Loss of the Parkinson's disease-linked gene DJ-1 perturbs mitochondrial dynamics.

Growing evidence highlights a role for mitochondrial dysfunction and oxidative stress as underlying contributors to Parkinson's disease (PD) pathogenesis. DJ-1 (PARK7) is a recently identified recessive familial PD gene. Its loss leads to increased susceptibility of neurons to oxidative stress and death. However, its mechanism of action is not fully understood. Presently, we report that DJ-1 deficiency in cell lines, cultured neurons, mouse brain and lymphoblast cells derived from DJ-1 patients display aberrant mitochondrial morphology. We also show that these DJ-1-dependent mitochondrial defects contribute to oxidative stress-induced sensitivity to cell death since reversal of this fragmented mitochondrial phenotype abrogates neuronal cell death. Reactive oxygen species (ROS) appear to play a critical role in the observed defects, as ROS scavengers rescue the phenotype and mitochondria isolated from DJ-1 deficient animals produce more ROS compared with control. Importantly, the aberrant mitochondrial phenotype can be rescued by the expression of Pink1 and Parkin, two PD-linked genes involved in regulating mitochondrial dynamics and quality control. Finally, we show that DJ-1 deficiency leads to altered autophagy in murine and human cells. Our findings define a mechanism by which the DJ-1-dependent mitochondrial defects contribute to the increased sensitivity to oxidative stress-induced cell death that has been previously reported.

Reconstruction of the palatal aponeurosis with autogenous fascia lata in secondary radical intravelar veloplasty: a new method.

Velopharyngeal insufficiency in cleft patients with muscular insufficiency detected by nasendoscopy is commonly treated by secondary radical intravelar veloplasty, in which the palatal muscles are reoriented and positioned backwards. The dead space between the retro-displaced musculature and the posterior borders of the palatal bone remains problematic. Postoperatively, the surgically achieved lengthening of the soft palate often diminishes due to scar tissue formation in the dead space, leading to reattachment of the reoriented muscles to the palatal bone and to decreased mobility of the soft palate. To avoid this, the dead space should be restored by a structure imitating the function of the missing palatal aponeurosis. The entire dead space was covered using a double layer of autogenous fascia lata harvested from the lateral thigh, which should allow sufficient and permanent sliding of the retro-positioned musculature. A clinical case of a 9-year-old boy who underwent the operation is reported. Postoperatively, marked functional improvements were observable in speech assessment, nasendoscopy and nasometry. The case reported here suggests that the restoration of the dead space may be beneficial for effective secondary palatal repair. Fascia lata seems to be a suitable graft for this purpose.

The tolerance of ambiguity in late cochlear-implanted pre-lingually deaf juveniles.

OBJECTIVES: To examine the ambiguity tolerance, i.e. the ability to perceive new, contradictory and complex situations as positive challenges, of pre-lingually deafened adolescents who received a cochlear implant after their eighth birthday and to identify those dimensions of ambiguity tolerance which correlate significantly with specific variables of their oral communication. DESIGN AND SETTING: Clinical survey at an academic tertiary referral center. PARTICIPANTS AND MAIN OUTCOME MEASURES: A questionnaire concerning communication and subjectively perceived changes compared to the pre-cochlear implant situation was completed by 13 pre-lingually deafened patients aged between 13 and 23 years, who received their cochlear implants between the ages of 8 and 17 years. The results were correlated with the 'Inventory for Measuring Ambiguity Tolerance'. RESULTS: The patients showed a lower ambiguity tolerance with a total score of 134.5 than the normative group with a score of 143.1. There was a positive correlation between the total score for ambiguity tolerance and the frequency of 'use of oral speech', as well as between the subscale 'ambiguity tolerance towards apparently insoluble problems' and all five areas of oral communication that were investigated. Comparison of two variables of oral communication, which shows a significant difference pre- and postoperatively, yields a positive correlation with the subscale 'ambiguity tolerance towards the parental image'. CONCLUSIONS: Pre-lingually deafened juveniles with cochlear implant who increasingly use oral communication seem to regard the limits of a cochlear implant as an interesting challenge rather than an insoluble problem.

Psychiatric comorbidity in patients with spasmodic dysphonia: a controlled study.

OBJECTIVES: To study the prevalence of psychiatric comorbidity assessed by a structured clinical interview in patients with spasmodic dysphonia (SD) compared with patients suffering from vocal fold paralysis (VFP). METHODS: In 48 patients with SD and 27 patients with VFP, overall psychiatric comorbidity was studied prospectively using the Structured Clinical Interview for DSM-IV Axis I disorders. Physical disability and psychometric variables were assessed with standardised self-rating questionnaires. RESULTS: 41.7% of SD subjects and 19.5% of the control group met DSM-IV clinical criteria for current psychiatric comorbidity (p<0.05). Significant predictors of psychiatric comorbidity in SD were severity of voice impairment and subjective assessment of "satisfaction with health". As a limitation, the severity of voice impairment in patients with SD was nearly twice as high, and their illness had lasted nearly twice as long. CONCLUSIONS: We found a high prevalence of psychiatric comorbidity in patients with SD. The significant correlation between current psychiatric comorbidity and the extent of voice pathology may point to an especially strong interaction between somatic and psychiatric complaints in SD.

Decreased left ventricular function, myocarditis, and coronary arteriolar medial thickening following monocrotaline administration in adult rats.

Decreased right as well as left ventricular function can be associated with pulmonary hypertension (PH). Numerous investigations have examined cardiac function following induction of pulmonary hypertension with monocrotaline (MCT) assuming that MCT has no direct cardiac effect. We tested this assumption by examining left ventricular function and histology of isolated and perfused hearts from MCT-treated rats. Experiments were performed on 50 male Sprague-Dawley rats [348 +/- 6 g (SD)]. Thirty-seven rats received MCT (50 mg/kg sc; MCT group) while the remainder did not (Control group). Three weeks later, pulmonary artery pressure was assessed echocardiographically in 20 MCT and 8 Control rats. The hearts were then excised and perfused in the constant pressure Langendorff mode to determine peak left ventricular pressure (LVP), the peak instantaneous rate of pressure increase (+dP/dtmax) and decrease (-dP/dtmax), as well as the rate pressure product (RPP). Histological sections were subsequently examined. Pulmonary artery pressure was higher in the MCT-treated group compared with the Control group [12.9 +/- 6 vs. 51 +/- 35.3 mmHg (P < 0.01)]. Left ventricular systolic function and diastolic relaxation were decreased in the MCT group compared with the Control group (+dP/dtmax 4,178 +/- 388 vs. 2,801 +/- 503 mmHg/s, LVP 115 +/- 11 vs. 83 +/- 14 mmHg, RPP 33,688 +/- 1,910 vs. 23,541 +/- 3,858 beats x min(-1) x mmHg(-1), -dP/dtmax -3,036 +/- 247 vs. -2,091 +/- 389 mmHg/s; P < 0.0001). The impairment of cardiac function was associated with myocarditis and coronary arteriolar medial thickening. Similarly depressed ventricular function and inflammatory infiltration was seen in 12 rats 7 days after MCT administration. Our findings appear unrelated to the degree of PH and indicate a direct cardiotoxic effect of MCT.

Continuous or repeated prolonged cisplatin infusions in children: a prospective study on ototoxicity, platinum concentrations, and standard serum parameters.

BACKGROUND: To overcome the ototoxicity of cisplatin, single bolus infusions were replaced by repeated prolonged infusions of lower doses or by continuous infusions at still lower infusion rates. However, considering ototoxicity little is, in fact, known about the tolerance of repeated prolonged or continuous infusion in children. PROCEDURE: Auditory function was monitored along with plasma concentrations of free and total platinum (Pt), and with standard serum parameters (sodium, potassium, calcium, magnesium, phosphate, chloride, and creatinine) in 24 children receiving cisplatin by continuous infusion for the treatment of neuroblastoma and osteosarcoma or by repeated 1 or 6 hr infusions for the treatment of germ cell tumors. RESULTS: Hearing deteriorated in 10/15 osteosarcoma patients, 2/3 neuroblastoma patients, and 1/6 patients with germ cell tumors. Ototoxicity occurred after cumulative doses between 120 and 360 mg/m(2) cisplatin. In osteosarcoma patients, ototoxicity was associated with a comparatively higher mean plasma concentration of free Pt. However, Pt plasma concentrations did not discriminate between patients with or without ototoxicity. In patients experiencing ototoxicity serum creatinine increased by 45% compared to pre-treatment levels (mean). Serum creatinine increased by 26% in patients without ototoxicity (P < 0.05, Mann-Whitney Rank sum test). Despite standardized hydration, discrete but significant changes of potassium, sodium, magnesium, and phosphate were observed during and/or after cisplatin infusion, which, however, did not discriminate between patients with and without ototoxicity. CONCLUSIONS: While continuous cisplatin infusions are less nephrotoxic than repeated prolonged infusions, we observed considerable ototoxicity in patients treated with continuous cisplatin infusions, which necessitates further evaluations on the tolerance of continuous cisplatin infusions in children.

[The cochlear implant--evolution of hearing and language with an artificial inner ear]. / Das Cochlea-Implantat--Entwicklung von Gehör und Sprache mit einem künstlichen Innenohr.

One of the most spectacular progresses in modern medicine is the possibility to replace a deaf ear, a sensory organ in total by an implantable electronic prosthesis, a so-called cochlear implant (CI). The CI stimulates the auditory nerve by electrical pulses and thus generates the sensation of hearing along the auditory pathway. One of the most impressive aspects of cochlear implantation is the fact that small children with profound deafness who were able a few years ago to learn spoken language only to very limited extent may achieve nowadays an almost normal language development. Duration and intensity of the training of listening and spoken language vary considerably as a function of etiology and time of deafness. Most important for the development of language is sufficient stimulation of the auditory pathway during early childhood. Early diagnosis of a severe to profound deafness is most important in order to fit hearing aids or a cochlear implant without a time delay. Affected children need intensive training by professionals specialized in education and speech therapy. Adults and adolescents who lost their hearing when language acquisition was established may understand spoken language only a few weeks after receiving a cochlear implant. Several individuals are able to use the telephone. Preliminary results after bilateral cochlear implantation of children and adults show advantages. Not only do these subjects report "better hearing with two CI as compared to hearing with one CI," but some of them developed directional hearing in a rather short time lag after fitting the second implant. And in addition they achieve better speech discrimination in environmental noise.

Anti-inflammatory potential of melanocortin receptor-directed drugs.

Melanocortin receptor-based drug discovery is particularly active in the field of neuroendocrine systems and is mostly related to food intake and novel obesity therapies. The immunomodulatory and anti-inflammatory effects of nonpeptidic, low molecular weight compounds activating the melanocortin-1 receptor (MC1R) provide a new principle for treating various types of inflammation, such as dermal, joint, and gastrointestinal, probably by virtue of the effects acting through modulation of proinflammatory and anti-inflammatory cytokines. Several reports demonstrate that alpha-MSH, for example, has anti-inflammatory effects in different models. The aim of our study was to design, synthesize, and characterize compounds that bind to and activate the MC1R in vitro. The binding affinities are submicromolar to this receptor, and activation of the receptor (cAMP assay) varies from full agonists to partial agonists as well as antagonists. In vivo, the compounds exert prominent anti-inflammatory effects, with efficacy in the same range as that of dexamethasone, for example. The potential advantages of MC1R-based anti-inflammatory effects versus glucocorticosteroids, for example, are that the latter, albeit exerting prominent anti-inflammatory effects, also have many side effects that most likely will not characterize an MC1R-based anti-inflammatory drug.

Acoustically and electrically evoked responses of the human cortex before and after cochlear implantation.

Multi-channel auditory evoked potentials (AEP) were recorded before and after cochlear implantation (CI) from a patient suffering from severe high frequency hearing loss with residual, but highly fluctuating hearing around 250 Hz. Immediately after CI activation early components of the N1 were present. Later N1 components developed during the use of CI. The unique result of this single case study is the concordance of the cortical AEP pattern obtained by native and artificial peripheral stimulation, which can be regarded as an indicator for the adequate function of the CI.

Investigation of flow properties of powders by means of a uniaxial tester, in relation to direct tablet compression.

Unexpected poor flowability during commercial production of a direct compression tablet formulation initiated an investigation of the flow properties of the powder mixture and its components by means of a uniaxial tester. The failure function--a curve describing the strength of the powder bed as a junction of the maximum main stress that has consolidated the bed--of the powder mixture and its components was determined. The drug was more cohesive than the filler, which was somewhat more cohesive than the powder mixture. Three excipients--a hinder, a glidant and a lubricant constituting 3.5 w/w% of the formulation improved the flowability of the mixture of active ingredient and filler. The failure function discriminated powder mixtures with poor flow from mixtures with medium or good flow. However, it was not possible to discriminate medium from good flow by means of the failure function. Attempts to correlate univariately the flow property parameters of the powder mixtures with particle size data or flow property data of included active ingredient and filler batches failed. Therefore a multivariate approach was tested. Principal component analysis (PCA) and projection to latent structures by means of partial least squares (PLS) were employed. An excellent PCA model was obtained with the flow properties of the powder mixture. A good PCA model of tableting performance--based on tablet weight variation and tablet machine speed-was obtained.

[Status of hearing aid use by children in schools for the hearing impaired and deaf]. / Zum Stand der Hörgeräteversorgung bei Schülern und Schülerinnen der Schwerhörigen- und Gehörlosenschule.

To evaluate and possibly improve the hearing aid fittings of children attending the Westphalian School for the Hearing Impaired or the Westphalian School for the Deaf, regular pedaudiologic consulting hours were established at both schools. During a 2-year period, 115 children were examined once, 35 children twice, and 5 children three times. The examinations comprised ear microscopy, audiometry, and a check of the hearing aids with a 0.6-cm3 coupler (children up to 7 years) or 2-cm3 coupler, respectively. The following criteria were used to assess the quality of the hearing aid setting: status of the external auditory canal and middle ear, acceptance of wearing the hearing aid, status of the ear mold, technical status of the hearing aid, and its setting. The results were related to four variables: gender, type of school, age, and mean hearing loss. Overall, just 40.9% of all children showed satisfactory hearing aid performance at the first examination and just 37.1% at the second. A significant influence of the variables on the hearing aid performance was documented for hearing loss only. The higher the hearing loss, the more likely the children were to have good hearing aid status. Analysis of the different parameters revealed that an incorrect setting was the main problem, with a rate of 20.9%; the rate of the other parameters varied from 6.1% to 15.7%. Thus, no parameter was of major relevance to the results. The results of the second examination were poorer in most parameters than those of the first. These alarming results, which are probably not only of regional significance, demonstrate that the hearing aid status of children attending schools for the hearing impaired or for the deaf is in urgent need of improvement.

The influence of maxillary central incisor position in complete dentures on /s/ sound production.

STATEMENT OF PROBLEM: The insertion of prosthodontic restorations often leads to speech defects, most of which are transient but nevertheless a source of concern to the patient. For the dental practitioner, there are few guidelines on designing a prosthetic restoration with maximum phonetic success. PURPOSE: This study investigated the effect of different maxillary central incisor positions on phonetic patterns. MATERIAL AND METHODS: The inclination angle of central incisor blocks in duplicate complete maxillary dentures was changed in a range of -30 degrees to +30 degrees from the original position (0 degrees). Test words and sentences were acoustically analyzed. Spectral parameters such as first peak, noise band (defined by upper and lower limits of the most intensively blackened frequency area), Fast Fourier Transformation power spectrum, energy spectrum, and time were investigated. Influences of oral stereognosis, hearing, and age as cofactors on /s/ articulation were also taken into account. RESULTS: The change of incisor block angle in both directions usually caused a poorer execution of the /s/ sound. The labial angulation seemed to have a greater effect than the palatal angulation. The most significant changes were those in the noise band and energy spectrum. CONCLUSION: Immediate phonetic adaptation of prosthetic restorations in the maxillary incisor region can be achieved only if the original position of the natural teeth is transferred to the denture. Although these misarticulations are, in most cases, likely to disappear within a few weeks, they may persist and even lead to psychosocial problems. A better understanding of the causes of misarticulation and the limits of adaptation according to certain morphologic parameters of dentures is important.

The influence of hypothermia on outer hair cells of the cochlea and its efferents.

Transient evoked otoacoustic emissions (TEOAE) were recorded in 21 guinea-pigs undergoing hypothermia. The minimal average body temperature during cooling was 26 degrees C/24.9 degrees C measured orally or rectally, respectively. The animals were subsequently warmed to normal body temperature. A clear influence of body temperature on TEOAE could be documented. During cooling the amplitude and reproducibilities decreased, disappearing completely at a mean temperature below 28.5 degrees C (oral) and 27.3 degrees C (rectal). The emissions reappeared during rewarming at a mean temperature of 30.1 degrees C (oral) and 30.8 degrees C (rectal). Contralateral auditory stimulation (CAS) led to a decrease of the amplitudes of TEOAE during cooling down to a mean of 33 degrees C/32 degrees C (oral/rectal temperature). During rewarming, influences of the CAS could be recognized, again at an oral temperature above 35 degrees C. The changes to the TEOAE observed in these experiments suggest that hypothermia affects not only the outer hair cells (OHC) of the cochlea but also the efferent supply to the cochlea.

A novel locus for autosomal dominant, non-syndromic hearing impairment (DFNA18) maps to chromosome 3q22 immediately adjacent to the DM2 locus.

Investigating a large German pedigree with non-syndromic hearing impairment of early onset and autosomal dominant mode of inheritance, linkage to known DFNA loci was excluded and in a subsequent genomic scan the phenotype was mapped to a 10-cM interval on chromosome 3q22; a maximum two-point lod score of 3.77 was obtained for the marker D3S1292. The new locus, DFNA18, is excluded from neighbouring deafness loci, DFNB15 and USH3, and it overlaps with the recently described DM2/PROMM locus. As hearing loss has been described as one feature of the PROMM phenotype, the DFNA18 gene might also be responsible for hearing loss in DM2/PROMM.

[Voice change and laryngeal obstruction caused by a median thyroglossal duct cyst]. / Stimmveränderung und laryngeale Obstruktion durch eine mediane Halszyste.

Thyroglossal duct cysts are common primary neck tumors, resulting from remnants of the ductus thyroglossus. They can occur at any point along the migratory path of the thyroid gland anlage until the 2nd or 3rd decade of life. The usual symptoms leading to the diagnosis are painless midline neck masses orfistulas. Despite their close proximity, the cysts normally do not affect the larynx. We report on the eighth case mentioned in the world literature of a thyroglossal duct cyst invading the larynx in a 62-year-old patient. Preoperatively, the voice of the patient sounded metallic, and the frequency of the voice field was reduced. Postoperatively, the voice onset was physiological, and the voice increased by an octave in the higher frequencies. The intonation of the voice was steady. The analysis of formants of the vowels "a" and "i" showed that the fourth formant of the vowel "i" was lower in frequency postoperatively.

Glutathione S-transferase genetic polymorphisms and individual sensitivity to the ototoxic effect of cisplatin.

One of the side effects of cisplatin therapy in malignant neoplasms is ototoxicity. This effect shows a wide inter-individual range which is more variable than the pharmacokinetic parameters. Oxidative stress has been implicated in cisplatin ototoxicity. The glutathione S-transferase (GST) supergene family encodes isoenzymes that appear to be critical in protection against oxidative stress. Certain GST loci are polymorphic, demonstrating alleles that are null (GSTM1 and GSTT1), encode low-activity variants (GSTP1) or are associated with variable inducibility (GSTM3). The aim of our study was to investigate genetic risk factors involved in the ototoxicity of cisplatin and to determine whether the polymorphisms in five GST genes affect the individual risk of ototoxicity by cisplatin. Two groups of patients were analyzed in this study: group H, 20 patients early and highly sensitive to the ototoxicity of cisplatin; and group N, 19 patients with no hearing impairment under comparable doses of the drug. We found a protective effect for the GSTM3*B allele with a frequency of 0.18 in the group with normal hearing after therapy versus 0.025 in the group with hearing impairment. (chi2=5.37; p=0.02).