Biochemical MRI Predicts Hip Osteoarthritis in an Experimental Ovine Femoroacetabular Impingement Model

BackgroundCam-type femoroacetabular impingement (FAI) resulting from an abnormal nonspherical femoral head shape leads to chondrolabral damage and is considered a cause of early osteoarthritis. A previously developed experimental ovine FAI model induces a cam-type impingement that results in localized chondrolabral damage, replicating the patterns found in the human hip. Biochemical MRI modalities such as T2 and T2* may allow for evaluation of the cartilage biochemistry long before cartilage loss occurs and, for that reason, may be a worthwhile avenue of inquiry.Questions/purposesWe asked: (1) Does the histological grading of degenerated cartilage correlate with T2 or T2* values in this ovine FAI model? (2) How accurately can zones of degenerated cartilage be predicted with T2 or T2* MRI in this model?MethodsA cam-type FAI was induced in eight Swiss alpine sheep by performing a closing wedge intertrochanteric varus osteotomy. After ambulation of 10 to 14 weeks, the sheep were euthanized and a 3-T MRI of the hip was performed. T2 and T2* values were measured at six locations on the acetabulum and compared with the histological damage pattern using the Mankin score. This is an established histological scoring system to quantify cartilage degeneration. Both T2 and T2* values are determined by cartilage water content and its collagen fiber network. Of those, the T2* mapping is a more modern sequence with technical advantages (eg, shorter acquisition time). Correlation of the Mankin score and the T2 and T2* values, respectively, was evaluated using the Spearman’s rank correlation coefficient. We used a hierarchical cluster analysis to calculate the positive and negative predictive values of T2 and T2* to predict advanced cartilage degeneration (Mankin ≥ 3).ResultsWe found a negative correlation between the Mankin score and both the T2 (p < 0.001, r = −0.79) and T2* values (p < 0.001, r = −0.90). For the T2 MRI technique, we found a positive predictive value of 100% (95% confidence interval [CI], 79%–100%) and a negative predictive value of 84% (95% CI, 67%–95%). For the T2* technique, we found a positive predictive value of 100% (95% CI, 79%–100%) and a negative predictive value of 94% (95% CI, 79%–99%).ConclusionsT2 and T2* MRI modalities can reliably detect early cartilage degeneration in the experimental ovine FAI model.

Clinical Relevance

T2 and T2* MRI modalities have the potential to allow for monitoring the natural course of osteoarthrosis noninvasively and to evaluate the results of surgical treatments targeted to joint preservation.     

Diabetes und Schlaganfall

Die Diabetologie - In der Schlaganfallversorgung spielen der Glukose- und Insulinmetabolismus sowohl in der Prävention, als auch der Akutbehandlung eine wichtige Rolle. Das relative Risiko...     

Design Modifications and Computational Fluid Dynamic Analysis of an Outflow Cannula for Cardiopulmonary Bypass

Cardiopulmonary bypass is a well-established technique during open heart surgeries. However, neurological complications due to insufficient cerebral oxygen supply occur and the severe consequences must not be neglected. Recent computational fluid dynamics (CFD) studies showed that during axillary cannulation the cerebral perfusion is strongly affected by the distance between the cannula tip and the vertebral artery branch. In this study we use two modifications of the cannula design to analyze the flow characteristics by means of CFD and experimental validation with particle image velocimetry (PIV). One approach applies a spin to the blood stream with a helical surface in the cannula cross section. Another approach uses radial bores in a constricted cannula tip to split the outflow jet. The additional helicity improves the perfusion of the cerebral vessels and suppresses the blood suction in the right vertebral artery observed with a standard cannula. The cannula with a helix throughout the entire length changes the blood flow from ?124 to 32 mL/min in comparison with an unmodified design and has the lowest prediction of blood damage. Separating the blood stream does not deliver satisfying results. The PIV measurements validate the simulations and correspond with the velocity distribution as well as vortex locations.     

Channelrhodopsin-2–XXL,a powerful optogenetic tool for low-light applications

Channelrhodopsin-2 (ChR2) has provided a breakthrough for the optogenetic control of neuronal activity. In adult Drosophila melanogaster, however, its applications are severely constrained. This limitation in a powerful model system has curtailed unfolding the full potential of ChR2 for behavioral neuroscience. Here, we describe the D156C mutant, termed ChR2-XXL (extra high expression and long open state), which displays increased expression, improved subcellular localization, elevated retinal affinity, an extended open-state lifetime, and photocurrent amplitudes greatly exceeding those of all heretofore published ChR variants. As a result, neuronal activity could be efficiently evoked with ambient light and even without retinal supplementation. We validated the benefits of the variant in intact flies by eliciting simple and complex behaviors. We demonstrate efficient and prolonged photostimulation of monosynaptic transmission at the neuromuscular junction and reliable activation of a gustatory reflex pathway. Innate male courtship was triggered in male and female flies, and olfactory memories were written through light-induced associative training.Identifying causal relationships between neuronal activity and animal behavior is a fundamental goal of neuroscience. Crucially, this task requires testing whether defined neuronal populations are sufficient for eliciting behavioral modules. The development of light-gated ion channels that can be genetically targeted to specific cells has provided a unique solution to this challenge. In pioneering work, such optogenetic effectors or actuators were originally used as multicomponent approaches (1–3). The introduction of Channelrhodopsin-1 (ChR1) (4) and especially ChR2 as a light-sensitive cation channel (5) dramatically advanced the field by providing an efficient and straightforward single-component strategy for stimulating neuronal activity (6, 7).Besides cell-specific targeting of appropriate effector elements, precise neuronal control by optogenetics demands efficient light delivery to the neurons of interest. For behavioral studies, photostimulation is ideally accomplished in intact, freely moving organisms and accompanied by functional readouts. The combination of a rich, well-characterized behavioral repertoire and elegant molecular genetics has contributed to Drosophila’s strong impact on behavioral neurogenetics (8, 9). However, low light transmission through the pigmented cuticle presupposes high light intensities for using ChR2 in flies. This obstacle greatly complicates the experimental setup for freely moving animals, and the required light energies can cause heat damage when stimulation is applied over extended time periods. Moreover, limited cellular availability of all-trans-retinal (hereafter retinal for short) demands adding high retinal concentrations as a dietary supplement. If optical access to target cells is not provided by a translucent body wall (e.g., as in nematodes, zebrafish, and Drosophila larvae), an alternative solution is the implantation of an optical fiber directly into the brain. Although this approach has been used successfully in mammals (10), such an invasive procedure is infeasible for the study of intact small organisms.Due to these restrictions in Drosophila, ChR2 has not reached the popularity attained in other organisms, and instead the field has turned mainly to thermogenetic neuronal stimulation (11–13). As with all techniques, there are also drawbacks to using temperature as a stimulus, such as undesired background activity and a multitude of temperature-sensitive cellular processes and behavioral responses. Photo-liberation of caged ATP, combined with genetic targeting of ATP-gated ion channels, has been introduced as a different optogenetic technique in Drosophila (3, 14). However, its applications are constrained by invasive, time-consuming procedures for injection of caged ATP and a limited experimental time window.Here, we introduce improved ChR2 variants as an alternative approach to address these shortcomings in Drosophila. Compared with wild-type ChR2 (ChR2-wt), expression of these mutants in target cells led to strongly enhanced photocurrents. We provide the first report, to our knowledge, of ChR2-T159C (15, 16) in flies and describe a ChR2 variant, ChR2-XXL (extra high expression and long open state), that is characterized by an extended open-state lifetime, elevated cellular expression, enhanced axonal localization, and reduced dependence on retinal addition. As a consequence, this mutant does not require dietary retinal supplementation to depolarize cells, evoke synaptic transmission, and activate neuronal networks at very low irradiance. These features enabled behavioral photostimulation in freely moving flies using diffuse low-intensity light.