[Clinical features and complication rates in type 2 diabetes mellitus clusters on five variables: glycated hemoglobin, age at diagnosis, body mass index, HOMA-IR, HOMA-B].

BACKGROUND: Diabetes mellitus (T2DM) is a serious medical and social problem. Now they are studying the possibility of a new stratification of diabetes. The possibility of cluster analysis for different durations of diabetes, in different cohorts to identify phenotypic clusters of T2DM and validation by reproducing clusters is relevant. AIM: Identify clusters of type 2 diabetes mellitus in patients with different disease duration based on five variables: HbA1c, age at diagnosis, BMI, HOMA-IR, HOMA-B and study the clinical features and complication rates in each cluster in the Novosibirsk region. MATERIALS AND METHODS: Cluster analysis of K-means was performed in 2131 patients with T2DM, aged 44 to 70 years, with a duration of diabetes of 6.42±5.66 years, living in the Novosibirsk region based on 5 variables - HbA1c, age at -diagnosis, BMI, HOMA-IR, HOMA-B. All patients a complete clinical and laboratory examination. The insulin resistance index in the HOMA (HOMA-IR, u) and the ß-cell function assessment index (HOMA-B) were calculated using the calculator -version 2.2.3 at www.dtu.ox.ac.uk. RESULTS: Cluster analysis revealed: Cluster 1 included 455 patients with preserved ß-cell function (HOMA-B 82.97±23.28%), moderate insulin resistance (HOMA-IR 5.57±4.72) and higher diastolic BP; Cluster 2 in 1658 patients with reduced function of ß-cells (HOMA-B 21.71±12.51%), the lowest indices of insulin resistance (HOMA-IR 3.50±2.48) and was characterized by a longer duration of diabetes, high fasting glycemia , HbA1c, higher eGFR and MAU, men compared with women had a 31% higher risk of developing diabetic neuropathy and 28% more diabetic nephropathy; Cluster 3 in 18 patients with high function of ß-cells (HOMA-B 228.53±63.32%), severe insulin resistance (HOMA-IR 6.92±4.77), features were high incidence of men, shorter duration of diabetes, lower fasting glycemia and HbA1c, lower diastolic BP and eGFR, high incidence of early development of diabetic retinopathy after 4.00±3.6 years. CONCLUSION: Cluster analysis in patients with different durations of diabetes mellitus confirmed the possibility of using cluster analysis to identify T2DM phenotypes in the Russian population. The clusters differed in the clinical characteristics of patients, the frequency and risk of diabetic complications. These results have potential value for early stratification of therapy.

Hypoglycemic syndrome in hepatic epithelioid hemangioendothelioma, successful treatment - liver transplantation from a living related donor.

Hypoglycemic syndrome occurs not only in endocrine diseases but can complicate the course of many somatic diseases and tumors of pancreatic and extra-pancreatic localization. Development of hypoglycemia in liver tumors is associated with a decrease in the volume of functioning liver tissue, increased consumption, and utilization of glucose by the tumor tissue, inhibition of gluconeogenesis and glycogenolysis, and secretion of insulin-like peptides. Hypoglycemia in liver tumors is rarely the first symptom of the disease and usually occurs in patients with large tumor sizes and symptoms of tumor intoxication. Epithelioid hemangiendothelioma of the liver is the primary malignant neoplasm from the group of mesenchymal tumors, it occurs less than in 1% of cases of all malignant neoplasms of the liver. The clinical course of epithelioid hemangiendothelioma of the liver is highly variable. There are slowly and rapidly progressing variants. The diagnosis is based on the results of histological and immunohistochemical examination of the postoperative material. In the literature there is no description of hypoglycemia in epithelioid hemangiendothelioma. We report a patient with severe hypoglycemic syndrome, which was due to an epithelioid hemangioendothelioma of the liver. Pharmacological treatment of hypoglycemia was ineffective. The presence of massive bilobar tumor made it impossible to use a liver resection. Hepatectomy with living related liver transplantation was life-saving procedure and made it possible to eliminate hypoglycemia.

[Primary hyperparathyroidism in Russia according to the registry].

BACKGROUND: There are no large-scale epidemiological studies on primary hyperparathyroidism (PHPT) in Russia. The high prevalence of the disease, the high risk of disability and death in this cohort of patients requires the study of the epidemiological and clinical structure of PHPT to determine the extent of medical care. AIM: Evaluate the frequency of PHPT detection and characterize its clinical forms in Russia using an online registry. METHODS: The object of the study is the database of the State Register of Patients with PHPT 1914 patients from 71 regions of the Russian Federation. New cases of the disease, as well as dynamic indicators are recorded when patients visit outpatient clinics or medical institutions. The analysis of data made at the end of December 2017 was carried out. The following parameters were evaluated: demographic and clinical indicators; indicators of phosphorus-calcium metabolism, the main forms of PHPT and its course, the primary characteristic of PHPT in hereditary syndromes and parathyroid carcinoma. Results are presented as mean and standard deviations, or medians and quartiles; descriptive statistics of qualitative attributes absolute and relative frequencies. RESULTS: the total number of patients with PHPT in the registry on 31 of December 2017 was 1914 cases (0.001% of the population of the Russian Federation). Identification of PHPT was 1.3 cases per 100 thousand of the population in Russia, 7.6 cases in Moscow, 6.1 cases per 100 thousand in the Moscow region. The average age of patients at the time of diagnosis was 55.6 10 years. The active phase of the disease was registered in 84.6% of patients (1620/1914), most of whom had a symptomatic PHPT 67.1% (1087/1620), and 32.9% a asymptomatic disease (533/1620). Symptomatic disease with visceral complications was detected in 15.8% cases (172/1087), with bone complications in 48.4% (526/1087). The mixed form of the disease was detected in 35.8% of patients with manifest form (389/1087). Normocalcemic variant PHPT (nPHPT) was registered in 14.5% cases (234/1620). Sporadic PHPT occurs in 83% of cases (1592/1914). 326 patients (17%) had a suspicion for hereditary form of the disease: average age was 31.2 12.3 years. A genetic analysis was conducted in 61 patients (3.2%): showed the mutation in the MEN1 gene in 2.9% of cases (55/1914) and the mutation in the CDC73 gene in 0.3% of cases (6/1914) (HPT-JT syndrome). Parathyroid carcinoma was confirmed in 1.8% of all patients (35/1914). Surgical treatment was performed in 64.5% of patients (1234/1914). Remission was achieved in 94% of cases (1160/1234), in 6% of cases relapse after surgical treatment or persistence of PHPT was recorded. CONCLUSION: detection of PHPT in the Russian Federation raised in comparison to 2016, which is associated with an active start of registration of patients in the regions. At this stage, it is necessary to modify the principles of registration and control, to make a platform for gathering information and calculating the necessary volumes of medical care for PHPT patients.

Plasmid-based gene therapy with hepatocyte growth factor stimulates peripheral nerve regeneration after traumatic injury.

Peripheral nerve injury remains a common clinical problem with no satisfactory treatment options. Numerous studies have shown that hepatocyte growth factor (HGF) exerts neurotrophic effect in motor, sensory, and parasympathetic neurons in addition to mitogenic, morphogenic, angiogenic, antiapoptotic, antifibrotic, and anti-inflammatory effect on various tissues and cells. In our study we examined efficacy of gene therapy with HGF-bearing plasmid (pC4W-hHGF) to improve consequences of traumatic nerve injury in mice. Treatment by pC4W-hHGF led to restoration of nerve structure and functional recovery compared to similar parameters in control animals. Compound action potentials (CAP) in experimental groups treated with 100 or 200 µg of pC4W-hHGF demonstrated increased amplitude and latency decrease compared to spontaneous recovery control group. In HGF-treated mice histological analysis showed a three-fold increase in axon number in nerve portion located distal to the lesion site compared to control. Moreover, significant functional recovery of n. peroneus communis triggered by pC4W-hHGF gene therapy was observed using the footprints analysis. Obtained results provide evidence for plasmid-based HGF gene therapy as a potential treatment for traumatic injury of peripheral nerve.

Dynamics of Stability of Orientation Maps Recorded with Optical Imaging.

Orientation selectivity is an important feature of visual cortical neurons. Optical imaging of the visual cortex allows for the generation of maps of orientation selectivity that reflect the activity of large populations of neurons. To estimate the statistical significance of effects of experimental manipulations, evaluation of the stability of cortical maps over time is required. Here, we performed optical imaging recordings of the visual cortex of anesthetized adult cats. Monocular stimulation with moving clockwise square-wave gratings that continuously changed orientation and direction was used as the mapping stimulus. Recordings were repeated at various time intervals, from 15 min to 16 h. Quantification of map stability was performed on a pixel-by-pixel basis using several techniques. Map reproducibility showed clear dynamics over time. The highest degree of stability was seen in maps recorded 15-45 min apart. Averaging across all time intervals and all stimulus orientations revealed a mean shift of 2.2 ±â€¯0.1°. There was a significant tendency for larger shifts to occur at longer time intervals. Shifts between 2.8° (mean ±â€¯2SD) and 5° were observed more frequently at oblique orientations, while shifts greater than 5° appeared more frequently at cardinal orientations. Shifts greater than 5° occurred rarely overall (5.4% of cases) and never exceeded 11°. Shifts of 10-10.6° (0.7%) were seen occasionally at time intervals of more than 4 h. Our findings should be considered when evaluating the potential effect of experimental manipulations on orientation selectivity mapping studies.

Assessment of systemic cellular inflammatory response after spontaneous intracerebral hemorrhage.

OBJECTIVE: After spontaneous intracerebral hemorrhage (ICH) a local and systemic inflammatory response is activated. Interleukin-6 (IL) is one of most relevant orchestrators of inflammatory responses in the brain and is released from multiple immune cells, including neutrophils. Herby we assessed the relevance of systemic inflammation in patients suffering ICH. METHODS: From October 2010 to October 2011 we included in our routine of laboratory investigations besides to C-reactive protein (CRP), the addition of IL-6 and an analysis of the subpopulation of circulating blood cells. Values at admission, at 3rd and 7th day after admission were evaluated. We analyzed 43 patients with non-traumatic ICH; stroke-related ICH or tumor associated hemorrhage were excluded. Outcome variables were 30 and 90-day mortality and NIHSS at discharge. A natural logarithmic transformation of IL-6, lymphocytes, and monocytes was used. RESULTS: 8.6% died within 30-days and mortality increased to 39.5% at 90th day. Total leukocytes and neutrophils as well as IL-6 at admission were statistically significant increased among patients who died within 30days after ICH onset (p=0.002). IL-6 and CRP in follow-up (3rd and 7th day) were higher among patients with poor outcome (NIHSS >15). The number of circulating lymphocytes and monocytes was not different in measurement. Leukocytes and neutrophils at 3rd day after admission were augmented in patients with respiratory infection and CRP in follow-up increased if some kind of infection was clinically or microbiologically detected. IL-6 at admission and in follow-up and monocytes at 7th day were related to ICH volume. CRP-values at 3rd or 7th day but not at admission were associated to bigger ICH-volume. The values of IL-6 were highly correlated to 30-day mortality and volume of ICH as CRP only with ICH volume. CONCLUSION: After ICH onset a systemic activation of immune system seems to be induced and may be influencing outcome. Peripheral recruitment of leukocytes, especially neutrophils could be a target for future therapeutic interventions. Because of the tighter correlation of IL-6 at admission, it might be more accurate for prognostic issues than CRP.

[CAT'S VISUAL AREA 18 INTERMODULAR INTERACTIONS DEVELOPMENT UNDER DIFFERENT VISUAL ENVIRONMENT].

Primary visual cortex contains a set of modules, and their postnatal development depends on a combination of internal genetic and external (defined by visual environment) factors. In order to examine a development of intermodular interactions in visual cortex of kittens subjected to rhythmic light stimulation (15 Hz and 50 Hz frequencies, groups RLS-15 and RLS-50), we investigate an intermodular signal correlation by mean of optical imaging technique. Data was compared with control kittens and with kittens reared with no visual experience in total darkness (group DARK). A significant reduction of the intermodular correlation coefficient was obtained in the group RLS-15; the correlation coefficient values in the groups RLS-50 and DARK was not affected. Thus 15 Hz rhythmic light stimulation during sensitive periods of development disrupts an efficacy of intermodular neuronal connections.

[Binocularly co-activation modulate development of functional modular systems in cats visual cortex].

Using optical imaging technique and method for histochemical cytochrome oxidase revealing we investigated in three kitten's groups (two experimental and one control) a rhythmically light stimulation on ontogenetic development of orientation columns and cytochrome oxidase blobs in visual area 18. Experimental animals were stimulated by rhythmical light for 3 hrs or 12 hrs per day respectively. It was first obtained that binocular co-activation per se, not accompanied by strabismus, indeed influences cortical columns formation during critical period. We show an opposite effect of stimulation on two different types of cortical columns, and also revealed that these affects are have retained for at least 2 weeks after stimulation was terminated. It was obtained that duration of rhythmically light stimulation determines a volume of functional and anatomic alterations: alterations revealed were more pronounced in animals stimulated for12 hrs per day.

[Quality of neuronal signal registered in the monkey motor cortex with chronically implanted multiple microwires].

Disconnection of central and peripheral parts of motor system leads to severe forms of disability. However, current research of brain-computer interfaces will solve the problem of rehabilitation of patients with motor disorders in future. Chronic recordings of single-unit activity in specialized areas of cerebral cortex could provide appropriate control signal for effectors with multiple degrees of freedom. In present article we evaluated the quality of chronic single-unit recordings in the primary motor cortex of awake behaving monkeys obtained with bundles of multiple microwires. Action potentials of proper quality were recorded from single units during three months. In some cases up to 7 single units could be extracted on a channel. Recording quality stabilized after 40 days since electrodes were implanted. Ultimately, functionality of multiple electrodes bundle makes it highly usable and reliable instrument for obtaining of control neurophysiologic signal from populations of neurons for brain-computer interfaces.

["Podmoskovie"--health resort institution of the Federal Drug Control Service of the Russian Federation celebrates the 20th anniversary].

The article is dedicated to the 20th anniversary of the Federal government health resort institution of the Federal Drug Control Service of the Russian Federation (FGI "Health resort "Podmoskovie" of the Federal Drug Control Service of the Russian Federation). In this health resort were developed treatment programs for patients with abnormalities of the cardiovascular, respiratory and digestive systems; methods of ultrasonic, laser and magnetic therapy, atmospheric hypoxic, herbal medicine, speleotherapy are employed. Widely used natural healing factors of Ruza district of the Moscow region such as climate therapy, treatment with mineral water group of X type of Smolensk from own wells and balneo-mudtherapy. Over the past 20 years 70 000 patients received an appropriate treatment in this health resort.

[Long-term recording of single unit activity and criteria for estimation of stability].

Stable single-unit recording in the brain of vertebrates allows to investigate processes underlying neural plasticity. In applied aspect long-term single-unit recording can be useful for development of invasive brain--computer interface. Here we propose a criterion for identification of neurons that were recorded for more than one day. Based only on the spike forms classification yields ambiguous result. Additional parameters (such as form of interspike interval histogram or certain parameters of that histogram) decreased misclassification probability considerably. Using proposed criterion we were able to identify 82 neurons that were recoded for more than one day. In extreme case activity of one neuron was observed for 94 days.

[Effect of propofol on functional response of neuronal population in cat primary visual cortex].

The impact of system anesthetic propofol on strength of functional response was investigated in population of primary visual cortex neurons. Elaborated protocol of anesthesia allowed appropriate depth of anesthesia and artifact free experimental data recording. At the start of experiment optical access to the surface of cortex was provided. Propofol was used as main general anesthetic. Control of anesthesia depth was carried out by monitoring of physiological parameters. Effect ofpropofol on functional response was evaluated by intrinsic optical imaging. Stability of neuronal response was estimated during whole experiment and after single injection ofpropofol. It was shown that extended administration ofpropofol do not have negative influence on strength of recorded neuronal signal. At the same time bolus of propofol depresses amplitude of response. Practical recommendations are suggested for conduction of longitudinal neurophysiological experiments using propofol as main anesthetic.

[Comparison of its and orientation tuning dynamics in neurons located in different functional domains of cat's primary visual cortex].

Orientation tuning and its dynamics of cat's primary visual cortex neurons located in pinwheel centers and orientation columns were studied during development of response in time. Functional domains in the Cortex were revealed by intrinsic signal optical imaging on functional and vascular maps of cortex. Both maps were used for precise placement of electrodes during recordings. Orientation tuning dynamic of each neuron was analyzed by temporary slices technique. Several types of neurons were observed in different functional domains: neurons with stable preferred orientation (14.5%); cells with preferred orientation dynamically shifted by 102 +/- 5 degrees (40.8%) and neurons with mixed dynamics type (44.7%). In pinwheel centers neurons with stable preferred orientation are differed from neurons with unstable preferred orientation in their features. In particular, they are showing greater response strength for preferred orientation. In orientation columns neurons with stable tuning are demonstrating larger latent periods for all orientations including preferred and non-preferred in comparison to cells with unstable response dynamics. We observed better detection quality of stable orientation neurons than in unstable preferred orientation neurons. Further coding features of neurons belonging to one functional type but located in different domains were compared. In general, located in pinwheel centers stable neurons have shorter latencies and stronger responses than for the stable cells located in orientation columns. Detection features were similar for this functional type of neurons. Unstable neurons located in different functional domains don't differ from each other in orientation tuning characteristics. Functional significance of neurons with stable and unstable preferred orientation located in pinwheel center and orientation columns in visual information processing are discussed.

[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.

[Treatment of diabetes mellitus in dialysis patients].

Diabetes mellitus is a key cause of chronic kidney disease (CKD) in developed contries. Disorders of glucose metabolism regulation in CKD are explained by insulin resistance, decreased insulin clearance, weak hormonal response to hypoglycemia. These disturbances appear in inhibition of glomerular filtration rate under 60 ml/min. Hemodialysis treatment raises the risk of hypoglycemic conditions due to glucose elimination from blood circulation during the sessions and improvement of sensitivity to insulin. Use of glucose-containing solutions for dialysis, step-by-step achievement of normoglycemia, monitoring of blood glucose during dialysis sessions are recommended for reducing the risk of hypoglycemic conditions in DM patients on dialysis. Insulin is the most common preparation in the treatment with use of hemodialysis in diabetics. Tiasolidindions (pioglitason, rosiglitason) and analogues of dipeptidilpeptidase of type IV (sitagliptin, saxagliptin) can be administered in type 2 diabetics without insulin insufficiency. As solutions for peritoneal dialysis contain glucose, such dialysis may entail such metabolic complications as fat accumulation, metabolic syndrome. Intraperitoneal introduction of insulin allows avoiding hyperinsulinemia and in some cases to decrease the risk of hypoglycemia. Side effects of intraperitoneal insulin administration are significant absorption of insulin on the surface of the systems for intraperitoneal dialysis, higher rate of peritonitis, subcapsular hepatic steatosis. In the absence of controlled studies the mode of insulin administration in patients on peritoneal dialysis should be chosen individually basing on potential risk and benefit for the patient and experience of the dialysis center. It should be remembered that adequate sugar-reducing treatment is necessary for prevention of complications and prolongation of survival of diabetics on dialysis.

[Overlapping of optical answers for cross-like figures and oriented bars in the cats primary visual cortex].

For the first time by the optical method the population activity of neurons in cat primary visual cortex was observed simultaneously for detectors participating in analysis of first-order (orientation) and second-order (line intersection) features. The maps for cross-like figures and oriented single bars were compared. The comparative analysis allowed us to estimate the degree of overlapping of the activated regions and parts of cortex that were free from overlap. Overlapping zones provided the evidence for the fact that neuronal detectors for line intersections are located in the same neuronal columns as neurons detecting orientations. Differences were observed between maps for vertically oriented and oblique crosses. Those differences were pronounced not only in topography but also in degree of overlapping of activity zones. This may evidence on different contribution of neurons detecting basic and intermediate orientations.

Processing of functional maps of the cat visual cortex obtained using intrinsic optical signals.

Functional structures of the primary visual cortex, particularly clearly apparent structures such as orientation columns, are studied by recording the brain's intrinsic optical signals. These reflect changes in local neuron metabolism and cerebral blood flow induced by functional loading. Despite the advantages of this method, mapping of neurons with weak signals can be hindered by noise generated by the global and local components of optical signals associated with physiological processes occurring in the body as well as equipment factors. This generates the need to correct functional optical maps to eliminate noise effects. The present report describes a new method of processing functional maps using approximations to identify and remove the global components of the optical signal and other interference from maps. The results are compared with data obtained by traditional map processing methods.

[Clinical and metabolic risk factors for cardiovascular autonomic neuropathy in patients with type 2 diabetes mellitus].

AIM: to study clinical and metabolic risk factors for cardiovascular autonomic neuropathy in patients with type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: One hundred and fifty-seven patients were examined. According to the results of ECG tests and cardiointervalography, the patients were divided into 2 groups: 1) 45 patients without cardiovascular autonomic neuropathy; 2) 112 patients with this condition. RESULTS: The T2DM patients with cardiovascular autonomic neuropathy significantly differed from those without autonomic disorders in DM duration, insulin level, insulin resistance indices (HOMA-IR, FIRI), atherogenicity coefficient, and high-density lipoprotein levels. The glycated hemoglobin level of more than 9% affected the values of autonomic ECG tests. CONCLUSION: In patients with T2DM, the development of cardiovascular autonomic neuropathy is affected by not only the duration of DM and the decompensation of carbohydrate metabolism, but also by hyperinsulinemia and insulin resistance, the low level of high-density lipoproteins, and the high coefficient of atherogenicity.