Сравнительное исследование микроциркуляторных и структурных параметров фовеальной аваскулярной зоны у пациентов с глаукомой и сахарным диабетом

PURPOSE: To study the parameters of the foveal avascular zone (FAZ) and its relationship with the functional, structural and hemodynamic macular indicators in patients with primary open-angle glaucoma (POAG) and type 2 diabetes mellitus.MATERIALS AND METHODS: The study included 103 patients (161 eyes), who were divided into 3 groups: the 1st group — 58 eyes (31 patients) with 1st stage of POAG and diabetes; the 2nd group — 53 eyes (36 patients) with 1st stage of POAG; the 3rd group — 50 eyes (36 patients) with diabetes. The patients underwent a complete ophthalmological examination, including optical coherence tomography with angiography mode using a Cirrus 5000 Angioplex machine (“Carl Zeiss Meditec”). Functional, structural, hemodynamic parameters, FAZ area, FAZ perimeter, circularity index were evaluated.RESULTS: The lowest functional indicators were noted in the group of patients with a combined course of POAG and diabetes (best corrected visual acuity (BCVA) 0.63±0.19, MD -4.01±1.52 dB, visual field index 94.69±3.09%) and structural indicators (RNFL 79.91±12.66 μm and GCL+IPL 66.33±15.39 μm), accompanied by a decline in blood density and perfusion (wiPD 28.87±9.08%, wiVD 13.15±3.19/mm), a decrease in FAZ area almost by 2 times (0.62±0.03 mm2), an increase in its perimeter to 3.54±1.57 mm. The circularity index was significantly lower in groups 1 and 3 (0.59±0.11 and 0.58±0.09, respectively) compared with the 2nd group (POAG): 0.66±0.1. The results of the correlation analysis showed a statistically significant inverse dependence of the area and perimeter of FAZ on all hemodynamic parameters.CONCLUSION: The combined course of POAG and diabetes, even in the initial stages of the disease, is accompanied by pronounced structural changes, deterioration of hemodynamic parameters and impaired microcirculation of the macula. Dynamic monitoring of the area and perimeter of the avascular zone, the circularity index is important for the control and early diagnosis of macular microcirculation disorders, risk assessment and the rate of progression of optic neuropathy in patients with glaucoma.ЦЕЛЬ. Изучение параметров фовеальной аваскулярной зоны (ФАЗ) и ее связи с функциональными, структурными и гемодинамическими показателями макулы у пациентов с первичной открытоугольной глаукомой (ПОУГ) и сахарным диабетом (СД) 2 типа.МАТЕРИАЛЫ И МЕТОДЫ. В исследование включены 103 пациента (161 глаз), которые были разделены на 3 группы: 1-я группа — 58 глаз (31 пациент) с ПОУГ I стадии и СД; 2-я группа — 53 глаза (36 пациентов) с ПОУГ I стадии; 3-я группа — 50 глаз (36 пациентов) с СД. Пациентам проведено полное офтальмологическое обследование, включая оптическую когерентную томографию в режиме ангиографии на аппарате Cirrus 5000 Angioplex («Carl Zeiss Meditec»). Оценивали функциональные, структурные, гемодинамические параметры, параметры ФАЗ: площадь, периметр, индекс циркулярности.РЕЗУЛЬТАТЫ. В группе пациентов сочетанного течения ПОУГ и СД отмечены самые низкие функциональные (максимально корригированная острота зрения (МКОЗ) 0,63±0,19, показатель MD -4,01±1,52 дБ, индекс поля зрения 94,69±3,09%) и структурные показатели (RNFL 79,91±12,66 мкм, GCL+IPL 66,33±15,39 мкм), сопровождающиеся снижением плотности кровотока и перфузии (wiPD 28,87±9,08%, wiVD 13,15±3,19 мм), уменьшением площади ФАЗ почти в 2 раза (0,62±0,03 мм2), увеличением ее периметра до 3,54±1,57 мм. Индекс циркулярности был достоверно ниже в 1 и 3-й группах (0,59±0,11 и 0,58±0,09 соответственно) по сравнению со 2-й группой (ПОУГ, 0,66±0,1). Результаты корреляционного анализа показали статистически значимую обратную зависимость площади и периметра ФАЗ от всех гемодинамических параметров.ЗАКЛЮЧЕНИЕ. Сочетанное течение ПОУГ и СД даже на начальных стадиях заболевания сопровождается выраженными структурными изменениями, ухудшением гемодинамических показателей и нарушением микроциркуляции макулы. Проведение динамического мониторинга площади и периметра аваскулярной зоны, индекса циркулярности имеет значение для контроля и ранней диагностики нарушений макулярной микроциркуляции, оценки риска и скорости прогрессирования глаукомной оптической нейропатии

Анализ динамики структурных и гемодинамических параметров макулярной области у пациентов с первичной открытоугольной глаукомой и сахарным диабетом при долгосрочном наблюдении

PURPOSE. To study the changes in structural and hemodynamic parameters of the retina and foveolar avascular zone (FAZ) over time in patients with primary open-angle glaucoma (POAG) and diabetes mellitus (DM) observed in long-term follow-up.MATERIALS AND METHODS. The study included 258 patients (258 eyes) divided into five groups: group 1 — 58 patients (58 eyes) with stage I POAG and DM; group 2 — 50 patients (50 eyes) with stage I POAG; group 3 — 50 patients (50 eyes) with stage III POAG and DM; group 4 — 50 patients (50 eyes) with stage III POAG; group 5 — 50 patients (50 eyes) with DM. Patients underwent comprehensive ophthalmological examination, spectral domain optical coherence tomography (SD-OCT), optical coherence tomo-graphy angiography (OCT-A) of the macular region. The follow-up lasted 24 months.RESULTS. Analysis of the initial parameters in groups of patients with comorbidities showed the lowest values compared to controls, which were progressively worsening. MD in the group with DM + stage I POAG had reliably decreased after 12 months (by 5.05%), after 24 months by 12.12% (p≤0.05). The speed of GCL+IPL loss in groups 1 and 3 during the first year of observation was almost equal for initial and advanced glaucoma — 1.35 (-2.03%) and 1.32 (-2.36%) µm/year, but in group 3 the loss had doubled after two years (2.48 (-4.44%) and 1.41 (2.12%) µm/year). Deterioration of hymodynamic parameters in the macular region in groups 1 and 3 was noted primarily in the inner sectors (whole image vessel density in parafovea (PF wiVD) -0.79% during the first, and -2.57% during the second year in initial glaucoma, -0.6% and -1.24% in advanced, whole image vessel density in parafovea (PF wiVD) -0.2% and -1.22%, -0.66% and -1.56%, respectively). Parameters of FAZ had changed significantly after 2 years in patients with stage I POAG and DM: its area size had increased by 10.2%, perimeter by 4.49%, circularity index had decreased by 3.17%.CONCLUSION. Comorbidity of POAG and DM is accompanied by development and quick progression of significant changes in structural and hemodynamic parameters of the retina as observed by this long-term follow-up.ЦЕЛЬ. Изучить динамику структурных и гемодинамических параметров сетчатки и фовеолярной аваскулярной зоны (ФАЗ) у пациентов с первичной открытоугольной глаукомой (ПОУГ) на фоне сахарного диабета (СД) при долгосрочном наблюдении.МАТЕРИАЛЫ И МЕТОДЫ. В исследование включены 258 пациентов (258 глаз), которые разделены на следующие группы: 1-я группа ‒ 58 пациентов (58 глаз) с ПОУГ I стадии и СД; 2-я группа ‒ 50 пациентов (50 глаз) с ПОУГ I стадии; 3-я ‒ 50 пациентов (50 глаз) с ПОУГ III стадии и СД; 4-я ‒ 50 пациентов (50 глаз) с ПОУГ III стадии; 5–я ‒ 50 пациентов (50 глаз) с СД. Пациентам проведено полное офтальмологическое обследование, спектральная оптическая когерентная томография (ОКТ), оптическая когерентная томография с функцией ангиографии (OКT-A) макулы. Срок наблюдения 24 месяца.РЕЗУЛЬТАТЫ. Анализ исходных показателей в группах коморбидных пациентов показал самые низкие значения по сравнению с контрольными группами, ухудшающиеся по мере прогрессии заболевания. MD в группе СД+ПОУГ I стадии достоверно снизился через 12 месяцев (на 5,05%), через 24 месяца (на 12,12%, р≤0,05). Скорость потери комплекса ганглиозных клеток сетчатки и внутреннего плексиформного слоя сетчатки (GCL+IPL) в 1 и 3-й группах за первый год исследования была практически одинакова для начальной и далекозашедшей стадий — 1,35 (-2,03%) и 1,32 (-2,36%) мкм/год, но в 3-й группе через 2 года потеря увеличилась вдвое — 2,48 (-4,44%) и 1,41 (-2,12%) мкм/год. Ухудшение гемодинамики макулярной области в 1 и 3-й группах преимущественно отмечено во внутренних секторах (PF wiPD -0,79% за первый и -2,57% второй год при начальной стадии, -0,6 и -1,24% — при далекозашедшей глаукоме, PF wiVD-0,2% и -1,22%, -0,66 и -1,56% соответственно). Показатели ФАЗ за 2 года значимо изменились у пациентов с СД+ПОУГ I стадии: площадь увеличилась на 10,2%, периметр на 4,49%, а индекс циркулярности уменьшился на 3,17%.ЗАКЛЮЧЕНИЕ. Сочетанное течение ПОУГ и СД сопровождается развитием выраженных структурных и гемодинамических изменений сетчатки с высокой скоростью прогрессии при долгосрочном наблюдении

Association of Mitochondrial DNA Variations with Lung Cancer Risk in a Han Chinese Population from Southwestern China

Mitochondrial DNA (mtDNA) is particularly susceptible to oxidative damage and mutation due to the high rate of reactive oxygen species (ROS) production and limited DNA-repair capacity in mitochondrial. Previous studies demonstrated that the increased mtDNA copy number for compensation for damage, which was associated with cigarette smoking, has been found to be associated with lung cancer risk among heavy smokers. Given that the common and “non-pathological” mtDNA variations determine differences in oxidative phosphorylation performance and ROS production, an important determinant of lung cancer risk, we hypothesize that the mtDNA variations may play roles in lung cancer risk. To test this hypothesis, we conducted a case-control study to compare the frequencies of mtDNA haplogroups and an 822 bp mtDNA deletion between 422 lung cancer patients and 504 controls. Multivariate logistic regression analysis revealed that haplogroups D and F were related to individual lung cancer resistance (OR = 0.465, 95%CI = 0.329–0.656, p<0.001; and OR = 0.622, 95%CI = 0.425–0.909, p = 0.014, respectively), while haplogroups G and M7 might be risk factors for lung cancer (OR = 3.924, 95%CI = 1.757–6.689, p<0.001; and OR = 2.037, 95%CI = 1.253–3.312, p = 0.004, respectively). Additionally, multivariate logistic regression analysis revealed that cigarette smoking was a risk factor for the 822 bp mtDNA deletion. Furthermore, the increased frequencies of the mtDNA deletion in male cigarette smoking subjects of combined cases and controls with haplogroup D indicated that the haplogroup D might be susceptible to DNA damage from external ROS caused by heavy cigarette smoking

The Phylogeny of the Four Pan-American MtDNA Haplogroups: Implications for Evolutionary and Disease Studies

Only a limited number of complete mitochondrial genome sequences belonging to Native American haplogroups were available until recently, which left America as the continent with the least amount of information about sequence variation of entire mitochondrial DNAs. In this study, a comprehensive overview of all available complete mitochondrial DNA (mtDNA) genomes of the four pan-American haplogroups A2, B2, C1, and D1 is provided by revising the information scattered throughout GenBank and the literature, and adding 14 novel mtDNA sequences. The phylogenies of haplogroups A2, B2, C1, and D1 reveal a large number of sub-haplogroups but suggest that the ancestral Beringian population(s) contributed only six (successful) founder haplotypes to these haplogroups. The derived clades are overall starlike with coalescence times ranging from 18,000 to 21,000 years (with one exception) using the conventional calibration. The average of about 19,000 years somewhat contrasts with the corresponding lower age of about 13,500 years that was recently proposed by employing a different calibration and estimation approach. Our estimate indicates a human entry and spread of the pan-American haplogroups into the Americas right after the peak of the Last Glacial Maximum and comfortably agrees with the undisputed ages of the earliest Paleoindians in South America. In addition, the phylogenetic approach also indicates that the pathogenic status proposed for various mtDNA mutations, which actually define branches of Native American haplogroups, was based on insufficient grounds

Beringian Standstill and Spread of Native American Founders

Native Americans derive from a small number of Asian founders who likely arrived to the Americas via Beringia. However, additional details about the intial colonization of the Americas remain unclear. To investigate the pioneering phase in the Americas we analyzed a total of 623 complete mtDNAs from the Americas and Asia, including 20 new complete mtDNAs from the Americas and seven from Asia. This sequence data was used to direct high-resolution genotyping from 20 American and 26 Asian populations. Here we describe more genetic diversity within the founder population than was previously reported. The newly resolved phylogenetic structure suggests that ancestors of Native Americans paused when they reached Beringia, during which time New World founder lineages differentiated from their Asian sister-clades. This pause in movement was followed by a swift migration southward that distributed the founder types all the way to South America. The data also suggest more recent bi-directional gene flow between Siberia and the North American Arctic

A comparative study of structural and microcirculatory parameters in patients with primary open-angle glaucoma and diabetes mellitus

Purpose: to study the structural and microcirculatory changes in the optic nerve and retina in patients with primary open-angle glaucoma (POAG)  in diabetes using OCT  and OCT-A.Material  and methods. The study involved 156 eyes of 104 patients, divided into 4 groups: group 1 — 47 eyes (26 patients aged 66.96 ± 6.05) with stage I POAG and diabetes, group 2 — 36 eyes (24 patients aged 64.64 ± 7.91) with stage I POAG; group 3 — 36 eyes (28 patients aged 63.03 ± 7.10) with stage III POAG and diabetes; group 4 — 37 eyes (26 patients, aged 69.70 ± 7.44) with stage III POAG. All patients underwent a complete ophthalmologic examination, spectral OCT, OCT-A of the optic disc and the macula.Results. In groups 1 and 3 (with POAG and diabetes), a decrease in the parameters of best corrected visual acuity and MD was revealed, which became worse as glaucoma progressed. A thinning of retinal nerve fiber layer (RNFL), neuroretinal rim, ganglion cells and inner plexiform layer (GCL  + IPL) was noted, with the lowest values in patients with stage III POAG and diabetes. The analysis of hemodynamics showed a pronounced decrease in perfusion (39.04 ± 3.42 %) as well as vascular density of the optic disc (0.35 ± 0.04 / mm) and the macular area (22.96 ± 5.82 % and 12.19 ± 4.04 / mm) in stage III of POAG and diabetes. This decrease is strongly correlated with functional  and structural changes, the stage of glaucoma and the presence of diabetes.Conclusion. A comparative  analysis of structural, functional and vascular changes between groups of patients with stage I and III POAG, both accompanied and unaccompanied by diabetes, revealed signs of significant deterioration in perfusion of the optic nerve and retina in patients with diabetes. In combined  glaucoma and diabetes, early diagnosis, monitoring and adequate timely therapy require careful attention of specialists

Pharmacogenetic Association between Allelic Variants of the Autophagy-Related Genes and Anti-Vascular Endothelial Growth Factor Treatment Response in Neovascular Age-Related Macular Degeneration

Background: Age-related macular degeneration (AMD) is the leading cause of late-onset blindness in elderly. The occurrence and development of AMD is a multifactorial complex process where autophagy plays an important role. The first-line drugs for neovascular AMD (nAMD) are inhibitors of VEGF, with up to 30% of patients having an incomplete response to treatment. Genetic factors may influence the response to anti-VEGF therapy and explain treatment outcome variability. We aimed to estimate the role of polymorphic markers of the MTOR (rs1064261, rs1057079, rs11121704, rs2295080), SQSTM1 (rs10277), ULK1 (rs11246867, rs3088051), MAP1LC3A (rs73105013) and ATG5 (rs573775) genes in the development of nAMD and the efficacy of anti-VEGF therapy response. Methods: Genotyping by allele-specific PCR was performed in 317 controls and 315 nAMD patients in the Russian population. Of them, 196 treatment-naive nAMD patients underwent three monthly intravitreal injections (IVIs) of aflibercept. Genotypic frequencies were compared with OCT markers of therapy effectiveness and best-corrected visual acuity (BCVA) measures. The main outcomes were the BCVA gain and decrease in central retinal thickness (CRT). Results: MTOR-rs1057079-C, MTOR-rs11121704-C and MTOR-rs2295080-G alleles were associated with an increased risk of nAMD. The BCVA was increased in 117 (59.7%) patients by 10 [5–20] letters, did not changed in 59 (30.1%), and was decreased in 20 (10.2%) patients. ULK1-rs3088051 was associated with BCVA change. Among patients with the TT and CT genotypes for ULK1-rs3088051, an improvement in visual acuity was noted in 67.6% and 53.8% of cases, while in patients with the CC genotype, an increase in BCVA was recorded in 37.5% of cases (p = 0.01). The decrease in CRT was associated with SQSTM1-rs10277 (p = 0.001): it was significantly higher in TT (93 [58–122] mkm) and CT (66 [30–105] mkm) carriers compared to the CC genotype (47 [24–68] mkm). Other SNPs did not show significant associations with the outcome of anti-VEGF treatment. Conclusions: MTOR gene polymorphisms are moderately associated with the risk of nAMD. SQSTM1-rs10277 and ULK1-rs3088051 may influence short-term response to intravitreal anti-VEGF treatment. The results suggest that autophagy could be a target for future drugs to overcome resistance to anti-VEGF therapy

Первичная открытоугольная глаукома у пациентов с сахарным диабетом: патогенетические и клинические параллели развития (обзор литературы)

Primary open-angle glaucoma as a chronic progressive neuropathy, characterized by functional and structural changes in the optic nerve, is one of the main causes of blindness and disability. With a general prevalence of 3% in the population of patients with diabetes mellitus, the risk of its development increases by 1.4 times and increases with the duration of the disease. The role of glycemia level as an important risk factor for the development and progression of the disease is shown. Similar pathogenetic mechanisms of the development of the disease define them as neurodegenerative, with determining mechanisms for the development of cellular apoptosis associated with excessive release of glutamate, the formation of reactive oxygen species, end products of glycation and oxidation of lipids, with mitochondrial disorders. The theory of “Brain diabetes” considers glaucoma to be a type 4 diabetes. In this case, the role of compensation for carbohydrate metabolism in the absence of which insulin resistance exacerbates transsynaptic neurodegeneration becomes crucial. The central theory of insulin resistance in patients with diabetes explains the mechanisms of glaucoma due to impaired trabecular outflow, vascular changes (amyloid angiopathy) and glial activation. The use of metformin and insulin reduces the risk of development and the severity of the progression of the glaucoma process. A study of the structural and angiographic parameters of optical coherence tomography showed a similar decrease in the volume of the ganglion cell complex, the average thickness of the retinal nerve fiber layer, and the peripapillary density of the capillary layer in patients with glaucoma and diabetes. Their comorbid course is accompanied by pronounced structural and functional changes due to the neurodegenerative process, which determines the variants of their progress, the risk of early progression and severe loss of visual function. Patients with glaucoma in the presence of diabetes should be closely monitored by specialists, be informed about the risks and the need for both adequate glycemic control and the monitoring of functional and structural changes in the optic nerve and retina.Первичная открытоугольная глаукома как хроническая прогрессирующая нейропатия, характеризующаяся функциональными и структурными изменениями зрительного нерва, является одной из основных причин слепоты и инвалидности. При общей распространенности в популяции 3%, среди пациентов с сахарным диабетом (СД) риск заболеваемости глаукомой увеличивается в 1,4 раза и возрастает по мере увеличения продолжительности заболевания. Показана роль уровня гликемии как важного фактора риска развития и прогрессии патологии. Сходные патогенетические механизмы развития заболевания определяют их как нейродегенеративные вследствие развития клеточного апоптоза, связанного с избыточным освобождением глутамата, образованием активных форм кислорода, конечных продуктов гликирования и окисления липидов, с митохондриальными нарушениями. Теория «мозгового диабета» рассматривает глаукому как диабет 4 типа. При этом определяющей становится роль компенсации углеводного обмена, при отсутствии которой инсулинорезистентность усугубляет транссинаптическую нейродегенерацию. Центральная теория резистентности к инсулину у пациентов с СД объясняет механизмы развития глаукомы за счет нарушения трабекулярного оттока, сосудистых изменений (амилоидная ангиопатия) и глиальной активации. Использование метформина и инсулина снижает риск развития и тяжесть прогрессирования глаукомного процесса. Исследования структурных и ангиографических параметров оптической когерентной томографии показали сходное уменьшение объема комплекса ганглиозных клеток, средней толщины слоя нервных волокон сетчатки, перипапиллярной плотности капиллярного слоя у пациентов с глаукомой и СД. Коморбидное их течение сопровождается выраженными структурными и функциональными изменениями вследствие нейродегенеративного процесса, что предопределяет варианты их течения, риск ранней прогрессии и тяжелой потери зрительных функций. Пациенты с глаукомой на фоне СД должны находиться под более пристальным наблюдением специалистов, быть информированы о рисках и необходимости как адекватного гликемического контроля, так и мониторинга функциональных и структурных изменений зрительного нерва и сетчатки