early (< 1y) or late (> 1y) anthracycline-induced cardiotoxicity between 1995 and 2020 were included. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) to Results Forty-two patients that had developed cardiotoxicity (mean age at time of diagnosis 54yrs) fulfilled the inclusion criteria and agreed to genetic testing. The majority of patients had been treated for lymphoma (52.4%) or breast cancer (38.1%). Total equivalent dose of anthracyclines averaged 285.5 mg/m² doxorubicin. Patients showed an average reduction in LVEF of 27.1% (+- 10.1). In 18 patients (42.9 %), a variant could be identified; 15 patients carried a variant of unknown significance (VUS) and 3 carried a likely pathogenic variant. In total 29 variants different variants were identified in 18 distinct individuals. Genetic yield was independent of anthracycline-dose and the presence of other cardiovascular risk factors. The genetic yield in cardiotoxicity patients did not differ significantly from this in DCM-controls (18/42 VUS, 5/42 (likely) pathogenic variants, p = 0.19). After initiation of standard heart failure therapy, 6 (33.3%) of variant carriers showed incomplete recovery of cardiac function, compared to only 3 (12.5%) of patients who did not carry a variant (p=0.103). Conclusion Prevalence of genetic variants in anthracycline-induced cardiotoxicity is similar to that in isolated dilated cardiomyopathy. This finding supports a second-hit mechanism in which anthracycline chemotherapy, uncovers a genetically determined cardiomyopathy. As such, genetic variants in cardiomyopathy genes could improve individualized risk stratification prior to anthracycline chemotherapy and can assist in personalized prevention of this feared side effect of chemotherapy.

The current study assessed the effect of mitral regurgitation (MR) on thrombotic risk in nonrheumatic atrial fibrillation (AF). AF carries a thrombotic risk related to left atrial blood stasis. The prevalence of atrial thrombosis, defined as the presence of left atrial appendage thrombus and/or left atrial spontaneous echo contrast grade2, was determined in 686 consecutive nonrheumatic AF patients without (adequate) anticoagulation scheduled for transesophageal echocardiography before electrical cardioversion and was related to the severity of MR adjusted for the CHA

Experimental investigations on the uptake of divalent cations (Sr, Co and Zn) onto illite (Illite du Puy, Le-Puy-en-Velay, France) were carried out by three different international research groups (Institute for Nuclear Waste Disposal, KIT (Germany), Group Waste & Disposal, SCK-CEN, (Belgium) and Laboratory for Waste Management, PSI (Switzerland)) in the framework of the European FP7 CatClay project. The dependence of solid-liquid distribution ratios (Rd values) on pH at trace metal conditions (sorption edges) and on the metal ion concentration (sorption isotherms) was determined in dilute suspensions of homo-ionic Na-illite (Na-IdP) under controlled N2 atmosphere. The experimental results were modelled using the 2 Site Protolysis Non Electrostatic Surface Complexation and Cation Exchange (2SPNE SC/CE) sorption model. The sorption of Sr depends strongly on ionic strength, while a rather weak pH dependence is observed in a pH range between 3 and 11. The data were modelled with cation exchange reactions, taking into account competition with H, K, Ca, Mg and Al, and surface complexation on weak amphotheric edge sites at higher pH values. The sorption of Co on Na-IdP, however, is strongly pH dependent. Cation exchange on the planar sites and surface complexation on strong and weak amphoteric edge sites were used to describe the Co sorption data. Rd values for Co derived from in-diffusion measurements on compacted Na-IdP samples (bulk-dry density of 1700 kg m−3) between pH 5.0 and 9.0 are in good agreement with the batch sorption data. The equivalence of both approaches to measure sorption was thus confirmed for the present test system. In addition, the results highlight the importance of both major and minor surface species for the diffusive transport behaviour of strongly sorbing metal cations. While surface complexes at the edge sites determine largely the Rd value, the diffusive flux may be governed by those species bound to the planar sites, even at low fractional occupancies. The pH dependent sorption determined for trace Zn concentrations showed large Rd values across the entire pH range with almost no dependence on the background electrolyte concentration. Additional sorption experiments carried out at substantial fractional Zn loadings demonstrated that the selectivity for the exchange of Na+ for Zn2+ at the planar sites could not explain the large Rd values measured at low pH and trace Zn concentrations. This suggests that another mechanism is ruling Zn uptake under these conditions.

Glauconite has a radiocaesium interception potential that is comparable to illite, suggesting that glauconite containing sands may be an effective geological barrier for radiocaesium. However, glauconite is present as coarse pellets (∼0.5 mm diameter) and considerable sorption non-equilibrium may occur during reactive transport in these permeable sands. Here, we analysed trace caesium (Cs) sorption kinetics in agitated batch suspensions to predict reactive transport at variable flow rates in glauconite containing sands. Batch sorption experiments showed that Cs+ sorption KD values in agitated suspension of glauconite sand of the Diest Fm (Dessel Member) increased by a factor 6 to 8 between 48 h and 94 days at trace Cs+ concentration (∼10−9 M). A breakthrough (BT) experiment was set up with 13 packed columns of the same Fm that were leached with 10−6 M Cs+ at variable flow rates equivalent to water residence times 0.07–3.4 days for a duration of 154 days. The BT was observed in treatments with the higher flow rates after 890–1170 pore volumes. The breakthrough expressed in pore volumes revealed earlier breakthrough at only the highest flow rate, indicating chemical non-equilibrium in that treatment. The BT curves were modelled with HP1 (Hydrus-PhreeqC), thereby relying on batch data obtained at 90 days and assuming local reaction equilibrium. The BT curves were well predicted with this model, corroborating local equilibrium except at the highest flow rates. It is concluded that Cs+ sorption on highly permeable glauconite sands is sufficiently fast to delay breakthrough with flow rates below 2.4 m d−1. Only in high flow rate, unrealistic for the Neogene and Paleogene formations, early breakthrough could occur.

The Neogene-Paleogene glauconite sands are investigated for radionuclide sorption in the framework of the Belgian radioactive waste disposal program. This study was set up to measure the adsorption of radiostrontium (85Sr) on the sands and on glauconite fractions to identify factors explaining variable sorption among different formations. Batch 85Sr sorption experiments were set up with 45 different glauconite sands and glauconite fractions (125-250 μm) in a background solution of 1 mM CaCl2.H2O and 0.5 mM KCl. The distribution coefficients (KD) for 85Sr2+ ranged 23-65 L kg-1 for the intact sands and ranged 50-144 L kg-1 for the glauconite fractions. The KD values strongly correlated with the CEC (R2 = 0.62 for sands and 0.82 for glauconite fractions) and corresponded well with CEC based predictions based on two existing models calibrated to soils. The KD on the complete sand is proportional to the glauconite content and the KD of the glauconite fraction if no other clay minerals are present in significant amounts. Sorption equilibrium was reached within 48 h in the complete sands, in milled complete sands, in glauconite fractions and in milled glauconite fractions, suggesting no diffusive boundaries in the glauconite pellets. It is concluded that glauconite sands have a suitably high retention of radiostrontium and the sorption strength is in line with that of other geological barriers when judged from the CEC. ispartof: JOURNAL OF ENVIRONMENTAL RADIOACTIVITY vol:233 ispartof: location:England status: published

Enhanced mass transfer rates have been frequently observed in diffusion studies with alkaline and earth alkaline elements in compacted clay minerals and clay rocks. Whether this phenomenon – often termed surface diffusion – is also relevant for more strongly sorbing species is an open question. We therefore investigated the diffusion of Sr 2+ , Co 2+ and Zn 2+ in compacted illite with respect to variations of the concentration of the background electrolyte, pH and carbonate. New experimental techniques were developed in order to avoid artefacts stemming from the confinement of the clay sample. A distinct dependence of the effective diffusion coefficients on the concentration of the background electrolyte was observed for all three elements. A similar correlation was found for the sorption distribution ratio ( R d ) derived from tracer breakthrough in the case of Sr 2+ , while this dependence was much weaker for Co 2+ and Zn 2+ . Model calculations using Phreeqc resulted in a good agreement with the experimental data when it was assumed that the cationic species, present in the electrical double layer (EDL) of the charged clay surface, are mobile. Species bound to the specific surface complexation sites at the clay edges were assumed to be immobile. An assessment of the mobility of the type of cationic elements studied here in argillaceous media thus requires an analysis of their distribution among specifically sorbed surface species and species in the EDL. The normal approach of deriving unknown effective diffusion coefficients from reference values of an uncharged water tracer may significantly underestimate the mobility of metal cations in argillaceous media.

Sudden cardiac death (SCD) has an enormous impact on those who are left behind, evoking strong feelings of anxiety and incomprehension because such a dramatic event was not anticipated. Moreover, over the last decade a prominent genetic contribution to the pathogenesis of SCD has been unveiled. As many inherited cardiac diseases show an autosomal dominant pattern of inheritance, the risk of carrying the same inherited predisposition is a real concern for the relatives. In this article, we discuss the major causes of primary electrical disorders, cardiomyopathies and thoracic aortic dissection and address issues in genotype-phenotype correlation, personalized management and cardiogenetic counselling.

The mitochondrial DNA (mtDNA) is highly variable, containing large numbers of pathogenic mutations and neutral polymorphisms. The spectrum of homoplasmic mtDNA variation was characterized in 730 subjects and compared with known pathogenic sites. The frequency and distribution of variants in protein coding genes were inversely correlated with conservation at the amino acid level. Analysis of tRNA secondary structures indicated a preference of variants for the loops and some acceptor stem positions. This comprehensive overview of mtDNA variants distinguishes between regions and positions which are likely not critical, mainly conserved regions with pathogenic mutations and essential regions containing no mutations at all.

Contaminated riparian soils can release metals to surface water. Periodic waterlogging affects metal mobility but the processes and soil factors governing net trends are not well understood. Experiments were combined with geochemical modelling to identify processes explaining the dynamics of zinc (Zn) in contaminated soils following waterlogging. Samples were collected from 12 Spodosols near streams in a metal-contaminated area and four similar but uncontaminated soils were sampled in a reference area. Air-dried samples were submerged and incubated under N 2 . The soil redox potential decreased from 470 mV initially to approximately 30 mV over 2 months. The pore-water Zn concentrations surprisingly increased over the same period by, on average, a factor of 18 (range 0.6-80; immobilization in one soil only) despite an increase in pH of 1.8 units, on average. Dissolved organic matter (DOM) in the soil solution increased during waterlogging but the observed increase in Zn solubility could not be explained by increased complexation with DOM, because the estimated Zn 2+ activity also increased by a factor of 18 on average (range 0.2-82). Speciation modelling suggests that Zn mobilization during waterlogging results from Fe 2+ displacing sorbed Zn 2+ from particulate organic matter and from dissolution of Zn-bearing Fe/Mn oxyhydroxides. This hypothesis is supported by the significant positive correlation (r = 0.87, n = 13) between the factor change in pore-water Zn concentration and the ratio of dithionite-extractable Fe to organic carbon content. These results show that Fe dynamics are important for predicting the fate of trace metals in anoxic soils.

Otosclerosis is a common form of hearing loss, characterized by disordered bone remodeling in the otic capsule. Within the otosclerotic foci, several immunocompetent cells and immune-modulating factors can be found. Different etiological theories involving the immune system have been suggested. However, a genetic component is clearly present. In large otosclerosis families, seven autosomal-dominant loci have been found, but none of the disease-causing genes has been identified. This study focused on the exploration of the second otosclerosis locus on chromosome 7q34-36 (OTSC2), holding the T-cell receptor beta locus (TRB locus). A significantly lower T-cell receptor-beta (TCR-beta) mRNA expression and percentage of blood circulating TCR-alphabeta(+) T cells was detected in OTSC2 patients compared with controls and patients with the complex form of the disease. Further analysis illustrated more significant disturbances in specific T-cell subsets, including an increased CD28(null) cell population, suggesting a disturbed T-cell development and ageing in OTSC2 patients. These disturbances could be associated with otosclerotic bone remodeling, given the known effects of immunocompetent cells on bone physiology. These data implicate the TRB locus as the causative gene in the OTSC2 region and represent an important finding in the elucidation of the disease pathology.Genes and Immunity advance online publication, 25 February 2010; doi:10.1038/gene.2010.3.

Summary Slow immobilization of trace metals in soil, termed ‘fixation’, affects their natural attenuation but it is still unclear which reactions occur. Twenty-eight soils were selected to assess the role of Fe oxides and carbonates on fixation of Cu, Cd, Zn and Ni. Soils included samples from 2 toposequences (Vietnam, Spain) and 13 European topsoils with different soil characteristics (pH 3.4–7.7). Samples were amended with 250 mg Zn kg−1, 100 mg Cu kg−1, 80 mg Ni kg−1 and 2.5 mg Cd kg−1 as metal salts and incubated for 850 days. Fixation was measured as the increase of the fraction of added metals that were not isotopically exchangeable. Fixation increased with time and was, averaged over all the soils, 43% (Cu), 41% (Zn), 41% (Ni) and 28% (Cd) after 850 days. Metal fixation within samples from each toposequence was generally positively related to total Fe oxide concentration (Fed) for Zn, Ni and Cd. However, the fixation of Cd, Zn and Ni was mainly explained by pH and not by Fed when considering all soils. Fixation of Zn and Cd in soils with pH >7.0 increased with increasing concentrations of carbonates at initial ageing times. Fixed fractions of Zn, Ni and Cd were significantly released when experimentally removing 50% of carbonates by acidification. Fixation of Cu was most poorly related to soil properties. Our data suggest that fixation of Cd, Zn and Ni is related to a pH-dependent diffusion into oxides and that of Cd and Zn also to diffusion and/or coprecipitation in carbonates. Fixation of Ni at neutral pH may also be related to stabilization of precipitates that form readily in soil.

GJB2 (Gap Junction protein beta type 2; Connexin 26, CX26) is known for its contribution to nonsyndromic recessive deafness (NSRD). One particular mutation, 35delG, a deletion of one guanine from a stretch of six leading to a frame shift early in the gene, has a high prevalence in populations from European descent. 35delG testing therefore has become a standard test in genetic diagnostic laboratories. Most of the currently available methods for the detection of 35delG are relatively time consuming, and not suited for high-throughput diagnostic testing. Within this paper we present a real-time PCR genotyping assay based on melting curve analysis, requiring only a single preparation step before the actual analysis. The assay was optimized on a panel of 48 samples with known 35delG genotypes and subsequently tested using a large Belgian population (N = 460) with unknown 35delG status. For the latter set of samples, real-time PCR results were validated with SNAPShot, an assay used in our laboratory for diagnostic purposes. The real-time PCR genotyping method has proven to be highly reliable, rapid, cost-effective, and suitable for high-throughput screening. We believe that this genetic test for 35delG will find widespread applications in the DNA diagnostic field.

Age-related hearing impairment (ARHI) is the most common sensory impairment seen in the elderly. It is a complex disorder, with both environmental as well as genetic factors contributing to the impairment. The involvement of several environmental factors has been partially elucidated. A first step towards the identification of the genetic factors has been made, which will result in the identification of susceptibility genes, and will provide possible targets for the future treatment and/or prevention of ARHI. This paper aims to give a broad overview of the scientific findings related to ARHI, focusing mainly on environmental and genetic data in humans and in animal models. In addition, methods for the identification of contributing genetic factors as well as possible future therapeutic strategies are discussed.

Udgivelsesdato: 2006-Aug BACKGROUND AND AIMS: Perturbation of differentiation of the crypt-villus axis of the human small intestine is associated with several intestinal disorders of clinical importance. At present, differentiation of small intestinal enterocytes in the crypt-villus axis is not well characterised. SUBJECTS AND METHODS: Expression profiling of microdissected enterocytes lining the upper part of crypts or the middle of villi was performed using the Affymetrix X3P arrays and several methods for confirmation. RESULTS: A total of 978 differentially expressed sequences representing 778 unique UniGene IDs were found and categorised into four functional groups. In enterocytes lining the upper part of crypts, cell cycle promoting genes and transcription/translation related genes were predominantly expressed, whereas in enterocytes lining the middle of villi, high expression of cell cycle inhibiting genes, metabolism related genes, and vesicle/transport related genes was found. CONCLUSION: Two types of enterocytes were dissected at the molecular level, the non-absorptive enterocyte located in the upper part of crypts and the absorptive enterocyte found in the middle of villi. These data improve our knowledge about the physiology of the crypt-villus architecture in human small intestine and provide new insights into pathophysiological phenomena, such as villus atrophy, which is clinically important.

Background: Three mutations in the DFNA5 gene have been described in three families with autosomal dominant non-syndromic hearing impairment. Although these mutations are different at the genomic DNA level, they all lead to skipping of exon 8 at the mRNA level. We hypothesise that hearing impairment associated with DFNA5 is caused by a highly unusual mechanism, in which skipping of one specific exon leads to disease that is not caused by other mutations in this gene. We hypothesise that this represents a very specific “gain of function” mutation, with the truncated protein exerting a deleterious new function. Methods: We performed transfection experiments in mammalian cell lines (HEK293T and COS-1) with green fluorescent protein (GFP) tagged wildtype and mutant DFNA5 and analysed cell death with flow cytometry and fluorescence microscopy. Results: Post-transfection death of HEK293T cells approximately doubled when cells were transfected with mutant DFNA5 –GFP compared with wildtype DFNA5–GFP. Cell death was attributed to necrotic events and not to apoptotic events. Conclusion: The transfection experiments in mammalian cell lines support our hypothesis that the hearing impairment associated with DFNA5 is caused by a “gain of function” mutation and that mutant DFNA5 has a deleterious new function.

A novel DFNA5 mutation was found in a Dutch family, of which 37 members were examined. A nucleotide substitution was identified in the splice acceptor site of intron 7, leading to skipping of exon 8 in part of the transcripts. The mutation was found in 18 individuals. Sensorineural hearing impairment was non-syndromic and symmetric. In early life, presumably congenitally, hearing impairment amounted to 30 dB in the high frequencies. Progression was most pronounced at 1 kHz (1.8 dB/year). Speech recognition was relatively good with a phoneme score of about 50% at the age of 70. Onset age was 37 years, and recognition deteriorated by 1.3% per year. The recognition score deteriorated by 1.0% per decibel threshold increase from a mean pure-tone average (PTA at 1, 2 and 4 kHz) of 63 dB onwards. Vestibular function was generally normal. The second mutation identified in the DFNA5 gene results in hearing impairment, similar to that in the original DFNA5 family in terms of pure-tone thresholds, but with more favourable speech recognition.

Valuable techniques to measure effective diffusion coefficients in porous media are an indispensable prerequisite for a proper understanding of the migration of chemical-toxic and radioactive micropollutants in the subsurface and geosphere. The present article discusses possible pitfalls and difficulties in the classical through-diffusion technique applied to situations where large diffusive fluxes of cations in compacted clay minerals or clay rocks occur. The results obtained from a benchmark study, in which the diffusion of 85 Sr 2 + tracer in compacted illite has been studied using different experimental techniques, are presented. It is shown that these techniques may yield valuable results provided that an appropriate model is used for numerical simulations. It is further shown that effective diffusion coefficients may be systematically underestimated when the concentration at the downstream boundary is not taken adequately into account in modelling, even for very low concentrations. A criterion is derived for quasi steady-state situations, by which it can be decided whether the simplifying assumption of a zero-concentration at the downstream boundary in through-diffusion is justified or not. The application of the criterion requires, however, knowledge of the effective diffusion coefficient of the clay sample. Such knowledge is often absent or only approximately available during the planning phase of a diffusion experiment.

Studies of tinnitus are often conducted on patient populations presenting for treatment. It is, however, difficult to generalise prevalence numbers and aetiological results from these studies to a healthy, elderly population. The first aim of our study was to determine the prevalence of tinnitus in an otologically screened population between 55 and 65 years old. Secondly, both prevalence and the specific characteristics of tinnitus were compared in subjects with either a flat audiogram, a high-frequency gently sloping audiogram or a high-frequency steeply sloping audiogram.1147 subjects (549 males and 598 females) were recruited through population registers and underwent thorough clinical and audiological examinations. Subjects who reported tinnitus in the general questionnaire about medical history and environmental exposure were invited to complete an additional questionnaire on tinnitus history.The prevalence of tinnitus was 19.3% according to the general questionnaire on medical health and environmental exposure and 11.8% according to the additional detailed tinnitus-specific questionnaire. Furthermore, our results indicate that gender has a significant effect (tinnitus is more common in males than in females), as does audiometric configuration (tinnitus is more common in subjects with a high-frequency steeply sloping audiogram than in subjects with a flat audiogram). Both effects were significant in noise-/solvent-exposed subjects, as well as in non-exposed subjects. Finally, comparison of "tinnitus characteristics" in subjects categorised by audiogram configuration revealed significant differences in loudness, pitch, temporal variability and family history of tinnitus.

Contains fulltext : 53710.pdf (Publisher’s version ) (Closed access) BACKGROUND: Age-related hearing impairment (ARHI) is the most common sensory impairment in older people, affecting 50% of those aged 80 years. The proportion of older people is increasing in the general population, and as a consequence, the number of people affected with ARHI is growing. ARHI is a complex disorder, with both environmental and genetic factors contributing to the disease. The first studies to elucidate these genetic factors were recently performed, resulting in the identification of the first two susceptibility genes for ARHI, NAT2 and KCNQ4. METHODS: In the present study, the association between ARHI and polymorphisms in genes that contribute to the defence against reactive oxygen species, including GSTT1, GSTM1 and NAT2, was tested. Samples originated from seven different countries and were combined into two test population samples, the general European population and the Finnish population. Two distinct phenotypes for ARHI were studied, Z(low) and Z(high), representing hearing in the low and high frequencies, respectively. Statistical analysis was performed for single polymorphisms (GSTM1, GSTT1, NAT2*5A, NAT2*6A, and NAT2*7A), haplotypes, and gene-environment and gene-gene interactions. RESULTS: We found an association between ARHI and GSTT1 and GSTM1 in the Finnish population sample, and with NAT2*6A in the general European population sample. The latter finding replicates previously published data. CONCLUSION: As replication is considered the ultimate proof of true associations in the study of complex disorders, this study provides further support for the involvement of NAT2*6A in ARHI.

Age-related hearing impairment (ARHI) is the most common sensory impairment among the elderly. It is a complex disorder influenced by genetic as well as environmental factors. SNPs in a candidate susceptibility gene, KCNQ4, were examined in two independent Caucasian populations. Two quantitative trait locus (QTL) values were investigated: Zhigh and Zlow, a measure of high and respectively low frequency hearing loss. In the first population, the statistical analysis of 23 genotyped SNPs spread across KCNQ4 resulted in significant p-values for two SNPs for Zhigh—SNP9 (NT_004511:g.11244177A>T) and SNP15 (NT_004511:g.11257005C>T; NP_004691:p.Ala259Ala), and one SNP for Zlow—SNP12 (NT_004511:g.11249550A>T). The linkage disequilibrium (LD) structure of KCNQ4 was subsequently determined in a 34-kb region surrounding the significant SNPs, resulting in three LD-blocks. LD-block 1 contains SNP9 and covers an area of 5 kb, LD-block 2 measures 5 kb and surrounds SNP13 (NT_004511:g.11253513A>G) to SNP18 (NT_004511:g.11257509G>A; NP_004691:p.Thr293Thr), and LD-block 3 spans 7 kb. Five tag-SNPs of block 1 and 2, and 2 extra SNPs were subsequently genotyped in the second population. Again, several SNPs were positively associated with ARHI: one SNP (SNP18) for the high frequencies and three SNPs (SNP9, SNP12, and SNP18) for the low frequencies, although only a single SNP (SNP12) resulted in significant p-values in both populations. Nevertheless, the associated SNPs of both populations were all located in the same 13-kb region in the middle of the KCNQ4 gene. Hum Mutat 27(10), 1007–1016, 2006. © 2006 Wiley-Liss, Inc.

Nearly all genes for autosomal recessive nonsyndromal inherited hearing loss (ARNSHL) localized thus far cause prelingual severe to profound or profound hearing impairment. Of the 25 reported loci, most have been identified using single consanguineous families. Six of these genes have been cloned and encode a variety of proteins, including ion channels, extracellular matrix components, cytoskeletal components, and proteins essential for synaptic vesicular trafficking. One of these genes appears to be responsible for approximately 50% of all congenital severe to profound or profound hearing loss in many world populations, and mutations in two other genes can lead to either syndromic or nonsyndromic forms of deafness. The identification of additional genes that cause ARNSHL and elucidation of their function will refine our understanding of auditory physiology at the molecular level.

A gene for an autosomal dominant form of progressive sensorineural hearing loss (DFNA5) was previously assigned by us to a 15-cM region on chromosome 7p15. In this study, the DFNA5 candidate region was refined to less than 2 cM, and completely cloned in a YAC contig. The HOXA1 gene located in 7p15 was considered to be a good candidate gene for DFNA5 as it harbours mutations leading to developmental defects of the inner ear in mice. However, the refinement of the candidate region of DFNA5 excludes the HOXA1 gene as a candidate for DFNA5. We cloned a novel candidate gene (CG1, candidate gene 1), which is expressed in human fetal cochlea, from the DFNA5 candidate region. The complete cDNA sequence of CG1, encoding a 423 amino acid protein of unknown function, was determined. Mutation analysis of the CG1 gene in DFNA5 patients, however, could not reveal a disease-causing mutation.

We performed linkage analysis in a Belgian family with autosomal dominant midfrequency hearing loss, which has a prelingual onset and a nonprogressive course in most patients. We found LOD scores >6 with markers on chromosome 11q. Analysis of key recombinants maps this deafness gene (DFNA12) to a 36-cM interval on chromosome 11q22-24, between markers D11S4120 and D11S912. The critical regions for the recessive deafness locus DFNB2 and the dominant locus DFNA11, which were previously localized to the long arm of chromosome 11, do not overlap with the candidate interval of DFNA12.

The procedures used in the investigation of low back pain and sciatica have been subjected to a double statistical analysis to determine their diagnostic accuracy, since contradictory opinions have been experessed in the literature. It was found that only lumbar phlebography was more accurate than the most simple procedure, the clinical examination. Myelography is more accurate than clinical examination only in making a positive diagnosis. In this case, it equals the reliability of lumbar phlebography, but so does plain film radiography which however leads to a positive diagnosis less constantly. Lumbar phlebography is the most accurate procedure for making a nagative diagnosis, mainly by avoiding a false negative conclusion. A comparison is made with the statements in the literature and the complementary use of the different procedures is proposed for the investigation of low back pain and sciatica.

Fifty to eighty percent of autosomal recessive congenital severe to profound hearing impairment result from mutations in a single gene, GJB2, that encodes the protein connexin 26. One mutation of this gene, the 35delG allele, is particularly common in white populations. We report evidence that the high frequency of this allelic variant is the result of a founder effect rather than a mutational hot spot in GJB2, which was the prevailing hypothesis. Patients homozygous for the 35delG mutation and normal hearing controls originating from Belgium, the UK, and the USA were genotyped for different single nucleotide polymorphisms (SNPs). Four SNPs mapped in the immediate vicinity of GJB2, while two were positioned up to 76 kb from it. Significant differences between the genotypes of patients and controls for the five SNPs closest to GJB2 were found, with nearly complete association of one SNP allele with the 35delG mutation. For the most remote SNP, we could not detect any association. We conclude that the 35delG mutation is derived from a common, albeit ancient founder. Keywords: connexin 26; GJB2; 35delG; founder effect