Absence of the Fragile X messenger ribonucleoprotein alters response patterns to sounds in the auditory midbrain.

Among the different autism spectrum disorders, Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. Sensory and especially auditory hypersensitivity is a key symptom in patients, which is well mimicked in the Fmr1 -/- mouse model. However, the physiological mechanisms underlying FXS's acoustic hypersensitivity in particular remain poorly understood. Here, we categorized spike response patterns to pure tones of different frequencies and intensities from neurons in the inferior colliculus (IC), a central integrator in the ascending auditory pathway. Based on this categorization we analyzed differences in response patterns between IC neurons of wild-type (WT) and Fmr1 -/- mice. Our results report broadening of frequency tuning, an increased firing in response to monaural as well as binaural stimuli, an altered balance of excitation-inhibition, and reduced response latencies, all expected features of acoustic hypersensitivity. Furthermore, we noticed that all neuronal response types in Fmr1 -/- mice displayed enhanced offset-rebound activity outside their excitatory frequency response area. These results provide evidence that the loss of Fmr1 not only increases spike responses in IC neurons similar to auditory brainstem neurons, but also changes response patterns such as offset spiking. One can speculate this to be an underlying aspect of the receptive language problems associated with Fragile X syndrome.

Integrated Care in Switzerland: Strengths and Weaknesses of a Federal System.

INTRODUCTION: Switzerland's fragmented healthcare system mirrors its federal structure and mix of cultures and languages. Although the Swiss have a higher life expectancy than most of their neighbours, their healthcare system faces similar challenges that call for more integrated care (IC). AIM/METHOD: This article aims to provide insight into the specificities of and latest developments in Switzerland's healthcare system and how they may have influenced the development and implementation of IC there. DESCRIPTION/DISCUSSION: The number of local IC initiatives has been growing steadily for 20 years. With a certain lag, various policies supporting IC have been established. Among them, a recent democratic debate on the federal mandatory health insurance law could either induce a radical move towards centralised support for IC or continue to support scattered local IC initiatives. CONCLUSION: In the future, Switzerland's healthcare system will probably navigate between local IC initiatives and centralised, federal support for IC initiatives. This will be the reflection of a very Swiss way forward in a world without clear evidence on whether centralised or decentralised initiatives are more successful at developing IC.

Hearing and Vocalizations in the Naked Mole-Rat.

Since their discovery, naked mole-rats have been speaking to us. Early field studies noted their extensive vocalizations, and scientists who are fortunate enough to spend time with these creatures in the laboratory setting cannot help but notice their constant peeping, chirruping and grunting (Hill et al., Proc Zool Soc Lond 128:455-514, 1957). Yet, few dwell on the function of these chirps and peeps, being instead drawn to the many other extraordinary aspects of naked mole-rat physiology detailed throughout this book. Still, no biology is complete without a description of how an organism communicates. While the field of naked mole-rat bioacoustics and acoustic communication has been largely silent for many years, we highlight recent progress in understanding how and what Heterocephalus glaber hears and which vocalizations it uses. These efforts are essential for a complete understanding of naked mole-rat cooperation, society and even culture.

Investigation of the Effect of End Mill-Geometry on Roughness and Surface Strain-Hardening of Aluminum Alloy AA6082.

Micro-milling is a promising technology for micro-manufacturing of high-tech components. A deep understanding of the micro-milling process is necessary since a simple downscaling from conventional milling is impossible. In this study, the effect of the mill geometry and feed per tooth on roughness and indentation hardness of micro-machined AA6082 surfaces is analyzed. A solid carbide (SC) single-tooth end-mill (cutting edge radius 670 nm) is compared to a monocrystalline diamond (MD) end-mill (cutting edge radius 17 nm). Feed per tooth was varied by 3 µm, 8 µm and 14 µm. The machined surface roughness was analyzed microscopically, while surface strain-hardening was determined using an indentation procedure with multiple partial unload cycles. No significant feed per tooth influence on surface roughness or mechanical properties was observed within the chosen range. Tools' cutting edge roughness is demonstrated to be the main factor influencing the surface roughness. The SC-tool machined surfaces had an average Rq = 119 nm, while the MD-tool machined surfaces reached Rq = 26 nm. Surface strain-hardening is influenced mainly by the cutting edge radius (size-effect). For surfaces produced with the SC-tool, depth of the strain-hardened zone is higher than 200 nm and the hardness increases up to 160% compared to bulk. MD-tool produced a thinner strain-hardened zone of max. 60 nm while the hardness increased up to 125% at the surface. These findings are especially important for the high-precision manufacturing of measurement technology modules for the terahertz range.

Mechanisms underlying auditory processing deficits in Fragile X syndrome.

Autism spectrum disorders (ASD) are strongly associated with auditory hypersensitivity or hyperacusis (difficulty tolerating sounds). Fragile X syndrome (FXS), the most common monogenetic cause of ASD, has emerged as a powerful gateway for exploring underlying mechanisms of hyperacusis and auditory dysfunction in ASD. This review discusses examples of disruption of the auditory pathways in FXS at molecular, synaptic, and circuit levels in animal models as well as in FXS individuals. These examples highlight the involvement of multiple mechanisms, from aberrant synaptic development and ion channel deregulation of auditory brainstem circuits, to impaired neuronal plasticity and network hyperexcitability in the auditory cortex. Though a relatively new area of research, recent discoveries have increased interest in auditory dysfunction and mechanisms underlying hyperacusis in this disorder. This rapidly growing body of data has yielded novel research directions addressing critical questions regarding the timing and possible outcomes of human therapies for auditory dysfunction in ASD.

Nanoindentation of Aluminum Single Crystals: Experimental Study on Influencing Factors.

Results from nanoindentation of aluminum single crystals deliver valuable information as model systems for understanding technical aluminum alloys. The effect of the crystal orientation and the azimuthal indenter orientation on indentation hardness and modulus was studied by Vickers indentation (max. load 10 mN) on single crystal surfaces with (100), (110), and (111) orientations. The average indentation hardness varied, depending on the crystallographic orientation, by 1.8%. The anisotropy of the elastic modulus (1.1% of the average modulus) is lowered (indentation averaging effect). This is predicted by explicit approximation of the contact problem (conical indenter, orthotropic material). It was found that indentation hardness and modulus vary periodically with the azimuthal indenter orientation on (100)- and (110)-oriented surfaces (relative amplitude of 1.8% for indentation hardness and 2.6% of the modulus). This is attributed to the combined effect of the indenter geometry and crystal symmetry. For the first time, this effect was quantified for aluminum single crystals.

The LRRC8/VRAC anion channel facilitates myogenic differentiation of murine myoblasts by promoting membrane hyperpolarization.

Skeletal muscle myoblast differentiation involves elaborate signaling networks, including the activity of various ion channels and transporters. Several K+ and Ca2+ channels have been shown to affect myogenesis, but little is known about roles of Cl- channels in the associated processes. Here, we report that the leucine-rich repeat containing family 8 (LRRC8)/volume-regulated anion channel (VRAC) promotes mouse myoblast differentiation. All LRRC8 subunits of heteromeric VRAC were expressed during myotube formation of murine C2C12 myoblasts. Pharmacological VRAC inhibitors, siRNA-mediated knockdown of the essential VRAC subunit LRRC8A, or VRAC activity-suppressing overexpression of LRRC8A effectively reduced the expression of the myogenic transcription factor myogenin and suppressed myoblast fusion while not affecting myoblast proliferation. We found that inhibiting VRAC impairs plasma membrane hyperpolarization early during differentiation. At later times (more than 6 h after inducing differentiation), VRAC inhibition no longer suppressed myoblast differentiation, suggesting that VRAC acts upstream of K+ channel activation. Consequently, VRAC inhibition prevented the increase of intracellular steady-state Ca2+ levels that normally occurs during myogenesis. Our results may explain the mechanism for the thinning of skeletal muscle bundles observed in LRRC8A-deficient mice and highlight the importance of the LRRC8/VRAC anion channel in cell differentiation.

Analysis of excitatory and inhibitory neuron types in the inferior colliculus based on Ih properties.

The inferior colliculus (IC) is a large midbrain nucleus that integrates inputs from many auditory brainstem and cortical structures. Despite its prominent role in auditory processing, the various cell types and their connections within the IC are not well characterized. To further separate GABAergic and non-GABAergic neuron types according to their physiological properties, we used a mouse model that expresses channelrhodopsin and enhanced yellow fluorescent protein in all GABAergic neurons and allows identification of GABAergic cells by light stimulation. Neuron types were classified upon electrophysiological measurements of the hyperpolarizing-activated current (Ih) in acute brain slices of young adult mice. All GABAergic neurons from our sample displayed slow-activating Ih with moderate amplitudes, whereas a subset of excitatory neurons showed fast-activating Ih with large amplitudes. This is in agreement with our finding that immunoreactivity against the fast-gating hyperpolarization-activated and cyclic-nucleotide-gated 1 (HCN1) channel was present around excitatory neurons, whereas the slow-gating HCN4 channel was found perisomatically around most inhibitory neurons. Ih properties and neurotransmitter types were correlated with firing patterns to depolarizing current pulses. All GABAergic neurons displayed adapting firing patterns very similar to the majority of glutamatergic neurons. About 15% of the glutamatergic neurons showed an onset spiking pattern, always in combination with large and fast Ih. We conclude that HCN channel subtypes are differentially distributed in IC neuron types and correlate with neurotransmitter type and firing pattern. In contrast to many other brain regions, membrane properties and firing patterns were similar in GABAergic neurons and about one-third of the excitatory neurons. NEW & NOTEWORTHY Neuron types in the central nucleus of the auditory midbrain are not well characterized regarding their transmitter type, ion channel composition, and firing pattern. The present study shows that GABAergic neurons have slowly activating hyperpolarizing-activated current (Ih) and an adaptive firing pattern whereas at least four types of glutamatergic neurons exist regarding their Ih properties and firing patterns. Many of the glutamatergic neurons were almost indistinguishable from the GABAergic neurons regarding Ih properties and firing pattern.

Enhanced Excitatory Connectivity and Disturbed Sound Processing in the Auditory Brainstem of Fragile X Mice.

Hypersensitivity to sounds is one of the prevalent symptoms in individuals with Fragile X syndrome (FXS). It manifests behaviorally early during development and is often used as a landmark for treatment efficacy. However, the physiological mechanisms and circuit-level alterations underlying this aberrant behavior remain poorly understood. Using the mouse model of FXS (Fmr1 KO), we demonstrate that functional maturation of auditory brainstem synapses is impaired in FXS. Fmr1 KO mice showed a greatly enhanced excitatory synaptic input strength in neurons of the lateral superior olive (LSO), a prominent auditory brainstem nucleus, which integrates ipsilateral excitation and contralateral inhibition to compute interaural level differences. Conversely, the glycinergic, inhibitory input properties remained unaffected. The enhanced excitation was the result of an increased number of cochlear nucleus fibers converging onto one LSO neuron, without changing individual synapse properties. Concomitantly, immunolabeling of excitatory ending markers revealed an increase in the immunolabeled area, supporting abnormally elevated excitatory input numbers. Intrinsic firing properties were only slightly enhanced. In line with the disturbed development of LSO circuitry, auditory processing was also affected in adult Fmr1 KO mice as shown with single-unit recordings of LSO neurons. These processing deficits manifested as an increase in firing rate, a broadening of the frequency response area, and a shift in the interaural level difference function of LSO neurons. Our results suggest that this aberrant synaptic development of auditory brainstem circuits might be a major underlying cause of the auditory processing deficits in FXS.SIGNIFICANCE STATEMENT Fragile X Syndrome (FXS) is the most common inheritable form of intellectual impairment, including autism. A core symptom of FXS is extreme sensitivity to loud sounds. This is one reason why individuals with FXS tend to avoid social interactions, contributing to their isolation. Here, a mouse model of FXS was used to investigate the auditory brainstem where basic sound information is first processed. Loss of the Fragile X mental retardation protein leads to excessive excitatory compared with inhibitory inputs in neurons extracting information about sound levels. Functionally, this elevated excitation results in increased firing rates, and abnormal coding of frequency and binaural sound localization cues. Imbalanced early-stage sound level processing could partially explain the auditory processing deficits in FXS.

Perinatal nicotine exposure impairs the maturation of glutamatergic inputs in the auditory brainstem.

KEY POINTS: Chronic perinatal nicotine exposure causes abnormal auditory brainstem responses and auditory processing deficits in children and animal models. The effect of perinatal nicotine exposure on synaptic maturation in the auditory brainstem was investigated in granule cells in the ventral nucleus of the lateral lemniscus, which receive a single calyx-like input from the cochlear nucleus. Perinatal nicotine exposure caused a massive reduction in the amplitude of the excitatory input current. This caused a profound decrease in the number and temporal precision of spikes in these neurons. Perinatal nicotine exposure delayed the developmental downregulation of functional nicotinic acetylcholine receptors on these neurons. ABSTRACT: Maternal smoking causes chronic nicotine exposure during early development and results in auditory processing deficits including delayed speech development and learning difficulties. Using a mouse model of chronic, perinatal nicotine exposure we explored to what extent synaptic inputs to granule cells in the ventral nucleus of the lateral lemniscus are affected by developmental nicotine treatment. These neurons receive one large calyx-like input from octopus cells in the cochlear nucleus and play a role in sound pattern analysis, including speech sounds. In addition, they exhibit high levels of α7 nicotinic acetylcholine receptors, especially during early development. Our whole-cell patch-clamp experiments show that perinatal nicotine exposure causes a profound reduction in synaptic input amplitude. In contrast, the number of inputs innervating each neuron and synaptic release properties of this calyx-like synapse remained unaltered. Spike number and spiking precision in response to synaptic stimulation were greatly diminished, especially for later stimuli during a stimulus train. Moreover, chronic nicotine exposure delayed the developmental downregulation of functional nicotinic acetylcholine receptors on these neurons, indicating a direct action of nicotine in this brain area. This presumably direct effect of perinatal nicotine exposure on synaptic maturation in the auditory brainstem might be one of the underlying causes for auditory processing difficulties in children of heavy smoking mothers.

Transforming Primary Care Practice and Education: Lessons From 6 Academic Learning Collaboratives.

Adoption of new primary care models has been slow in academic teaching practices. We describe a common framework that academic learning collaboratives are using to transform primary care practice based on our analysis of 6 collaboratives nationally. We show that the work of the collaboratives could be divided into 3 phases and provide detail on the phases of work and a road map for those who seek to emulate this work. We found that learning collaboratives foster transformation, even in complex academic practices, but need specific support adapted to their unique challenges.

From healthcare to health: A proposed pathway to population health.

Innovations in payment are encouraging clinical-community partnerships that address health determinants. However, little is known about how healthcare systems transform and partner to improve population health. We synthesized views of population health experts from nine organizations and illustrated the resulting model using examples from four health systems. The transformation requires a foundation of primary care, connectors and integrators that span the boundaries, sharing of goals among participants, aligned funding and incentives, and a supporting infrastructure, all leading to a virtuous cycle of collaboration. Policies are needed that will provide funding and incentives to encourage spread beyond early adopter organizations.

Structural Changes and Lack of HCN1 Channels in the Binaural Auditory Brainstem of the Naked Mole-Rat (Heterocephalus glaber).

Naked mole-rats (Heterocephalus glaber) live in large eu-social, underground colonies in narrow burrows and are exposed to a large repertoire of communication signals but negligible binaural sound localization cues, such as interaural time and intensity differences. We therefore asked whether monaural and binaural auditory brainstem nuclei in the naked mole-rat are differentially adjusted to this acoustic environment. Using antibody stainings against excitatory and inhibitory presynaptic structures, namely the vesicular glutamate transporter VGluT1 and the glycine transporter GlyT2 we identified all major auditory brainstem nuclei except the superior paraolivary nucleus in these animals. Naked mole-rats possess a well structured medial superior olive, with a similar synaptic arrangement to interaural-time-difference encoding animals. The neighboring lateral superior olive, which analyzes interaural intensity differences, is large and elongated, whereas the medial nucleus of the trapezoid body, which provides the contralateral inhibitory input to these binaural nuclei, is reduced in size. In contrast, the cochlear nucleus, the nuclei of the lateral lemniscus and the inferior colliculus are not considerably different when compared to other rodent species. Most interestingly, binaural auditory brainstem nuclei lack the membrane-bound hyperpolarization-activated channel HCN1, a voltage-gated ion channel that greatly contributes to the fast integration times in binaural nuclei of the superior olivary complex in other species. This suggests substantially lengthened membrane time constants and thus prolonged temporal integration of inputs in binaural auditory brainstem neurons and might be linked to the severely degenerated sound localization abilities in these animals.

Heterogeneity of Intrinsic and Synaptic Properties of Neurons in the Ventral and Dorsal Parts of the Ventral Nucleus of the Lateral Lemniscus.

The ventral nucleus of the lateral lemniscus (VNLL) provides a major inhibitory projection to the inferior colliculus (IC). Neurons in the VNLL respond with various firing patterns and different temporal precision to acoustic stimulation. The present study investigates the underlying intrinsic and synaptic properties of various cell types in different regions of the VNLL, using in vitro electrophysiological recordings from acute brain slices of mice and immunohistochemistry. We show that the biophysical membrane properties and excitatory input characteristics differed between dorsal and ventral VNLL neurons. Neurons in the ventral VNLL displayed an onset-type firing pattern and little hyperpolarization-activated current (Ih). Stimulation of lemniscal inputs evoked a large all-or-none excitatory response similar to Calyx of Held synapses in neurons in the lateral part of the ventral VNLL. Neurons that were located within the fiber tract of the lateral lemniscus, received several and weak excitatory input fibers. In the dorsal VNLL onset-type and sustained firing neurons were intermingled. These neurons showed large Ih and were strongly immunopositive for the hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) subunit. Both neuron types received several excitatory inputs that were weaker and slower compared to ventrolateral VNLL neurons. Using a mouse model that expresses channelrhodopsin under the promotor of the vesicular GABA transporter (VGAT) suggests that dorsal and ventral neurons were inhibitory since they were all depolarized by light stimulation. The diverse membrane and input properties in dorsal and ventral VNLL neurons suggest differential roles of these neurons for sound processing.

Comparison of Health Care Experience and Access Between Young and Older Adults in 11 High-Income Countries.

PURPOSE: Young adults (18-24 years) frequently report poorer health care access and experience than older adults. We aimed to investigate how differences between young and older adults vary across 11 high-income countries. METHODS: A total of 20,045 participants from 11 high-income countries (i.e., Australia, Canada, France, Germany, the Netherlands, New Zealand, Norway, Sweden, Switzerland, United Kingdom, United States) participating in the Commonwealth Fund 2013 International Health Policy Survey. We compared young adults (18-24 years) with older adults (25-34; 35-49; 50-64; 65+ years) on three aspects of health care: overall satisfaction, cost barriers to access, and four indicators of consultation quality relating to adequate information, time, involvement, and explanation. RESULTS: Across all participants, young adults reported significantly worse overall satisfaction (63.6% vs. 70.3%; p < .001) and more frequent cost barriers (21.3% vs. 15.2%; p < .001) than older adults. Country-level analyses showed that young adults reported lower overall satisfaction than older adults in five of 11 countries (Australia, Canada, Norway, Switzerland, United States) and more frequent cost barriers in six of 11 countries (Canada, France, Germany, Switzerland, Norway, United States). In five countries (Australia, Canada, France, Norway, Switzerland), most patient experience indicators were less positive among young adults than those among older adults. In three countries (Netherlands, New Zealand, United Kingdom), there was no significant difference between young and older adults on any indicator. CONCLUSIONS: Associations between age and health care access/experience varied markedly between countries, suggesting that poor access and experience among young adults is not inevitable and may be amenable to policy/practice interventions.

Laser engravings as reason for mechanical failure of titanium-alloyed total hip stems.

INTRODUCTION: Two revisions of broken ß-titanium total hip stems had to be performed in our hospital after 2 and 4 years in situ. Since both fractures were located at the level of a laser engraving, a failure analysis was conducted. MATERIALS AND METHODS: Both retrieved hip stems were disinfected and collected in our retrieval database after patient's signed agreement. Each fragment was macroscopically photographed. Fracture surfaces were analyzed using scanning electron microscopy (SEM). Quantification of element content was conducted using energy dispersive X-ray (EDX) analysis. RESULTS: Both stems show fatigue fracture, as displayed by the lines of rest on the fracture surface. The origin of fracture was identified directly at the laser engraving of the company logo at both stems by means of SEM. The EDX analysis showed an oxygen level beneath the laser engraving about twice as high as in the substrate, causing material embrittlement. CONCLUSIONS: Laser engravings need to be reduced to a minimum of necessary information, and should be placed at locations with minimum mechanical load. Biomechanical analyses are recommended to identify less loaded areas in implant components to avoid such implant failures.

Tonotopic organization of the hyperpolarization-activated current (Ih) in the mammalian medial superior olive.

Neuronal membrane properties can largely vary even within distinct morphological cell classes. The mechanisms and functional consequences of this diversity, however, are little explored. In the medial superior olive (MSO), a brainstem nucleus that performs binaural coincidence detection, membrane properties at rest are largely governed by the hyperpolarization-activated inward current (Ih) which enables the temporally precise integration of excitatory and inhibitory inputs. Here, we report that Ih density varies along the putative tonotopic axis of the MSO with Ih being largest in ventral, high-frequency (HF) processing neurons. Also Ih half-maximal activation voltage and time constant are differentially distributed such that Ih of the putative HF processing neurons activate faster and at more depolarized levels. Intracellular application of saturating concentrations of cyclic AMP removed the regional difference in hyperpolarization-activated cyclic nucleotide gated (HCN) channel activation, but not Ih density. Experimental data in conjunction with a computational model suggest that increased Ih levels are helpful in counteracting temporal summation of phase-locked inhibitory inputs which is particularly prominent in HF neurons.

Comparative posthearing development of inhibitory inputs to the lateral superior olive in gerbils and mice.

Interaural intensity differences are analyzed in neurons of the lateral superior olive (LSO) by integration of an inhibitory input from the medial nucleus of the trapezoid body (MNTB), activated by sound from the contralateral ear, with an excitatory input from the ipsilateral cochlear nucleus. The early postnatal refinement of this inhibitory MNTB-LSO projection along the tonotopic axis of the LSO has been extensively studied. However, little is known to what extent physiological changes at these inputs also occur after the onset of sound-evoked activity. Using whole-cell patch-clamp recordings of LSO neurons in acute brain stem slices, we analyzed the developmental changes of inhibitory synaptic currents evoked by MNTB fiber stimulation occurring after hearing onset. We compared these results in gerbils and mice, two species frequently used in auditory research. Our data show that neither the number of presumed input fibers nor the conductance of single fibers significantly changed after hearing onset. Also the amplitude of miniature inhibitory currents remained constant during this developmental period. In contrast, the kinetics of inhibitory synaptic currents greatly accelerated after hearing onset. We conclude that tonotopic refinement of inhibitory projections to the LSO is largely completed before the onset of hearing, whereas acceleration of synaptic kinetics occurs to a large part after hearing onset and might thus be dependent on proper auditory experience. Surprisingly, inhibitory input characteristics, as well as basic membrane properties of LSO neurons, were rather similar in gerbils and mice.

Dynamics of binaural processing in the mammalian sound localization pathway--the role of GABA(B) receptors.

The initial binaural processing in the superior olive represents the fastest computation known in the entire mammalian brain. Although the binaural system has to perform under very different and often highly dynamic acoustic conditions, the integration of binaural information in the superior olivary complex (SOC) has not been considered to be adaptive or dynamic itself. Recent evidence, however, shows that the initial processing of interaural level and interaural time differences relies on well-adjusted interactions of both the excitatory and the inhibitory projections, respectively. Under static conditions, these inputs seem to be tightly balanced, but may also require dynamic adjustment for proper function when the acoustic environment changes. GABA(B) receptors are at least one mechanism rendering the system more dynamic than considered so far. A comprehensive description of how binaural processing in the SOC is dynamically regulated by GABA(B) receptors in adults and in early development is important for understanding how spatial auditory processing changes with acoustic context.