Congenital malformations, including neural tube defects (NTDs), are significantly increased in the offspring of diabetic mothers. We previously reported that in the embryos of a mouse model of diabetic pregnancy, NTDs are associated with reduced expression of the gene Pax-3, which encodes a transcription factor that regulates neural tube development, and that reduced expression of Pax-3 leads to neuroepithelial apoptosis. In this study, we used three approaches to test whether glucose alone could be responsible for these adverse effects of diabetes on embryonic development. First, primary culture of embryo tissue in medium containing 15 mmol/l glucose inhibited Pax-3 expression compared with culture in medium containing 5 mmol/l glucose. Second, inducing hyperglycemia in pregnant mice by subcutaneous glucose administration significantly inhibited Pax-3 expression (P < 0.05), as demonstrated by quantitative reverse transcription-polymerase chain reaction assay of Pax-3 mRNA, and also increased neural tube apoptosis (P < 0.05). NTDs were significantly increased in glucose-injected pregnancies when blood glucose levels were >250 mg/dl (P < 0.002) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.37). Third, phlorizin administration to pregnant diabetic mice reduced blood glucose levels and the rate of NTDs. As seen with glucose-injected pregnancies, the rate of NTDs in phlorizin-treated diabetic pregnancies was related to the severity of hyperglycemia, since NTDs were significantly increased in severely hyperglycemic (>250 mg/dl) diabetic pregnancies (P < 0.001) but not in moderately hyperglycemic pregnancies (150-250 mg/dl, P = 0.35). These two findings, that elevated glucose alone can cause the changes in Pax-3 expression observed during diabetic pregnancy and that the NTD rate rises with significant increases in blood glucose levels, suggest that congenital malformations associated with diabetic pregnancy are caused by disruption of regulatory gene expression in the embryo in response to elevated glucose.

ABSTRACT:RESULTS :Educational Objective: The participants should be able to understand the potential role of individualized electrical stimulation of the auditory system in the suppression of tinnitus in patients with cochlear implants.Objectives: Tinnitus is a debilitating condition in which one perceives sound in the absence of external stimuli. Most treatments consist of masking the tinnitus with an external sound that is louder than the tinnitus. We hypothesize that there exists a characteristic tinnitus signature map in each individual that, when found, can be utilized to suppress their tinnitus at a level that is significantly softer than the tinnitus itself.Study Design: Prospective randomized single blinded study in a unique individual with a unilateral cochlear implant in an ear with persistent tinnitus and normal hearing in the non-implanted ear.Methods: Monopolar electrical stimulation at rates from 40 Hz to 10 kHz, stimulation levels from threshold to the tinnitus mixing point, and stimulation placement from apex to base were administered over a time period of 3 to 10 minutes. Successful suppression was defined as the complete elimination of the subject's tinnitus.

Problem To determine the degree of tinnitus suppression in cochlear implant patients by systematically varying stimulation parameters as a function of rate, level, and electrode. Methods Five cochlear implant subjects with ipsilateral or bilateral tinnitus were included. Implants were stimulated at a basal, middle, and apical electrode, at 100pps and 5000 pps, at perceived level quieter than the tinnitus and at the most comfortable loudness level. Patients reported stimulus and tinnitus perception on a ten-point scale every 30 seconds during and after stimulus delivery. Results All subjects reported near or complete suppression of tinnitus under one or more test conditions. Complete accommodation to the stimulus occurred often, thus during suppression patients perceived very little sound or total silence. Residual inhibition lasted up to twenty minutes. Two of the subjects noted suppression when low rate stimulation was delivered to an apical electrode. One patient responded only to high rate stimulation to an apical electrode. The remaining two patients reported suppression under multiple conditions. One subject had the most dramatic and consistent effects with low rate stimulation to a middle electrode; high rate stimulation caused rebound tinnitus of up to five minutes. Conclusion All patients experienced tinnitus suppression with electrical stimulation. Low rate stimulation overall was more effective in our subject group, and in two cases was the only effective suppressor. Significance Previous studies utilized only high rates of stimulation, and treatment failures occurred. Electrical stimulation is an effective, reproducible, and well-tolerated treatment for tinnitus but stimulus customization is required on an individual basis.

Objective 1) Customize amplitude-modulated (AM) and frequency-modulated (FM) acoustic stimuli to suppress tinnitus. 2) Understand the theoretical mechanisms underlying tinnitus suppression. Methods A double-staircase adaptive procedure was utilized to match both the frequency and intensity of the tinnitus. Minimal masking levels for both noise and pure tones were acquired. In a double-blinded procedure, sinusoidally amplitude- and frequency-modulated stimuli were administered. Pre- and post-stimulation tinnitus loudness levels were compared to quantify the effects of suppression and residual inhibition of tinnitus. Multivariate analysis was performed to evaluate independent predictors of tinnitus suppression. Different types and severity of tinnitus and hearing loss were correlated with the effective sounds. Results At present, 18 patients aged 35 to 75 (mean 58.3) with Tinnitus Handicap Index (THI) scores ranging from 12 to 90 (mean 52.6) have been evaluated. Significant associations were found between the duration of the AM and FM stimuli and the effect on tinnitus suppression. 10 out of 18 (56%) patients had a reduction in their tinnitus loudness by 30% or more. Upon comparison with the masking level, reduction in the subjects’ tinnitus was observed when a lower intensity of the modulated stimuli was presented. Subject characteristics that correlated with a significant reduction of the tinnitus will be discussed in detail. Conclusions AM and FM stimuli can decrease the percept of tinnitus significantly. It is postulated that AM and FM stimuli produce synchronized cortical responses to more efficiently compete against tinnitus-induced synchrony.