Distribution of the High-Affinity Binding Site and Intracellular Target of Botulinum Toxin Type A in the Human Bladder

Background

Botulinum toxin type A (BoNTA) has been successfully used in the treatment of refractory detrusor overactivity. The toxin is internalized after binding a high-affinity receptor, synaptic vesicle protein 2 (SV2), which is exposed in the cell membrane during the exocytosis process. In the cytoplasm, BoNTA cleaves specific sites of synaptosomal-associated protein 25 (SNAP-25), preventing the assembly of the synaptic fusion complex SNARE and blocking exocytosis.

Objective

In the present work, the distribution of SV2 and SNAP-25 was first investigated in human bladders. The neurochemistry of BoNTA-sensitive structures was then investigated using markers for parasympathetic, sympathetic, and sensory fibers.

Design, setting, and participants

Human bladders were obtained from cadaveric organ donors (age range: 19–74 yr).

Measurements

Bladder sections were processed for single or dual immunofluorescence staining with antibodies against SV2, SNAP-25, β-3 tubulin, vesicular acetylcholine transporter, tyrosine hydroxilase, and calcitonin gene-related peptide.

Results and limitations

SV2 and SNAP-25 immunoreactive fibers were distributed throughout the suburothelium and muscular layer. Double labeling showed extensive colocalization of both proteins in nerve fibers. SV2 is more expressed in parasympathetic fibers than in sympathetic or sensory fibers. No expression was found in urothelial or muscular cells. Because only normal bladders were used, this distribution should be applied with caution to pathologic bladders.

Conclusions

SV2 and SNAP-25 colocalize abundantly throughout the urinary bladder. SV2 is more abundant in cholinergic, parasympathetic fibers. These nerves are suggested to be the main target for BoNTA action in the human urinary bladder.     

Treatment of recalcitrant generalized granuloma annulare with adalimumab

Granuloma annulare is a benign, usually self-limited, dermatosis of unknown cause. Generalized lesions occur in approximately 15 percent of patients with GA and may cause mild to severe cosmetic disfigurement. The treatment of generalized granuloma annulare can be challenging. We report the case of a 36-year-old male patient with a generalized granuloma annulare who had failed topical and systemic glucocorticoids, systemic retinoids, dapsone, minocycline, PUVA therapy, and hydroxicloroquine and was successfully treated with adalimumab, an anti-TNF-α monoclonal antibody. Adalimumab may be an additional option in the treatment of recalcitrant forms of granuloma annulare.     

Intravenous lidocaine for fibromyalgia syndrome: an open trial

Fibromyalgia is a disorder characterized by chronic widespread pain. In this study, we investigated the effect of intravenous infusions of lidocaine in pain and quality of life of patients with fibromyalgia. Twenty-three consecutive patients were included in the study, which consisted on five sequential intravenous 2% lidocaine infusions with rising dosages (2–5 mg/kg, days 1–5). Fibromyalgia Impact Questionnaire (FIQ), Health Assessment Questionnaire, and a visual analog scale (VAS) for pain were applied before the first lidocaine infusion, immediately after the fifth infusion and 30 days after the fifth infusion. A significant improvement was observed in the FIQ scores after the fifth infusion (73.52 ± 16.56 vs 63.29 ± 21.21, p = 0.02), which was maintained after 30 days (73.52 ± 16.56 vs 63.85 ± 24.59, p = 0.04). Similar results were seen concerning the VAS: 8.19 ± 1.76 vs 6.84 ± 2.44, p = 0.01 and 8.19 ± 1.76 vs 7.17 ± 2.35, p = 0.05, respectively. Intravenous lidocaine infusions are safe and effective in the management of fibromyalgia.     

Auditory processing,acoustic reflex and phonological expression

It is thought that a close relationship exists between auditory processing, the acoustic reflex and speech.AimA retrospective study to evaluate these three aspects in children with and without phonological disorders and seek any relationship among them.Material Methods46 children were enrolled: 24 had normal speech abilities and 22 had phonological disorders. All children underwent auditory processing and acoustic reflex threshold testing.DesignCross-sectional contemporary.ResultsAuditory processing and acoustic reflex thresholds were abnormal in all children with phonological disorders. This was not the case in children with normal speech development.ConclusionChanges in the auditory processing and acoustic reflex thresholds are closely related to speech difficulties.     

Default mode and task‐positive networks connectivity during the N‐Back task in remitted depressed patients with or without emotional residual symptoms

Clinical remission of depression may be associated with emotional residual symptoms. We studied the association of emotional blunting, rumination with neural networks dynamics in remitted depressed patients and cognitive performance during an N‐Back task. Twenty‐six outpatients in remission of depression (Hamilton Depressive rating scale score <7) performed an N‐Back task during fMRI assessment. All patients had been treated by paroxetine for a minimum of 4 months. Two subgroups of patients [Nonemotionally blunted (NEB) = 14 and emotionally blunted (EB) = 12] were determined. To identify functional network maps across participants, the Network Detection using Independent Component Analysis approach was employed. Within and between Task Positive Network (TPN) and Default Mode Network (DMN) connectivity were assessed and related to variability of performance on the N‐Back task and rumination. EB and NEB patients were not different for the level of accurate responses at the N‐Back. However over the entire working memory task, the negative correlation between DMN and TPN was significantly lower in the EB than NEB group and was differently related to cognitive performance and rumination. The stronger the negative correlation between DMN and TPN was, the less variable the reaction time during 3‐Back task in NEB patients. Moreover the greater the negative correlation between DMN and TPN was, the lower the rumination score in EB patients. Emotional blunting may be associated with compromised monitoring of rumination and cognitive functioning in remitted depressed patients through altered cooperation between DMN and TPN. The study suggests clinical remission in depression is associated with biological heterogeneity. Hum Brain Mapp 38:3491–3501, 2017. © 2017 Wiley Periodicals, Inc.