[Machine learning methods in differential diagnosis of ACTH-dependent hypercortisolism].

AIM: To develop a noninvasive method of differential diagnosis of ACTH-dependent hypercortisolism, as well as to evaluate the effectiveness of an optimal algorithm for predicting the probability of ectopic ACTH syndrome (EAS) obtained using machine learning methods based on the analysis of clinical data. MATERIALS AND METHODS: As part of a single-center, one-stage, cohort study, a retrospective prediction of the probability of EAS among patients with ACTH-dependent hypercortisolism was carried out. Patients were randomly stratified into 2 samples: training (80%) and test (20%). Eleven machine learning algorithms were used to develop predictive models: Linear Discriminant Analysis, Logistic Regression, elastic network (GLMNET), Support Vector machine (SVM Radial), k-nearest neighbors (kNN), Naive Bayes, binary decision tree (CART), C5.0 decision tree algorithms, Bagged CART, Random Forest, Gradient Boosting (Stochastic Gradient Boosting, GBM). RESULTS: The study included 223 patients (163 women, 60 men) with ACTH-dependent hypercortisolism, of which 175 patients with Cushing's disease (CD), 48 - with EAS. As a result of preliminary data processing and selection of the most informative signs, the final variables for the classification and prediction of EAS were selected: ACTH level at 08:00 hours, potassium level (the minimum value of potassium in the active stage of the disease), 24-h urinary free cortisol, late-night serum cortisol, late-night salivary cortisol, the largest size of pituitary adenoma according to MRI of the brain. The best predictive ability in a training sample of all trained machine learning models for all three final metrics (ROC-AUC (0.867), sensitivity (90%), specificity (56.4%)) demonstrated a model of gradient boosting (Generalized Boosted Modeling, GBM). In the test sample, the AUC, sensitivity and specificity of the model in predicting EAS were 0.920; 77.8% and 97.1%, respectively. CONCLUSION: The prognostic model based on machine learning methods makes it possible to differentiate patients with EAS and CD based on basic clinical results and can be used as a primary screening of patients with ACTH-dependent hypercortisolism.

[Diagnostic value of bilateral inferior petrosal sinus sampling in various modifications and methods of radiation and radionuclide imaging in the diagnosis and differential diagnosis of ACTH-dependent endogenous hypercortisolism].

AIM: To analyze the diagnostic performance of bilateral inferior petrosal sinus sampling (BIPSS) with desmopressin as a stimulation agent and prolactin measurements to control catheter position with or without the ACTH/prolactin normalized ratio calculation in the differential diagnosis of ACTH-dependent endogenous hypercortisolism, and the diagnostics performance of ectopic ACTH-syndrome (EAS) visualization. MATERIALS AND METHODS: A single-center diagnostic study with a retrospective analysis of the data was carried out. The study included patients with ACTH-dependent endogenous hypercorticism with no visualization of pituitary adenoma on MRI or adenoma sizes less than 6 mm. All patients underwent BIPSS with and without calculation of the ACTH/prolactin normalized ratio. Visualization of an EAS included pituitary MRI (to exclude EAS), whole-body CT scan with contrast, and somatostatin receptor scintigraphy with 99mTc-Tectrotide and CT (99mTc-Tectrotide SPECT). The final verification was based on immunohistochemical confirmation of the tumor or stable remission of Cushing's disease (CD) after surgical treatment. Statistical data processing was carried out by using IBM SPSS Statistics 23. Confidence intervals were calculated using the JavaStat online calculator. RESULTS: 230 BIPSS were performed in 228 patients (166 women, 62 men), of which 178 patients were verified as CD and 50 cases were EAS of various localization. The effectiveness of catheterization of petrosal sinuses was 96.9%. The sensitivity of BIPSS without ACTH/prolactin ratio calculation (n=70) was 95.9% (95% CI 86.3-98.9), specificity was 92% (95% CI 75.0-97.8), for the BIPSS with additional determination of ACTH/prolactin-normalized ratio (n=51) - 97.3% (95% CI 86.2-99.5) and 93.8% (95% CI 71.7-98.9), respectively. The use of the MRI method for this sample of patients had a sensitivity of 60.2% (95% CI 52.6-67.5), specificity of 59.2% (95% CI 44.2-73.0), the total body CT with contrast has a sensitivity of 74% (95% CI 59.7-85.4), specificity of 100% (95% CI 97.95-100). The diagnostic accuracy for 99mTc-Tectrotide SPECT in NET visualization has a sensitivity of 73.3% (95% CI 44.9-92.2), specificity of 100% (95% CI 95.3-100). CONCLUSION: BIPSS with desmopressin stimulation and prolactin measurements to control catheter position, as well as the additional calculation of the ACTH/prolactin-normalized ratio, is an optimal method for the differential diagnosis of EAS. Patients who are identified an EAS on BIPSS may be further referred for 99mTc-Tectrotide SPECT and CT for tumor visualization.

[Clinical features, diagnostics and treatment of FGF23 secreting tumors: series of 40 clinical cases].

INTRODUCTION: Tumor-induced osteomalacia is an acquired rare disease manifested by hypophosphatemic osteomalacia due to excessive secretion of fibroblast growth factor 23 (FGF23). FGF 23 is a non-classical hormone secreted by bone tissue (osteocytes) and regulates phosphorus metabolism.The aim of this work is to present clinical experience in the diagnosis, treatment and rehabilitation of patients with tumor-induced osteomalacia. MATERIALS AND METHODS: 40 patients with clinically-confirmed tumor-induced osteomalacia were included in the study, 34 of whom had the tumor localized, 27 underwent surgical treatment and 21 achieved stable remission. RESULTS: The median age was 48 [41; 63] years, 43% were men, the time left from the the onset of the disease was 8 [4; 10] years. Biochemical findings were hypophosphatemia 0.47 [0.4; 0.53] mmol/l, a decrease in the tubular reabsorption phosphate 62 [52; 67]%, and an increase in alkaline phosphatase of 183 [112; 294] units/l. At the time of diagnosis, 100% had multiple pathological fractures, only 10% could move independently, and 77.5% classified the pain as unbearable (8-10 points according to the 10-point pain syndrome scale ). Among the methods used to detect tumors, the most sensitive were scintigraphy with tectrotide with SPECT/CT 71.4% (20/28) and MRI 90% (18/20). In 35% of cases, the tumor was localized in soft tissues and in 65% in bone tissue; The tumor was most often detected in the lower extremities, followed by the head in frequency of localization. 18 patients currently have no remission and they receive conservative treatment (phosphorus and alfacalcidol n=15 and burosumab n=3). In case of achieving remission (n=21), regression of clinical symptoms and restoration of bone and muscle mass was observed. Extensive excision of the tumor without prior biopsy resulted in the best percentage of remission - 87%. CONCLUSION: Tumor-induced osteomalacia is characterized by severe damage to bone and muscle tissue with the development of multiple fractures, muscle weakness and severe pain syndrome. In laboratory diagnostics, attention should be paid to hypophosphatemia, a decrease in the tubular reabsorption phosphate index and increased alkaline phosphatase. The use of functional diagnostic methods with a labeled somatostatin analogue to the subtype 2 receptor and MRI with contrast enhancement are the most accurate methods of topical diagnostics. In case of localization of the tumor, a wide excision without a preliminary biopsy is recommended.

[Thyrotropin-secreting pituitary adenomas: clinical features and results of treatment in 45 patients].

BACKGROUND: Thyrotropin-secreting pituitary adenomas (TSH-PA) are a rare cause of thyrotoxicosis and account for 0.5-2% of all pituitary adenomas. Taking into account the rarity of the disease, it is extremely important to analyze each case of TSH-PA. AIM: To analyze the clinical characteristics and treatment outcomes of patients with TSH-PA, as well as to determine preoperative and early postoperative factors that predict long-term remission. MATERIALS AND METHODS: In a single-center retrospective study we analyzed clinical signs, laboratory and instrumental studies, as well as the treatment outcomes of patients with TSH-PA from 2010 to 2023. Preoperative factors, as well as TSH level measured on day 3 postoperatively, were evaluated for their ability to predict long-term remission when comparing groups of patients with and without remission. RESULTS: The study included 45 patients with TSH-PA (14 men, 31 women), with a median age of 45 years [30; 57]. The most common clinical manifestations of TSH-PA were: cardiac arrhythmia in 37 (82.2%) patients, thyroid pathology in 27 (60%), neurological disorders in 24 (53.35%). Most PAs were macroadenomas (n=35, 77.8%). Preoperatively, 28 (77.8%) patients received somatostatin analogs, and 20 (71.4%) patients were euthyroid at the time of surgery. Surgical treatment was performed in 36 (80%) patients, postoperative remission was achieved in 31 cases (86.1%). Administration of somatostatin analogues to patients with no remission/relapse after surgery lead to the remission in 100% of cases (4/4). A 1 mm increase in PA size raised the odds of recurrence/no remission by 1.15-fold,and PA invasion during surgery - by  5.129 fold. A TSH level on day 3 postoperatively above 0.391 mIU/L (AUC, 0.952; 95% CI 0.873-1.000; standard error 0.04; p<0.001) identifies patients with relapse/absence of remission after surgical treatment (sensitivity = 100%, specificity = 88.9%). CONCLUSION: The TSH-PA in the structure of PAs is extremely rare, and as a result, most of them are misdiagnosed and detected already at the stage of macroadenoma. The most effective method of treatment is transnasal transsphenoidal adenomectomy. Somatostatin analogues can be used as second-line therapy if surgical treatment is ineffective. We have proposed a possible model for postoperative TSH levels (>0.391 mU/l) to predict recurrence of TSH-PA, which requires validation on an expanded number of cases.

[Hypophysitis and reversible hypopituitarism developed after COVID-19 infection - a clinical case report].

AIM: To present a clinical case of reversible hypopituitarism due to hypophysitis developed after COVID-19 infection. MATERIALS AND METHODS: A patient with residual clinical manifestations of hypopituitarism underwent clinical evaluation at the time of symptoms of hypopituitarism and in follow-up. Morning serum cortisol (171-536 nmol/l) was measured by electrochemiluminescence immunoassay. Morning ACTH (7.2-63.3 pg/ml), prolactin (66-436 mU/l), TSH (0.25-3.5 mIU/L), fT4 (9-19 pmol/l) and fT3 (2.6-5.7 pmol/l) were measured by chemiluminescence immunoassay. Data were analyzed throughout the course of the disease. RESULTS: A 35-year-old female developed clinical symptoms of hypopituitarism two months after recovery from a confirmed COVID-19 infection. Laboratory investigation confirmed hypocorticism, hypothyroidism, hypogonadism and the patient was prescribed appropriate hormonal therapy in January 2021. Four months later the symptoms were alleviated (April 2021) and there were signs of recovery shown by imaging and hormonal: morning serum cortisol 227 nmol/l, morning ACTH 33.96 pg/ml, prolactin 68.3 mU/l, TSH 2.626 mIU/L, fT4 10.75 pmol/l, fT3 3.96 pmol/l. Thyroid hormone was discontinued, but hypogonadism and hypocorticism persisted with estradiol - 51.48 pmol/l, 24h urine cortisol level - 41.8 nmol/day. MRI results showed that the signs of hypophysitis were alleviated in comparison with MRI from January 2021. Full recovery of pituitary axis was reported in October 2021, with recovery of normal menstrual cycle. Furthermore, hormonal profile was likewise normal. CONCLUSION: This report provides evidence of delayed damage to the pituitary gland after infection with the COVID-19, with recovery of its function and structure. To date, the mechanisms of such an impact are not entirely clear; further collection of data on such cases and analysis is required.

[Survival predictors in patients with ectopic acth syndrome].

AIM: To determine significant factors affecting the survival of patients with ectopic ACTH syndrome (EAS). MATERIALS AND METHODS: A multi-center, observational study with a retrospective analysis of patients with EAS. The end point of the study was the fatal outcome of patients from various causes. In order to identify predictors of survival or mortality, univariate and multifactorial Cox regression analyses were carried out. ROC-analysis was used to determine the prognostic threshold values of individual predictors. The survival analysis was carried out using the Kaplan-Mayer method. Statistical data processing was carried out by using IBM SPSS Statistics 23. RESULTS: The age of patients at the time of diagnosis ranged from 12 to 76 years (Me 40 years [28;54]). The age of the studied population was 55 years [38; 64] for women and 42 years [32; 54] for men. The median period of observation was 50 months [13;91], with a maximum follow-up of 382 months. 92 patients (60,9%) had bronchopulmonary NET, 17 (11,3%) - thymic carcinoid, 8 - pancreatic NET, 5 -pheochromocytoma, 1- cecum NET, 1- appendix carcinoid tumor, 1 - medullary thyroid cancer and 26 (17,2%) patients had an occult NET. The primary tumor was removed in 101 patients (66,9%). Bilateral adrenalectomy was performed in 42 (27,8%) cases. Metastases were revealed in 23,2% (n=35) of patients. Relapse of the disease was observed in 24,4%, long-term remission was preserved in 64 patients (74,4%). Death occurred in 42 patients (28%). The average age of survivors was 47,0±15,2 versus 53,5±15,6 years for the deceased (p=0,022). The average survival time from diagnosis for the deceased was 32 months, Me 16,5 months [7;54]. Multivariate analysis revealed that the following factors have a direct impact on survival: age of diagnosis ≥51 years (OR 4,493; 95% CI 2,056-9,818, p<0,001), bronchopulmonary neuroendocrine tumor (NET) (OR 0,281; 95% CI 0,119-0,665, p=0,004), the presence of distant metastases (OR 2,489; 95% CI 1,141-5,427, p=0,022), late-night salivary cortisol (LNSC) ≥122,2 nmol/L (OR 2,493; 95% CI 1,014-6,128, p=0,047). CONCLUSION: The prognosis of patients with EAS is influenced by the age of diagnosis, NET localization, distant metastases and level of LNSC. The most common cause of ectopic ACTH syndrome was bronchopulmonary NET which was associated with the best survival rate.

[The clinical practice guidelines for primary hyperparathyroidism, short version].

Primary hyperparathyroidism (PHPT) is an endocrine disorder of parathyroid glands characterized by excessive secretion of parathyroid hormone (PTH) with an upper normal or elevated blood calcium level. Classical PHPT refers to a symptomatic, multi-system disorder, wich can lead to a significant decrease in the quality of life, disability of patients, and even an increased risk of premature death. Hypercalcemia and the catabolic effect of PTH on various cells are considered as the main pathogenetic mechanisms of the PHPT associated complications. In the last two decades, there has been an increase in the incidence of PHPT, mainly due to the mild forms of the disease, primarily due to the routine calcium screening in North America, Western Europe and, Asia. High prevalence of the disease, as well as the variety of clinical manifestations, cause the attention of different specialists - physicians, rheumatologists, urologists, nephrologists, cardiologists and other doctors. This review cover the main issues of Russian guidelines for the management of PHPT, approved in 2020, including laboratory and instrumental methods, differential diagnosis, surgical and conservative approach, short-term and long-term follow-up. This guidelines also include the recommendations for special groups of patients with hereditary forms of PHPT, parathyroid carcinoma, PHPT during pregnancy.

[Vitamin D deficiency in Russia: the first results of a registered, non-interventional study of the frequency of vitamin D deficiency and insufficiency in various geographic regions of the country].

BACKGROUND: In Russian Federation, there are no large-scale cross-sectional multicenter epidemiological studies assessing the prevalence of vitamin D deficiency and insufficiency in different geographical latitudes. Insufficient solar insolation and inadequate vitamin D content in food dictate the need to study the epidemiological structure of low vitamin D status in Russia. AIM: To assess the incidence of vitamin D deficiency and insufficiency among the population living in the regions of the Russian Federation located at latitudes from 45 ° to 70 °. MATERIALS AND METHODS: The first stage of the Russian multicenter non-interventional registry study using the «crosssectional¼ method was carried out from March 2020 to May 2020. RESULTS: In regions that represent a geographically representative sample of regions of the Russian Federation with a high risk of developing low levels of vitamin D, it's deficiency was noted in 55.96%, and the level of deficiency and insufficiency was recorded in 84.01%. CONCLUSION: Close attention to the wide scale of the problem of vitamin D deficiency and insufficiency in the Russian Federation will contribute to the progressive formation of various educational and preventive programs necessary to strengthen health and improve the quality of life of the population.

[Clinical and laboratory characteristics and results of treatment of patients with ACTH-producing neuroendocrine tumors of various localization].

AIM: To study the clinical, biochemical characteristics, treatment results and follow-up of patients with ectopic ACTH syndrome EAS (ACTH adrenocorticotropic hormone ). MATERIALS AND METHODS: A retrospective, observational, single-center study of 130 patients with EAS. Demographic information of patients, medical history, results of laboratory and instrumental investigations at the pre- and postoperative stages and follow-up of EAS were analyzed. RESULTS: The mean age at the diagnosis ranged from 12 to 74 years (Me 40 years [28; 54]). The duration of the disease from the onset of symptoms to the verification of the diagnosis varied from 2 to 168 months (Me 17.5 months [7; 46]). Eighty-one (62,3%) patients had bronchopulmonary NET, 9 thymic carcinoid, 7 pancreatic NET, 5 pheochromocytoma, 1 cecum NET, 1 appendix carcinoid tumor, 1 medullary thyroid cancer and 25 (19.2%) had an occult source of ACTH. The median follow-up period of patients was 27 months [9.75; 61.0] with a maximum follow-up of 372 months. Currently, primary tumor was removed in 82 (63.1%) patients, bilateral adrenalectomy was performed in 23 (18%) patients, in 16 of them there was an occult source of ACTH-producing NET and in 7 patients in order to control hypercortisolism after non-successful surgical treatment. Regional and distant metastases were revealed in 25 (19.2%) patients. At the time of the last observation 59 (72%) patients were exhibited a full recovery, 12 (14.6%) had relapse of the disease and 26 (20%) died from multiple organ failure (n=18), pulmonary embolism (n=4), surgical complications (n=2), disseminated intravascular coagulation syndrome (n=1) or COVID-19 (n=1). CONCLUSION: In our cohort of patients bronchopulmonary NET are the most frequent cause of EAS (62.3%). Surgical treatment leads to remission of hypercortisolism in 72% cases; the proportion of relapse (14.6%) and fatal outcome (20%) remains frequent in EAS.

[The first Russian multicenter non-interventional registry study to study the incidence of vitamin D deficiency and insufficiency in Russian Federation].

AIM: To assess the incidence of vitamin D deficiency and insufficiency among the adult population living in the regions of the Russian Federation located at latitudes from 45 to 70. MATERIALS AND METHODS: Russian multicenter non-interventional registry study using the "cross-sectional" method. RESULTS: In this study, 72.1% of the examined have the status of vitamin D deficiency and insufficiency, while an adequate level was diagnosed in 27.8% of cases. When assessing the degree of vitamin D deficiency depending on the season, statistically significant differences (p0.00001) were found between the periods: vitamin D deficiency or insufficiency was observed in 84.2% of autumn and in 62.4% of spring. The highest incidence of vitamin D deficiency and insufficiency was recorded in males compared with females (p=0.013, 79 and 70.3% respectively). Vitamin D deficiency is observed in young people in the age subgroup of 1825 years (p0.001, 54% in the study as a whole) much more often than in older people Conclusion. The widespread high prevalence of vitamin D deficiency in the Russian Federation is not related to geographic region of residence, but to some extent depends on the season. The high-risk group for vitamin D deficiency and insufficiency is young men. The significant role of vitamin D in the human body justifies the need to supplement and clarify a single concept for the prevention, diagnosis and treatment of conditions associated with deficiency, so higher implementation of National Clinical Guidelines is needed.

[Vitamin D metabolite and calcium phosphorus metabolism in in patients with primary hyperparathyroidism on the background of bolus therapy with colecalciferol].

BACKGROUND: Vitamin D (25-hydroxyvitamin D [25(ОН)D]) deficiency (<20 ng/mL) and insufficiency (20-29 ng/mL) are common in primary hyperparathyroidism (PHPT), but data regarding the vitamin D metabolism in this population is limited. AIM: The aim of this study is to estimate the vitamin D metabolites and their relationship with the main parameters of phosphorus-calcium metabolism in patients with PHPT at baseline and on the background of a single dose of cholecalciferol 150,000 IU. MATERIALS AND METHODS: A single-center interventional, dynamic, prospective, comparative study has been carried out. The study included 54 participants, divided into two groups: the 1st group included 27 patients with confirmed PHPT, the 2nd control group (n = 27), matched on gender (p = 0.062). The study included 4 visits; the baseline laboratory examination and a bolus dose of cholecalciferol were performed at the visit 1, the subsequent visits included a dynamic laboratory examination. RESULTS: Vitamin D deficiency (<20 ng/ml) was detected in 69% of patients with PHPT. In the PHPT group (before cholecalciferol therapy), there was a direct association of 1.25(OH)2 D3 with albumin-corrected and ionized calcium, as well as between the 25(OH)D3 /24.25(OH)2 D3 ratio with PTH and magnesium. After taking of cholecalciferol, the levels of 1.25(OH)2 D3 and 25(OH)D3 /24.25(OH)2 D3 were significantly increased, and the levels of 25(OH)D3 /1.25(OH)2 D3 were significantly declined at all visits among patients with PHPT. The common 25(OH)D level was comparable to the control group, however the levels of 1,25(OH)2 D3 in patients with PHPT were 55% higher at baseline, and after taking of cholecalciferol 150,000 IU. They remained increased by 3-7 days by an additional 23-36%, significantly higher than those in the control group: 44%, 74% and 65%, at visits 2, 3 and 4, respectively (p<0.05). The taking of 150,000 IU cholecalciferol in the PHPT group did not lead to a significant increase in hypercalcemia and hypercalciuria, which indicates the safety of this dose in patients with mild hypercalcemia (albumin corrected calcium <3 mmol/l). None of the study participants experienced any side effects. CONCLUSION: The completely comprehensive assessment of vitamin D metabolites was carried out for the first time in patients with PHPT before and after using a bolus dose of cholecalciferol. The results confirmed the differences of vitamin D metabolism in chronic excessive secretion of PTH compared to control group, which is new data in the pathogenesis of the disease, and can be used to develop optimal regimens for cholecalciferol taking in this population.

[The role of vitamin D in seasonal acute respiratory viral infections and COVID-19].

A link between vitamin D deficiency and susceptibility to infectious diseases was suggested over a hundred years ago. Epidemiological studies show a strong association between seasonal fluctuations in vitamin D levels and the incidence of various infectious diseases, including septic shock, acute respiratory infections, and influenza. Our understanding of vitamin D metabolism and its extra-skeletal functions has improved significantly over the past three decades, and the discovery that the vitamin D receptor and 1a-hydroxylase, an enzyme needed to convert vitamin D to its active form, is present in the cells of the immune system, revolutionized in this area. Recent studies have shown that vitamin D regulates the expression of specific endogenous antimicrobial peptides in immune cells, modulates the immune response and the course of autoimmune processes; these actions indicate the potential role of vitamin D in modulating the immune response to various infectious diseases. This publication reviews the literature on the effects of vitamin D on immunity, its potential in the prevention and treatment of viral diseases, with a particular focus on COVID-19.

[Hereditary Cushing's syndrome caused by primary bilateral macronodular adrenal hyperplasia due to ARMC5 mutation with concomitant primary hyperparathyroidism: the first known case in Russia].

Primary bilateral macronodular adrenal hyperplasia (PBMAH), a genetically heterogeneous disease, is a rare cause of Cushing's syndrome. Until recently, few cases were attributed to mutations in known genes. However, in 2013, ARMC5, a newly discovered tumor suppressor gene, was identified. Further studies have shown that mutations in the ARMC5 gene are found in 25-55% of all PBMAH cases. This article describes a clinical case of hereditary Cushing's syndrome caused by PBMAH in a 37-year old patient. The patient's family history is remarkable for the presence of Cushing's syndrome and PBMAH in the patient's mother. Bilateral adrenalectomy was performed as the treatment of choice. Genetic analysis using whole-exome sequencing confirmed the hereditary cause of the disease, revealing a germline heterozygous mutation in the ARMC5 gene. The patient also had concomitant mild primary hyperparathyroidism, which had not been observed before in genetic carriers with the ARMC5 mutation.

Effects of endogenous hypercortisolism on bone mRNA and microRNA expression in humans.

Hypercortisolism in humans suppresses osteoblastogenesis and osteoblast function through the upregulation of Wnt-signaling antagonists (sclerostin, Dkk1) and changes in microRNAs levels (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) which are associated with mesenchymal stem-cell commitment to adipocytes or cartilage cells over the osteoblasts. INTRODUCTION: The purpose of this study was to evaluate the responses of bone to chronic glucocorticoid (GC) excess by measuring the levels of selected mRNA and microRNA (miR) in bone samples of patients with Cushing's disease (CD). METHODS: Bone samples were obtained during transsphenoidal adenomectomy from the sphenoid bone (sella turcica) from 16 patients with clinically and biochemically evident CD and 10 patients with clinically non-functioning pituitary adenomas (NFPA) matched by sex, age, and body mass index. Quantitative polymerase chain reactions (qPCR) were used to examine the expression of genes (mRNA and miRs) known to be involved in bone remodeling regulation based on studies in animals and cell culture. RESULTS: Hypercortisolism was associated with the downregulation of genes involved in osteoblast function and maturation (ACP5, ALPL, BGLAP, COL1A1, COL1A2, BMP2, RUNX2, TWIST1). An excess of GC caused increased expression of Wnt-signaling antagonists (Dkk1, SOST) and changes in the levels of miRs that are known to suppress osteoblastogenesis (miR-125b-5p, miR-218-5p, miR-34a-5p, miR-188-3p, miR-199a-5p) p < 0.05, q < 0.1. Interestingly, compensatory mechanisms were found in long-term hypercortisolism: upregulation of Wnt10b, LRP5, and LRP6; downregulation of SFRP4; changes in miRs involved in osteoblastogenesis (miR-210-5p, miR-135a-5p, miR-211, miR-23a-3p, miR-204-5p); and downregulation of genes associated with osteoclastogenesis. None of these changes prevented the suppression of bone formation. CONCLUSIONS: An excess of endogenous GC in humans suppresses bone formation through the upregulation of Wnt-signaling antagonists and dysregulation of miRs involved in mesenchymal stem-cell commitment. Both Wnt-signaling antagonists and miRs seem to be promising targets for further research in therapeutic intervention in glucocorticoid-induced osteoporosis.

[CDC73 mutations in young patients with primary hyperparathyroidism: A description of two clinical cases]. / Mutatsii v gene CDC73 u molodykh patsientok s pervichnym giperparatireozom (opisanie dvukh klinicheskikh sluchaev).

The article describes two clinical cases of severe primary hyperparathyroidism (PHPT) caused by parathyroid carcinoma in young female patients who underwent molecular genetic testing to rule out the hereditary forms of PHPT. In both patients, heterozygous germline nonsense mutations of tumor suppressor gene CDC73 encoding parafibromin (p.R91X and p.Q166X) were identified using next-generation sequencing with Ion Torrent Personal Genome Machine (Thermo Fisher Scientific - Life Technologies, USA). It is the first description of CDC73 mutations in Russia, one of the mutations is described for the first time in the world. Identification of germline mutations in the CDC73 gene in patients with PHPT necessitates regular lifelong screening for other manifestations of hyperparathyroidism-jaw tumor syndrome (HPT-JT), PHPT recurrence due to parathyroid carcinoma as well, and identification of mutation carriers among first-degree relatives.

[The canonical Wnt/ß-catenin pathway: From the history of its discovery to clinical application]. / Kanonicheskii signal'nyi put' Wnt/ß-katenin: ot istorii otkrytiia do klinicheskogo primeneniia.

The Wnt/ß signaling pathway (Wnt-SP) is a phylogenetically ancient mechanism that regulates development and maintains tissue homeostasis through the control of cell proliferation, differentiation, migration, and apoptosis. The accurate regulation of the canonical Wnt/ß-catenin signaling pathway (Wnt-SP) is critical for embryogenesis and postnatal development; and impaired signal transduction at one of its stages leads to various diseases, including organ malformations, cancers, metabolic and neurodegenerative disorders. The literature review discusses the biological role of the canonical Wnt-SP in the development of the skeleton and in the remodeling of bone tissue. The Wnt signal transmission changes observed during genetic mutations cause various human skeletal diseases. Understanding the functional mechanism involved in the development of bone abnormality could open new horizons in the treatment of osteoporosis, by affecting the Wnt-SP. The design of antibodies to sclerostin, a Wnt-SP inhibitor, is most promising now. The paper summarizes the studies that have investigated the canonical Wnt-SP and designed drugs to treat osteoporosis.

[Role of microRNA in oncogenesis of pituitary tumors and their practical significance]. / Rol' mikroRNK v onkogeneze opukholei gipofiza i ikh prakticheskaia znachimost'.

Microribonucleic acids (miRNAs) are a class of noncoding RNAs that regulate posttranscriptional gene expression. These molecules are regulators of cell proliferation, metabolism, apoptosis, and differentiation. MiRNAs are not degraded by RNAases and their concentrations can be measured in different body fluids, including serum. The expression of miRNAs varies in intact tissues and tumors, including pituitary adenomas. Pituitary tumors are encountered in 22.5% of the population and, in a number of cases, may be asymptomatic, but in case of invasion or/and hormone overproduction, their clinical presentation is severe with multiple symptoms leading to disability and even death. The mechanisms for the development and progression of pituitary tumors and the markers for remission and recurrence have not been adequately investigated. This literature review discusses the biological significance of miRNAs in pituitary tumors and the potential value of circulating miRNAs as biomarkers.

[Epigenetic Aspects of Osteoporosis].

This review describes the epigenetic regulation of osteoblastogenesis and osteoclastogenesis and its future implementation in the diagnosis and treatment of osteoporosis. A considerable part of the review is dedicated to the microRNAs (miRNAs). miRNAs are small regulatory factors that regulate gene expression, by post-transcriptional regulation of genes playing an important role in numerous cellular processes, including cell differentiation and apoptosis. Recently, a number of studies have revealed that miRNAs participate in bone homeostasis and their role in the pathogenesis of osteoporosis is practically evident. In this review, we highlight the miRNAs involved in bone remodelling and their roles in osteoporosis. miRNAs are stable molecules which make them promising potential markers for bone remodeling and osteoporosis.

[Multiple endocrine neoplasia type 1 syndrome with three classical components and chiasm glioma: specific features of target organ lesions and a clinical observation].

The article briefly reviews the specific features of target-organ lesions in multiple endocrine neoplasia type 1 (MEN1) syndrome and a clinical case of genetically confirmed MEN1 syndrome in a young female patient. Despite the relative rarity of this disease, timely diagnosis, treatment and screening for its main components are very important for the overall prognosis of patients with MEN1 and their first-degree relatives who are MEN1 gene mutation carriers. The described case is noteworthy for a number of specific features. The authors could find no account of optic chiasm glioma within the framework of MEN1 in the literature. Moreover, therapy-resistant somatoprolactinoma engages attention, which points to its aggressive nature with pituitary adenoma that is not been clearly visualized on magnetic resonance imaging. Of interest is the order of detection of neoplasms, in particular the manifestation of hypoglycemic episodes as a sign of organic hyperinsulinism. which have been initially regarded as epileptic seizures, after the use of sustained-release somatostatin analogues for the treatment of acromegaly.