Using Blood and Plasma MicroRNAs as a Non-Invasive Biomarker in Patients with Colorectal Cancer.

BACKGROUND: A high percentage of oncological patients die yearly because of colorectal cancer (CRC). Worldwide, CRC represents the fourth leading cause of death among oncological patients. Numerous studies have been conducted in order to identify new biomarkers for the early diagnosis of patients with CRC. From this point of view, an ideal biomarker is represented by the expression of microRNAs. In this paper, we wish to summarize the expressions of microRNAs in CRC and to present the pathophysiological and genetic interactions that microRNAs have with protein systems in these patients. METHODS: For this paper, we looked into the studies available in scientific databases such as PubMed. For the search the following keywords have been used: "miRNAs expression", "colorectal cancer", "genetic polymorphisms in CRC", and "genetic biomarkers in CRC". RESULTS: Modifying the expression of microRNAs can be used successfully both in diagnosing patients with CRC and in following their response to chemotherapy. Numerous studies have shown high specificity for certain microRNA species in the case of CRC. An extraordinary advantage of these biomarkers is represented by their non-invasive sampling from urine and blood. Moreover, a series of connections of microRNAs in some mechanisms involved in the appearance and development of CRC have been shown. Therefore, microRNAs can be named as the biomarker of the future, as well as the epigenetic targeted treatment for patients with CRC. CONCLUSIONS: The expression of microRNAs can be successfully used in the evaluation and non-invasive monitoring of patients with CRC. However, further studies are needed regarding the expression of microRNAs and the connections these species have in the pathological mechanisms specific for CRC.

Role of nitric oxide in optic nerve head blood flow regulation during an experimental increase in intraocular pressure in healthy humans.

The present study set out to investigate whether nitric oxide, a potent vasodilator, is involved in the regulatory processes in optic nerve head blood flow during an experimental increase in intraocular pressure (IOP). The study was conducted in a randomized, double-masked, placebo-controlled, three way cross-over design. 12 healthy subjects were scheduled to receive either L-NMMA (an unspecific nitric oxide synthase inhibitor), phenylephrine (an α-adrenoceptor agonist) or placebo on three different study days. Optic nerve head blood flow was measured using laser Doppler flowmetry and IOP was increased stepwise with a suction cup. Mean arterial pressure (MAP) and IOP were measured non-invasively and ocular perfusion pressure (OPP) was calculated as OPP = 2/3 MAP-IOP. Administration of L-NMMA and phenylephrine significantly increased MAP and therefore OPP at rest (p < 0.01). L-NMMA significantly reduced baseline blood flow in the optic nerve head (p < 0.01). Application of the suction cup induced a significant increase in IOP and a decrease in OPP (p < 0.01). During the stepwise increase in IOP, some autoregulatory potential was observed until OPP decreased approximately -30% below baseline. None of the administered substances had an effect on this autoregulatory behavior (p = 0.49). The results of the present study confirm that the human optic nerve head shows some regulatory capacity during a decrease in OPP. Nitric oxide is involved in the regulation of basal vascular tone in the optic nerve head but does not seem to be involved in the regulatory mechanisms during an acute increase in IOP in young healthy subjects.

[Different significance in normal subjects and in glaucoma patients tested with Optopol PTS-910, in the galucoma program]. / Variabilitatea intertest la subiectii normali si glaucomatosi testati cu programul glaucom--perimetrul Optopol PTS-910.

PURPOSE: to quantify the inter-test variability (dB) for the Optopol PTS automated perimeter, Glaucoma Fast threshold program. MATERIALS AND METHOD: A prospective study was performed on 166 glaucomatous patients and a control group of 30 normal subjects, tested by complete ophthalmological exam and automated perimetry (Optopol PTS-910). The visual field was tested weekly for 4 consecutive weeks. The visual field defects were classified according to the Aulhorn-Karmeyer descriptive scale. RESULTS: For the control group, the medium inter-test variability was of 1.57 +/- 0.24 dB, lower next to fixation and increasing towards the 50 degree isopter. The medium inter-test variability increases along with the perimetric stage :1.57 +/- 0.66 dB for pre-perimetric glaucoma, 2.13 + 1.04 dB for non-specific defects group, 3.23 + 1.01 dB for the stage 1, 3.52 + 2.61 dB, for the stage 2, 3.65 + 1.19dB for the stage 3 and 5.82 +/- 1.67dB for the stage 4. For the cases of preperimetric glaucoma and non-specific defects, a similar profile of variability to the normal subjects can be observed. For the stages 2-4, the profile of the areas with maxim inter-test variability moves towards the relative scotoma and the surrounding area. CONCLUSIONS: A better description of the inter-test variability and the evolution of this intricate parameter of the retinal light sensitivity is useful for the differential diagnostic between the real change and the "background noise" in early detection of the functional progression in glaucoma.

Meibomian gland changes in breast cancer patients treated with docetaxel-partial results.

Aim: The purpose of the present study was to demonstrate that the narrowing and/ or atrophy of the Meibomian glands is the cause of the occurrence of hyperlacrimation in women who suffer from breast cancer and who have docetaxel in their treatment regimen. Method: The study involved 10 patients diagnosed with breast cancer, who received docetaxel as treatment (study group), and 10 breast cancer patients receiving other chemotherapy treatment (control group). The study was a prospective, controlled and comparative. We mainly analyzed two very important indicators, non-invasive tear film breaking time (NKBUT) and meibography. Results: A decrease and/ or narrowing of Meibomian glands in the study group (breast cancer patients treated with docetaxel) was observed on the meibography. Also, a decrease of the NKBUT was observed in the study group. The average variation of NKBUT in docetaxel patients (22%) and the average variation of meiboscopy in docetaxel patients (33%) showed the effect of docetaxel over time compared to patients who received other anticancer therapy, in whom the mean variation was very small, natural. Conclusions: The action of docetaxel at the level of the two studied indicators (NKBUT and Meiboscopy) was noteworthy at the level of the study group, the changes observed in the Meibomian glands being reversible. They resolved within a few weeks of completion of docetaxel treatment. Abbreviations: RE = right eye, OSD = ocular surface disease, NKBUT = noninvasive keratography tear breaking time.

Serum Neurofilaments and OCT Metrics Predict EDSS-Plus Score Progression in Early Relapse-Remitting Multiple Sclerosis.

(1) Background: Early disability accrual in RRMS patients is frequent and is associated with worse long-term prognosis. Correctly identifying the patients that present a high risk of early disability progression is of utmost importance, and may be aided by the use of predictive biomarkers. (2) Methods: We performed a prospective cohort study that included newly diagnosed RRMS patients, with a minimum follow-up period of one year. Biomarker samples were collected at baseline, 3-, 6- and 12-month follow-ups. Disability progression was measured using the EDSS-plus score. (3) Results: A logistic regression model based on baseline and 6-month follow-up sNfL z-scores, RNFL and GCL-IPL thickness and BREMSO score was statistically significant, with χ2(4) = 19.542, p < 0.0001, R2 = 0.791. The model correctly classified 89.1% of cases, with a sensitivity of 80%, a specificity of 93.5%, a positive predictive value of 85.7% and a negative predictive value of 90.62%. (4) Conclusions: Serum biomarkers (adjusted sNfL z-scores at baseline and 6 months) combined with OCT metrics (RNFL and GCL-IPL layer thickness) and the clinical score BREMSO can accurately predict early disability progression using the EDSS-plus score for newly diagnosed RRMS patients.

Uncommon association between vascular Ehlers-Danlos syndrome and ocular complications.

Ehlers-Danlos syndromes (EDS) represent a group of rare inherited disorders that affect connective tissues. There are 13 types of disease, most of them affecting joints or skin; symptoms usually include loose joints, joint pain, stretchy velvety skin, abnormal scar formation. However, the most serious type of disease is vascular EDS (vEDS), or EDS type 4 because patients may suffer vessels dissections or internal organs lesions, followed by bleeding, which endangers patient's life, but also thromboembolic events. We present two clinical cases of vEDS managed in our clinic in 1 year distance. In both cases, patients were active young persons (in their thirties, and respectively, twenties), both with multiple non-traumatic vascular dissections, and severe ocular complications: arterio-venous fistula with massive exophthalmia, and central retinal artery occlusion, respectively. Both cases were challenging since the life of the patients were threatened by their condition. However, in both cases, prompt treatment and finding the right trigger of the ocular pathology and vascular injuries helped doctors to provide proper and prompt medical care, in order to prevent future similar events to happen and to preserve a good quality of life for these patients.

Biocompatible Materials for Orbital Wall Reconstruction-An Overview.

The reconstruction of an orbit after complex craniofacial fractures can be extremely demanding. For satisfactory functional and aesthetic results, it is necessary to restore the orbital walls and the craniofacial skeleton using various types of materials. The reconstruction materials can be divided into autografts (bone or cartilage tissue) or allografts (metals, ceramics, or plastic materials, and combinations of these materials). Over time, different types of materials have been used, considering characteristics such as their stability, biocompatibility, cost, safety, and intraoperative flexibility. Although the ideal material for orbital reconstruction could not be unanimously identified, much progress has been achieved in recent years. In this article, we summarise the advantages and disadvantages of each category of reconstruction materials. We also provide an update on improvements in material properties through various modern processing techniques. Good results in reconstructive surgery of the orbit require both material and technological innovations.

Outcomes of Diabetic Retinopathy Post-Bariatric Surgery in Patients with Type 2 Diabetes Mellitus.

Bariatric surgery is an emerging therapeutic approach for obese type 2 diabetes mellitus (T2DM) patients, with proven benefits for achieving target glucose control and even remission of diabetes. However, the effect of bariatric surgery upon diabetic retinopathy is still a subject of debate as some studies show a positive effect while others raise concerns about potential early worsening effects. We performed a systematic review, on PubMed, Science Direct, and Web of Science databases regarding the onset and progression of diabetic retinopathy in obese T2DM patients who underwent weight-loss surgical procedures. A total of 6375 T2DM patients were analyzed. Most cases remained stable after bariatric surgery (89.6%). New onset of diabetic retinopathy (DR) was documented in 290 out of 5972 patients (4.8%). In cases with DR at baseline, progression was documented in 50 out of 403 (12.4%) and regression in 90 (22.3%). Preoperative careful preparation of hemoglobin A1c (HbA1c), blood pressure, and lipidemia should be provided to minimize the expectation of DR worsening. Ophthalmologic follow-up should be continued regularly in the postoperative period even in the case of diabetic remission. Further randomized trials are needed to better understand the organ-specific risk factors for progression and provide personalized counseling for T2DM patients planned for bariatric surgery.

Update on Myopia Risk Factors and Microenvironmental Changes.

The focus of this update is to emphasize the recent advances in the pathogenesis and various molecular key approaches associated with myopia in order to reveal new potential therapeutic targets. We review the current evidence for its complex genetics and evaluate the known or candidate genes and loci. In addition, we discuss recent investigations regarding the role of environmental factors. This paper also covers current research aimed at elucidating the signaling pathways involved in the pathogenesis of myopia.

Endocannabinoid System and Ocular Vascularization.

The focus of this review is the role of endocannabinoid system in ocular and systemic circulation. By critically examining preclinical and clinical research, we explore the cannabinoid receptors localization and vascular implications as well as their interaction with other anti-inflammatory drugs. The objective is to transfer knowledge on the use of cannabinoids, specifically their effect on ocular circulation and intraocular pressure, and provide a better understanding of the endocannabinoid system complexity in modulating local and systemic circulations in order to identify potential uses and limitations of cannabinoid-based therapeutics.

Topical administration of Metamizole and its implications on vascular reactivity in Wistar rats- Experimental research.

Aim: The aim of this paper was to describe the possible implications of topical (ocular) administration of Metamizole on vascular reactivity of the iris in Wistar rats. No other study regarding its topical use was found. Methods: Male adult Wistar rats were anaesthetized with Ketamine 100 mg /kg body weight - injected intraperitoneally - while maintaining spontaneous respiration and the blink reflex. After selecting the area of interest (long posterior ciliary artery - LPCA), manual adjustments of the image magnitude, clarity, and brightness were made, and the experiment began. The image recording lasted 10 minutes. Results: Metamizole induced a slight vasoconstriction that started with the initial moment for all the doses used. After the topical administration of Metamizole, we did not observe an increase of the vascular diameter of LPCA in a dose dependent manner. The saline solution used as a negative control did not modify the vessel diameter. Conclusions: Metamizole (dipyrone) is a non-opioid drug, which is commonly used in human and veterinary medicine. It is the most popular first-line analgesic in various populations. In some cases, this agent is still incorrectly classified as a non-steroidal anti-inflammatory drug. The high analgesic efficacy of metamizole, as well as its spasmolytic effect, makes it a very important pharmaceutical agent that could be used in the therapy of various eye disorders in humans and in animals. Abbreviations: COX = Cyclooxygenase; LPCA = Long Posterior Ciliary Artery; PRP = panretinal photocoagulation; PDR = proliferative diabetic retinopathy; Sec = second(s); VSPR = very severe non proliferative diabetic retinopathy.

Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci.

Exfoliation syndrome (XFS) is the most common known risk factor for secondary glaucoma and a major cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A, have previously been associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results across populations, and to identify new variants associated with XFS. We identified a rare protective allele at LOXL1 (p.Phe407, odds ratio (OR) = 25, P = 2.9 × 10-14) through deep resequencing of XFS cases and controls from nine countries. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 × 10-8). We identified association signals at 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

FIGHTING MULTIPLE DRUG RESISTANCE: EFFECTS OF UV-ACTIVATED CHLORPROMAZINE ON RABBIT'S EYE PSEUDOTUMOURS.

INTRODUCTION: Multiple drug resistance requires a flexible approach to find medicines able to overcome it. One method could be the exposure of existing medicines to UV laser beams to generate active photoproducts against bacteria and/or malignant tumors. METHODS: The interaction of Chlorpromazine (CPZ) (irradiated with 266 nm pulsed laser beams) was studied at concentrations of 10 mg/ml and 20 mg/ ml in ultrapure water, with pseudotumors of rabbits eyes. RESULTS: The use of CPZ water solution exposed to 266 nm in the treatment of pseudotumor tissues produced on rabbit eyes showed that treatment results depend on initial (before irradiation) CPZ concentration and exposure time. At this stage, one could not specify which out of the generated photoproducts, individual or as a group, was/were efficient in pseudotumor cure but overall effects were observable. Application of CPZ irradiated solutions on rabbit eyes pseudotumors seemed to produce a faster recovery of tissues with respect to control, untreated eyes. CONCLUSIONS: Histologic findings in the treated tissues showed a good anti-inflammatory response. The results obtained open perspectives to fight MDR and/or development of pseudotumoral processes with substances that were not initially made for this purpose (non-antibiotics, for instance).

ASSESSMENT OF CLINICAL AND IMAGISTIC STRUCTURAL PROGRESSION IN GLAUCOMA.

Glaucoma is a progressive optic neuropathy, characterized by loss of retinal ganglion cells and retinal nerve fiber layer as well as visual field loss. Therefore, in glaucoma, the correlation between structure and function is important, since it can be useful for tracking glaucomatous changes and for following the progression of the disease.

Relation of retinal blood flow and retinal oxygen extraction during stimulation with diffuse luminance flicker.

Cerebral and retinal blood flow are dependent on local neuronal activity. Several studies quantified the increase in cerebral blood flow and oxygen consumption during activity. In the present study we investigated the relation between changes in retinal blood flow and oxygen extraction during stimulation with diffuse luminance flicker and the influence of breathing gas mixtures with different fractions of O2 (FiO2; 100% 15% and 12%). Twenty-four healthy subjects were included. Retinal blood flow was studied by combining measurement of vessel diameters using the Dynamic Vessel Analyser with measurements of blood velocity using laser Doppler velocimetry. Oxygen saturation was measured using spectroscopic reflectometry and oxygen extraction was calculated. Flicker stimulation increased retinal blood flow (57.7 ± 17.8%) and oxygen extraction (34.6 ± 24.1%; p < 0.001 each). During 100% oxygen breathing the response of retinal blood flow and oxygen extraction was increased (p < 0.01 each). By contrast, breathing gas mixtures with 12% and 15% FiO2 did not alter flicker-induced retinal haemodynamic changes. The present study indicates that at a comparable increase in blood flow the increase in oxygen extraction in the retina is larger than in the brain. During systemic hyperoxia the blood flow and oxygen extraction responses to neural stimulation are augmented. The underlying mechanism is unknown.

Calculation of central retinal artery diameters from non-invasive ocular haemodynamic measurements in type 1 diabetes patients.

PURPOSE: The aim of the study was to compare the diameter of the central retinal artery (CRA) between patients with diabetes mellitus and healthy subjects in vivo. CRA diameters were calculated from retinal haemodynamic parameters measured with noninvasive measurement techniques. METHODS: Sixteen patients with type 1 diabetes with no or mild diabetic retinopathy and 16 age-matched healthy controls were included in this study. Total retinal blood flow was assessed by combining bidirectional laser Doppler velocimetry in all veins entering the optic disc with measurements of retinal vessel diameters using a Dynamic Vessel Analyser. Blood flow velocity in the CRA was measured with colour Doppler imaging (CDI). The diameter of the CRA in the optic nerve was then calculated for each subject using the individual ocular haemodynamic data. RESULTS: Calculated CRA diameters were significantly larger in patients with diabetes (180 ± 13 µm) compared with healthy controls (166 ± 10 µm, p = 0.001). No significant differences were found in retinal blood flow, retinal artery or vein diameters or mean flow velocity of the CRA. CONCLUSION: The data of the present study show increased calculated CRA diameter in patients with type 1 diabetes with no or mild retinopathy. Blood flow velocity measurements in retrobulbar vessels using CDI need to be interpreted with caution in terms of retinal blood flow, because no information about vessel diameters is obtained by this technique.

Reproducibility of retinal vessel oxygen saturation measurements in healthy young subjects.

PURPOSE: An adequate oxygenation and perfusion is essential for the function of the inner retina. Recently, several techniques for the measurement of retinal oxygen saturation became available. We set out to evaluate reproducibility of the measurements using a modified Retinal Vessel Analyzer. METHODS: A total of 20 healthy female and male subjects aged between 18 and 35 years (22.9 ± 3.9; mean ± SD) were included. The measurement of retinal oxygen saturation with the retinal oximeter employed in this study is based on optical reflectometry using the different absorption characteristics of oxygenated and deoxygenated haemoglobin. The intraclass correlation coefficients and the coefficients of variation (CV) for test-retest, short-term as well as day-to-day measurements were calculated. RESULTS: The intraclass correlation coefficients were between 0.91 and 0.94 for retinal branch arteries and between 0.84 and 0.88 for retinal branch veins. In retinal arteries, we calculated a test-retest CV of 3.24 ± 3.18% for oxygen saturation measurements. In retinal veins, data were slightly less reproducible with a CV of 4.92 ± 3.57%. Short-term reproducibility of both measurement cycles on each study day was in the same range (CV in retinal arteries: 2.91 ± 2.42% and CV in retinal veins: 4.76 ± 3.14%). The day-to-day coefficient of variation was slightly higher (CV in retinal arteries: 3.97 ± 2.87% and CV in retinal veins: 6.18 ± 3.36%). CONCLUSION: The reproducibility of haemoglobin oxygen saturation measurements using the retinal oximeter is acceptable. Further studies on the validity of the obtained results are, however, required.