Klinik und Poliklinik für Hals-, Nasen-, Ohrenheilkunde

Activation of Wnt signaling through β-catenin/TCF complexes is a key event in the development of various tumors, in particular colorectal and liver tumors. Wnt signaling is controlled by the negative regulator conductin/axin2/axil, which induces degradation of β-catenin by functional interaction with the tumor suppressor APC and the serine/threonine kinase GSK3β. Here we show that conductin is upregulated in human tumors that are induced by β-catenin/Wnt signaling, i.e., high levels of conductin protein and mRNA were found in colorectal and liver tumors but not in the corresponding normal tissues. In various other tumor types, conductin levels did not differ between tumor and normal tissue. Upregulation of conductin was also observed in the APC-deficient intestinal tumors of Min mice. Inhibition of Wnt signaling by a dominant-negative mutant of TCF downregulated conductin but not the related protein, axin, in DLD1 colorectal tumor cells. Conversely, activation of Wnt signaling by Wnt-1 or dishevelled increased conductin levels in MDA MB 231 and Neuro2A cells, respectively. In time course experiments, stabilization of β-catenin preceded the upregulation of conductin by Wnt-1. These results demonstrate that conductin is a target of the Wnt signaling pathway. Upregulation of conductin may constitute a negative feedback loop that controls Wnt signaling activity.

BACKGROUND: The Fédération Internationale de Football Association (FIFA) World Cup, held in Germany from June 9 to July 9, 2006, provided an opportunity to examine the relation between emotional stress and the incidence of cardiovascular events. METHODS: Cardiovascular events occurring in patients in the greater Munich area were prospectively assessed by emergency physicians during the World Cup. We compared those events with events that occurred during the control period: May 1 to June 8 and July 10 to July 31, 2006, and May 1 to July 31 in 2003 and 2005. RESULTS: Acute cardiovascular events were assessed in 4279 patients. On days of matches involving the German team, the incidence of cardiac emergencies was 2.66 times that during the control period (95% confidence interval [CI], 2.33 to 3.04; P<0.001); for men, the incidence was 3.26 times that during the control period (95% CI, 2.78 to 3.84; P<0.001), and for women, it was 1.82 times that during the control period (95% CI, 1.44 to 2.31; P<0.001). Among patients with coronary events on days when the German team played, the proportion with known coronary heart disease was 47.0%, as compared with 29.1% of patients with events during the control period. On those days, the highest average incidence of events was observed during the first 2 hours after the beginning of each match. A subanalysis of serious events during that period, as compared with the control period, showed an increase in the incidence of myocardial infarction with ST-segment elevation by a factor of 2.49 (95% CI, 1.47 to 4.23), of myocardial infarction without ST-segment elevation or unstable angina by a factor of 2.61 (95% CI, 2.22 to 3.08), and of cardiac arrhythmia causing major symptoms by a factor of 3.07 (95% CI, 2.32 to 4.06) (P<0.001 for all comparisons). CONCLUSIONS: Viewing a stressful soccer match more than doubles the risk of an acute cardiovascular event. In view of this excess risk, particularly in men with known coronary heart disease, preventive measures are urgently needed.

Osteogenesis and angiogenesis are two closely correlated processes during bone growth, development, remodelling and repair. Vascular endothelial growth factor (VEGF) is an essential mediator during the process of angiogenesis. Based on an extensive literature search, which was carried out using the PubMed database and the keywords of osteogenesis, VEGF, endochondral ossification and intramembranous ossification, this manuscript reviews the role of VEGF in ossification, with emphasis on its effect in endochondral and intramembranous ossification. Osteogenesis and angiogenesis are closely correlated processes. VEGF acts as an essential mediator during these processes. It not only functions in bone angiogenesis but also in various aspects of bone development. Vascular endothelial growth factor (VEGF) plays roles in both blood vessel formation (angiogenesis) and bone formation (osteogenesis). Scientists knew that VEGF is a trigger for vascularization. However, a growing body of work suggests that it also modulates the behavior of cells that form and remodel bone. After reviewing the literature, a team led by Yan-Qi Yang of the University of Hong Kong, China, compiled the evidence supporting this dual role for VEGF. Long bones such as limbs are formed by a mechanism called ‘endochondral ossification’, and numerous studies suggest that VEGF regulates this process directly and indirectly through its angiogenic effects. Other bones, like those in the face, form from connective tissue via ‘intramembranous ossification’. VEGF similarly helps to coordinate migration and differentiation of bone cells during this process.

Combined electric and acoustic stimulation (EAS) of the auditory system is a new therapy for patients with severe to profound high- and mid-frequency hearing loss but remaining low-frequency hearing. In a prospective study, 13 patients with low-frequency hearing of better than 60 dB below 1 kHz were implanted with a MED-EL COMBI 40+ cochlear implant. Pure tone thresholds as well as monosyllabic word scores and Hochmair-Schulz-Moser sentences in quiet and in noise were measured with hearing aids, cochlear implant alone and in the combined stimulation mode (EAS) in the same ear. Hearing could be partially preserved in 11 out of the 13 patients. All patients scored significantly higher with cochlear implant alone than with hearing aids. Seven patients scored higher in the EAS mode than with cochlear implant alone for sentences in noise, 4 remained unchanged, and 2 could not use EAS. Synergistic effects of EAS were most prominent for hearing in noise with increases of up to 72% as compared to cochlear implant alone.

Overdiagnosis of Parkinson's disease (PD) is suggested by specialist review of community diagnosis, and in postmortem studies. In specialist centers 4 to 15% of patients entered into clinical trials as early PD do not have functional imaging support for a PD diagnosis. In a European multicenter, prospective, longitudinal study, we compared clinical diagnosis with functional SPECT imaging using [123I]FP-CIT (DaTSCAN, GE Healthcare). Repeat observations were performed over 3 years in patients with tremor and/or parkinsonism in whom there was initial diagnostic uncertainty between degenerative parkinsonism and nondegenerative tremor disorders. Video-recording of clinical features was scored independently of functional imaging results by two blinded clinicians at 36 months (= gold standard clinical diagnosis). Three readers, unaware of the clinical diagnosis, classified the images as normal or abnormal by visual inspection. The main endpoint was the sensitivity and specificity of SPECT imaging at baseline compared with the gold standard. In 99 patients completing the three serial assessments, on-site clinical diagnosis overdiagnosed degenerative parkinsonism at baseline in diagnostically uncertain cases compared with the gold standard clinical diagnosis (at 36 months), the latter giving a sensitivity of 93% and specificity of 46%. The corresponding baseline [123I]FP-CIT SPECT results showed a mean sensitivity of 78% and a specificity of 97%. Inter-reader agreement for rating scans as normal or abnormal was high (Cohen's kappa = 0.94-0.97).

OBJECTIVE: Vectors based on recombinant adeno-associated virus 2 (AAV-2) are a promising tool for cardiac gene transfer. However, potential therapeutic applications need to consider the predominant transduction of the liver once AAV-2 vectors enter the systemic circulation. We therefore aimed to increase efficiency and specificity of cardiac vector delivery by combining transcriptional and cell surface targeting. METHODS: For analysis of transcriptional targeting, recombinant AAV vectors were generated harboring a luciferase reporter gene under control of the cytomegalovirus (CMV) promoter or the 1.5-kb cardiac myosin light chain promoter fused to the CMV immediate-early enhancer (CMV(enh)/MLC1.5). Luciferase activities were determined in representative organs three weeks after intravenous injection of the vector into adult mice. Transductional targeting was studied using luciferase-reporter constructs crosspackaged into capsids of AAV serotypes 1 to 6 and modified AAV-2 capsids devoid of binding their primary receptor heparan sulfate proteoglycan. RESULTS: Intravenous injections of AAV-2 vectors harboring the CMV(enh)/MLC1.5 promoter enabled a specific and 50-fold higher reporter gene expression in left ventricular myocardium of adult mice compared to vectors containing the CMV promoter. Comparison of AAV-2 vector genomes crosspackaged into capsids of AAV-1 to -6 showed that AAV-1, -4, -5, and -6 capsids increased cardiac transduction efficiency by about 10-fold. However, transduction of other organs such as the liver was also increased after systemic administration. In contrast, AAV-2-based vectors with ablated binding to their primary receptor heparan sulfate proteoglycan enabled a significantly increased efficiency of cardiac gene transfer and reduced transduction of the liver. CONCLUSIONS: Combining transcriptional targeting by the CMV(enh)/MLC1.5 promoter and AAV vectors devoid of binding the AAV-2 primary receptor results in an efficient cardiac gene transfer with a significantly reduced hepatic transduction.

STUDY OBJECTIVES: Long-duration (> or = 6 months) polysomnographic studies of insomnia medications are lacking. This study evaluated the long-term efficacy of ramelteon, a selective MT1/MT2 melatonin-receptor agonist used for insomnia treatment. DESIGN: Six-month, randomized, double-blind, placebo-controlled study. SETTING: Forty-six investigative sites in the United States, Europe, Russia, and Australia. PARTICIPANTS: Four hundred fifty-one adults (age > or = 18 years) with chronic primary insomnia. INTERVENTIONS: Ramelteon, 8 mg, or placebo 30 minutes before bedtime nightly for 6 months. MEASUREMENTS: Sleep was evaluated by polysomnography and morning questionnaires on the first 2 nights of Week 1; the last 2 nights of Months 1, 3, 5, and 6; and Nights 1 and 2 of the placebo run-out. Next-morning residual effects as well as adverse effects and vital signs were recorded at each visit. Rebound insomnia and withdrawal effects were evaluated during placebo run-out. RESULTS: Over the 6 months of treatment, ramelteon consistently reduced latency to persistent sleep compared with baseline and with placebo; significant decreases were observed at Week 1 and Months 1, 3, 5, and 6 (P < 0.05). Ramelteon significantly reduced subjective sleep latency relative to placebo at Week 1, Month 1, and Month 5 (P < 0.05), with reductions nearing statistical significance at Months 3 and 6 (P < or = 0.08). No significant next-morning residual effects were detected during ramelteon treatment. No withdrawal symptoms or rebound insomnia were detected after ramelteon discontinuation. Most adverse events were mild or moderate in severity. CONCLUSIONS: In adults with chronic insomnia, long-term ramelteon treatment consistently reduced sleep onset, with no next-morning residual effects or rebound insomnia or withdrawal symptoms upon discontinuation.

BACKGROUND: This study evaluated the prognostic value of a three-grade staging system of spinal involvement using magnetic resonance imaging (MRI) in patients with multiple myeloma and determined its usefulness as an independent parameter in the staging system of Durie and Salmon. METHODS: Seventy-seven previously untreated patients with multiple myeloma underwent MRI of the thoracic and lumbar spine with unenhanced T1-weighted spin echo and short-tau inversion time inversion recovery sequences. The patients were evaluated according to their infiltration patterns and the extent of bone marrow involvement was staged using a three-grade scale: Stage I, no focal or diffuse infiltration; Stage II, 1-10 foci or mild diffuse infiltration; Stage III, more than 10 foci or strong diffuse infiltration. RESULTS: The infiltration patterns had no significant effect on survival. Of 77 patients, 25 would have been understaged using the standard staging system of Durie and Salmon without the findings of MRI and 8 patients would have been understaged if the staging was based only on MRI. The combination of the staging system of Durie and Salmon and MRI was highly significant with respect to survival (P < 0.0001, log rank analysis). MRI staging I-III was independent of the staging system of Durie and Salmon (Cox regression model). CONCLUSIONS: A three-grade staging of spinal MRI provides a significant prognostic tool for patients with multiple myeloma. The authors propose including it in the staging system of Durie and Salmon.

The deafness caused by early onset hypothyroidism indicates that thyroid hormone is essential for the development of hearing. We investigated the underlying roles of the TRalpha1 and TRbeta thyroid hormone receptors in the auditory system using receptor-deficient mice. TRalpha1 and TRbeta, which act as hormone-activated transcription factors, are encoded by the Thra and Thrb genes, respectively, and both are expressed in the developing cochlea. TRbeta is required for hearing because TRbeta-deficient (Thrb(tm1/tm1)) mice have a defective auditory-evoked brainstem response and retarded expression of a potassium current (I(K,f)) in the cochlear inner hair cells. Here, we show that although TRalpha1 is individually dispensable, TRalpha1 and TRbeta synergistically control an extended array of functions in postnatal cochlear development. Compared with Thrb(tm1/tm1) mice, the deletion of all TRs in Thra(tm1/tm1)Thrb(tm1/tm1) mice produces exacerbated and novel phenotypes, including delayed differentiation of the sensory epithelium, malformation of the tectorial membrane, impairment of electromechanical transduction in outer hair cells, and a low endocochlear potential. The induction of I(K,f) in inner hair cells was not markedly more retarded than in Thrb(tm1/tm1) mice, suggesting that this feature of hair cell maturation is primarily TRbeta-dependent. These results indicate that distinct pathways mediated by TRbeta alone or by TRbeta and TRalpha1 together facilitate control over an extended range of functions during the maturation of the cochlea.

The success and safety of standard catheter radiofrequency ablation may be limited for ablation of atrial fibrillation and ventricular tachycardia. The aim of this study was to characterize and compare different cooled and noncooled catheter systems in terms of their specific lesion geometry, incidence of impedance rise, and crater and coagulum formation to facilitate appropriate catheter selection for special indications. The study investigated myocardial lesion generation of three cooled catheter systems (7 Fr, 4-mm tip): two saline irrigation catheters with a showerhead-type electrode tip (sprinkler) and a porous metal tip and an internally cooled catheter. Noncooled catheters (7 Fr) had a large tip electrode (8 mm) and a standard tip electrode (4 mm). RF energy was delivered on isolated porcine myocardium superfused with heparinized pig blood (37 degrees C) at power settings of 10-40 W. Both irrigated systems were characterized by a large lesion depth (8.1 +/- 1.6 mm) and a large lesion diameter (13.8 +/- 1.6 mm). In comparison, internally cooled lesions showed a similar lesion depth (8.0 +/- 1.0 mm), but a significantly smaller lesion diameter (12.3 +/- 1.2 mm,P = 0.04). Large tip lesions had a similar lesion diameter (14.5 +/- 1.6 mm), but a significantly smaller lesion depth (6.3 +/- 1.0 mm,P = 0.002) compared to irrigated lesions. However, lesion volume was not significantly different between the three cooled and the large tip catheter. To induce maximum lesion size, power requirements were three times higher for the irrigation systems and two times higher for the internally cooled and the large tip catheter compared to the standard catheter. Impedance rise was rarest with irrigated and large tip ablation. In case of impedance rise crater formation was a frequent observation (61-93%). Irrigated catheters prevented coagulum formation most effectively. Irrigated rather than internally cooled ablation appears to be most adequate for the induction of deep and long lesions at a low rate of impedance rise and thrombus formation. Large tip ablation may be feasible for the creation of long linear lesions, however, with an increased risk of thrombus formation.

BACKGROUND: At present, the flexible endoscopic evaluation of swallowing (FEES) is one of the most commonly used methods for the objective assessment of swallowing. This multicenter trial prospectively collected data on the safety of FEES and also assessed the impact of this procedure on clinical dysphagia management. METHODS: Patients were recruited in 23 hospitals in Germany and Switzerland from September 2014 to May 2017. Patient characteristics, professional affiliation of the FEES examiners (physicians or speech and language therapists), side-effects and cardiorespiratory parameters, severity of dysphagia and clinical consequences of FEES were documented. RESULTS: 2401 patients, mean age 69.8 (14.6) years, 42.3% women, were included in the FEES-registry. The most common main diagnosis was stroke (61%), followed by Parkinson's disease (6.5%). FEES was well tolerated by patients. Complications were reported in 2% of examinations, were all self-limited and resolved without sequelae and showed no correlation to the endoscopist's previous experience. In more than 50% of investigations FEES led to changes of feeding strategies, in the majority of cases an upgrade of oral diet was possible. DISCUSSION: This study confirmed that FEES, even when performed by less experienced clinicians is a safe and well tolerated procedure and significantly impacts on the patients' clinical course. Implementation of a FEES-service in different clinical settings may improve dysphagia care. TRIAL REGISTRATION: ClinicalTrials.gov NCT03037762, registered January 31st 2017.

Adult human neural crest-derived stem cells (NCSCs) are of extraordinary high plasticity and promising candidates for the use in regenerative medicine. Here we describe for the first time a novel neural crest-derived stem cell population within the respiratory epithelium of human adult inferior turbinate. In contrast to superior and middle turbinates, high amounts of source material could be isolated from human inferior turbinates. Using minimally-invasive surgery methods isolation is efficient even in older patients. Within their endogenous niche, inferior turbinate stem cells (ITSCs) expressed high levels of nestin, p75(NTR), and S100. Immunoelectron microscopy using anti-p75 antibodies displayed that ITSCs are of glial origin and closely related to nonmyelinating Schwann cells. Cultivated ITSCs were positive for nestin and S100 and the neural crest markers Slug and SOX10. Whole genome microarray analysis showed pronounced differences to human ES cells in respect to pluripotency markers OCT4, SOX2, LIN28, and NANOG, whereas expression of WDR5, KLF4, and c-MYC was nearly similar. ITSCs were able to differentiate into cells with neuro-ectodermal and mesodermal phenotype. Additionally ITSCs are able to survive and perform neural crest typical chain migration in vivo when transplanted into chicken embryos. However ITSCs do not form teratomas in severe combined immunodeficient mice. Finally, we developed a separation strategy based on magnetic cell sorting of p75(NTR) positive ITSCs that formed larger neurospheres and proliferated faster than p75(NTR) negative ITSCs. Taken together our study describes a novel, readily accessible source of multipotent human NCSCs for potential cell-replacement therapy.

CONTEXT: Somatic mutations in PRKACA gene, encoding the catalytic subunit of protein kinase A (PKA), have been recently found in a high proportion of sporadic adenomas associated with Cushing's syndrome. The aim was to analyze the PRKACA mutation in a large cohort of patients with adrenocortical masses. METHODS: Samples from nine European centers were included (Germany, n = 4; Italy, n = 4; France, n = 1). Samples were drawn from 149 patients with nonsecreting adenomas (n = 32 + 2 peritumoral), subclinical hypercortisolism (n = 36), Cushing's syndrome (n = 64 + 2 peritumoral), androgen-producing tumors (n = 4), adrenocortical carcinomas (n = 5 + 2 peritumoral), and primary bilateral macronodular adrenal hyperplasias (n = 8). Blood samples were available from patients with nonsecreting adenomas (n = 15), subclinical hypercortisolism (n = 10), and Cushing's syndrome (n = 35). Clinical and hormonal data were collected. DNA amplification by PCR of exons 6 and 7 of the PRKACA gene and direct sequencing were performed. RESULTS: PRKACA heterozygous mutations were found in 22/64 samples of Cushing's syndrome patients (34%). No mutations were found in peritumoral tissue and blood samples or in other tumors examined. The c.617A>C (p.Leu206Arg) occurred in 18/22 patients. Furthermore, two novel mutations were identified: c.600_601insGTG/p.Cys200_Gly201insVal in three patients and c.639C>G+c.638_640insATTATCCTGAGG/p.Ser213Arg+p.Leu212_Lys214insIle-Ile-Leu-Arg) in one. All the mutations involved a region implicated in interaction between PKA regulatory and catalytic subunits. Patients with somatic PRKACA mutations showed higher levels of cortisol after dexamethasone test and a smaller adenoma size, compared with nonmutated subjects. CONCLUSIONS: These data confirm and extend previous observations that somatic PRKACA mutations are specific for adrenocortical adenomas causing Cushing's syndrome.

PURPOSE: To compare high-resolution T2-weighted images of the liver with and without integrated parallel acquisition techniques (iPAT) using either breath-hold sequences in combination with prospective acquisition motion correction (PACE) or respiratory triggering. MATERIALS AND METHODS: Ten volunteers and 10 patients underwent each four different high-resolution fast spin echo (FSE) T2-weighted sequences with 5 mm slice thickness and a full 320 matrix: a multi-breath-hold FSE sequence with and without iPAT and PACE and a respiratory-triggered FSE sequence with and without iPAT. Image quality was rated with a five-point scale by two independent readers. Signal intensity measurements were performed on a water phantom. RESULTS: The sequences with iPAT required a substantially shorter acquisition time without loss of image quality. Overall image quality was rated equal for all sequences by both readers. Image time for nine slices with iPAT was 13 seconds (19 seconds without iPAT) with multi-breath-hold and on average 4:00 minutes (7:02 minutes without iPAT) with respiratory triggering. Imaging with the PACE technique resulted in more correct positioning of the image stacks. CONCLUSION: T2-weighted fast imaging with iPAT is feasible and results in high-quality images within a short acquisition time. Overall image quality is not negatively affected by iPAT.

Concepts for ventricular function tend to assume that the majority of the myocardial cells are aligned with their long axes parallel to the epicardial ventricular surface. We aimed to validate the existence of aggregates of myocardial cells orientated with their long axis intruding obliquely between the ventricular epicardial and endocardial surfaces and to quantitate their amount and angulation. To compensate for the changing angle of the long axis of the myocytes relative to the equatorial plane of the ventricles with varying depths within the ventricular walls, the so-called helical angle, we used pairs of cylindrical knives of different diameters to punch semicircular slices from the left ventricular wall of pigs, the slices extending from the epicardium to the endocardium. The slices were pinned flat, fixed in formaldehyde, embedded in paraffin, sectioned, stained with azan or hematoxilin and eosin, and analyzed by a new semiautomatic procedure. We made use of new techniques in informatics to determine the number and angulation of the aggregates of myocardial cells cut in their long axis. The alignment of the myocytes cut longitudinally varied markedly between the epicardium and the endocardium. Populations of myocytes, arranged in strands, diverge by varying angles from the epicardial surface. When paired knives of decreasing diameter were used to cut the slices, the inclination of the diagonal created by the arrays increases, while the lengths of the array of cells cut axially decreases. The visualization of the size, shape, and alignment of the myocytic arrays at any side of the ventricular wall is determined by the radius of the knives used, the range of helical angles subtended by the alignment of the myocytes throughout the thickness of the wall, and their angulation relative to the epicardial surface. Far from the majority of the ventricular myocytes being aligned at angles more or less tangential to the epicardial lining, we found that three-fifths of the myocardial cells had their long axes diverging at angles between 7.5 and 37.5 degrees from an alignment parallel to the epicardium. This arrangement, with the individual myocytes supported by connective tissue, might control the cyclic rearrangement of the myocardial fibers. This could serve as an important control of both ventricular mural thickening and intracavitary shape.

A nonlinear model predictive control (NMPC) for the thermal management (TM) of plug-in hybrid electric vehicles (PHEVs) is presented. TM in PHEVs is crucial to ensure high components' performance and durability in all possible climate scenarios. A drawback of accurate TM solutions is the higher electrical consumption due to the increasing number of low-voltage actuators used in the cooling circuits. Hence, more complex control strategies are needed for minimizing components' thermal stress and, at the same time, electrical consumption. In this context, NMPC proves to be a powerful method for achieving multiple objectives in multiple input multiple output systems. This paper proposes an NMPC for the TM of the high-voltage battery and the power electronics cooling circuit in a PHEV. It distinguishes itself from the previously NMPC reported methods in the automotive sector by the complexity of its controlled plant, which is highly nonlinear and controlled by numerous variables. The implemented model of the plant, which is based on experimental data and multidomain physical equations, has been validated using six different driving cycles logged in a real vehicle, obtaining a maximum error, in comparison with the real temperatures of 2°C. For one of the six cycles, an NMPC software-in-the loop (SIL) is presented, where the models inside the controller and for the controlled plant are the same. This simulation is compared with the finite-state machine-based strategy performed in the real vehicle. The results show that NMPC keeps the battery at healthier temperatures and reduces the cooling electrical consumption by more than 5%. In terms of the objective function, which is an accumulated and weighted sum of the two goals, this improvement amounts to 30%. Finally, the online SIL presented in this paper suggests that the used optimizer is fast enough for a future implementation in the vehicle.

To classify sleep related rhythmic movement disorder (SRMD) based on clinical, polysomnographic and videometric evaluation in a predominantly adult population, twenty-four patients (four females) aged 11-67 years identified by polysomnography and videometry were classified for type of SRMD, its duration and frequency during wakefulness and in the different sleep stages. SRMD persisted unto child- and adulthood in all patients. SRMD is not restricted to sleep-wake transition, occurs most frequently in wake, stages NREM 1 and 2, but also in REM and slow wave sleep. Most patients have one form of SRMD, few have two forms in one night. Longest duration is in wakefulness. Duration does not differ from one sleep cycle to another. Sleep is not fragmented by SRMD, and sleep stages generally do not change when SRMD occurs. Only few patients have short awakenings after SRMD. In four patients with sleep apnea SRMD coincided frequently with the onset of the apnea related arousal. Two patients had a family history of SRMD. In contrast to the ICSD-2 SRMD seems to persist into adulthood frequently with male preponderance. Familial forms are rare. SRMD in the investigated population is always occurring during sleep, even if patients reported it to occur strictly at wake-sleep transition. Polysomnography is a useful method to uncover SRMD aggravated by other sleep disorders and allows insight in some aspects of the pathology of this disorder, which is not well understood. In the adult patients it is not associated with mental pathologies and can be triggered by sleep apnea.

BACKGROUND AND PURPOSE: We sought to demonstrate that tumor necrosis factor (TNF)-α, via sphingosine-1-phosphate signaling, has the potential to alter cochlear blood flow and thus, cause ischemic hearing loss. METHODS: We performed intravital fluorescence microscopy to measure blood flow and capillary diameter in anesthetized guinea pigs. To measure capillary diameter ex vivo, capillary beds from the gerbil spiral ligament were isolated from the cochlear lateral wall and maintained in an organ bath. Isolated gerbil spiral modiolar arteries, maintained and transfected in organ culture, were used to measure calcium sensitivity (calcium-tone relationship). In a clinical study, a total of 12 adult patients presenting with typical symptoms of sudden hearing loss who were not responsive or only partially responsive to prednisolone treatment were identified and selected for etanercept treatment. Etanercept (25 mg s.c.) was self-administered twice a week for 12 weeks. RESULTS: TNF-α induced a proconstrictive state throughout the cochlear microvasculature, which reduced capillary diameter and cochlear blood flow in vivo. In vitro isolated preparations of the spiral modiolar artery and spiral ligament capillaries confirmed these observations. Antagonizing sphingosine-1-phosphate receptor 2 subtype signaling (by 1 μmol/L JTE013) attenuated the effects of TNF-α in all models. TNF-α activated sphingosine kinase 1 (Sk1) and induced its translocation to the smooth muscle cell membrane. Expression of a dominant-negative Sk1 mutant (Sk1(G82D)) eliminated both baseline spiral modiolar artery calcium sensitivity and TNF-α effects, whereas a nonphosphorylatable Sk1 mutant (Sk1(S225A)) blocked the effects of TNF-α only. A small group of etanercept-treated, hearing loss patients recovered according to a 1-phase exponential decay (half-life=1.56 ± 0.20 weeks), which matched the kinetics predicted for a vascular origin. CONCLUSIONS: TNF-α indeed reduces cochlear blood flow via activation of vascular sphingosine-1-phosphate signaling. This integrates hearing loss into the family of ischemic microvascular pathologies, with implications for risk stratification, diagnosis, and treatment.

OBJECTIVE: The purpose of the study was to investigate speech reception in noise in subjects who had undergone bilateral implantation with multichannel cochlear implants. METHODS: Nine adults with bilateral MED-EL implants were included in the study. The subjects were tested using both implants and the better implant only. Tests were performed in a symmetrical setup, which ideally eliminates any head shadow effect. Speech tests included sentences in quiet and at various signal-to-noise ratios. From the results, the gain in signal-to-noise ratios at the speech reception threshold was determined. RESULTS: All subjects showed a substantial gain in signal-to-noise ratios of approximately 4 dB on average. In addition, the gain in signal-to-noise ratios was essentially stable for as long as 4.4 years. CONCLUSIONS: The results indicate that bilateral cochlear implant users are able to binaurally process speech.

This special issue of Ambio compiles a series of contributions made at the 8th International Phosphorus Workshop (IPW8), held in September 2016 in Rostock, Germany. The introducing overview article summarizes major published scientific findings in the time period from IPW7 (2015) until recently, including presentations from IPW8. The P issue was subdivided into four themes along the logical sequence of P utilization in production, environmental, and societal systems: (1) Sufficiency and efficiency of P utilization, especially in animal husbandry and crop production; (2) P recycling: technologies and product applications; (3) P fluxes and cycling in the environment; and (4) P governance. The latter two themes had separate sessions for the first time in the International Phosphorus Workshops series; thus, this overview presents a scene-setting rather than an overview of the latest research for these themes. In summary, this paper details new findings in agricultural and environmental P research, which indicate reduced P inputs, improved management options, and provide translations into governance options for a more sustainable P use.