Multiscale photonic imaging of the native and implanted cochlea

The cochlea of our auditory system is an intricate structure deeply embedded in the temporal bone. Compared with other sensory organs such as the eye, the cochlea has remained poorly accessible for investigation, for example, by imaging. This limitation also concerns the further development of technology for restoring hearing in the case of cochlear dysfunction, which requires quantitative information on spatial dimensions and the sensorineural status of the cochlea. Here, we employed X-ray phase-contrast tomography and light-sheet fluorescence microscopy and their combination for multiscale and multimodal imaging of cochlear morphology in species that serve as established animal models for auditory research. We provide a systematic reference for morphological parameters relevant for cochlear implant development for rodent and nonhuman primate models. We simulate the spread of light from the emitters of the optical implants within the reconstructed nonhuman primate cochlea, which indicates a spatially narrow optogenetic excitation of spiral ganglion neurons.

In the case of profound sensorineural hearing impairment, cochlear implants (CIs) partially restore hearing by providing auditory information to the brain via electrical stimulation of the spiral ganglion neurons (SGNs). CIs enable speech understanding in the majority of the ∼700,000 users worldwide. However, current clinical CIs are limited by their wide current spread (1) resulting in poor coding of spectral information (2). Recently, cochlear optogenetics was proposed for stimulating the auditory nerve by light (3–10). As light can be better confined in space, the spread of excitation in the cochlea is lower (3, 9–11) and, hence, future optical CIs (oCIs) promise improved speech comprehension—especially in noisy background—as well as greater music appreciation.For the technical development of oCIs toward a future medical device, major efforts are currently being undertaken to devise multichannel optical stimulators for the cochlea (10, 12–17). As is the case for the electrodes of current CIs, future oCIs will place multiple stimulation channels, here microscale emitters, along the tonotopic axis of the cochlea. Further development of the oCIs requires precise estimates of parameters such as scala tympani size, optimal probe stiffness, and bending radius. Moreover, cochlear optogenetics employs gene transfer to the SGNs for which adeno-associated viruses (AAVs) seem promising candidate vectors (3–5, 8). AAV delivery has used injection of virus suspension via the round window (4, 8) or directly into Rosenthal’s canal (5, 9, 10). Therefore, the volumes of Rosenthal’s canal and the scalae tympani, vestibuli and media needed to be evaluated in order to estimate the required virus load for injection. Finally, the sensorineural status of the cochlea is highly relevant for future gene therapy and CI stimulation, and hence, quantitative imaging of sensory cells and neurons is an important objective.Here, we employed multiscale X-ray phase-contrast tomography (XPCT) and light-sheet fluorescence microscopy (LSFM) and provide an analysis of cochlear morphology for mice, rats, gerbils, guinea pigs, and marmosets. Each of these animal models offers unique advantages for auditory research. The mouse is readily available for genetic manipulation (e.g., ref. 18). Channelrhodopsin-expressing transgenic lines are available also for rats (19, 20) that offer a larger cochlea and can carry heavier implants than mice (21–24). Similarly, gerbils and guinea pigs are established rodent models for auditory research with larger-sized cochleae. Moreover, gerbils, which have low-frequency hearing more similar to humans, have already been employed for cochlear optogenetics (5, 9, 10, 24). Finally, we analyzed the cochlea of the common marmoset, as an established nonhuman primate model for auditory research (e.g., refs. 25, 26). Marmosets possess a rich vocalization repertoire and share a pitch perception mechanism with humans (27). Therefore, we compared cochlear insertion of newly designed oCIs with electrical cochlear implants (eCI) and modeled the optical spread of excitation in the marmoset cochlea.     

The Torg-Pavlov ratio for the prediction of acute spinal cord injury after a minor trauma to the cervical spine

Background contextAcute cervical spinal cord injury (SCI) has been observed in some patients after a minor trauma to the cervical spine. The discrepancy between the severity of the trauma and the clinical symptoms has been attributed to spinal canal stenosis. However, to date, there is no universally established radiological parameter for identifying critical spinal stenosis in these patients. The spinal canal–to–vertebral body ratio (Torg-Pavlov ratio) has been proposed for assessing developmental spinal canal stenosis. The relevance of the Torg-Pavlov ratio for predicting the occurrence and severity of acute cervical SCI after a minor trauma to the cervical spine has not yet been established.PurposeTo investigate the Torg-Pavlov ratio values of the cervical spine in patients suffering from acute cervical SCI after a minor trauma to the cervical spine and the use of the Torg-Pavlov ratio for identifying patients at risk of cervical SCI and predicting the severity and course of symptoms.Study design/settingRetrospective radiological study of consecutive patients.Patient sampleForty-five patients suffering from acute cervical SCI and 68 patients showing no neurologic symptoms after a minor trauma to the cervical spine.Outcome measuresMidvertebral sagittal cervical spinal canal diameter and the sagittal vertebral body diameter. Calculation of the Torg-Pavlov ratio values.MethodsConventional lateral radiographs of the cervical spine (C3–C7) were analyzed to determine the Torg-Pavlov ratio values. Receiver operating characteristic curves were calculated for evaluating the classification accuracy of the Torg-Pavlov ratio for predicting SCI.ResultsThe Torg-Pavlov ratio values in the SCI group were significantly (p<.04) smaller compared with that in the control group. A Torg-Pavlov ratio cutoff value of 0.7 yielded the greatest positive likelihood ratio for predicting the occurrence of SCI. However, there were no significant differences in the Torg-Pavlov ratio values between the different American Spinal Injury Association Impairment Score groups and between patients with complete, partial, and no recovery of symptoms.ConclusionsDevelopmental cervical spinal canal stenosis assessed by the Torg-Pavlov ratio was characteristic for patients suffering from acute cervical SCI after a minor trauma to the cervical spine. Patients at risk of SCI after a minor trauma to the cervical spine can be identified by applying a Torg-Pavlov ratio cutoff value of 0.7. Other factors in addition to the spinal canal–to–vertebral body ratio affect the severity and course of symptoms as a result of cervical SCI.     

Local and transient inhibition of p21 expression ameliorates age‐related delayed wound healing

Nonhealing chronic wounds in the constantly growing elderly population represent a major public health problem with high socioeconomic burden. Yet, the underlying mechanism of age‐related impairment of wound healing remains elusive. Here, we show that the number of dermal cells expressing cyclin‐dependent kinase inhibitor p21 was elevated upon skin injury, particularly in aged population, in both man and mouse. The nuclear expression of p21 in activated wound fibroblasts delayed the onset of the proliferation phase of wound healing in a p53‐independent manner. Further, the local and transient inhibition of p21 expression by in vivo delivered p21‐targeting siRNA ameliorated the delayed wound healing in aged mice. Our results suggest that the increased number of p21⁺ wound fibroblasts enforces the age‐related compromised healing, and targeting p21 creates potential clinical avenues to promote wound healing in aged population.     

Investigations of Platelet Function in Whole Blood with BAPA as Anticoagulant

BACKGROUND: Citrate anticoagulation of blood results in non-physiologically low calcium concentration and rapid deterioration of platelet viability. Benzylsulfonyl-D-Arg-Pro-4-amidinobenzylamide (BAPA) as anticoagulant maintains the physiological calcium level and seems to retain platelet function (PF) over a time period of at least 24 h. We evaluated PF in BAPA-anticoagulated peripheral whole blood (WB) between 0.5 and 30 h after blood collection. METHODS: In WB from 21 healthy volunteers (15 women, 6 men, age range 19-57 years) platelet aggregation (PA) was determined by impedance method and ATP release by luminometry. Platelet response was tested by ADP (10 and 20 μmol/l) and collagen (1 and 2 μg/ml) between 0.5 and 30 h after blood collection. RESULTS: Parameters of ADP-induced PA showed stable values until 6.5 h after blood collection followed by a significant decline. PA in response to collagen was stable up to 25 h of storage. ATP release induced by collagen displayed a continuous, significant decrease over time. CONCLUSION: Preservation of platelet response in BAPA-anticoagulated blood depends on the applied agonist showing that collagen-induced PA is more stable compared to ADP known as a weak agonist in WB.     

Beneficial effects of cannabinoids (CB) in a murine model of allergen-induced airway inflammation: role of CB1/CB2 receptors

The endocannabinoid system (ECS) consists of two cannabinoid (CB) receptors, namely CB₁ and CB₂ receptor, and their endogenous (endocannabinoids) and exogenous (cannabinoids, e.g. delta-9-tetrahydrocannabinol (THC)) ligands which bind to these receptors. Based on studies suggesting a role of THC and the ECS in inflammation, the objective of this study was to examine their involvement in type I hypersensitivity using a murine model of allergic airway inflammation. THC treatment of C57BL/6 wildtype mice dramatically reduced airway inflammation as determined by significantly reduced total cell counts in bronchoalveolar lavage (BAL). These effects were greatest when mice were treated during both, the sensitization and the challenge phase. Furthermore, systemic immune responses were significantly suppressed in mice which received THC during sensitization phase. To investigate a role of CB_1/2 receptors in this setting, we used pharmacological blockade of CB₁ and/or CB₂ receptors by the selective antagonists and moreover CB₁/CB₂ receptor double-knockout mice (CB₁^−/−/CB₂^−/−) and found neither significant changes in the cell patterns in BAL nor in immunoglobulin levels as compared to wildtype mice. Our results indicate that the activation of the ECS by applying the agonist THC is involved in the development of type I allergies. However, CB₁/CB₂ receptor-independent signalling seems likely in the observed results.     

Synergistic effects of planning and self-efficacy on physical activity

Many individuals are motivated to improve their physical activity levels but often fail to act on their good intention. This study examines the roles of planning and self-efficacy in the prediction of physical activity. A total of 290 participants (77% women, mean age = 41.9 years) were surveyed three times. Intentions, planning, and physical activity were specified as a mediator chain. Results reveal that intentions were partly translated into physical activity by planning. Self-efficacy moderated this mediation, reflected by a planning × self-efficacy interaction (p < .05) on physical activity accounting for 16% of the variance in behavior. If a person is self-efficacious, planning seems more likely to be translated into physical activity.     

Efficacy of exercise training in pulmonary arterial hypertension associated with congenital heart disease

Background

The objective of this prospective study was to assess the efficacy of exercise training as add-on to medical therapy in patients with congenital heart disease associated pulmonary arterial hypertension (CHD–APAH).

Methods

Patients with invasively confirmed CHD–APAH received in-hospital exercise training for 3 weeks and continued at home. Efficacy parameters were evaluated at baseline, after 3 and 15 weeks. Medical treatment remained unchanged. Worsening events and survival rate were assessed in a follow-up period of 21 ± 14 months.

Results

Twenty consecutive CHD–APAH patients (16 female, 4 male, mean pulmonary arterial pressure 60 ± 23 mm Hg) were included. Patients significantly improved the mean distance walked in 6 min compared to baseline by 63 ± 47 m after 3 weeks (p < 0.001) and by 67 ± 59 m after 15 weeks (p = 0.001). Quality of life-score (p = 0.05), peak oxygen consumption (p = 0.002) and maximal workload (p = 0.003) improved significantly by exercise training after 15 weeks. The 1- and 2‐year survival rates were 100%, the transplantation-free survival rate was 100% after 1 year and 93% after 2 years.

Conclusion

Exercise training as add-on to medical therapy may be effective in patients with CHD–APAH and improved work capacity, quality of life and further prognostic relevant parameters. It was associated with an excellent long-term survival. Further randomized controlled studies are needed to confirm these results.