RESUMEN

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.

Asunto(s)

RESUMEN

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.

Asunto(s)

RESUMEN

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.

Asunto(s)

RESUMEN

OBJECTIVES: 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. METHODS: 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. RESULTS: 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.

Asunto(s)

RESUMEN

INTRODUCTION AND AIM: Tinnitus is a common condition affecting approximately 20% of the older population. There is increasing evidence that changes in the central auditory system following cochlear malfunctioning are responsible for tinnitus. To date, few investigators have studied the influence of genetic factors on tinnitus. The present report investigates the presence of a familial effect in tinnitus subjects. METHODS: In a European multicentre study, 198 families were recruited in seven European countries. Each family had at least 3 siblings. Subjects were screened for causes of hearing loss other than presbyacusis by clinical examination and a questionnaire. The presence of tinnitus was evaluated with the question "Nowadays, do you ever get noises in your head or ear (tinnitus) which usually last longer than five minutes". Familial aggregation was tested using three methods: a mixed model approach, calculating familial correlations, and estimating the risk of a subject having tinnitus if the disorder is present in another family member. RESULTS: All methods demonstrated a significant familial effect for tinnitus. The effect persisted after correction for the effect of other risk factors such as hearing loss, gender and age. The size of the familial effect is smaller than that for age-related hearing impairment, with a familial correlation of 0.15. CONCLUSION: The presence of a familial effect for tinnitus opens the door to specific studies that can determine whether this effect is due to a shared familial environment or the involvement of genetic factors. Subsequent association studies may result in the identification of the factors responsible. In addition, more emphasis should be placed on the effect of role models in the treatment of tinnitus.

Asunto(s)

RESUMEN

OBJECTIVE: This study examines whether parental Expressed Emotion (EE) ratings, based on the Camberwell Family Interview (CFI), are predictive of the course of illness in a sample of Dutch families with an adolescent eating disorder patient. Levels of EE at first assessment and at the termination of treatment are reported. METHOD: The study was designed as a prospective follow-up study and involved 49 adolescent eating disorder patients (DSM-III-R) and their parents. Patient and family assessments were conducted at intake (T1), at the termination of treatment (T2), and at follow-up (T3) 1 year later. The Morgan-Russell Outcome Assessment Schedule, which was adjusted to accommodate bulimics, yielded the average outcome score (AOS) which served as our outcome measure. RESULTS: The levels of parental EE at first assessment were low. During the treatment period the levels decreased further. We used a stepwise multiple regression analysis, with the parental EE variables as independent variables, to predict the AOS at T2 and T3. This way we showed that the mothers' Critical Comments (CC) rating explained 28 to 34% of the outcome variance. The mothers' CC rating was also the best predictor of outcome when compared to other possible predictor variables. DISCUSSION: The results underscore the importance of involving the family in the treatment of adolescent eating disorders. Specific attention should be given to the mother's thoughts, feelings, and behavior concerning her ill daughter. Helping the mother and daughter to differentiate and separate through a constructive noncritical approach to the presenting problems may be a crucial factor in breaking through the perpetuating cycle of criticism and illness.

Asunto(s)

Asunto(s)

RESUMEN

The present study was designed to investigate whether the metabolism of the opiate analgesic alfentanil in humans is subject to the debrisoquine 4-hydroxylation polymorphism. The role of a specific cytochrome P-450 form, debrisoquine 4-hydroxylase, in the metabolism of alfentanil was investigated by competitive inhibition experiments over the concentration range 4-100 microM. Alfentanil was incubated with human liver microsomes in the presence of an NADPH-generating system. Alfentanil and its major metabolites were quantified in the incubates by reversed phase high-performance liquid chromatography (HPLC). Alfentanil was rapidly metabolized, yielding noralfentanil as the main metabolite. Kinetically, alfentanil metabolism occurred monophasically and the kinetic parameters were 22.8 microM for Km app and 3.86 nmol alfentanil metabolized min-1.mg protein-1 for Vm app. Debrisoquine was a weak, noncompetitive inhibitor of alfentanil metabolism and of the formation of its major metabolites, with Ki values between 2.00 and 3.21 mM. It can be concluded that alfentanil is not metabolized in vitro by the human cytochrome P-450 form involved in debrisoquine 4-hydroxylation; therefore, the in vivo disposition of the drug is most likely not affected by deficiency of this enzyme.

Asunto(s)

Asunto(s)