Glycine mediated alterations in intracellular pH

Glycinergic transmission shapes the coding properties of the lateral superior olivary nucleus (LSO). We investigated intracellular pH responses in the LSO to glycine using BCECF-AM in brain slices. With extracellular bicarbonate, glycine produced an alkalinization followed by an acidification while, in the nominal absence of bicarbonate, glycine produced acidifications. Separately, in whole-cell recordings from LSO neurons, glycine caused hyperpolarization followed by long-lasting depolarization. While the bicarbonate-dependent intracellular alkalinization could be related to chloride/bicarbonate exchange, bicarbonate-independent acidification may be triggered by depolarization.     

Developmental hearing loss eliminates long-term potentiation in the auditory cortex

Severe hearing loss during early development is associated with deficits in speech and language acquisition. Although functional studies have shown a deafness-induced alteration of synaptic strength, it is not known whether long-term synaptic plasticity depends on auditory experience. In this study, sensorineural hearing loss (SNHL) was induced surgically in developing gerbils at postnatal day 10, and excitatory synaptic plasticity was examined subsequently in a brain slice preparation that preserves the thalamorecipient auditory cortex. Extracellular stimuli were applied at layer 6 (L6), whereas evoked excitatory synaptic potentials (EPSPs) were recorded from L5 neurons by using a whole-cell current clamp configuration. In control neurons, the conditioning stimulation of L6 significantly altered EPSP amplitude for at least 1 h. Approximately half of neurons displayed long-term potentiation (LTP), whereas the other half displayed long-term depression (LTD). In contrast, SNHL neurons displayed only LTD after the conditioning stimulation of L6. Finally, the vast majority of neurons recorded from control prehearing animals (postnatal days 9-11) displayed LTD after L6 stimulation. Thus, normal auditory experience may be essential for the maturation of synaptic plasticity mechanisms.     

Hearing loss prevents the maturation of GABAergic transmission in the auditory cortex

Inhibitory neurotransmission is a critical determinant of neuronal network gain and dynamic range, suggesting that network properties are shaped by activity during development. A previous study demonstrated that sensorineural hearing loss (SNHL) in gerbils leads to smaller inhibitory potentials in L2/3 pyramidal neurons in the thalamorecipient auditory cortex, ACx. Here, we explored the mechanisms that account for proper maturation of gamma-amino butyric acid (GABA)ergic transmission. SNHL was induced at postnatal day (P) 10, and whole-cell voltage-clamp recordings were obtained from layer 2/3 pyramidal neurons in thalamocortical slices at P16-19. SNHL led to an increase in the frequency of GABAzine-sensitive (antagonist) spontaneous (s) and miniature (m) inhibitory postsynaptic currents (IPSCs), accompanied by diminished amplitudes and longer durations. Consistent with this, the amplitudes of minimum-evoked IPSCs were also reduced while their durations were longer. The alpha1- and beta2/3 subunit-specific agonists zolpidem and loreclezole increased control but not SNHL sIPSC durations. To test whether SNHL affected the maturation of GABAergic transmission, sIPSCs were recorded at P10. These sIPSCs resembled the long SNHL sIPSCs. Furthermore, zolpidem and loreclezole were ineffective in increasing their durations. Together, these data strongly suggest that the presynaptic release properties and expression of key postsynaptic GABA(A) receptor subunits are coregulated by hearing.     

Hearing loss alters the subcellular distribution of presynaptic GAD and postsynaptic GABAA receptors in the auditory cortex

We have shown previously that auditory experience regulates the maturation of excitatory synapses in the auditory cortex (ACx). In this study, we used electron microscopic immunocytochemistry to determine whether the heightened excitability of the ACx following neonatal sensorineural hearing loss (SNHL) also involves pre- or postsynaptic alterations of GABAergic synapses. SNHL was induced in gerbils just prior to the onset of hearing (postnatal day 10). At P17, the gamma-aminobutyri acid type A (GABA(A)) receptor's beta2/3-subunit (GABA(A)beta2/3) clusters residing at plasma membranes in layers 2/3 of ACx was reduced significantly in size (P < 0.05) and number (P < 0.005), whereas the overall number of immunoreactive puncta (intracellular + plasmalemmal) remained unchanged. The reduction of GABA(A)beta2/3 was observed along perikaryal plasma membranes of excitatory neurons but not of GABAergic interneurons. This cell-specific change can contribute to the enhanced excitability of SNHL ACx. Presynaptically, GABAergic axon terminals were significantly larger but less numerous and contained 47% greater density of glutamic acid decarboxylase immunoreactivity (P < 0.05). This suggests that GABA synthesis may be upregulated by a retrograde signal arising from lowered levels of postsynaptic GABA(A)R. Thus, both, the pre- and postsynaptic sides of inhibitory synapses that form upon pyramidal neurons of the ACx are regulated by neonatal auditory experience.     

Developmental plasticity of auditory cortical inhibitory synapses

Functional inhibitory synapses form in auditory cortex well before the onset of normal hearing. However, their properties change dramatically during normal development, and many of these maturational events are delayed by hearing loss. Here, we review recent findings on the developmental plasticity of inhibitory synapse strength, kinetics, and GABAA receptor localization in auditory cortex. Although hearing loss generally leads to a reduction of inhibitory strength, this depends on the type of presynaptic interneuron. Furthermore, plasticity of inhibitory synapses also depends on the postsynaptic target. Hearing loss leads reduced GABAA receptor localization to the membrane of excitatory, but not inhibitory neurons. A reduction in normal activity in development can also affect the use-dependent plasticity of inhibitory synapses. Even moderate hearing loss can disrupt inhibitory short- and long-term synaptic plasticity. Thus, the cortex did not compensate for the loss of inhibition in the brainstem, but rather exacerbated the response to hearing loss by further reducing inhibitory drive. Together, these results demonstrate that inhibitory synapses are exceptionally dynamic during development, and deafness-induced perturbation of inhibitory properties may have a profound impact on auditory processing.     

Volumetric changes of the upper airway following maxillary and mandibular advancement using cone beam computed tomography

The objective of this project was to retrospectively evaluate changes in volume of different compartments of the upper airway in response to maxillary, mandibular, and bimaxillary advancement surgeries and to predict the extent of volumetric changes associated with these surgical movements. Pre- and post-surgical cone beam computed tomography scans of 36 patients were evaluated for changes in nasal cavity, nasopharyngeal, oropharyngeal, and hypopharyngeal compartments. The amount of movement for each surgery was measured from skeletal landmarks to reference planes and was correlated with volumetric changes. Maxillary advancement of 4.0 ± 2.2 mm increased the oropharyngeal volume significantly (41.40%), and mandibular advancement of 3.8 ± 1.6 mm also significantly increased the oropharyngeal volume (21.17%). Bimaxillary advancement of 5.1 ± 1.3 mm for the maxilla and 6.4 ± 3.1 mm for the mandible significantly increased nasopharyngeal (27.45%), oropharyngeal (66.39%), and hypopharyngeal (52.48%) volumes. Furthermore, for every millimeter anterior movement, oropharyngeal volume increased by 2319.2 ± 771.8 mm³. Bimaxillary advancement showed a greater increase than isolated maxillary and mandibular advancement in all pharyngeal compartments. Every millimeter of advancement in the bimaxillary group led to a significant increase in oropharyngeal volume, while every millimeter downward movement showed a significant increase in nasopharyngeal volume.     

Assessment of clinical efficacy and safety in a randomized double-blind study of etanercept and sulfasalazine in patients with ankylosing spondylitis from Eastern/Central Europe,Latin America,and Asia

Despite the demonstrated efficacy of etanercept for the treatment of ankylosing spondylitis (AS), sulfasalazine is often prescribed, especially in countries with limited access to biologic agents. The objective of this subset analysis of the ASCEND trial was to compare the efficacy of etanercept and sulfasalazine in treating patients with AS from Asia, Eastern/Central Europe, and Latin America. A total of 287 patients, 190 receiving etanercept 50 mg once weekly and 97 receiving sulfasalazine 3 g daily, from eight countries were included in this subset analysis. Differences in disease activity and patient-reported outcomes assessing health-related quality-of-life (HRQoL) parameters in response to treatment were analyzed using the Cochran–Mantel–Haenszel test for categorical efficacy endpoints and analysis of covariance model for continuous variables. At week 16, a significantly greater proportion of patients receiving etanercept achieved ASAS20 (79.0 %) compared with patients receiving sulfasalazine (61.9 %; p = 0.002). At week 16, treatment with etanercept also resulted in significantly better responses than sulfasalazine for ASAS40 (64.7 vs. 35.1 %; p < 0.001), ASAS5/6 (48.1 vs. 26.3 %; p < 0.001), proportion of patients achieving 50 % response in Bath AS Disease Activity Index (65.8 vs. 42.3 %; p < 0.001), partial remission (35.3 vs. 17.5 %; p = 0.002), and all HRQoL parameters. Both treatments were well tolerated. Etanercept was significantly more effective than sulfasalazine in the treatment of patients with AS from Asia, Central/Eastern Europe, and Latin America.