Search

Glaucoma is a neurodegenerative disease that affects the retinal ganglion cells (RGCs). The main risk factor is elevated intraocular pressure (IOP), but the actual cause of the disease remains unknown. Emerging evidence indicates that metabolic dysfunction plays a central role. The aim of the current study was to determine and compare the effect of universal hypoxia on the metabolomic signature in plasma samples from healthy controls (n = 10), patients with normal-tension glaucoma (NTG, n = 10), and ocular hypertension (OHT, n = 10). By subjecting humans to universal hypoxia, we aim to mimic a state in which the mitochondria in the body are universally stressed. Participants were exposed to normobaric hypoxia for two hours, followed by a 30 min recovery period in normobaric normoxia. Blood samples were collected at baseline, during hypoxia, and in recovery. Plasma samples were analyzed using a non-targeted metabolomics approach based on liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). Multivariate analyses were conducted using principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA), and univariate analysis using the Wilcoxon signed-rank test and false discovery rate (FDR) correction. Unique metabolites involved in fatty acid biosynthesis and ketone body metabolism were upregulated, while metabolites of the kynurenine pathway were downregulated in OHT patients exposed to universal hypoxia. Differential affection of metabolic pathways may explain why patients with OHT initially do not suffer or are more resilient from optic nerve degeneration. The metabolomes of NTG and OHT patients are regulated differently from control subjects and show dysregulation of metabolites important for energy production. These dysregulated processes may potentially contribute to the elevation of IOP and, ultimately, cell death of the RGCs. [ABSTRACT FROM AUTHOR]

Aims/Purpose: To determine the effect of hypoxia on the plasma metabolic signature of patients with normal‐tension glaucoma (NTG) and ocular hypertension (OHT), compared to healthy controls. Methods: Metabolomic profiles of plasma from patients with NTG (n = 10) and OHT (n = 10) were compared to age‐matched controls (n = 10) to investigate the signature of hypoxia. Participants underwent two hours of exposure to normobaric hypoxia, followed by a 30‐min recovery period in normobaric normoxia. Blood samples were collected at baseline, during hypoxia, and recovery. Plasma samples were analysed using a non‐targeted metabolomics approach based on liquid chromatography coupled with high‐resolution mass spectrometry (LC‐HRMS). Multivariate analyses were conducted using principal component analysis (PCA) and orthogonal partial least squares‐discriminant analysis (OPLS‐DA), as well as univariate analysis with Wilcoxon signed‐rank test and false discovery rate (FDR) correction. Results: Overall, controls, OHT, and NTG patients had similar regulatory patterns. Only few metabolites involved in fatty acid biosynthesis, ketone body metabolism and kynurenine pathway were affected in OHT patients exposed to hypoxia, whereas metabolites related to energy production were not modified in NTG and OHT patients. No differences were found when comparing them pairwise at baseline, or during hypoxia and recovery. Conclusions: OHT patients have altered regulation of ketogenesis and kynurenine pathway, that may explain why they do not suffer from degeneration of the optic nerve. The metabolomes of NTG and OHT patients are regulated differently from controls, and omit to regulate metabolites that are important for energy production. This can potentially contribute to neurodegeneration and ultimately cell death in retinal ganglion cells. [ABSTRACT FROM AUTHOR]

Distant progression (DP) in oropharyngeal squamous cell carcinoma (OPSCC) has significant impact on morbidity and mortality. This study systematically reviewed the literature on studies reporting location and timing of DP after human papillomavirus (HPV)+ or HPV− OPSCCs. PubMed, EMBASE, and the Cochrane Library were systematically searched for studies reporting DP in patients treated with curative intend for an OPSCC. Outcome was site of and time to DP stratified on HPV‐status. Seven studies (n = 1564; 77% HPV+) were included in which 313 patients (20%) developed a DP (70% HPV+). The most common site of DP was the lungs (n = 232) regardless of HPV‐status. Patients with HPV+ tumors were more prone to dissemination involving multiple sites (risk ratio = 16.49). There was no difference in time to DP when stratified on HPV‐status (P = .10). The pattern of but not time to DP was significantly different in patients with OPSCC when stratified on HPV‐status. [ABSTRACT FROM AUTHOR]

The main risk factor for primary open-angle glaucoma (POAG) is increased intraocular pressure (IOP). It is of interest that about half of the patients have an IOP within the normal range (normal-tension glaucoma, NTG). Additionally, there is a group of patients with a high IOP but no glaucomatous neurodegeneration (ocular hypertension, OHT). Therefore, risk factors other than IOP are involved in the pathogenesis of glaucoma. Since the retina has a very high oxygen-demand, decreased autoregulation and a fluctuating oxygen supply to the retina have been linked to glaucomatous neurodegeneration. To assess the significance of these mechanisms, we have utilized a human experimental model, in which we stress participants with a fluctuating oxygen supply. Levels of oxidative stress molecules, antioxidants, and lipid mediators were measured in the plasma. Patients with NTG, OHT, and control subjects were found to have similar levels of oxidative stress markers. In contrast, patients with OHT had a higher level of total antioxidant capacity (TAC) and pro-homeostatic lipid mediators. Thus, we suggest that OHT patients manage fluctuating oxygen levels more efficiently and, thus, are less susceptible to glaucomatous neurodegenerations, due to enhanced systemic antioxidant protection. [ABSTRACT FROM AUTHOR]

Purpose: Autoregulation is essential for a constant circulation of O2. The apparent dissimilarity of vulnerability towards increased intraocular pressure in patients with normal‐tension glaucoma (NTGs) and individuals with ocular hypertension (OHTs) has been linked to disturbed autoregulation. The retina is particularly O2‐dependent and susceptible towards oxidative stress. The purpose was to evaluate the impact of a fluctuating O2 level on retinal vessel diameters and plasma levels of vasoregulators, nitric oxide (NO) and endothelin‐1 (ET‐1), and total antioxidant capacity (TAC) in strictly characterized NTGs, OHTs and age‐matched controls. Methods: NTGs (n = 10–16), OHTs (n = 9–10) and controls (n = 9–14) were exposed to 2 h of hypoxia followed by 30 min of normoxia. Fundus pictures and blood samples were taken before hypoxia ("baseline"), during hypoxia ("hypoxia") and after hypoxia ("recovery"). NO, ET‐1 and TAC was measured in plasma. Retinal arterial and vein diameters were measured with MATLAB. Results: Retinal arteries dilated in NTGs and OHTs during hypoxia, while controls constricted. No significant changes were seen in retinal veins. During hypoxia controls and NTGs increased plasma levels of ET‐1 and NTGs sustained a high level in recovery. OHTs did not regulate ET‐1 but maintained a lower level compared to NTGs during hypoxia and recovery. No significant differences were seen in NO. OHTs had a higher TAC compared to NTGs and controls throughout the experiment. Conclusions: The present study suggests a link between NTG and dysfunctional autoregulation. ET‐1 increase in controls and NTGs during hypoxia. As a vasoconstrictor, a vascular constriction is expected as evident in controls. The observed dilation in NTGs therefore might indicate that molecular mechanisms for vasoregulation are abolished. Surprisingly, OHTs present a similar pattern of autoregulation to NTGs but there is a prominent difference in the TAC. The higher level of TAC in OHTs compared to NTGs and controls indicates that the antioxidant defence might be important in providing resistance towards glaucomatous neurodegeneration. [ABSTRACT FROM AUTHOR]