Drug-based Therapies for Auditory Trauma

Deafness is one of the most common health conditions in the developed countries, and worldwide, an estimated 70 million people are deaf. For people with severe to profound hearing loss, a cochlear implant is the only treatment today. The most common forms of severe hearing loss and deafness are related to morphological changes in the cochlea. Aim: The aim of these studies was to investigate several therapeutic compounds, including nucleosides and nucleotides, two types of neurotrophic factors, and two oxysterols, to determine if they could preserve spiral ganglion neuron (SGN) survival and maintain SGN electrical responsiveness, as determined by measuring electrically-evoked auditory brainstem response (eABR) in deafened guinea pigs. It was also important to investigate the compounds’ effectiveness when delivered into the inner ear several weeks after deafening (“Delayed treatment”). In some experiments, the animals stayed in the study for several weeks after cessation of treatment to determine if eABR threshold remained and the extent of SGN survival after treatment cessation. Methods: All animals in these studies were deafened with the ototoxic compound neomycin sulfate by intracochlear or transtympanic infusion. They received a cochlear implant and an osmotic pump for inner ear drug delivery. To determine any changes in hearing (i.e., SGN electrical responsiveness), electrically-evoked brainstem response was measured weekly. After the last measurement cochleae were collected for morphological analysis. Results: We found that nucleosides and nucleotides seem to have a trophic effect on spiral ganglion neurons, showing low eABR thresholds and a statistically significant (p<0.001) SGN survival compared with the control group. Results from the study with glial cell line-derived neurotrophic factor (GDNF) showed that delayed GDNF treatment helped to prevent loss of electrical responsiveness and auditory nerve cell death up to four weeks after GDNF cessation. Cometin, a new neurotrophic factor, showed low eABR thresholds but with fewer surviving SGNs. The oxysterols study showed a different pattern compared to all our previous studies. In the acute study both oxysterols showed low eABR thresholds compared to the control group, but SGN survival was equal to the control group that did not received any treatment. In the delayed treatment study only one of the oxysterols showed lower eABR thresholds during the whole experiment compared to the control group. Despite that, SGN survival was equally low in the oxysterol groups and the control group. Of the therapeutic agents tested in this study GDNF was most the promising compound

Dendrogenin A and B two new steroidal alkaloids increasing neural responsiveness in the deafened guinea pig

Aim: To investigate the therapeutic potential for treating inner ear damage of two new steroidal alkaloid compounds, Dendrogenin A and Dendrogenin B, previously shown to be potent inductors of cell differentiation. Methods: Guinea pigs, unilaterally deafened by neomycin infusion, received a cochlear implant followed by immediate or a two-week delayed treatment with Dendrogenin A, Dendrogenin B, and, as comparison artificial perilymph and glial cell-line derived neurotrophic factor. After a 4-week treatment period the animals were sacrificed and the cochleae processed for morphological analysis. Electrically-evoked auditory brainstem responses were measured weekly throughout the experiment. Results: Following immediate or delayed Dendrogenin treatment the electrical responsiveness was significantly maintained, in a similar extent as has been shown using neurotrophic factors. Histological analysis showed that the spiral ganglion neurons density was only slightly higher than the untreated group. Conclusions: Our results suggest that Dendrogenins constitute a new class of drugs with strong potential to improve cochlear implant efficacy and to treat neuropathy/synaptopathy related hearing loss. That electrical responsiveness was maintained despite a significantly reduced neural population suggests that the efficacy of cochlear implants is more related to the functional state of the spiral ganglion neurons than merely their number

Seasonal plankton dynamics in Kongsfjorden during two years of contrasting environmental conditions

Seasonal plankton time-series data are presented from Kongsfjorden from two years with contrasting environmental conditions. Kongsfjorden (west coast of Spitsbergen – 79°N) integrates inputs from Atlantic and Arctic waters, and glacier run-off, and is thus a prime location to study impacts on ecosystem dynamics of key environmental drivers that are relevant across the Arctic. Despite extensive research in Kongsfjorden, seasonally-resolved data are scarce. From late April/early May to early September 2019 and 2020, we conducted pelagic sampling at a mid-fjord station at mostly weekly to bi-weekly resolution investigating the environmental drivers of phyto- and zooplankton community composition and phenology. During spring 2019, Atlantic water masses with temperatures > 1 °C were found throughout the upper 250 m of the water column, and little sea ice occurred in the fjord. Spring 2020, in turn, was characterized by the presence of local water masses with sub-zero temperatures and relatively extensive sea-ice cover. The most striking contrast between the two years was the difference in phytoplankton spring bloom composition. In 2019, the spring bloom was dominated by the colonial stage of the haptophyte Phaeocystis pouchetii and diatoms played a minor role, while the spring bloom in 2020 was dominated by diatoms of the genus Thalassiosira succeeded by P. pouchetii. Selective grazing by large copepods and water mass structure seem to have been the decisive factors explaining the marked difference in diatom spring bloom biomass between the years while similar spring abundances of P. pouchetii in both years indicated that this species was less impacted by those factors. Our data suggest that differences in spring bloom composition impacted trophic transfer and carbon export. Recruitment of the dominant copepods Calanus finmarchicus and C. glacialis, Cirripedia and euphausiid larvae as well as the export of carbon to the seabed was more efficient during the diatom-dominated compared to the P. pouchetii–dominated spring bloom. In summer, the plankton composition shifted towards a flagellate-dominated community characterized by mixo- and heterotrophic taxa adapted to a lower nutrient regime and strong top-down control by copepod grazers. However, residual silicic acid after the P. pouchetii–dominated spring bloom fueled a late summer diatom bloom in 2019. Our data provide a first glimpse into the environmental drivers of plankton phenology and underline that high-resolution monitoring over many annual cycles is required to resolve the ephemeral variations of plankton populations against the backdrop of climate change.publishedVersio

Leads in Arctic pack ice enable early phytoplankton blooms below snow-covered sea ice

© The Author(s), 2017. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Scientific Reports 7 (2017): 40850, doi:10.1038/srep40850.The Arctic icescape is rapidly transforming from a thicker multiyear ice cover to a thinner and largely seasonal first-year ice cover with significant consequences for Arctic primary production. One critical challenge is to understand how productivity will change within the next decades. Recent studies have reported extensive phytoplankton blooms beneath ponded sea ice during summer, indicating that satellite-based Arctic annual primary production estimates may be significantly underestimated. Here we present a unique time-series of a phytoplankton spring bloom observed beneath snow-covered Arctic pack ice. The bloom, dominated by the haptophyte algae Phaeocystis pouchetii, caused near depletion of the surface nitrate inventory and a decline in dissolved inorganic carbon by 16 ± 6 g C m−2. Ocean circulation characteristics in the area indicated that the bloom developed in situ despite the snow-covered sea ice. Leads in the dynamic ice cover provided added sunlight necessary to initiate and sustain the bloom. Phytoplankton blooms beneath snow-covered ice might become more common and widespread in the future Arctic Ocean with frequent lead formation due to thinner and more dynamic sea ice despite projected increases in high-Arctic snowfall. This could alter productivity, marine food webs and carbon sequestration in the Arctic Ocean.This study was supported by the Centre for Ice, Climate and Ecosystems (ICE) at the Norwegian Polar Institute, the Ministry of Climate and Environment, Norway, the Research Council of Norway (projects Boom or Bust no. 244646, STASIS no. 221961, CORESAT no. 222681, CIRFA no. 237906 and AMOS CeO no. 223254), and the Ministry of Foreign Affairs, Norway (project ID Arctic), the ICE-ARC program of the European Union 7th Framework Program (grant number 603887), the Polish-Norwegian Research Program operated by the National Centre for Research and Development under the Norwegian Financial Mechanism 2009–2014 in the frame of Project Contract Pol-Nor/197511/40/2013, CDOM-HEAT, and the Ocean Acidification Flagship program within the FRAM- High North Research Centre for Climate and the Environment, Norway

Leads in Arctic pack ice enable early phytoplankton blooms below snow-covered sea ic

publishedVersio

Prevention - and intervention therapies in auditory trauma

Hearing impairment is one of the most common health conditions in developed countries. It is estimated that approximately 70 million people worldwide are deaf. For patients with a severe to profound hearing loss a cochlear implant (CI) is the only treatment today. The function of a CI depends in part of the survival and electrical responsiveness of the spiral ganglion neurons (SGNs), the target of the CI. In order to access the electrical responsiveness in animal models, electrically-evoked auditory brainstem responses (eABRs) were recorded. The survival of SGN was estimated by calculating the density of the SGN in Rosenthal´s canal. Neurotrophic factors due to their neurotrophic support in the cochlea are important in the development and maintenance of the auditory system. Therefore we performed two studies with glial cell line-derived neurotrophic factor (GDNF) treatment, one acute and one with a delayed onset of GDNF treatment. Normal hearing guinea pigs were deafened intracochlear (acute) or by transtympanic injection (delayed) with neomycin. The animals received a CI that consisted of a combined electrode (for eABR measurement) and cannula (for intracochlear infusion). Animals were treated in both studies with GDNF for 4 weeks. The study with delayed onset also received a posttreatment with daily injections (i.p.) of antioxidants or saline. Control animals were deafened and received intracochlear infusion of artificial perilymph. Nucelosides and nucleotides are known to function as neurotransmitters and neuromodulater and have recently been shown to have a neurotrophic effect on neurons. Here we tested UTP and uridine in an acute study on deafened guinea pigs. Electrical responsiveness was recorded by eABR measurements and the density of the SGN was investigated. Both studies with GDNF treatment showed a significant difference in eABR thresholds (p<0.001) and SGN density (p<0.001) compared to the control groups. Furthermore, UTP and uridine showed similar results even if not so pronounced. We concluded that GDNF treatment in deafened animals inhibits the degeneration of the SGN even 4 weeks after end of treatment. It is possible that after a critical time following inner ear trauma endogenous survival factors are activated and able to maintain the surviving SGN population. Nucleotides and nucleosides are novel drugs in inner ear treatment and it is possible that drugs acting on purinoreceptors can be of clinical interest for developing new treatment strategies for the injured inner ear

A mandibular protruding device in obstructive sleep apnea and snoring

The overall purpose behind treatment in sleep-breathing disorders is to ease breathing and thereby reduce the risk of morbidity. The mandibular protruding device (MPD) is one method of treating both obstructive sleep apnea (OSA) and snoring. The aims of the studies were to study MPD users after 2 years and evaluate the following aspects of the MPD: subjective and objective effects on sleep, influences on airway passages and hard tissues, and the incidence and types of adverse events of the masticatory system including temporomandibular disorders. Further aims were to evaluate the impact of body posture and the effects of the MPD on pharyngeal width and to validate two methods for measuring mandibular protrusion and MPD advancement. MATERIALS AND METHODS: Seventy-seven subjects with OSA or snorers without OSA, were admitted to the study after a medical examination, which included a somnographic registration. The patients completed questionnaires regarding sleep quality and symptoms from the masticatory system, and underwent a clinical jaw function examination, were given an MPD, and were subjected to lateral cephalometric examination. Two follow-ups, 6 months and 2 years after MPD treatment were conducted. The study population comprised 65 patients at the 2-year follow-up. RESULTS: At the 2-year follow-up, a significant reduction of the subjective complaints was noted by 90% of the MPD users. In the objective evaluation, the oxygen desaturation index (ODI) of the OSA group (n=39) decreased significantly from a mean of 14.7 to 3.1 and the mean arterial oxygen saturation (SaO2) increased significantly from 78% to 89%. The snorers maintained their initial values. In the total group, MPD treatment significantly increased most pharyngeal measures and lifted the hyoid bone. The pharyngeal area decreased significantly - by more than 50% - when the patient was supine, and the velum area increased significantly. At the 2-year follow-up, on upright cephalogram without MPD, the pharyngeal area had significantly increased and the velum area had significantly decreased. The mandible was posteriorly rotated (P&lt;0.01) as well as the lower incisors were proclined (P&lt;0.05). Mandibular advancement and vertical opening with an MPD, as measured with a ruler, compared well with measurements taken from a cephalogram. At the 2-year follow-up significant changes in the mean mandibular range of protrusion (+0.6 mm), overjet (-0.5 mm), and overbite (-0.8 mm) were registered. Nine of the 65 patients had developed a lateral open bite, and 2 were aware of the change. The reported frequency of headache was significantly reduced. At the 2-year follow-up there was a significant reduction in pain during mandibular movements. CONCLUSIONS:MPD treatment significantly reduced subjective complaints of sleep disturbances and significantly reduced ODI values among OSA patients. A high MPD compliance rate after 2 years (84%) indicated a well-tolerated treatment and a low rate of side effects were noted. The key factor in OSA and snoring is the obstruction of pharynx. The MPD treatment significantly increased the pharyngeal passages and significantly reduced the size of velum and thereby facilitated the breathing

"Får barn inte leka kan de inte heller lära för livet" : Förskollärares perspektiv på barns lek och användandet av lek i förskolans verksamhet

Learning for life through play Preschool teachers’ perspective of children’s play and the use of play in the nursery setting Studien behandlar förskollärares perspektiv på barns lek i förskolan och hur de använder sig av lek i verksamheten. Syftet med studien är att få en större uppfattning om hur förskollärare ser på barns lek, hur de anser sig använda leken i verksamheten och om deras synsätt på något sätt präglar hur barns lek kommer till uttryck i förskolans verksamhet. Problempreciseringen i studien innefattas av: Hur anser förskollärare att de använder sig av barns lek i förskolans verksamhet? Vad anser förskollärare om barns olika lekar i förskolan? samt Vilken roll anser förskollärare att de har i barns lek på förskolan? Studien bygger på intervjuer med åtta förskollärare. Resultatet visar på att de intervjuade förskollärarna utgår ifrån barns intresse i leken för att skapa ett lärande och genom lek kan barn bearbeta sina erfarenheter. Leken bidrar till att barn lättare kan ta till sig lärsituationer och att förskollärarna skapar olika förutsättningar med hjälp av olika material och idéer. Barn som leker lär sig olika förhållningssätt som till exempel att bli en lyhörd och inkännande individ. Barn ska få utrymme till att leka olika lekar men det är innehållet som blir föremål för styrning. Förskollärarnas närvaro i barns lek är grundläggande, men närvaron kan gestalta sig på olika sätt. Det självständiga barnet formas genom förskollärarnas förhållningssätt i leken

The outcome of oral appliance therapy on position-dependent obstructive sleep apnea : A multicenter randomized controlled trial

Introduction: This multicenter trial on patients with obstructive sleep apnea (OSA) treated with an oral appliance aimed to determine the effect of sleeping positions. Methods: A cohort of 314 patients with OSA were enrolled and evaluated at 8 weeks and 1 year, focusing on treatment effects. At baseline and the 2 follow-ups, new polygraphic registration comparing the proportion of treatment responders without position-dependent OSA (non-position-dependent OSA [non-POSA]) and with POSA was used. Results: At the 8-week and 1-year follow-up, 205 and 139 patients were included, respectively. The proportion of responders (apnea-hypopnea index [AHI] &lt;10 and/or &gt;= 50% reduction in AHI) was 56% for the non-POSA group and 69% for the POSA group (not significant [NS]). The responders increased at the 1-year follow-up: 68% and 77% for the non-POSA and POSA groups (NS), respectively. The absolute change in AHI in all sleeping positions at 8 weeks was -12.9 (interquartile range, -25.0 to -0.5) in the non-POSA group and -10.5 (interquartile range, -19.9 to -5.3; NS) in the POSA group. However, the decrease in supine AHI was significantly greater among subjects with POSA. In contrast, the decrease in nonsupine AHI was significantly greater in the non-POSA group, an effect that remained at the 1-year follow-up. Conclusions: Our hypothesis that subjects with POSA at baseline would have a higher treatment response rate after oral appliance treatment compared with subjects without POSA was rejected. However, those with POSA had a significantly higher supine AHI decrease, and those without POSA had significantly less nonsupine AHI

Post-Treatment Effects of Local GDNF Administration to the Inner Ears of Deafened Guinea Pigs

For patients with profound hearing loss, a cochlear implant is the only treatment available today. The function of a cochlear implant depends in part on the function and survival of spiral ganglion neurons. Following deafferentation, glial cell-derived neurotrophic factor (GDNF) is known to affect spiral ganglion neuron survival. The purpose of this study was to assess delayed GDNF treatment after deafening, the effects of cessation of GDNF treatment, and the effects of subsequent antioxidants on responsiveness and survival of the spiral ganglion neurons. Three-week deafened (by local neomycin administration) guinea pigs were implanted in the scala tympani with a combined cochlear implant electrode and cannula. GDNF (1 μg/mL) or artificial perilymph was then delivered for 4 weeks, following which the animals received systemic ascorbic acid + Trolox® or saline for an additional 4 weeks. Thresholds for electrically-evoked auditory brain stem responses (eABRs) were significantly elevated at 3 weeks with deafness, stabilized with GDNF, and showed no change with GDNF cessation and treatment with antioxidants or saline. The populations of spiral ganglion neurons were reduced with deafness (by 40% at 3 weeks and 70% at 11 weeks), and rescued from cell death by GDNF with no further reduction at 8 weeks following 4 weeks of cessation of GDNF treatment equally in both the antioxidant- and saline-treated groups. Local growth factor treatment of the deaf ear may prevent deterioration in electrical responsiveness and rescue auditory nerve cells from death; these effects outlast the period of treatment, and may enhance the benefits of cochlear implant therapy for the deaf