Long-term renal outcome in children with OCRL mutations: retrospective analysis of a large international cohort.

Background: Lowe syndrome (LS) and Dent-2 disease (DD2) are disorders associated with mutations in the OCRL gene and characterized by progressive chronic kidney disease (CKD). Here, we aimed to investigate the long-term renal outcome and identify potential determinants of CKD and its progression in children with these tubulopathies. Methods: Retrospective analyses were conducted of clinical and genetic data in a cohort of 106 boys (LS: 88 and DD2: 18). For genotype-phenotype analysis, we grouped mutations according to their type and localization. To investigate progression of CKD we used survival analysis by Kaplan-Meier method using stage 3 CKD as the end-point. Results: Median estimated glomerular filtration rate (eGFR) was lower in the LS group compared with DD2 (58.8 versus 87.4 mL/min/1.73 m2, P < 0.01). CKD stage II-V was found in 82% of patients, of these 58% and 28% had moderate-to-severe CKD in LS and DD2, respectively. Three patients (3%), all with LS, developed stage 5 of CKD. Survival analysis showed that LS was also associated with a faster CKD progression than DD2 (P < 0.01). On multivariate analysis, eGFR was dependent only on age (b = -0.46, P < 0.001). Localization, but not type of mutations, tended to correlate with eGFR. There was also no significant association between presence of nephrocalcinosis, hypercalciuria, proteinuria and number of adverse clinical events and CKD. Conclusions: CKD is commonly found in children with OCRL mutations. CKD progression was strongly related to the underlying diagnosis but did not associate with clinical parameters, such as nephrocalcinosis or proteinuria.

Reduction of tinnitus severity by the centrally acting muscle relaxant cyclobenzaprine: an open-label pilot study.

Tinnitus, the phantom perception of sounds, is a highly prevalent disorder. Although a wide variety of drugs have been investigated off label for the treatment of tinnitus, there is no approved pharmacotherapy. We report an open-label exploratory pilot study to assess the effect of muscle relaxants acting on the central nervous system on tinnitus patients. Cyclobenzaprine at high (30 mg) and low doses (10 mg), orphenadrine (100 mg), tizanidine (24 mg) and eperisone (50 mg) were administered to a maximum of 20 patients per group over a 12-week period. High-dose cyclobenzaprine resulted in a significant reduction in the Tinnitus Handicap Inventory (THI) score between baseline and week 12 in the intention-to-treat sample. On the other hand, other treatments were not effective. These results were confirmed in an explorative analysis where baseline corrected THI and Clinical Global Impression scores at week 12 were compared between groups. The present open trial presents a new promising pharmacotherapy for tinnitus that should be validated in placebo-controlled double-blind trials.

Transcranial magnetic stimulation for the treatment of depression: feasibility and results under naturalistic conditions: a retrospective analysis.

An increasing number of controlled studies strongly support an antidepressant effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex. However, these data come from highly selected study populations. Whether rTMS is a feasible therapeutic tool for the treatment of depression under naturalistic condition has not yet been addressed. Here, we report results from 232 depressive patients [aged 20-76 years, baseline Hamilton Depression Rating Score (HDRS-21) 24.0 ± 7.3] treated with rTMS add-on to continued psychopharmacological treatment in a naturalistic clinical setting. Two thousand stimuli of 20-Hz rTMS were applied daily over the left dorsolateral prefrontal cortex with an intensity of 110% of motor threshold. Treatment duration was individually planned and varied between 10 and 20 sessions. In average, patients received 13 ± 6.1 rTMS sessions. In 90% of the cases, treatment was terminated regularly. No severe side effects were observed. Only four patients stopped rTMS treatment because of side effects. Ratings with the HDRS-21 before and after treatment were available in 130 patients. The average improvement of the HDRS-21 in this subsample was 9.0 ± 9.2 points. Fifty-three patients had an improvement of 50% or more. These results document that rTMS is feasible, safe and well tolerated under naturalistic conditions.

The Intersection of Urban and Global Health.

Providers from high-income countries are often drawn to practicing medicine in settings identified as having greater need, whether that be in a low- or middle-income country or within an underserved area within their own high-income country. Despite sharing the goal of fostering health equity, global health and urban health are often considered in dichotomous ways. This article points a lens at the intersection of these 2 fields, highlighting what they can learn from each other.

Auditory cortex is implicated in tinnitus distress: a voxel-based morphometry study.

Neuroimaging studies of tinnitus suggest the involvement of wide-spread neural networks for perceptual, attentional, memory, and emotional processes encompassing auditory, frontal, parietal, and limbic areas. Despite sparse findings for tinnitus duration and laterality, tinnitus distress has been shown to be related to changes in non-auditory cortical areas. The aim of this study was to correlate tinnitus characteristics with grey matter volume in two large samples of tinnitus patients. High-resolution brain images were obtained using a 1.5 T magnetic resonance imaging scanner and analysed by means of voxel-based morphometry. In sample one (n = 257), tinnitus distress correlated negatively with grey matter volume in bilateral auditory areas including the Heschl's gyrus and insula, that is, the higher the tinnitus distress the lower the grey matter volume. The effects of this correlation were small, but stable after correction for potential confounders such as age, gender, and audiometric parameters. This negative correlation was replicated in a second independent sample (n = 78). Our results support the notion that the role of the auditory cortex in tinnitus is not restricted to perceptual aspects. The distress observed was dependent on grey matter alterations in the auditory cortex, which could reflect reverberations between perceptual and distress networks.

Treatment of chronic tinnitus with repeated sessions of prefrontal transcranial direct current stimulation: outcomes from an open-label pilot study.

Tinnitus is the perception of sound in the absence of an environmental sound source. Abnormal activity in central auditory pathways is considered as the neuronal correlate of tinnitus. However, there is increasing evidence from neuroimaging studies for an additional involvement of the frontal cortex in the pathophysiology of tinnitus, especially concerning its attentional and emotional aspects. Recently, in a subgroup of tinnitus patients, temporary reduction of tinnitus intensity and tinnitus-related distress has been reported after bifrontal tDCS with the anode over the right and the cathode over the left dorsolateral prefrontal cortex (DLPFC). The aim of this study was to investigate whether repeated application of bifrontal tDCS results in longer-lasting reduction of tinnitus and may represent a potential treatment approach. Thirty-two patients with chronic and treatment-resistant tinnitus received six sessions of bifrontal tDCS (1.5 mA, 30 min, two sessions per week) with the anode over the right and the cathode over the left DLPFC. Treatment outcome was assessed with several standardized tinnitus questionnaires, numeric rating scales, and a depression scale. In the entire group, beneficial effects of bifrontal tDCS on tinnitus were found for numeric rating scores of loudness, unpleasantness, and discomfort, but not in tinnitus or depression scales. Exploratory analysis revealed an effect of gender on treatment effects with female patients demonstrating a better response in several scores. Our open-label pilot study suggests some beneficial effect of bifrontal tDCS (anode right and cathode left) in the treatment of severe tinnitus, warranting further controlled studies.

Modulation of human motor cortex excitability by valproate.

RATIONALE: Valproate is widely used in the treatment of epilepsy, bipolar disorder, and chronic pain disorders, but its exact mechanisms of action is still incompletely understood. OBJECTIVES: Here we used transcranial magnetic stimulation to explore effects of a single dose of 800 mg valproate on motor cortex excitability in healthy volunteers. METHODS: Motor threshold, peripheral maximum M-wave, cortical silent period short intracortical inhibition, intracortical facilitation, and motor evoked potential recruitment were assessed before and 1.5 h after the administration of valproate in 15 (eight male, seven female) healthy volunteers. RESULTS: None of the measures of cortical excitability were found to be altered significantly after valproate. CONCLUSION: These results are in line with previous findings of unaffected intracortical excitability after a single dose of valproate, suggesting that valproate's immediate in vivo actions do not resemble the effects of classic GABAergic compounds.

Transcranial magnetic stimulation for the treatment of tinnitus: 4-year follow-up in treatment responders--a retrospective analysis.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) over the temporal cortex has been proposed as a new approach for the treatment of tinnitus. Even if most studies have shown beneficial effects, there is only limited knowledge about clinical predictors for treatment response and about the duration of treatment effects. OBJECTIVE: In this study, we compared clinical characteristics of rTMS responders and nonresponders and assessed long-term outcome in the responder group. METHOD: Results from 235 patients, who were treated with rTMS because of chronic tinnitus were analysed. Patients received either a standard protocol of low-frequency rTMS (n = 188; 110% motor threshold, 1 Hz, 2000 stimuli/day) over the left temporal cortex or combined frontal and temporal rTMS (n = 47; 110% motor threshold, 1000 stimuli at 20 Hz, left dorsolateral prefrontal cortex plus 1000 stimuli at 1 Hz left temporal cortex). Response criterion was defined as an improvement of at least 10 points in the tinnitus questionnaire (TQ) score between baseline and the follow-up assessment 90 days after treatment. RESULTS: For the entire study group there was a highly significant effect of treatment on the TQ score. Fifty patients (21.3%) were responders according to the above mentioned definition. The response criterion was fulfilled by 19.7% of the patients receiving left temporal rTMS and by 26% of the patients receiving combined rTMS. The only significant difference between responders and nonresponders was a higher baseline score of the TQ in the responder group. There were no significant differences in all other assessed patient parameters (gender, age, tinnitus duration, tinnitus laterality, motor threshold, handedness). Ninety days after treatment the average TQ reduction in the responder group was 18.2 points as compared with baseline. At the two long-term follow-up assessments (2.12 ± 1.17 years and 3.9 ± 1.17 years after treatment) the improvement in the responder group was still 14.2, respective 14.4 points. CONCLUSIONS: These data underscore the clinical relevance of rTMS in the treatment of tinnitus. A potential explanation for the observed long-lasting clinical effects is that rTMS interferes with tinnitus related neuronal activity and thus facilitates the intrinsic ability of the brain to restore normal function.

Repetitive transcranial magnetic stimulation for tinnitus treatment: no enhancement by the dopamine and noradrenaline reuptake inhibitor bupropion.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) of the temporal cortex has shown beneficial effects in patients with chronic tinnitus. Recent preclinical data in healthy controls suggest that the effects of low-frequency rTMS can be enhanced by dopaminergic drugs. OBJECTIVE: We investigated whether application of the dopamine reuptake inhibitor bupropion increases the clinical effects of low-frequency rTMS over the auditory cortex in tinnitus patients. SUBJECTS AND METHODS: Eighteen subjects with chronic tinnitus received 10 sessions of 1 Hz rTMS (2000 pulses/day, 110% motor threshold) applied to the left temporal cortex. In addition, these subjects received one dosage of 150 mg bupropion (Wellbutrin XL/Elontril) 4 hours before each TMS session. Treatment outcome was assessed with a tinnitus questionnaire over a 3-month period. Treatment effects were compared with a control group of 100 tinnitus patients matched for age, tinnitus duration, and tinnitus questionnaire baseline scores, who received the same rTMS treatment without prior bupropion application. RESULTS: For the whole sample, there was a significant effect of rTMS treatment over time. There were no significant differences between the bupropion and the control group. CONCLUSIONS: Our data suggest that 150 mg bupropion administration does not enhance the effect of rTMS in the treatment of tinnitus.