[Endocrine disorders after combined chemoradiotherapy in Hodgkin Lymphoma survivors].

BACKGROUND: Hodgkin's lymphoma (HL) is one of the most common malignant lymphoproliferative diseases. Chemotherapy and radiotherapy used in the treatment of LH induce a number of toxic effects leading to dysfunction of endocrine system. Hormonal disorders in HL and their relationships with the therapy used remain to be clarified. AIM: To assess disorders of the endocrine function of thyroid, parathyroid glands and gonads in HL survivors. MATERIALS AND METHODS: Screening of endocrine dysfunction of the thyroid, parathyroid glands and gonads was performed in 160 adult patients with HL, 55 men and 105 women, at remission stage induced by chemotherapy or chemoradiotherapy. Forty healthy subjects, matched by age, were acted as control. The levels of TSH, T3, free T4, PTH, FSH, LH, free testosterone, dehydroepiandrosterone sulfate (DHEA-S), and sex-hormone binding globulin (SHBG) were measured in blood serum by ELISA. Bone mineral density (BMD) was assessed by DEXA. RESULTS: Hypothyroidism (25%), hyperparathyroidism (15.6%) and hypogonadism (29% of men and 25.3% of women) were the most prevalent endocrine disorders in LH survivors. Hypothyroidism was significantly more common in patients after chemoradiotherapy than in those who received only chemotherapy (χ2=9.4, р=0.002). In patients with hyperparathyroidism, there were negative correlations between PTH levels and BMD in the lumbar spine (r=-0.74, p=0.00002) and in the femoral neck (r=-0.66, p=0.0003). Men with HL demonstrated lower free testosterone concentrations when compared to control (p=0.04); LH and FSH levels were elevated (p=0.0004 and p=0.04, respectively). In men with HL the levels of DHEA-S were reduced (p=0.0009). The increased SHBG concentrations were revealed in 13 (23.6%) men. Women of reproductive age with HL had higher levels of LH in the luteal phase (p=0.05) and FSH in the follicular phase (p=0.02) than controls. CONCLUSION: The data indicate a high prevalence of the dysfunctions of thyroid, parathyroid glands, and gonads in HL survivors. Screening for endocrine disorders in these patients is highly recommended.

Angioprotective and Follicle-Stimulating Effects of Administration of Bone Marrow Mesenchymal Stromal Cells in Chronic Inflammation of Internal Reproductive Organs.

Induced inflammation of reproductive organs in female Wistar rats was associated with an increase in the diameters of arteries and veins and number of blood vessels in the ovary medulla in combination with an increase in the number of lymphatic vessels; these changes were accompanied by reduction of the ovarian reserve and number of yellow bodies. Intravenous and submucosal injection of bone marrow multipotent mesenchymal stromal cells (BМ-ММSC) led to further increase in the diameters of arteries and veins and number of primordial and primary follicles. The injection of conditioned medium of BМ-ММSC cultures generally produced the same effects, which could demonstrate the secretory mechanisms of their influence on local angiogenesis and folliculogenesis.

Circadian Variations in Cellular Composition of Lymphoid Organs in Rats with Experimental Endomyometritis.

Circadian variations in the cellular composition of the lymphoid organs were studied in female Wistar rats under normal conditions and in experimental endomyometritis. The fractions of CD8+ cells (effector killers), CD25+ cells (activated/immature lymphocytes), as well as large, medium, small lymphocytes and monocytes/macrophages were assessed at 10.00 and 20.00 h. In the thymus and spleen of rats with endomyometritis, the number of parameters demonstrating significant circadian variations was lower than in intact animals. In the lymph nodes, morning/evening differences appeared for the number of CD8+ and CD25+ cells and monocytes/macrophages in the para-aortic lymph nodes, the number of large and small lymphocytes and CD8+ cells in inguinal lymph nodes, and in the number of large lymphocytes, CD8+ cells, and monocytes/macrophages in the ileal lymph nodes. Thus, the development of chronic inflammation in the uterine and vaginal mucosa was accompanied by desynchronosis in the immune system. Hence, circadian rhythms should be taken into consideration in the diagnosis and treatment of the disease.

Comparative Assessment of Leukocyte Infiltrate Composition in the Uterine and Vaginal Tissues in Rats with Experimental Endomyometritis Treated with Interferon-γ at Different Times of the Day.

The cell composition of leukocyte infiltrates in the endometrium, myometrium, and vaginal walls was studied in Wistar rats with modeled chronic endomyometritis after administration of IFNγ (0.1 µg/100 g body weight) in different daily regimens (10.00 or 20.00). Morning injections of this cytokine ameliorated inflammatory infiltration of the uterine wall and vagina, but increased the content of neutrophils in the endometrium. Evening cytokine injections reduced neutrophilic infiltration, enhanced mononuclear infiltration, and had no effect on plasmacytic infiltration of the uterine and vaginal walls. In the vaginal wall, both IFNγ administration schedules decreased neutrophil content. The data indicate the necessity to take into account the circadian rhythms in IFN therapy.

Changes in the Circulatory and Lymphatic Systems of Internal Genitals in Female Rats after Intravenous and Lymphotropic Administration of Multipotent Mesenchymal Stem Cells and Products Secreted by These Cells.

We studied the effects of intravenous and lymphotropic administration of bone marrow multipotent mesenchymal stromal cells and products secreted by these cells into conditioned medium on the blood and lymph circulation in the uterus and ovaries, as well as on folliculogenesis in female Wistar rats. It was shown that stromal cells and conditioned media of these cells administered via both routes lead to an increase in the number and diameter of blood vessels in the uterine wall and in the cortical layer of the ovaries. Neither mesenchymal stromal cells, not conditioned media affected the ovarian follicular apparatus.

Relationships between Body Composition and Plasma Levels of Pancreatic, Gut, and Adipose Tissue Hormones in db/db Mice, a Model of Type 2 Diabetes Mellitus.

We studied the relationships between body composition parameters and plasma levels of pancreatic, gut, and adipose tissue hormones regulating energy balance and glucose metabolism in diabetic db/db mice (BKS.Cg-Dock7m+/+Leprdb/J). The body composition parameters in mice aged 8, 12, and 16 weeks were assessed by magnetic resonance imaging. The concentrations of insulin, glucagon, ghrelin, glucagon-like peptide-1, glucose-dependent immunotropic peptide, leptin, resistin, and plasminogen activator-1 were measured by multiplex analysis at the age of 8 and 16 weeks. In comparison with non-diabetic control (db/+), db/db mice demonstrated high fat mass and reduced lean body mass and water content. In 8- and 16-week-old db/db mice, the levels of leptin (p<0.001), insulin (p<0.01), and glucagon-like peptide-1 (p<0.05) were elevated and the concentration of ghrelin (p<0.05) was reduced. The body weight and fat mass positively correlated with the levels of leptin, insulin, plasminogen activator-1, and glucagon-like peptide-1 and negatively correlated with ghrelin concentration. The results provide further details for characteristics of db/db mice, a widely used model of obesity and type 2 diabetes mellitus.

Effect of Linagliptin on the Ratio of Apoptosis Regulators in the Model of Non-Alcoholic Fatty Liver Disease in db/db Mice.

We studied the effects of dipeptidyl peptidase 4 (DPP4) inhibitor linagliptin on the expression of apoptosis regulator proteins Bcl-2 and Bad in the liver of db/db mice with genetically determined obesity and type 2 diabetes mellitus. The mice received daily linagliptin or saline (placebo) by gavage from week 10 to week 18 of life. In the liver of non-treated mice, the area positively stained for Bad was greater than the area of Bcl-2 expression, which created the conditions for apoptosis activation in liver at this age. Administration of linagliptin decreased Bad stained area and increased Bcl-2 stained area in the liver cells. At the same time, Bad stained area remained larger in treated mice than the area of Bcl-2 expression area, which attested to partial normalization of pro- and antiapoptotic protein balance.

[Ghrelin deficiency in patients with type 2 diabetes: the relationships with obesity, adipose tissue dysfunction and glucose variability].

AIM: Ghrelin, a peptide hormone mostly produced by stomach, plays an important role in regulation of feeding behavior, energy balance and glucose homeostasis. THE AIM: to determine the relationships between fasting serum levels of ghrelin, body composition, adipose tissue endocrine function and glucose variability (GV) in type 2 diabetic subjects with and without obesity. MATERIALS AND METHODS: We observed 124 individuals with type 2 diabetes, including 42 non - obese subjects and 82 patients with obesity. Thirty non - obese healthy subjects were acted as control. The concentrations of ghrelin, leptin, resistin, and visfatin in the fasting serum were determined by Multiplex analysis. Body composition was assessed with DEXA. The 24-hour and nocturnal GV parameters were derived from continuous glucose monitoring. RESULTS AND DISCUSSION: Ghrelin levels in patients with diabetes were decreased significantly as compared to control (p.

[Impact of Glycemic Variability on Cardiovascular Risk in Diabetes].

A growing body of evidences indicates the role of increased glucose variability (GV) as an independent cardiovascular risk factor in diabetes. It has been shown that high GV is associated with coronary and carotid atherosclerosis in diabetic subjects. The impact of enhanced glycemic fluctuations on vascular wall is mediated through non-enzymatic glycation, oxidative stress, activation of inflammatory pathways, and endothelial dysfunction. Thus, the effects of high GV exacerbate the influence of chronic hyperglycemia. The FinnDiane study established existence of a relationship between glycated hemoglobin (HbA1c) variability and cardiovascular events (myocardial infarction, coronary artery procedure including by-pass surgery or angioplasty, stroke, limb amputation because of ischemia, or a peripheral artery procedure) in patients with type 1 diabetes. In ADVANCE study visit-to-visit HbA1c and fasting glucose variability was associated with cardiovascular events in type 2 diabetic subjects; moreover, HbA1c variability was associated with all-cause mortality. In Verona Diabetes Study, fasting GV was predictor of cardiovascular mortality in elderly patients with type 2 diabetes. In-hospital glycemic excursions in patients with acute myocardial infarction and in diabetic patients undergoing percutaneous coronary intervention predict the risk of adverse cardiac events. The episodes of hypoglycemia in diabetic patients with high GV may contribute to an increased risk of arrhythmias, myocardial ischemia and infarction, and stroke. The data presented give support to notion that GV could be considered a new therapeutic target in patients with diabetes and cardiovascular disease.

Normoalbuminuric chronic kidney disease in diabetes.

Urinary albumin excretion (UAE) is widely used in clinical practice as indicator of diabetic kidney disease. According to the classical concept of the natural course of diabetic nephropathy, an increase in UAE usually precedes a decline in renal function. Meanwhile, a growing body of evidences indicates a high prevalence of normoalbuminuric chronic kidney disease (NA-CKD) in diabetic subjects, especially among patients with type 2 diabetes. An increase in NA-CKD prevalence can be results of improved glucose, blood pressure, and lipid control, widespread use of renin-angiotensin system blockers, and smoking cessation. It was shown that NA-CKD is more prevalent among women and is associated with arterial hypertension and coronary artery disease. The renal structure in subjects with NA-CKD is more heterogeneous when compared to patients with increased albuminuria, wherein interstitial changes and arteriolosclerosis could be the principal morphological findings, while signs of glomerulopathy may be absent. The prognostic value of NA-CKD needs to be clarified. It was shown that NA-CKD increases the risk of myocardial infarction, stroke and cardiovascular death in patients with diabetes. The search for alternative diagnostic markers for detecting of diabetic kidney disease in the absence of albuminuria, is of practical importance. The evaluations of the markers of tubular damage and interstitial fibrosis, as well as proteomic approaches, are considered as perspective diagnostic and prognostic options in NA-CKD. The study of pathogenesis, pathology, clinical course of NA-CKD in diabetic patients, as well as the development of more specific diagnostic and treatment options is a challenge for future research.

Melatonin-Aluminum Oxide-Polymethylsiloxane Complex on Apoptosis of Liver Cells in a Model of Obesity and Type 2 Diabetes Mellitus.

We studied the effects of a melatonin-aluminum oxide-polymethylsiloxane complex (complex M) on the expression of apoptosis regulators Bcl-2 and Bad in the liver of homozygous db/db BKS.Cg-Dock7m+/+Leprdb/J mice with obesity and type 2 diabetes. Complex M or placebo was administered daily through the gastric tube during weeks 8-16 of life. In mice with type 2 diabetes mellitus receiving placebo, enhanced immunohistochemical reactions for proapoptotic Bad protein and weak response for anti-apoptotic Bcl-2 protein were observed. Administration of complex M shifted the ratio of apoptosis regulators: the area of Bcl-2 expression significantly increased and against the background of reduced Bad expression area. These findings attest to antiapoptotic effect of complex M in the liver on the model of type 2 diabetes mellitus.

[Polymorphisms in Genes of Cytokines and Matrix Metalloproteinases Associated With Ischemic Heart Disease in Patients With Type 2 Diabetes].

OBJECTIVE: To examine associations between ischemic heart disease (IHD) and polymorphisms in cytokine genes (IL-1B, IL-4, IL-6, IL-10, TNFA, VEGF) and matrix metalloproteinase genes (MMP2, MMP3, MMP9) in patients with type 2 diabetes. MATERIAL AND METHODS: We studied 232 Caucasian diabetic subjects (33 men and 199 women aged 50-70 years). In 93 patients IHD was verified by treadmill test and/or coronary angiography (86 subjects with stable angina, 19 with previous myocardial infarction). Thirteen polymorphisms localized in the promoters of IL-1B (rs1143627), IL-4 (rs2243250), IL-6 (rs1800795), IL-10 (rs1800872, rs1800896), TNFA (rs361525, rs1800629, rs1800630), VEGF (rs699947, rs3025039), MMP2 (rs243865), MMP3 (rs3025058) and MMP9 (rs3918242) were investigated. RESULTS: Prevalence of G-allele and GG-genotype at -308 position of TNFA (rs1800629), as well as C-allele and CC-genotype at position +936 of VEGF (rs3025039) was higher in patients with IHD as compared to patients without IHD (OR=2.0, OR=2.2, OR=2.1, OR=2.4, respectively, all p=0.02). In logistic regression analysis, TNFA -308 A/G and VEGF +936 C/T polymorphisms showed associations with IHD (both p=0.009). These polymorphisms along with age, body mass index, duration of diabetes, low density and high density lipoprotein cholesterol were associated with IHD in multivariate models (p=0.0002 and p=0.00008, respectively). Nine combinations of TNFA -308 GG-genotype and variants of other genes demonstrated associations with IHD (p≤0.002). CONCLUSION: The polymorphisms in promoter regions of TNFA (rs1800629) and VEGF (rs3025039) are associated with IHD in patients with type 2 diabetes.

[Association of Serum Levels and Gene Polymorphism of Vascular Endothelium Growth Factor With Ischemic Heart Disease in Type 2 Diabetic Patients].

AIM: to study serum levels of vascular endothelium growth factor family peptides (VEGF-A, VEGF-C and VEGF-D) and functional gene polymorphisms of VEGFA gene (rs699947 and rs3025039) in patients with type 2 diabetes (T2D) depending on the presence of ischemic heart disease (IHD). MATERIALS AND METHODS: The study involved 196 Caucasian patients with T2D (age 43-70 years, 76 with IHD). The concentrations of VEGF-A, VEGF-C and VEGF-D in blood serum were determined by Multiplex assay. Twenty-four persons without diabetes and IHD served as controls. The genotyping of VEGFA polymorphism -2578A/C (rs699947) and +936C/ (rs3025039) was performed by TaqMan. RESULTS: Concentrations of VEGF-A and VEGF-C in patients with T2D were significantly lower than those in controls (p=0.03 and p=0.006, respectively). The level of VEGF-D showed a tendency to decrease (p=0.14). Patients with IHD, as compared to other patients, had higher levels of VEGF-A (p=0.04) and a tendency to VEGF-D increase (p=0.06). The concentration of VEGF-C was not different between groups. No relationships were found between VEGF-A, VEGF-C and VEGF-D levels, HbA1c or glucose variability parameters. C-allele and CC-genotype at +936 position of VEGFA were more frequent among patients with IHD (odds ratio 2.14 and 2.41, respectively, p=0.02). The rs699947 polymorphism was not related to IHD and VEGF-A levels. CONCLUSION: Patients with T2D have decreased serum levels of angiogenic factors VEGF-A and VEGF-C. VEGFA rs3025039 polymorphism is associated with presence of IHD and levels of circulating VEGF-A in these patients.

Effects of Melatonin, Aluminum Oxide, and Polymethylsiloxane Complex on the Expression of LYVE-1 in the Liver of Mice with Obesity and Type 2 Diabetes Mellitus.

The effects of melatonin, aluminum oxide, and polymethylsiloxane complex on the expression of LYVE-1 (lymphatic vessel endothelial hyaluronan receptor) in the liver were studied in db/db mice with experimental obesity and type 2 diabetes mellitus. The complex or placebo was administered daily by gavage from week 8 to week 16 of life. The animals receiving the complex exhibited enhanced, in comparison with the placebo group, immunohistochemical LYVE-1+ staining of endothelial cells in sinusoids. Enhanced expression of LYVE-1 was associated with less pronounced dilatation of interlobular arteries, veins, and lymphatic vessels. Thee findings suggest a protective effect of the complex towards structural changes in the liver of mice with obesity and type 2 diabetes.

[Acute-phase serum proteins and adipocytokines in women with type 2 diabetes mellitus: Relationships with body composition and blood glucose fluctuations]. / Belki ostroi fazy vospaleniya i adipotsitokiny v syvorotke krovi u zhenshchin s sakharnym diabetom 2-go tipa: vzaimosvyazi s sostavom tela i kolebaniyami urovnya glyukozy v krovi.

AIM: To estimate the relationships between the serum concentrations of acute-phase proteins (APPs) and adipocytokines, body composition (BC), and blood glucose (BG) fluctuations in women with type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: A total of 165 women with T2DM and 22 with a normal body mass index (BMI) at the age of 40 to 70 years were examined. The concentrations of high-sensitivity C-reactive protein (hs-CRP) and acid α1-glycoprotein (α1-AGP) were determined by ELISA. The levels of interleukins 6, 8, and 18 (IL-6, IL-8, IL-18), tumor necrosis factor-α (TNF-α), and plasminogen activator inhibitor type 1 (PAI-1) were measured by a multiplex analysis. Dual energy X-ray absorptiometry was used to estimate BC parameters. BG fluctuations were estimated via continuous glucose monitoring. RESULTS: The levels of hs-CRP, α1-AGP, IL-6, IL-8, IL-18, TNF-α, and PAI-1 were significantly higher in the obese women with T2DM than those in the control group. In the diabetic normal weight women, only hs-CRP, α1-AGP, and IL-8 concentrations exceeded those in the controls. The level of hs-CRP (other than α1-AGP) correlated positively with BMI, the mass of adipose tissue, body trunk (android), and gynoid fats. A multivariate regression analysis showed that adipose tissue mass and trunk fat proportion were independent predictors of hs-CRP levels. The concentrations of IL-6, IL-8, IL-18, PAI-1, and TNF-α correlated positively with waist-to-hip ratio, but demonstrated no associations with BMI and BC. Only the serum α1-AGP level showed a positive association with mean BG and its variability parameters. CONCLUSION: In the women with T2DM, the serum concentrations of APPs and adipocytokines correlate differently with the mass of adipose tissue, its distribution, and BG fluctuations. The findings indicate the multifactorial genesis of chronic inflammation in these patients.

Effect of Linagliptin on Structural Changes in the Kidney in Experimental Type 2 Diabetes Mellitus.

Effect of the dipeptidyl peptidase-4 inhibitor linagliptin on structural manifestations of diabetic nephropathy was studied in BKS.Cg-Dock7m+/+Leprdb/J mice (experimental model of type 2 diabetes mellitus). Linagliptin (10 mg/kg per day) or vehicle was administered by gavage over 8 weeks. Mesangial expansion, thickening of the basement membrane in glomerular capillaries and proximal tubules, and retraction of cytopodia were less pronounced in mice receiving linagliptin. The protective effect of linagliptin on the kidney structure was not associated with its hypoglycemic action.

[Increased serum concentrations of inflammatory cytokines in type 2 diabetic patients with chronic kidney disease].

AIM: To study the relationship between serum inflammatory cytokine levels in chronic kidney disease patients with type 2 diabetes. SUBJECTS AND METHODS: Sixty-four patients aged 43 to 70 years with a glomerular filtration rate (GFR) of > 30 ml/min/1.73 m2 were examined. A control group consisted of 15 healthy individuals. The serum concentration of macrophage colony-stimulating factor (M-CSF), macrophage inflammatory protein 1α (MIP-1α), macrophage migration inhibitory factor (MIF), interleukin 6 (IL-6), as well as the urinary excretion of albumin and type IV collagen was determined by enzyme immunoassay. RESULTS: In patients with a GFR of > 60 ml/min/1.73 m2, M-CSF and MIF concentrations proved to be significantly higher than those in the control group (p = 0.0003 and p = 0.001, respectively). In those with a GFR of 30-59 ml/min/1.73 m2, there was an increase in the levels of M-CSF (p < 0.0001), MIP-1α (p = 0.002), MIF (p = 0.02), and IL-6 (p = 0.02). The decline in GFR was associated with the higher levels of M-CSF (p = 0.02) and MIP-1α (p = 0.02) and with the higher urinary excretion of type IV collagen (p = 0.01). M-CSF, MIP-1α, and IL-6 correlated positively with the urinary excretion of albumin (r = 0.34, r = 0.28, and r = 0.28, respectively; all p < 0.05) and type IV collagen (r = 0.31, r = 0.4, and r = 0.43, respectively; all p < 0.05). CONCLUSION: The findings confirm the concept that chronic inflammation is involved in the development of diabetic kidney disease.

[Impaired angiogenesis and lymphangiogenesis in diabetes mellitus].

The review summarizes the results of the latest studies dealing with the mechanisms of impaired angio- and lymphangiogenesis in diabetes mellitus and the role of these disorders in the development of the disease and its vascular events.

[Urinary excretion of fibrogenic and antifibrotic growth factors in type 1 diabetic patients: the interrelationship with diabetic nephropathy].

AIM: To assess the relation between urinary excretion of profibrotic and antifibrotic growth factors, albuminuria and glomerular fibrosis in type 1 diabetic patients. MATERIALS AND METHODS: 64 patients with diabetes were examined, including 25 ones with normal albumin excretion rate (AER), 30 microalbuminuric and 9 macroalbuminuric patients. Urinary excretion of type IV collagen, transforming growth factor-beta 1] (TGF-beta 1), tumor necrosis factor-alpha (TNF-alpha), fibroblast growth factor-2 (FGF-2), hepatocyte growth factor (HGF) and bone morphogenetic protein-7 (BMP-7) was determined by ELISA and compared to control (10 healthy subjects). Renal biopsy specimens were assessed in 7 patients with normal AER and in 14 microalbuminuric patients. RESULTS: Type IV collagen, TGF-beta1 and TNF-alpha excretion was increased significantly in patients with micro- and macroalbuminuria as compared to control (all p<0.05). Excretion of FGF-2 was increased in macroalbuminuric patients only (p=0.003). No marked changes in excretion of antifibrotic growth factors (HGF and BMP-7) were observed. TNF-alpha and FGF-2 correlated positively with urinary type IV collagen (r=0.37 and r=0.31, respectively). The presence of glomerular fibrosis in renal biopsy specimens was associated with higher excretion of TGF-beta1, TNF-alpha and FGF-2 (all p<0.05). CONCLUSION: The results suggest that unbalance between profibrotic and antifibrotic growth factors in the kidneys plays an important role in pathogenesis of diabetic nephropathy. Urinary TGF-beta1, TNF-alpha and FGF-2 may offer new possibilities for detection of renal fibrosis in diabetic patients.

[Obesity and chronic kidney disease].

Obesity and overweight are now characterized as epidemics. It is shown that body overweight is associated with functional and structural changes in the kidneys. The results of epidemiological studies indicate that obesity can be the risk factor of chronic kidney disease (CKD) irrespective of the presence or absence of diabetes, arterial hypertension and other comorbidities. Manifestations of renal pathology in obese persons include microalbuminuria and proteinuria, hyperfiltration or impaired renal function. Glomerulomegaly and focal segmental glomerulosclerosis are the most typical structural signs of obesity-related nephropathy. More evidence is accumulated on the link between CKD in obesity and abnormalities in adypokine secretion (hyperleptinemia, lack of adiponectin), activation of rennin-angiotensin system, chronic inflammation, endothelial dysfunction, lipid accumulation, impaired renal hemodynamics and diminished nephron number related to body mass. A decrease of body weight following lifestyle modification or bariatric surgery leads to reduction in albuminuria and eliminates hyperfiltration in obese subjects. Thus, prevention and treatment of obesity may reduce CKD incidence in general population.