The role of cytokine gene polymorphism in the formation of arterial hypertension associated with metabolic syndrome.

We investigated the association of polymorphisms of genes tumor necrosis factors and their receptors (-308G/A TNFa, +250A/G Lta, +36 A/G TNFR1, +1663 A/G TNFR2) with the predisposition to the development of essential hypertension (EH) and the features of its clinical course in patients with metabolic syndrome. It has been demonstrated that the molecular genetic marker +36G TNFR1 (OR=1,25) is involved in the formation EH in individuals with metabolic syndrome. The risk of stage III EH in patients with metabolic syndrome is enhanced by genetic variants -308GA TNFa (OR=2,72), -308A TNFa (OR=2,72), +250G Lta (OR=1,80), and combinations thereof -308A TNFa with +1663G TNFR2 (OR=3,85), +250G Lta with +36G TNFR1 (OR=3,85), +250G Lta with +1663G TNFR2 (OR=3,85) while protective properties are inherent in -308GG TNFa (OR=0,32), +250AA Lta (OR=0,45), -308G TNFa (OR=0,37), +250A Lta (OR=0,56) and a combination of genetic markers -308GG TNFa with +250A Lta (OR=0,31), -308G TNFa with +250AA Lta (OR=0,39), -308G TNFa with +250A Lta (OR=0,31).

[Obesity: the modern view of a problem].

The article is a review of recent epidemiological observations concerning the prevalence of overweight and obesity in different countries among people of different gender, age. social and ethnic groups. It also presents and analyses health risks and comorbidities leading to disability and death as reported by domestic and foreign researchers. It was found that obesity has multifactorial pathogenesis directly related to energy balance, consumed and expended calories. The need of a multidisciplinary approach to the treatment and prevention of the disease is emphasized taking into consideration the influence of the environment and increasing urbanization on the development of the pathology as well as the role of government efforts to stimulate physical activity of the population in the framework of integral interdisciplinary programs and control over the quality of food. The priority areas for the correction of overweight include optimization of motor activity and diet correction.

[Peculiarities of the psychic state and quality of life in patients with duodenal ulcer in the context of chronomedicine].

Most clinicians consider duodenum ulcer as a psychosomatic disease. Objective: To show the interdependence of this condition and mental disorders and their relation to disturbances of melatonin production . Materials and Methods: 15 patients with seasonal DU and 15 healthy subjects of the control group were examined during 3 years using laboratory, endoscopic, and standard psychodiagnostic methods. Results. It was found that all patients with exacerbation of DU experienced enhanced anxiety, reduced background mood, and impaired quality of life based on general health and mental health scoring scales. The circadian rhythm of melatonin production was markedly distorted throughout the observation period but especially during exacerbations of the disease. Conclusions. The results indicate a high degree of correlation between DU and mental disorders caused by impaired production of melatonin. It suggests common etiological mechanisms of DU and psychosomatic symptom complex.

[Peculiarities of the strategy for the treatment of elderly patients with duodenal ulcer and concomitant metabolic syndrome].

The study showed that ulcer disease in patients with metabolic syndrome is characterized by painless clinical course, bowel disorders in the form of constipation, enhanced appetite, unmotivated requirement for hypoglycemic therapy predisposition to complications along with activation of the inflammatory process in duodenal mucosa, high H. pylori count. The data obtained were used to develop the age-specific strategy for the treatment of elderly patients with duodenal ulcer and concomitant metabolic syndrome.

[Stable isotope diagnostics in Russia; results and prospects, 13C-preparations, instruments, methods].

The basis of the highly effective method for diagnostics of many dangerous diseases with the use of breathing tests and stable 13C isotope-labeled preparations has been developed in Russia during the past years. The technology for manufacturing 13C-preparations using domestically produced starting materials satisfies the requirements for isotopes in this and many foreign countries. New instruments for respiratory tests and diagnostic methods make it possible to carry out diagnostics in large populations including that in the course of regular medical examination. This paper reports high efficacy of 13C-based breath tests for diagnostics of gastrointestinal disorders, possibilities and prospects for their further application in oncology, endocrinology, pulmonology, neurology, cardiology, surgery, etc. Special attention is given to the use of 13C-magnetic resonance techniques for visualization of tumours and blood vessels, studies of metabolic processes and energy balance in man and animals with the use of 13C-biomarkers. The main advantages of these new diagnostic approaches are high accuracy, safety (for both patients and personnel), simplicity, and possibility of application in different fields of medicine.

[Melatonin as a most important factor of natural electromagnetic fields impacting patients with hypertensive disease and coronary heart disease. Part 1].

Part 1 of this review is devoted to modern concepts of mechanisms of action of weak natural and artificial electromagnetic fields (EMF) on the cardiovascular system at the cellular, molecular, and atomic levels with the participation of Ca2+ and melatonin. EMF are known to affect Ca2+ homeostasis and suppress melatonin activity in a wide wavelength range. Ca2+ ions in pinealocytes are involved in regulation of cAMP synthesis that mediates conversion of serotonin into melatonin. Their leakage from pinealocytes results in a decrease of the cAMP level and thereby suppresses production of melatonin. At the same time, the cyclic circadian rhythm of melatonin secretion controls the overall activity of human body from eating to sleep and metabolism.

Altered neuroinflammatory, arachidonic acid cascade and synaptic markers in postmortem Alzheimer's disease brain.

Alzheimer's disease (AD), a progressive neurodegenerative disorder, is the leading cause of dementia in the elderly. A recent positron emission tomography imaging study demonstrated upregulated brain arachidonic acid (AA) metabolism in AD patients. Further, a mouse model of AD shows an increase in AA-releasing cytosolic phospholipase A(2) (cPLA(2)) in brain, and a reduction in cPLA(2) activity ameliorated cognitive deficits. These observations led us to hypothesize that there is an upregulation of AA cascade and neuroinflammatory markers in the brain of AD patients. To test this hypothesis, we measured protein and mRNA levels of AA cascade, neuroinflammatory and synaptic markers in postmortem frontal cortex from 10 AD patients and 10 age-matched controls. Consistent with our hypothesis, AD frontal cortex showed significant increases in protein and mRNA levels of cPLA(2)-IVA, secretory sPLA(2)-IIA, cyclooxygenase-1 and -2, membrane prostaglandin (PG) synthase-1 and lipoxygenase-12 and -15. Calcium-independent iPLA(2)-VIA and cytosolic PGE(2) synthase were decreased. In addition, interleukin-1ß, tumor necrosis factor-α, glial fibrillary acidic protein and CD11b were increased. AD postmortem brain also showed signs of cellular injury, including decreased synaptophysin and drebrin, pre- and postsynaptic markers. These results indicate that increased AA cascade and inflammatory markers could contribute to AD pathology. Altered brain AA cascade enzymes could be considered therapeutic targets for future drug development.

Chronic imipramine but not bupropion increases arachidonic acid signaling in rat brain: is this related to 'switching' in bipolar disorder?

Agents effective against mania in bipolar disorder are reported to decrease turnover of arachidonic acid (AA) in phospholipids and expression of calcium-dependent AA-selective cytosolic phospholipase A(2) (cPLA(2)) in rat brain. In contrast, fluoxetine, an antidepressant that is reported to switch bipolar depressed patients to mania, increases cPLA(2) expression and AA turnover in rat brain. We therefore hypothesized that antidepressants that increase switching to mania generally increase cPLA(2) and AA turnover in brain. To test this hypothesis, adult male CDF-344 rats were administered imipramine and bupropion, with reported high and low switching rates, respectively, at daily doses of 10 and 30 mg kg(-1) i.p., respectively, or i.p. saline (control) for 21 days. Frontal cortex expression of different PLA(2) enzymes and AA turnover rates in brain when the rats were unanesthetized were measured. Compared with chronic saline, chronic imipramine but not bupropion significantly increased cortex cPLA(2) mRNA activity, protein and phosphorylation, expression of the cPLA(2) transcription factor, activator protein-2alpha (AP-2alpha) and AA turnover in phospholipids. Protein levels of secretory phospholipase A(2), calcium-independent phospholipase A(2), cyclooxygenase (COX)-1 and COX-2 were unchanged, and prostaglandin E(2) was unaffected. These results, taken with prior data on chronic fluoxetine in rats, suggest that antidepressants that increase the switching tendency of bipolar depressed patients to mania do so by increasing AA recycling and metabolism in brain. Mania in bipolar disorder thus may involve upregulated brain AA metabolism.

Increased excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from bipolar disorder patients.

Reports of cognitive decline, symptom worsening and brain atrophy in bipolar disorder (BD) suggest that the disease progresses over time. The worsening neuropathology may involve excitotoxicity and neuroinflammation. We determined protein and mRNA levels of excitotoxicity and neuroinflammatory markers in postmortem frontal cortex from 10 BD patients and 10 age-matched controls. The brain tissue was matched for age, postmortem interval and pH. The results indicated statistically significant lower protein and mRNA levels of the N-methyl-D-aspartate receptors, NR-1 and NR-3A, but significantly higher protein and mRNA levels of interleukin (IL)-1beta, the IL-1 receptor (IL-1R), myeloid differentiation factor 88, nuclear factor-kappa B subunits, and astroglial and microglial markers (glial fibrillary acidic protein, inducible nitric oxide synthase, c-fos and CD11b) in postmortem frontal cortex from BD compared with control subjects. There was no significant difference in mRNA levels of tumor necrosis factor alpha or neuronal nitric oxide synthase in the same region. These data show the presence of excitotoxicity and neuroinflammation in BD frontal cortex, with particular activation of the IL-R cascade. The changes may account for reported evidence of disease progression in BD and be a target for future therapy.

Is phosphoadenosine phosphate phosphatase a target of lithium's therapeutic effect?

Lithium, which is approved for treating patients with bipolar disorder, is reported to inhibit 3'(2')-phosphoadenosine-5'-phosphate (PAP) phosphatase activity. In yeast, deletion of PAP phosphatase results in elevated PAP levels and in inhibition of sulfation and of growth. The effect of lithium on PAP phosphatase is remarkable for the low Ki (approximately 0.2 mM), suggesting that this system would be almost completely shut down in vivo with therapeutic levels of 1 mM lithium, thereby elevating PAP levels. To test the hypothesis that lithium inhibition of PAP phosphatase is pharmacologically relevant to bipolar disorder, we fed rats LiCl for 6 weeks, and assayed brain PAP levels after subjecting the brain to high-energy microwaving. We also measured PAP phosphatase mRNA and protein levels in frozen brain tissue of lithium-treated mice. Brain adenosine phosphates were extracted by trichloroacetic acid and assayed by HPLC with a gradient system of two phases. PAP phosphatase mRNA was measured by RT-PCR, and PAP phosphatase protein was measured by Western blotting. Brain PAP levels were below detection limit of 2 nmol/g wet weight, even following lithium treatment. Lithium treatment also did not significantly change brain PAP phosphatase mRNA or protein levels. These results question the relevance of PAP phosphatase to the therapeutic mechanism of lithium. A statistically significant 25% reduced brain ADP/ATP ratio was found following lithium treatment in line with lithium's suggested neuroprotective effects.

[Gastric and duodenal ulcer disease: morphofunctional, neuroendocrine and clinical parallels].

Morphofunctional state of gastric mucous tunic and neuroendocrine cells, and clinical indices at various stages of gastric and duodenal ulcer disease was studied. It was shown, that in clinico-endoscopic remission stage of disease intensity of pathogenetic mechanisms of some neuroimmune-endocrine and clinical indices remained.

[The influence of antisecretory agents on the antral gastric mucosa in patients with duodenal ulcer].

Changes in the antral gastric mucosa of patients with doudenal ulcer after a long-term administration of antisecretory agents were studied. The subjects were five patients with a different duration of the disease. The methods applied included light and electron microscopy of tissue samplings taken from the antral part of the stomach during the periods of exacerbation and remission. In addition to well-known morphological changes, cellular principalis not typical of antral gastric mucosa were found in one patient during exacerbation and remission periods.

[Irritated bowel syndrome: clinicomorphological aspects of treatment with melaxen].

The purpose of the study was to evaluate the clinical effectiveness of melatonin (melaxen, Unipharm, USA), and its influence on the ultrastructural and histological features on the colon mucosa (CM) in patients with irritable bowel syndrome (IBS) corresponding to Rome criteria II. Twenty-one patients with IBS were examined before and after the end of the therapy (one month upon the beginning of treatment). All the patients had non-specific morphological changes in the CM, which were more pronounced during exacerbation and less significant during remission. The study showed that in terms of stool normalization and sleep improvement in IBS patients the combination of basic therapy and melaxen was more effective than either the combination of basic therapy and psychotropic drugs or basic therapy alone. Basic therapy plus melaxen is comparable in its effects to basic therapy plus psychotropic drugs in terms of coping with pain syndrome and dyspeptic syndrome in IBS patients, the normalization of their mental status and life quality improvement. The treatment of IBS with melaxen proved to be more effective than other therapies, which was proved by histological and electron microscopic studies of the CM.

[Ultrastructural changes in cells of the antral gastric mucosa in patients with duodenal ulcers treated with melatonin]. / Ul'trastrukturnye izmeneniia kletok v antral'nom otdele slizistoi obolochki zheludka u bol'nykh iazvennoi bolezn'iu dvenadtsatiperstnoi kishki pri lechenii melatoninm.

AIM: To study ultrastructural condition of the cels in antral gastric mucosa in patients with duodenal ulcer on melatonin treatment. MATERIAL AND METHODS: Electron microscopy was made of biopsy specimens of antral stomach mucosa obtained from 14 patients with duodenal ulcer (DU) in exacerbation and in clinicoendoscopic remission after therapy with proton pump blockers (group 1) and after this therapy combined mth melatonin (group 2). RESULTS: In patients of group 2 there was an increased number of differentiated cover and principal cells, moderately differentiated parietal cells predominated. CONCLUSION: Melatonin is one of the drugs potentiating trophic processes in gastric mucosa.

Energy consumption by phospholipid metabolism in mammalian brain.

Until recently, brain phospholipid metabolism was thought to consume only 2% of the ATP consumed by the mammalian brain as a whole. In this paper, however, we calculate that 1.4% of total brain ATP consumption is consumed for the de novo synthesis of ether phospholipids and that another 5% is allocated to the phosphatidylinositide cycle. When added to previous estimates that fatty acid recycling within brain phospholipids and maintenance of membrane lipid asymmetries of acidic phospholipids consume, respectively, 5% and 8% of net brain ATP consumption, it appears that phospholipid metabolism can consume up to 20% of net brain ATP consumption. This new estimate is consistent with recent evidence that phospholipids actively participate in brain signaling and membrane remodeling, among other processes.

ATP synthesis is coupled to rat liver mitochondrial RNA synthesis.

Rat liver mitochondria respond to changes in energy demand by modulating the amount of RNA synthesized. Coupled rat liver mitochondria were used to determine the relationship between mitochondrial respiration, ATP levels, and mitochondrial transcription. This system included oxidizable substrates (malate and glutamate) and constituents that could support both mitochondrial respiration and transcription. The respiratory inhibitor rotenone, phosphorylation inhibitor oligomycin, and the uncoupler of oxidative phosphorylation carbonyl-cyanide p-triflouromethoxyphehylhydrazone inhibited RNA synthesis. Addition of ADP stimulated mitochondrial transcription and peak RNA synthesis was observed at 1-2 mM ADP. At ADP concentrations above 2 mM, RNA synthesis decreased. These results demonstrate that mitochondrial transcription is tightly coupled to ATP levels.

Mitochondrial cytochrome c oxidase subunit III is selectively down-regulated by aluminum exposure in PC12S cells.

Aluminum (Al) has been implicated in several neurological diseases including dialysis dementia and Alzheimer's disease (AD). One possible mechanism of Al neurotoxicity could involve alteration of mitochondrial gene expression. We exposed PC12 cells to 0.1-100 microM AlCl3 for 6h at pH 7.4. Internalized Al, measured by atomic absorption spectrometry, was linearly proportional to the extracellular Al concentration. Northern blot analyses showed that cytochrome c oxidase subunit III (COX III) mRNA was significantly reduced by 70% after addition of 1 microM AlCl3. Higher concentrations of AlCl3 did not show a significant further effect. These results suggest that Al neurotoxicity involves a specific impairment of cytochrome c oxidase.

Advances in osmotic opening of the blood-brain barrier to enhance CNS chemotherapy.

The blood-brain barrier (BBB) to water-soluble drugs and macromolecules can be opened in vivo by infusing a hypertonic solution of arabinose or mannitol into the carotid artery for 30 sec. Opening involves widening of tight junctions between endothelial cells of the cerebrovasculature and is mediated by endothelial cell shrinkage, vascular dilatation associated with removal of water from brain, and modulation of the contractile state of the endothelial cytoskeleton and junctional proteins by increased intracellular calcium. A 10-fold increase in BBB permeability to intravascular substances, lasting about 10 min following osmotic exposure, reflects both increased diffusion and bulk fluid flow from blood into brain. Furthermore, recent evidence indicates that the duration of peak BBB opening can be extended beyond 30 min, by pre-treatment with a Na(+)/Ca(2+) channel blocker. In experimental animals, the osmotic method has been used to grant wide access to brain of water-soluble drugs, peptides, antibodies, boron compounds for neutron capture therapy, viral vectors for gene therapy and enzymes. Ongoing multi-centre clinical studies suggest that the method, when used with intra-arterially administered anticancer drugs, can prolong survival in patients with malignant brain tumours, with minimal morbidity. However, controlled clinical trials are critical to see if the osmotic procedure with intra-arterial drugs enhances survival in brain tumour patients compared with intra-arterial drug alone.

Chronic exposure of neural cells to elevated intracellular sodium decreases mitochondrial mRNA expression.

Regulation of expression of mitochondrial DNA- (mtDNA-) encoded genes of oxidative phosphorylation can occur rapidly in neural cells subjected to a variety of physiological and pathological conditions. However, the intracellular signal(s) involved in regulating these processes remain unknown. Using mtDNA-encoded cytochrome oxidase subunit III (COX III), we show that its mRNA expression in a differentiated rat pheochromocytoma cell line PC12S is decreased by chronic exposure to agents that increase intracellular sodium. Treatment of differentiated PC12S cells either with ouabain, an inhibitor of Na/K-ATPase, or with monensin, a sodium ionophore, decreased the steady-state levels of COX III mRNA by 50%, 3-4 h after addition of the drugs. No significant reduction in mtDNA-encoded 12S rRNA or nuclear DNA-encoded beta-actin mRNA were observed. Removal of the drugs restored the normal levels of COX III mRNA. Determination of half-lives of COX III mRNA, 12S rRNA, and beta-actin mRNA revealed a selective decrease in the half-life of COX III mRNA from 3.3 h in control cells to 1.6 h in ouabain-treated cells, and to 1 h in monensin-treated cells. These results suggest the existence of a mechanism of posttranscriptional regulation of mitochondrial gene expression that is independent of the energetic status of the cell and may operate under pathological conditions.