Microvascular damage assessed by optical coherence tomography angiography for glaucoma diagnosis: a systematic review of the most discriminative regions

A growing number of studies have reported a link between vascular damage and glaucoma based on optical coherence tomography angiography (OCTA) imaging. This multitude of studies focused on different regions of interest (ROIs) which offers the possibility to draw conclusions on the most discriminative locations to diagnose glaucoma. The objective of this work was to review and analyse the discriminative capacity of vascular density, retrieved from different ROIs, on differentiating healthy subjects from glaucoma patients. PubMed was used to perform a systematic review on the analysis of glaucomatous vascular damage using OCTA. All studies up to 21 April 2019 were considered. The ROIs were analysed by region (macula, optic disc and peripapillary region), layer (superficial and deep capillary plexus, avascular, whole retina, choriocapillaris and choroid) and sector (according to the Garway–Heath map). The area under receiver operator characteristic curve (AUROC) and the statistical difference (p-value) were used to report the importance of each ROI for diagnosing glaucoma. From 96 screened studies, 43 were eligible for this review. Overall, the peripapillary region showed to be the most discriminative region with the highest mean AUROC (0.80 ± 0.09). An improvement of the AUROC from this region is observed when a sectorial analysis is performed, with the highest AUROCs obtained at the inferior and superior sectors of the superficial capillary plexus in the peripapillary region (0.86 ± 0.03 and 0.87 ± 0.10, respectively). The presented work shows that glaucomatous vascular damage can be assessed using OCTA, and its added value as a complementary feature for glaucoma diagnosis depends on the region of interest. A sectorial analysis of the superficial layer at the peripapillary region is preferable for assessing glaucomatous vascular damage

Effects of muscarinic receptor stimulation on Ca2+ transient, cAMP production and pacemaker frequency of rabbit sinoatrial node cells

We investigated the contribution of the intracellular calcium (Cai2+) transient to acetylcholine (ACh)-mediated reduction of pacemaker frequency and cAMP content in rabbit sinoatrial nodal (SAN) cells. Action potentials (whole cell perforated patch clamp) and Cai2+ transients (Indo-1 fluorescence) were recorded from single isolated rabbit SAN cells, whereas intracellular cAMP content was measured in SAN cell suspensions using a cAMP assay (LANCE®). Our data show that the Cai2+ transient, like the hyperpolarization-activated “funny current” (If) and the ACh-sensitive potassium current (IK,ACh), is an important determinant of ACh-mediated pacemaker slowing. When If and IK,ACh were both inhibited, by cesium (2 mM) and tertiapin (100 nM), respectively, 1 μM ACh was still able to reduce pacemaker frequency by 72%. In these If and IK,ACh-inhibited SAN cells, good correlations were found between the ACh-mediated change in interbeat interval and the ACh-mediated change in Cai2+ transient decay (r2 = 0.98) and slow diastolic Cai2+ rise (r2 = 0.73). Inhibition of the Cai2+ transient by ryanodine (3 μM) or BAPTA-AM (5 μM) facilitated ACh-mediated pacemaker slowing. Furthermore, ACh depressed the Cai2+ transient and reduced the sarcoplasmic reticulum (SR) Ca2+ content, all in a concentration-dependent fashion. At 1 μM ACh, the spontaneous activity and Cai2+ transient were abolished, but completely recovered when cAMP production was stimulated by forskolin (10 μM) and IK,ACh was inhibited by tertiapin (100 nM). Also, inhibition of the Cai2+ transient by ryanodine (3 μM) or BAPTA-AM (25 μM) exaggerated the ACh-mediated inhibition of cAMP content, indicating that Cai2+ affects cAMP production in SAN cells. In conclusion, muscarinic receptor stimulation inhibits the Cai2+ transient via a cAMP-dependent signaling pathway. Inhibition of the Cai2+ transient contributes to pacemaker slowing and inhibits Cai2+-stimulated cAMP production. Thus, we provide functional evidence for the contribution of the Cai2+ transient to ACh-induced inhibition of pacemaker activity and cAMP content in rabbit SAN cells

OCTA multilayer and multisector peripapillary microvascular modeling for diagnosing and staging of glaucoma

Purpose: To develop and assess an automatic procedure for classifying and staging glaucomatous vascular damage based on optical coherence tomography angiography (OCTA) imaging. Methods: OCTA scans (Zeiss Cirrus 5000 HD-OCT) from a random eye of 39 healthy subjects and 82 glaucoma patients were used to develop a new classification algorithm based on multilayer and multisector information. The averaged circumpapillary retinal nerve fiber layer (RNFL) thickness was also collected. Three models, support vector machine (SVM), random forest (RF), and gradient boosting (xGB), were developed and optimized for classifying between healthy and glaucoma patients, primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG), and glaucoma severity groups. Results: All the models, the SVM (area under the receiver operating characteristic [AUROC] 0.89 ± 0.06), the RF (AUROC 0.86 ± 0.06), and the xGB (AUROC 0.85 ± 0.07), with 26, 22, and 29 vascular features obtained after feature selection, respectively, presented a similar performance to the RNFL thickness (AUROC 0.85± 0.06) in classifying healthy and glaucoma patients. The superficial vascular plexus was the most informative layer with the infero temporal sector as the most discriminative region of interest. No significant differentiation was obtained in discriminating the POAG from the NTG group. The xGB model, after feature selection, presented the best performance in classifying the severity groups (AUROC 0.76± 0.06), outperforming the RNFL (AUROC 0.67± 0.06). Conclusions: OCTA multilayer and multisector information has similar performance to RNFL for glaucoma diagnosis, but it has an added value for glaucoma severity classification, showing promising results for staging glaucoma progression. Translational Relevance: OCTA, in its current stage, has the potential to be used in clinical practice as a complementary imaging technique in glaucoma management

Functional MR Imaging in prostate radiotherapy - relationship with prostate histology

The treatment of prostate cancer with radiotherapy might be improved by either increasing the radiation dose on the most important tumor areas with focal boosting or by reducing the dose on healthy prostate tissue by means of focal therapy. In both scenarios, selection of the tumor areas is a critical step. As local recurrences often originate at the side of the dominant tumor lesion, especially this region is important. Second criterion is the presence of aggressive characteristics like high Gleason score and high cell density. Multiparametric magnetic resonance imaging (MRI) is the modality of choice for the visualization of tumor areas. In this thesis, focus was on dynamic contrast-enhanced MRI and diffusion-weighted imaging. The main goal of this thesis was to understand the histological background of functional MRI of the prostate, to come to more robust, MRI-based voxel-wise prostate tumor delineation. To this end, we created a logistic regression model based on functional MRI parameters to predict tumor presence on a voxel level. Validation of the model on pathology specimen showed that the performance of the model was good, although not perfect. Correlation with prostate histology revealed in correctly detected tumor voxels high cell density, high microvessel density and a trend towards higher Gleason scores. On the other hand, non-detected tumor voxels had cell densities and microvessel densities resembling normal tissue. This indicates that the detection of voxels depends on their histological characteristics. Additionally, larger tumors volumes were associated with lower apparent diffusion coefficient values and higher expression levels of hypoxia-inducible factor 2α.These larger tumours are detected more frequently and determine outcome after radiotherapy. Altogether these results indicate that the clinically most important tumour voxels, which are likely in need of higher radiation doses, are detected accurately. In conclusion, this thesis addresses several aspects regarding prostate tumor voxel detection and delineation, in relation to histological characteristics. Relevant tumor voxels, most in need of aggressive treatment, can be detected with high accuracy. The obtained knowledge of histological characteristics of detected and missed tumor voxels is of relevance when in the future the treatment of prostate cancer becomes more personalized with focal boost and focal therapy

Searching for the holy grail in the Antipodes The market reform of the New Zealand health care system

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