Acromegaly had minimal effects on tested mRNAs specific to osteoblast or osteoclast function except for downregulated ALP expression. The expressions of miR known to be involved in mesenchymal stem cell commitment and downregulated TWIST1 expression suggest acromegaly has a negative effect on osteoblastogenesis.
Background: The registry is the main source of information about patients with acromegaly for assessing the quality of medical care, treatment effectiveness, determining the compliance of real clinical practice with existing standards and patient management. Aims: To analyze epidemiological, demographic and clinical characteristics of acromegaly in the Russian Federation and the effectiveness of various treatment methods. Materials and methods: The object of the study was the database of Russian registry of patients with pituitary tumors with specific analysis of patients with acromegaly only. We analyzed the data of 4114 patients with acromegaly stored on the online system in February 2019. Results: Based on the data 32% of patients had complete clinical and laboratory remission of acromegaly; percentage of patients with no remission was 68%, among them 22.5% had significant improvements in clinical symptoms and a decrease in GH and IGF1 without IGF1 normalization. The average age of patients at the onset of the disease was 42.7 years and at diagnosis 45.8 years. Men to women ratio was 1:2.6. In patients with acromegaly hypopituitarism was registered in 14.7% of cases and among them hypothyroidism (66%) and hypogonadism (52%) were registered more often. Among other complications the leading were diabetes mellitus (15.7%) and acromegalic arthropathy (15%). The proportion of patients receiving neurosurgical treatment increased from 35.7% to 49.6% in 2012-2019; the percentage of patients undergoing radiation therapy decreased significantly from 17.7% in 2012 to 0.8% in 2019. Remission was achieved in 40.47% after neurosurgery and 28.95% after medical treatment as a first line therapy p0.01. The number of patients receiving medical treatment at the time of the study was 1209. Among them 51% of patients treated with long-acting lanreotide and 24% receiving long-acting octreotide achieved remission (p0.0001) Conclusions: The remission rate of acromegaly remains suboptimal despite increased surgical activity, which corresponds to global trends. Long-acting lanreotide was significantly superior versus long-acting octreotide in the rate of acromegaly remission, which does not correspond with clinical trials and can be explained by the usage of different generic forms of octreotide, regional differences in medical supply and difficulties in long-acting octreotide injection vs lanreotide.
Context Excessive production of growth hormone causes marked multiorgan changes in patients with acromegaly, which may involve epigenetic mechanisms. Objective To evaluate differences in circulating microRNAs (miRNAs) associated with chronic growth hormone overproduction in adults. Design and setting A cross-sectional case-control study was conducted at a tertiary medical center. Participants We enrolled 12 consecutive patients with acromegaly along with 12 age and gender matched controls in the discovery phase of the study and then extended this cohort to 47 patients with acromegaly and 28 healthy controls for the validation study. Main Outcome Measures Plasma microRNAs were quantified by next-generation sequencing (NGS) in the discovery phase. Levels of selected miRNAs were validated on extended cohorts using RT-qPCR, compared between groups and correlated with clinical parameters. Results Based on NGS data, we selected three plasma miRNAs downregulated in patients with acromegaly compared to healthy controls: miR-4446-3p –1.317 (p=0.001), miR-215-5p –3.040 (p=0.005), miR-342-5p –1.875 (p=0.013) without multiplicity correction for all three miRNAs. These results were confirmed by RT-qPCR in the validation phase for two miRNAs out of three: miR-4446-3p (p <0.001, p-adj <0.001), AUC 0.862 (95% CI 0.723-0.936) p<0.001 and miR-215-5p (p <0.001, p-adj <0.001), AUC 0.829 (95% CI 0.698-0.907) p<0.001 to differentiate patients with acromegaly from healthy controls. Conclusions In a two-phase experiment using two different techniques we found and validated the downregulation of plasma miR-4446-3p and miR-215-5p in patients with acromegaly compared to healthy subjects, which makes them promising biomarkers for further research.
Под вторичным гиперпаратиреозом (ВГПТ) понимается избыточная секреция паратгормона (ПТГ) в ответ на хрони-ческую гипокальциемию. Наиболее тяжелые формы стой-кого вторичного гиперпаратиреоза развиваются у пациен-тов с терминальной почечной недостаточностью [1].По данным «Обзора общественного здравоохранения и исследования питания NHANES», среди населения США распространенность терминальной хронической болезни почек (ТХБП) с 1992 по 2002 г. увеличилась с 0,6 до 1,1% [2]. Результаты скрининговых исследований свидетельствуют о том, что частота выявления отдельных стадий ХБП при-мерно сопоставима вне зависимости от страны и популя-ции и около 10-17 % взрослого населения страдает ХБП. При этом диагностирована болезнь лишь у 1% населения. По последним данным ВГПТ составляет 20 -56% всех нару-шений фосфорно-кальциевого обмена при ХБП [3]. ПАТОГЕНЕЗ РАЗВИТИЯ ВТОРИЧНОГО ГИПЕРПАРАТИРЕОЗА ПРИ ХРОНИЧЕСКОЙ БОЛЕЗНИ ПОЧЕКУменьшение массы действующих нефронов при хро-нической почечной недостаточности (ХПН) ведет к гипер-фосфатемии, сопровождающейся реципрокным снижени-ем ионизированного кальция в крови. Гипокальциемия и гиперфосфатемия стимулируют синтез ПТГ околощито-видными железами. С гиперфосфатемией связывают воз-никновение резистентности скелета к кальциемическому действию ПТГ, что приводит к нарушению костного обме-на и усугубляет гипокальциемию. Кальций воздействует на процессы синтеза ПТГ через кальций-чувствительные рецепторы, представленные в околощитовидных желе-зах (ОЩЖ), количество и чувствительность к внеклеточ-ному кальцию которых при уремии также уменьшаются. При нарастании ХПН возникает дефицит синтезируемого Обзор литературы посвящен проблеме лечения вторичного гиперпаратиреоза (ВГПТ) у пациентов с терминальной стади-ей ХБП на гемодиализе. В основе патогенеза ВГПТ лежит депривация D-гормона с запуском патофизиологических механиз-мов нарушения костного ремоделирования, повышения ФРФ-23, ПТГ, изменениями содержания фосфора и кальция в сыво-ротке крови, нарушениями в чувствительности и регуляции кальций-чувствительного рецептора (КЧР), что в последующем приводит к значимым изменениям структуры костной ткани и кардиоваскулярным осложнениям. В списке препаратов, применяемых для лечения ВГПТ у диализных больных, значимое место занимают агонисты КЧР, до недавнего времени пред-ставленных единственным препаратом для приема внутрь -цинакальцетом с убедительно доказанной эффективностью. В настоящее время в США, Европе и России зарегистрирован новый кальцимиметик для внутривенного введения 3 раза в неделю -этелкальцетид. В обзоре представлены результаты клинических исследований этого препарата, показавшего преимущества в эффективности в сравнении с цинакальцетом и аналогичный профиль по побочным эффектам. Предпола-гается повышение приверженности к лечению ВГПТ у диализных пациентов за счет снижения кратности введения препа-рата и возможности его введения в диализных центрах.КЛЮЧЕВЫЕ СЛОВА: Вторичный гиперпаратиреоз; хроническая болезнь почек; гемодиализ; кальцимиметики; этелкальце-тид; цинакальцет; NOVEL TREATMENT OPTIONS...
BACKGROUND: For the last decades microRNAs (miR) have proven themselves as novel biomarkers for various types of diseases. Identification of specific circulating microRNA panel that differ patient with Cushing’s disease (CD) and ectopic ACTH syndrome (EAS) could improve the diagnostic procedure.AIM: to evaluate the differences in miR levels in plasma samples drained from inferior petrosal sinuses in patients with CD and EAS.MATERIALS AND METHODS: single-center, case-control study: we enrolled 24 patients with ACTH-dependent Cushing’s syndrome (CS) requiring bilateral inferior petrosal sinus sampling (BIPSS). Among them 12 subjects were confirmed as CD (males=2, females=10; median age 46,5 [IR 33,8;53,5]) and 12 as EAS (males=4, females=8, median age 54 [IR 38,75;60,75]). BIPSS was performed through a percutaneous bilateral approach. Once catheters were properly placed, blood samples were withdrawn simultaneously from each petrosal sinus and a peripheral vein. Plasma samples from both sinuses were centrifuged and then stored at -80 C. MiRNA isolation from plasma was carried out by an miRneasy Plasma/Serum Kit (Qiagen, Germany) on the automatic QIAcube station according to the manufacturer protocol. To prevent degradation, we added 1 unit of RiboLock Rnase Inhibitor (Thermo Fisher Scientific, USA) per 1 μL of RNA solution. The concentration of total RNA in the aqueous solution was evaluated on a NanoVue Plus spectrophotometer (GE Healthcare, USA). The libraries were prepared by the QIAseq miRNA Library Kit following the manufacturer standard protocols. MiR expression was then analyzed by sequencing on Illumina NextSeq 500 (Illumina, USA).RESULTS: 108 miRNAs were differently expressed (p <0,05) in inferior petrosal sinus samples of patients with CD vs EAS. We divided these miRNAs into 3 groups based on the significance of the results. The first group consisted of samples with the highest levels of detected miR in both groups. Four miRNAs were included: miR-1203 was downregulated in CD vs EAS — 36.74 (p=0,013), and three other were upregulated in CD vs EAS: miR-383-3p 46.36 (p=0,01), miR-4290 6.84 (p=0,036), miR-6717-5p 4.49 (p=0,031). This miRs will be validated in larger cohorts using RT-qPCR.CONCLUSION: Plasma miR levels differ in inferior petrosal samples taken from patients with CD vs EAS. These miRs need to be validated by different methods and in peripheral plasma samples in order to be used as potentially non-invasive biomarkers to differentiate ACTH-dependent CS.
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