Antithrombotic and antiplatelet effects of plant-derived compounds: a great utility potential for primary, secondary, and tertiary care in the framework of 3P medicine.

Thromboembolism is the third leading vascular disease, with a high annual incidence of 1 to 2 cases per 1000 individuals within the general population. The broader term venous thromboembolism generally refers to deep vein thrombosis, pulmonary embolism, and/or a combination of both. Therefore, thromboembolism can affect both - the central and peripheral veins. Arterial thromboembolism causes systemic ischemia by disturbing blood flow and oxygen supply to organs, tissues, and cells causing, therefore, apoptosis and/or necrosis in the affected tissues. Currently applied antithrombotic drugs used, e.g. to protect affected individuals against ischemic stroke, demonstrate significant limitations. For example, platelet inhibitors possess only moderate efficacy. On the other hand, thrombolytics and anticoagulants significantly increase hemorrhage. Contextually, new approaches are extensively under consideration to develop next-generation antithrombotics with improved efficacy and more personalized and targeted application. To this end, phytochemicals show potent antithrombotic efficacy demonstrated in numerous in vitro, ex vivo, and in vivo models as well as in clinical evaluations conducted on healthy individuals and persons at high risk of thrombotic events, such as pregnant women (primary care), cancer, and COVID-19-affected patients (secondary and tertiary care). Here, we hypothesized that specific antithrombotic and antiplatelet effects of plant-derived compounds might be of great clinical utility in primary, secondary, and tertiary care. To increase the efficacy, precise patient stratification based on predictive diagnostics is essential for targeted protection and treatments tailored to the person in the framework of 3P medicine. Contextually, this paper aims at critical review toward the involvement of specific classes of phytochemicals in antiplatelet and anticoagulation adapted to clinical needs. The paper exemplifies selected plant-derived drugs, plant extracts, and whole plant foods/herbs demonstrating their specific antithrombotic, antiplatelet, and fibrinolytic activities relevant for primary, secondary, and tertiary care. One of the examples considered is antithrombotic and antiplatelet protection specifically relevant for COVID-19-affected patient groups.

Abscopal Effects in Metastatic Cancer: Is a Predictive Approach Possible to Improve Individual Outcomes?

Patients with metastatic cancers often require radiotherapy (RT) as a palliative therapy for cancer pain. RT can, however, also induce systemic antitumor effects outside of the irradiated field (abscopal effects) in various cancer entities. The occurrence of the abscopal effect is associated with a specific immunological activation in response to RT-induced cell death, which is mainly seen under concomitant immune checkpoint blockade. Even if the number of reported apscopal effects has increased since the introduction of immune checkpoint inhibition, its occurrence is still considered rare and unpredictable. The cases reported so far may nevertheless allow for identifying first biomarkers and clinical patterns. We here review biomarkers that may be helpful to predict the occurrence of abscopal effects and hence to optimize therapy for patients with metastatic cancers.

Endothelin-1 axes in the framework of predictive, preventive and personalised (3P) medicine.

Endothelin-1 (ET-1) is involved in the regulation of a myriad of processes highly relevant for physical and mental well-being; female and male health; in the modulation of senses, pain, stress reactions and drug sensitivity as well as healing processes, amongst others. Shifted ET-1 homeostasis may influence and predict the development and progression of suboptimal health conditions, metabolic impairments with cascading complications, ageing and related pathologies, cardiovascular diseases, neurodegenerative pathologies, aggressive malignancies, modulating, therefore, individual outcomes of both non-communicable and infectious diseases such as COVID-19. This article provides an in-depth analysis of the involvement of ET-1 and related regulatory pathways in physiological and pathophysiological processes and estimates its capacity as a predictor of ageing and related pathologies,a sensor of lifestyle quality and progression of suboptimal health conditions to diseases for their targeted preventionand as a potent target for cost-effective treatments tailored to the person.

Targeting the Post-Irradiation Tumor Microenvironment in Glioblastoma via Inhibition of CXCL12.

Radiotherapy is a mainstay in glioblastoma therapy as it not only directly targets tumor cells but also depletes the tumor microvasculature. The resulting intra-tumoral hypoxia initiates a chain of events that ultimately leads to re-vascularization, immunosuppression and, ultimately, tumor-regrowth. The key component of this cascade is overexpression of the CXC-motive chemokine ligand 12 (CXCL12), formerly known as stromal-cell derived factor 1 (SDF-1). We here review the role of CXCL12 in recruitment of pro-vasculogenic and immunosuppressive cells and give an overview on future and current drugs that target this axis.

High-throughput monitoring of integration site clonality in preclinical and clinical gene therapy studies.

Gene transfer to hematopoietic stem cells with integrating vectors not only allows sustained correction of monogenic diseases but also tracking of individual clones in vivo. Quantitative real-time PCR (qPCR) has been shown to be an accurate method to quantify individual stem cell clones, yet due to frequently limited amounts of target material (especially in clinical studies), it is not useful for large-scale analyses. To explore whether vector integration site (IS) recovery techniques may be suitable to describe clonal contributions if combined with next-generation sequencing techniques, we designed artificial ISs of different sizes which were mixed to simulate defined clonal situations in clinical settings. We subjected all mixes to either linear amplification-mediated PCR (LAM-PCR) or nonrestrictive LAM-PCR (nrLAM-PCR), both combined with 454 sequencing. We showed that nrLAM-PCR/454-detected clonality allows estimating qPCR-detected clonality in vitro. We then followed the kinetics of two clones detected in a patient enrolled in a clinical gene therapy trial using both, nrLAM-PCR/454 and qPCR and also saw nrLAM-PCR/454 to correlate to qPCR-measured clonal contributions. The method presented here displays a feasible high-throughput strategy to monitor clonality in clinical gene therapy trials is at hand.

Spectral characteristics of the PhNR in the full-field flash electroretinogram of normals and glaucoma patients.

Flash electroretinogram responses were measured in normal subjects to different chromatic combinations of flashes and backgrounds. The amplitudes of the flash response components were measured at different flash strengths and could be described by a generalized Naka-Rushton function. The measurements were repeated at different background luminances to study adaptation effects. It was found that when flash strength and background luminance were expressed in photometric terms (cd s/m² and cd/m², respectively), then the responses were very similar for all chromatic combinations with the exception of the condition in which blue (peak wavelength 458 nm) was flashed upon an orange (peak wavelength 591 nm) background. We propose that in this condition, a second (possibly S-cone or rod-driven) mechanism intrudes. The negative response after the b-wave (here called "photopic negative response" or PhNR for all conditions) is thought to reflect ganglion cell activity and was also largest at this condition. Responses were measured to the 458 nm flash on 591 nm background and the reversed combination in a population of 39 normal subjects and 49 glaucoma patients. It was found that the PhNR amplitude was affected by glaucoma in all conditions. Other component parameters, reflecting responses and adaptation dynamics, were not altered. The best stimulus condition among the conditions used to separate the PhNR amplitude of normals and patients was a 1 cd s/m² 458 nm flash on a 10 cd/m² 591 nm background.

Solid corneal dermoids and subconjunctival lipodermoids: impact of differentiated surgical therapy on the functional long-term outcome.

PURPOSE: The functional long-term outcome after differentiated surgical therapy of solid corneal dermoids and subconjunctival lipodermoids with special regard to determinants for amblyopia will be assessed. METHODS: Forty-six consecutive patients undergoing surgery for solid epibulbar dermoids, subconjunctival lipodermoids, or both were included. Visual acuity, refraction, keratometry, and degree of amblyopia were determined. Surgical therapy for corneal dermoids consisted of lamellar sclerokeratectomy, lamellar keratoplasty, corneoscleroplasty, and lamellar removal with autologous episcleral transplant. Surgical therapy for lipodermoids consisted of excision and reduction of the volume of the tumor. Follow-up examination was performed on average 4.5 years after surgical intervention. RESULTS: A significant correlation between tumor volume and preoperative visual acuity could be observed in patients with solid corneal dermoids not occluding the optical axis. Visual acuity improved significantly from 0.21 +/- 0.4 to 0.35 +/- 0.4 after surgery of corneal dermoids. Most eyes had concomitant hyperopia. Postoperative visual acuity correlated positively with preoperative visual acuity (P = 0.0001). After tumor excision, hyperopia and astigmatism were not reduced significantly on average. Nineteen of 47 patients suffered from amblyopia. Amblyopia was more often observed in patients with preoperative hyperopia > or =2 diopters and astigmatism >2 diopters. Visual acuity, refraction, and astigmatism were not changed significantly by surgery in patients with subconjunctival lipodermoids. CONCLUSIONS: Epibulbar dermoids require differentiated surgical therapy. Amblyopia is a major threat of solid corneal dermoids. The incidence of amblyopia seems to depend on preoperative occlusion of the optical axis and preoperative degree of hyperopia and astigmatism.

Rod and S-cone driven ERG signals at high retinal illuminances.

The purpose of the present study was to investigate whether L- and M-cone driven responses can be influenced by concomitant modulation in the rods or the S-cones. In addition, it was studied whether a change in the state of adaptation in L- or M-cones can have a different influence on ERG data when simultaneously the mean number of photoisomerizations in either rods or S-cones is altered. It was found that rods and/or S-cones cannot be neglected when measuring L- or M-cone driven ERGs.

Carcinoma-associated retinopathy-an electrophysiological and immunohistochemical correlation.

PURPOSE: To correlate the clinical, electrophysiological, and immunohistochemical findings in patients suffering from carcinoma-associated retinopathy. METHODS: Four patients with visual loss were included in this retrospective, observational consecutive case series. Electrophysiology and immunohistochemical analysis were performed to confirm the diagnosis of carcinoma-associated retinopathy. RESULTS: Immunohistochemistry revealed a marked interindividual variability of antibody reactions against different retinal cell layers of individual patients. The electrophysiological changes corresponded to the respective immunohistochemical findings. CONCLUSION: Carcinoma-associated retinopathy is a heterogeneous disease, caused by different antiretinal antibodies and leading to different electrophysiological abnormalities. Diagnosis should not be delayed as undetected and thus untreated malignancy can be the cause.

Accidental focal laser injury--a correlation of electrophysiology, perimetry and clinical findings.

BACKGROUND: Laser injuries to the eyes occasionally occur in occupational accidents or during free-time activities. The aim of this study was to compare clinical and functional findings. METHODS: We describe a 34-year-old male complaining about reduced visual acuity after an accidental laser injury. We correlate changes in the multifocal ERG with visual field defects due to focal laser application 1.5 years after the trauma. RESULTS: A small central retinal scarring resulting in a perimetric defect and a focal reduction of amplitude in the multifocal ERG have been observed in an area closely corresponding to the area where the scarring and the field losses occurred. CONCLUSION: Structural and perimetric damage as a consequence of laser injury can be associated with focal change in multifocal ERG.

Electroretinographic responses that may reflect activity of parvo- and magnocellular post-receptoral visual pathways.

The electroretinogram (ERG) is a complex retinal response to visual stimuli that contains receptoral and post-receptoral components. Here, data are presented using stimuli that isolate the responses of L (long wavelength sensitive)- or M (middle wavelength sensitive)-cones or that stimulate the two simultaneously. The data show that at a temporal frequency of 12 Hz, ERG responses are L- to M-cone opponent with little inter-individual variability. Furthermore, the ratio of L- to M-cone-driven response strengths in the ERGs is about unity. These are also properties of the L- and M-cone opponent chromatic channel mediated by parvocellular activity. Similar to the parvocellular-mediated temporal sensitivity, the ERG response is robust to moderate changes in state of cone adaptation. Thus, the 12-Hz ERG shares distinct characteristics with the post-receptoral red-green sensitive parvocellular pathway. At higher temporal frequencies, the responses are not cone opponent, the inter-individual variability is larger, the mean L/M ratio is larger than unity, and the responses change more strongly when the state of cone adaptation is altered. These properties are reminiscent of the magnocellular non-opponent channel. The data suggest that under well-controlled conditions, the ERG can be used to study post-receptoral processes of the visual system.

Long-term reproducibility of screening for glaucoma with FDT-perimetry.

PURPOSE: Aim of this study was to evaluate the long-term reproducibility of frequency doubling technology (FDT) screening procedures. METHODS: Longitudinal data of 433 eyes of 294 patients with no progression of glaucomatous optic disc atrophy were retrospectively analyzed: 62 control eyes, 184 ocular hypertensive eyes, 104 preperimetric, and 83 perimetric open-angle glaucoma eyes. All subjects had annual tests with the FDT perimeter and a standardized ophthalmologic examination (ie, conventional perimetry, optic disc inspection, tonometry, lens opacity measurement for exclusion of cataract). The present analysis used a published overall screening score with case-wise recalculation of missed localized probability levels. We analyzed long-term variability by correlation analysis, sign tests, and limits of agreement (LoA) as introduced by Altman and Bland. All subjects had at least 2 annual tests. Three hundred twenty-six eyes had 2 annual tests with the C-20 procedure and at least 1 test with the N-30 protocol another year later. One hundred thirty-five eyes had 1 C-20 and 2 annual tests with the N-30 protocol. RESULTS: Analyses of repeated measurements revealed a significant learning effect (P<0.001, LoA: -4, 17) between the first and second examination but no significant difference between the second and following tests with the C-20 protocol (P>0.6, LoA: +/-9). In addition, there was no significant difference between second C-20 and N-30 tests (P>0.5, LoA: -12, 6). CONCLUSIONS: The study demonstrates the variability of FDT tests over several years. Longitudinal FDT-results in a clinical study showed a higher reproducibility if the first test was discarded. Reproducibility of screening with the N-30 protocol is comparable to the C-20 procedure if an overall score is considered.

Measurement of autofluorescence in the parapapillary atrophic zone in patients with ocular hypertension.

PURPOSE: The purpose of the study was to investigate area and intensity of parapapillary autofluorescence in patients with ocular hypertension and controls. PATIENTS AND METHODS: Forty-two consecutive patients with ocular hypertension and 25 controls were investigated in a controlled prospective cross-sectional trial. All patients and controls were members of the Erlangen Glaucoma registry and received complete ophthalmologic examination and detailed standardized glaucoma examination, including 24-h IOP measurement, perimetrie (G1, three phases) and 15 degrees stereographic slides of the optic disc. Additionally, patients and controls were investigated with VEP with blue on yellow pattern stimulation and confocal scanning laser ophthalmoscope (HRA II, Heidelberg Engineering, Dossenheim, Germany) to detect lipofuscin in the parapapillary atrophic zone. Eyes with retinal diseases or pathologic changes of retinal pigmentepithelium were excluded. Extension of parapapillary area with increased autofluorescence compared (qualitatively) to background autofluorescence around the optic disc and the level of autofluorescence (quantitatively) in the area of qualitatively increased autofluorescence was measured. Patients and controls did not differ significantly concerning age. RESULTS: The area of parapapillary autofluorescence was significant larger in patients with ocular hypertension than in the control group (0.21+/-0.17 mm(2) versus 0.07+/-0.06 mm(2); P<0.001, Mann-Whitney U-test). An increased latency of blue-on-yellow pattern VEP was seen in patients with OHT with increasing parapapillary autofluorescence area (r=0.496; P<0.001, Spearman-Rho test). CONCLUSION: Parapapillary autofluorescence is increased in patients with ocular hypertension. Patients with large area of parapapillary autofluorescence had also an increased latency in blue on yellow pattern VEP.

Pupillographic measurements with pattern stimulation: the pupil's response in normal subjects and first measurements in glaucoma patients.

PURPOSE: This study was undertaken to characterize the influence of contrast, luminance, and spatial frequency of a pattern stimulus on the pupil reaction of healthy subjects. First measurements with this technique in patients with glaucoma were compared with those in a control group. METHOD: Grating patterns were presented using a Maxwellian-view system to study series of contrast, luminance, and spatial frequency in three healthy subjects. The best two stimulus conditions were determined and were then used to examine 19 patients with open-angle glaucoma and 16 control subjects. RESULTS: In healthy subjects, an increasing contrast led to an increase in amplitude and a decrease in latency of the pupil reflex. Increasing luminance also resulted in an increase in the amplitude. The offset component of the pupil reflex was most pronounced at low spatial frequencies and the onset component at high spatial frequencies. When healthy subjects were compared with patients with glaucoma, control subjects generally had higher amplitudes, velocity, and acceleration of pupil constriction than did the patients with glaucoma. These differences were significant when the test was performed with a spatial frequency of 6.25 cyc/deg. CONCLUSIONS: Best stimulus conditions to elicit a pupil response to a pattern grating stimulus are 100% contrast and 55 cd/m(2) mean luminance. The choice of the spatial frequency determines which component of the pupil reflex is more pronounced. Differences between patients with glaucoma and healthy control subjects are demonstrable.

Pattern reversal ERG and VEP--comparison of stimulation by LED, monitor and a Maxwellian-view system.

PURPOSE: Pattern stimulation is widely used to detect inner retinal dysfunction. In this work we describe a pattern stimulation technique with LEDs and compare the results with conventional methods. METHODS: PERG and VEP were derived from three normal subjects. Three different techniques were used to generate a checkerboard pattern reversal stimulus: a 70 Hz monitor, a Maxwellian-view system equipped with a Xenon-arc lamp and a mechanical mirror system, and a LED array (Roland Consult) consisting of 100 white LEDs. Two kinds of luminance (125 and 340 cd/m2) and four temporal frequencies (4, 8, 12 and 24 reversals per second) were studied on three healthy subjects. Additionally, a luminance tuning experiment (30, 60, 90, 125 and 340 cd/m2) was performed on one subject. RESULTS: Comparison of different stimulation techniques shows reproducible responses of PERG and VEP with all three methods. The LED array leads to slightly smaller amplitudes than both other techniques, which we ascribe to the design of the LED field. No difference of peak times or phases was noticed between different stimulation techniques. A luminance dependency of PERG and VEP is noticeable using stimulation with LED: with decreasing luminance we measured increasing peak times of PERG and VEP and decreasing amplitude of PERG. CONCLUSION: We conclude that central retinal stimulation with checkerboard pattern reversal is possible with LED. It gives comparable results to monitor and Maxwellian-view system.

Pattern reversal ERG with LED-stimulation using cyclic summation technique.

PURPOSE: Multifocal pattern reversal stimulation can be used to detect inner retinal dysfunction. Commonly, the stimulus is generated on a monitor using m-sequence technique. We describe a pattern reversal ERG evoked by LED arrays using cyclic summation (CS). METHODS: One eye of eight healthy subjects was examined with an arrangement of 13 LED arrays. Each array consisted of 100 LEDs separated by thin walls. One of the fields was placed centrally, three fields each were placed above, below, left and right of the central field. CS technique at a temporal frequency of 16 reversals per second (RPS) was used for stimulation. Viewing distance was 30 cm, check size was 0.58 cyc/deg. Luminance of the bright fields was 340 cd/m2. RESULTS: Fourier analysis was performed. Centrally, the amplitude of the 2nd harmonic wave was highest (0.87 microV). In the first paracentral fields, amplitudes were 0.28 microV (nasally), 0.21 microV (superior, inferior and temporally). In the second paracentral fields, amplitudes were 0.11 microV (nasally), 0.09 microV (superior), 0.13 microV (inferior) and 0.15 microV (temporally). With exception of the temporal field (0.1 microV), in the outermost fields no reproducible ERG response could be recorded. CONCLUSION: Peripheral ERG responses to a pattern reversal stimulus can be recorded with LED stimulation using CS technique up to an eccentricity of 30 degrees. Responses are highest centrally and decrease with increasing distance to the centre.

Salzmann's nodular degeneration of the cornea: a review and case series.

Salzmann's nodular degeneration is a rare, noninflammatory, slowly progressive, degenerative condition. Bluish-white nodules raised above the surface of the cornea characterize it. It has usually developed in corneas with a history of phlyctenulosis, trachoma, vernal keratoconjunctivitis, measles, scarlet fever, and various other viral diseases. However, today the majority of cases have been seen without recognized previous keratitis. It is composed of dense irregularly arranged collagen tissue with hyalinization between epithelium and Bowman's layer or beyond. Manual removal, phototherapeutic keratectomy (PTK) with or without the use of topical mitomycin-C, lamellar or penetrating keratoplasty have been used in the treatment of this disease. Salzmann's nodular degeneration does not seem to consist of one clinical entity. In some cases, elevated and pannus-like tissue can be separated easily from the corneal surface leaving Bowman's layer almost untouched. In these eyes, subsequent PTK may be necessary to smooth the surface. Recurrences are rare in these eyes. In contrast, some eyes (often with major peripheral vascularization) are left with deep defects in Bowman's layer and superficial stroma after difficult mechanical removal of nodules. In these eyes, multiple masking/laser ablation procedures are mandatory to acquire a homogenous surface. In our experience, the required laser ablation depth is significantly greater and the best-corrected visual acuity to be expected is reduced in contrast to the eyes with easy removal of the nodules. In these eyes recurrences seem to occur more frequently after treatment. Of 35 eyes documented to have Salzmann's nodular degeneration during the last 15 years in our department, 22 needed PTK treatment. Visual acuity increased from 0.4 to 0.7 on average. As a routine, laser ablation should be combined with previous conventional removal of nodules and excessive pannus tissue. By doing so, lamellar and penetrating keratoplasty techniques are hardly ever required in those eyes.

Long-term outcome of excimer laser phototherapeutic keratectomy for treatment of Salzmann's nodular degeneration.

PURPOSE: To describe the technique and evaluate the long-term success of excimer laser phototherapeutic keratectomy (PTK) for treatment of Salzmann's nodular degeneration. SETTING: Department of Ophthalmology, University of Erlangen-Nürnberg, Erlangen, Germany. METHODS: This retrospective study comprised 22 eyes of 14 patients who consecutively had PTK for superficial corneal opacities in Salzmann's nodular degeneration between January 1990 and November 2003. In all cases, the nodules and as much pannus tissue as possible were removed with a hockey knife. Afterward, the laser ablation (MEL 60 or 70, Carl Zeiss-Meditec) was performed with repeated application of masking fluid to remove further scar tissue and smooth the surface. Intended depth of laser ablation ranged from 10 to 100 microm (mean: 41 microm +/- 43 [SD]). RESULTS: In 86% of eyes, visual acuity improved after PTK, from 0.4 +/- 0.2 preoperatively to 0.7 +/- 0.3 postoperatively. The mean myopic shift was 1.5 +/- 0.7 diopters [D]. Median refractive cylinder changed from 1.0 D preoperatively to 0.7 D postoperatively. The median surface regularity index/surface asymmetry index (SRI/SAI) of the TMS-1 topography analysis system (Tomey) decreased from 2.0/1.6 preoperatively to 1.2/1.2 postoperatively. In 4 (18%) of 22 eyes, a recurrence had to be treated by repeat PTK during a mean follow-up of 2.0 +/- 1.8 years. CONCLUSIONS: Results indicate that PTK is an effective and safe procedure for treatment of Salzmann's nodular degeneration. Laser ablation should be combined with prior mechanical removal of nodules and excessive pannus tissue.