[Metformin and malignant neoplasms: a possible mechanism of antitumor action and prospects for use in practice].

Metformin is a first-line antidiabetic drug for the treatment of type 2 diabetes mellitus (DM2); its molecular target is AMP-activated protein kinase (AMPK), which is involved in many metabolic processes. Metformin not only reduces blood glucose levels and improves insulin sensitivity, but also inhibits lipolysis and reduces cardiovascular risk in patients with DM2. In recent years, it has been proven that metformin slows down the aging process, stimulates hair growth, eliminates cognitive impairment, and also has an antitumor effect. Most basic studies have shown that metformin inhibits the growth of tumor cells and promotes cellular apoptosis, while clinical studies show contradictory results. This discrepancy can be explained by the difference in the concentration of metformin between basic and clinical studies. The maximum daily dose of metformin for patients with DM2 is 2500 mg / day, and the dose used in basic research was much higher. Metformin directly activates the AMPK signaling pathway, inhibits the production of reactive oxygen species, induces the activation of mTORC1, inhibits cyclin D1, which leads to a reduction in the risk of the occurrence and development of malignant neoplasms. In addition, metformin indirectly inhibits tumor growth, proliferation, invasion and metastasis by reducing the concentration of glucose in the blood, insulin resistance, as well as by reducing inflammation and affecting the tumor microenvironment. Glycolysis plays an important role in the energy metabolism of tumors, and metformin is able to have an inhibitory effect on it. Currently, studies of the mechanism of antitumor effects of metformin are becoming more extensive and in-depth, but there are still some contradictions.

[Clinical and functional outcomes of correcting low to moderate myopia with FemtoLASIK performed with Russian and Swiss femtolaser platforms]. / Kliniko-funktsional'nye rezul'taty korrektsii miopii slaboi i srednei stepenei metodom FemtoLASIK s ispol'zovaniem otechestvennoi i zarubezhnoi femtolazernykh ustanovok.

PURPOSE: To compare the effectiveness, safety, predictability and stability of FemtoLASIK procedure in low to moderate myopia using Femto Visum and Femto LDV Z6 femtosecond laser platforms and to evaluate the effect of these procedures on corneal higher-order aberrations. MATERIAL AND METHODS: Russian femtolaser platform (1 MHz) was used to form the corneal flap in the main group consisting of 98 patients (98 eyes) with mean spherical equivalent (SE) of -3.73±1.42 D. Swiss femtolaser platform (5 MHz) was used in the control group (94 patients, 94 eyes; mean SE -3.81±1.44 D). Excimer laser ablation was performed using the Russian platform (500 Hz) in both groups. All patients underwent complete ophthalmological examination. The follow-up period was 12 months. RESULTS: Twelve month postoperatively, in the '1 MHz' group uncorrected visual acuity (UCVA) of 1.0 or better was achieved in 91.8% of patients, and in the '5 MHz' group - in 90.4% (p>0.05). There were no registered losses of 2 or more lines of best-corrected visual acuity (BCVA) in either group. In the '1 MHz' group, predictability of targeted refraction within ±0.5 D was achieved in 91.8% of patients, within ±1.0 D - in 99.0%; in the '5 MHz' group - in 91.5% and 98.9% of patients, respectively (p>0.05). Root-mean-square (RMS) deviation of corneal higher-order aberrations in the 6-mm optical zone was increased by 0.072 µm (by 1.21 times) and by 0.077 µm (by 1.22 times) in the '1 MHz' and '5 MHz' groups (p>0.05), respectively. CONCLUSION: The FemtoLASIK procedures performed using Russian (1 MHz) and Swiss (5 MHz) femtosecond laser platforms are effective, safe, predictable, have stable postoperative visual and refractive outcomes, and lead to increase in RMS of corneal higher-order aberrations using both platforms in patients with low to moderate myopia. There were no statistically significant differences between the two femtolaser platforms (p>0.05) for all examined parameters.

[Certain morphometric characteristics of the normal maxillary sinus]. / Nekotorye morfometricheskie pokazateli verkhnecheliustnoi pazukhi v norme.

Maxillary sinus is more than any other paranasal sinuses amenable to various pathological conditions that may require the surgical treatment. The objective of the present work was to study the age-related and the individual specific anatomical features of the walls of the maxillary sinus and to develop the principles of sinus surgery based on the results of the anthropometric studies. We analyzed the cone-beam CT scans obtained from 586 patients at the age varying from 5 to 60 years who were allocated to six different groups. The measurement of different anthropometric indicators of the maxillary sinus was undertaken. The study has demonstrated the feasibility of using boron as a means to obtain the access to the maxillary sinus for the purpose of the external surgical intervention. The maxillary sinuses having the thickness of the anterolateral wall of more than 1.5 mm most frequently occurred in the patients under 12 years of age. The surgical access to the maxillary sinus through the lower nasal passage having the medial wall thickness greater than 1 mm proved to be limited; this feature was found to be characteristic of the patients at the age below 12 years. It is shown that the depth of the lower lateral wall in the nasal passage did not depend on the age of the patients; the same was true of the angle formed between this wall and the bottom of the nose. Taken together, the obtuse angle (more than 100°) and the depth of the lateral wall of the inferior nasal meatus of more than 5 mm facilitated the surgical access to the maxillary sinus through the inferior meatus.

[Visual rehabilitation of patients with large post-traumatic defects of the anterior eye segment through iris-lens diaphragm implantation]. / Sistema zritel'noi reabilitatsii patsientov s obshirnymi defektami struktur perednego otrezka glaznogo iabloka na osnove implantatsii iridokhrustalikovoi diafragmy.

The diversity of methodological approaches and lack of pathogenetically reasonable tactics for patients with combined ocular injuries became the basis for the development and systematization of surgical rehabilitation stages of patients, in whom post-traumatic cataract is combined with post-traumatic aniridia and corneal scarring. AIM: to construct a visual rehabilitation approach to patients with post-traumatic defects of the anterior eye segment following optical-reconstructive surgery that involved implantation of an iris-lens diaphragm (ILD). MATERIAL AND METHODS: We have analyzed 80 reconstructive cases with ILD implantation in patients with post-traumatic aniridia and corneal damage. These patients constituted the first study group (Group 1). We have also investigated 58 eyes with residual ametropy and stable visual function 1 year after ILD implantation before and after conducting a laser keratorefractive surgery. These patients were assigned to the second study group (Group 2). RESULTS: Rehabilitation approach to patients after anterior segment injuries that has been proposed allows to achieve high clinical and functional results and reduce the risk of intra- and postoperative complications. CONCLUSION: The proposed approach to patients after optical-reconstructive surgery with iris-lens diaphragm implantation followed by keratorefractive surgery is an effective method of visual rehabilitation of anterior eye segment post-traumatic defects.

Lack of association between increased mitochondrial DNA4977 deletion and ATP levels of sputum cells from chronic obstructive pulmonary disease patients versus healthy smokers.

In this study we looked at smokers with and without chronic obstructive pulmonary disease (COPD) patients in order to evaluate the incidence of 4977 base pair (bp) mtDNA (mtDNA4977) deletion and mtDNA copy number in sputum cells and in peripheral blood leukocytes (PBLs) in relation to mitochondrial function and oxidative stress status. Twenty-five COPD patients who were current smokers, 22 smokers and 23 healthy nonsmokers (for only PBLs studies) participated in this study. The 4977-bp deletion was detected in all examined samples within 40 cyles of PCR amplification, using a quantitative real time PCR. The frequency of the mtDNA4977 was significantly higher in the sputum cells of patients with COPD compared to smokers without COPD (p < 0.0001). This difference was not observed in PBLs. Levels of cellular oxidative stress were significantly higher in the sputum cells of subjects with COPD than in the smoker group. However, mtDNA copy number, mitochondrial membrane potential (ΔΨm) and cellular ATP levels in PBLs and sputum cells were not significantly different between the studied groups. The Pearson analysis revealed no correlations between the accumulation of mtDNA4977, and intracellular ATP content and ΔΨm values of the sputum cells, although there was a positive correlation between the increase in the percentage of deleted mtDNA4977 and the levels of cellular oxidative stress in COPD patients (r = 0.80, p < 0.0001). Our studies may suggest that the accumulation of mtDNA4977 in the sputum cells of smokers with COPD does not seem to have an important impact on mitochondrial dysfunction in relation to ATP production and ΔΨm when compared to those of healthy smokers.

[The effect of high-molecular weight chitosans on the antioxidant and immune systems of the honeybee].

High-molecular weight chitosan (200 kDa, 75% deacetylated) and N-succinoyl chitosan (300 kDa, 75% deacetylated) were shown to have a preadaptive effect and increase the lifespan of honeybees due to the induction of protective antioxidant and immune mechanisms. Chitosan with a molecular weight of 200 kDa had a fungistatic effect on a pathogenic fungus that causes ascospherosis, a disease of bee larvae and pupae.

Successful reversal of propionic acidaemia associated cardiomyopathy: evidence for low myocardial coenzyme Q10 status and secondary mitochondrial dysfunction as an underlying pathophysiological mechanism.

Dilated cardiomyopathy is a rare complication in propionic acidaemia (PA). Underlying pathophysiological mechanisms are poorly understood. We present a child of Pakistani consanguineous parents, diagnosed with late-onset PA at 18months of age. He presented a mild phenotype, showed no severe further decompensations, normal growth and psychomotor development on a low protein diet and carnitine supplementation. At 15years, a mildly dilated left ventricle was noticed. At 17years he presented after a 2-3month history of lethargy and weight loss with severe decompensated dilated cardiomyopathy. He was stabilised on inotropic support and continuous haemofiltration; a Berlin Heart biventricular assist device was implanted. He received d,l-hydroxybutyrate 200mg/kg/day, riboflavin and thiamine 200mg/day each and coenzyme Q10 (CoQ10). Myocardial biopsy showed endocardial fibrosis, enlarged mitochondria, with atypical cristae and slightly low respiratory chain (RC) complex IV activity relative to citrate synthase (0.012, reference range 0.014-0.034). Myocardial CoQ10 was markedly decreased (224pmol/mg, reference range 942-2738), with a marginally decreased white blood cell level (34pmol/mg reference range 37-133). The dose of CoQ10 was increased from 1.5 to 25mg/kg/day. Cardiomyopathy slowly improved allowing removal of the external mechanical cardiac support after 67days. We demonstrate for the first time low myocardial CoQ10 in cardiomyopathy in PA, highlighting secondary mitochondrial impairment as a relevant causative mechanism. According to these findings, a high-dose CoQ10 supplementation could be a potential adjuvant therapeutic to be considered in PA-related cardiomyopathy.

Cardiomyopathy in the congenital disorders of glycosylation (CDG): a case of late presentation and literature review.

The congenital disorders of glycosylation (CDG) are a recently described group of inherited multisystem disorders characterized by defects predominantly of N- and O-glycosylation of proteins. Cardiomyopathy in CDG has previously been described in several subtypes; it is usually associated with high morbidity and mortality and the majority of cases present in the first 2 years of life. This is the first case with presentation in late childhood and the article reviews current literature. An 11-year-old female with a background of learning difficulties presented in cardiac failure secondary to severe dilated cardiomyopathy. Prior to the diagnosis of CDG, her condition deteriorated; she required mechanical support (Excor Berlin Heart) and was listed for cardiac transplant. Investigations included screening for glycosylation disorders, and isoelectric focusing of transferrin revealed an abnormal type 1 pattern. Analysis of phosphomannomutase and phosphomannose isomerase showed normal enzyme activity, excluding PMM2 (CDG Ia) and MPI (CDG Ib). Lipid-linked oligosaccharide and mutational studies have not yet defined the defect. Despite aggressive therapy there were persistent difficulties achieving adequate anticoagulation and she developed multiple life-threatening thrombotic complications. She was removed from the transplant list and died from overwhelming sepsis 5 weeks following admission. This case emphasizes the need to screen all children with an undiagnosed cardiomyopathy for CDG, regardless of age, and where possible to exclude CDG before the use of cardiac bridging devices. It highlights the many practical and ethical challenges that may be encountered where clinical knowledge and experience are still evolving.

Neonatal extracorporeal membrane oxygenation: practice patterns and predictors of outcome in the UK.

OBJECTIVE: To review the UK neonatal extracorporeal membrane oxygenation (ECMO) service and identify predictors of outcome. DESIGN: Retrospective review of the national cohort. PATIENTS AND INTERVENTIONS: 718 neonates received ECMO for respiratory failure between 1993 and 2005. MEASUREMENTS AND RESULTS: Diagnoses were: 48.0% meconium aspiration syndrome (97.1% survivors), 15.9% congenital diaphragmatic hernia (CDH; 57.9% survivors), 15.9% sepsis (62.3% survivors), 9.5% persistent pulmonary hypertension (79.4% survivors), 5.6% respiratory distress syndrome (92.5% survivors) and 5.1% congenital lung abnormalities (24.3% survivors). The overall survival rate of 79.7% compared favourably with the worldwide Extracorporeal Life Support Organization (ELSO) Registry. Over the period of review, pre-ECMO use of advanced respiratory therapies increased (p<0.001), but ECMO initiation was not delayed (p = 0.61). The use of veno-venous (VV) ECMO increased (p<0.001) and average run time fell (p = 0.004). Patients treated with VV ECMO had a survival rate of 87.7% compared with 73.4% in the veno-arterial (VA) ECMO group; only 42.4% of those needing conversion from VV to VA ECMO survived. In non-CDH neonates, lower birth weight, lower gestational age, older age at ECMO and higher oxygenation index (OI) were associated with increased risk of death. In CDH neonates, lower birth weight and younger age at ECMO were identified as risk factors for death. CONCLUSION: The UK neonatal ECMO service achieves good outcomes and with overall survival rate reaching 80% compares favourably with international results. Advanced respiratory therapies are used widely in UK ECMO patients. Identification of higher OI and older age at ECMO as risk factors in non-CDH neonates reinforces the importance of timely referral for ECMO.

Paradoxical rescue from ischemic lung injury by inhaled carbon monoxide driven by derepression of fibrinolysis.

Carbon monoxide (CO) can arrest cellular respiration, but paradoxically, it is synthesized endogenously by heme oxygenase type 1 (Ho-1) in response to ischemic stress. Ho-1-deficient (Hmox1-/-) mice exhibited lethal ischemic lung injury, but were rescued from death by inhaled CO. CO drove ischemic protection by activating soluble guanylate cyclase and thereby suppressed hypoxic induction of the gene encoding plasminogen activator inhibitor-1 (PAI-1) in mononuclear phagocytes, which reduced accrual of microvascular fibrin. CO-mediated ischemic protection observed in wild-type mice was lost in mice null for the gene encoding PAI-1 (Serpine1). These data establish a fundamental link between CO and prevention of ischemic injury based on the ability of CO to derepress the fibrinolytic axis. These data also point to a potential therapeutic use for inhaled CO.

The endothelial response to oxygen deprivation: biology and clinical implications.

This review provides the theoretical background of phenotypic and gene-based changes in the vessel wall triggered by acute hypoxia. Only in the last few decades has the endothelium been ascribed a prominent role as a modulator of vascular homeostasis under both physiological and pathological conditions. Molecular mechanisms leading to endothelial activation are being rapidly elucidated and their contribution to vascular dysfunction during hypoxia becoming better understood. New insights gained from hypoxic cell culture and ischaemic organ models may ultimately lead to new treatment strategies. If nothing else, insights gained from vascular research will lead to a more complete understanding of the inflammatory processes in blood vessels and how they impact on human disease.

[Endothelial reactions to hypoxia]. / Reakce endotelu na hypoxii.

In the last decade endothelium was shown to play an active role in regulating vascular homeostasis. This review focuses on the endothelial reactions during pathological condition of hypoxia. Cascade of events leading to endothelial activation/dysfunction during hypoxia is described and consequences of our expanded understanding of vascular biology for current clinical practice are summarised.

Antisense intercellular adhesion molecule-1 (ICAM-1) oligodeoxyribonucleotide delivered during organ preservation inhibits posttransplant ICAM-1 expression and reduces primary lung isograft failure.

Transiently increased expression of leukocyte adhesion receptors after lung preservation contributes to early graft demise by recruiting leukocytes, activating complement, and causing microcirculatory stasis. We hypothesized that inhibiting intercellular adhesion molecule-1 (ICAM-1) expression even briefly may significantly improve lung graft function and that the preservation period might provide a unique window to deliver a therapeutic pulse of antisense oligonucleotide ICAM-1 to inhibit ICAM-1 expression after transplantation. Interleukin-1beta-treated rat pulmonary endothelial cells given a 20-mer phosphorothioate oligonucleotide comprising an antisense span targeted to the 3'-untranslated region of rat ICAM-1 demonstrated an oligonucleotide dose-dependent reduction in ICAM-1 expression. Using a cationic liposomal carrier, this same antisense oligonucleotide (but not the sense control) instilled into the pulmonary vasculature at the time of preservation reduced subsequent graft ICAM-1 expression and graft leukostasis and markedly improved oxygenation, pulmonary blood flow, and graft survival. These experiments demonstrate that the preservation period presents a window during which to target an anti-ICAM-1 expression strategy to inhibit early adhesion receptor expression and improve functional outcome after lung transplantation.

[Health status of female workers of oil-processing enterprises]. / Sostoianie zdorov'ia zhenshchin-rabotnits neftepererabatyvaiushchikh zavodov.

Women working at oil-processing enterprises are exposed to a group of toxic chemicals and influenced by some social and everyday factors. The women demonstrate functional disorders of nervous, cardiovascular systems, disturbances in menstrual and child-bearing functions. Occupational factors influence course of pregnancy, delivery and state of newborn.

Free and bound magnesium in fungi and yeasts.

The content of total, bound and osmotically free magnesium was estimated in various fungi and in the yeast Saccharomyces cerevisiae. Total magnesium increases at lower growth rates of Endomyces magnusii and Penicillium chrysogenum 140A as well as during the logarithmic stage of growth of Penicillium chrysogenum Q-176. The binding of magnesium requires orthophosphate, decreasing during lack of external phosphate when the intracellular concentration of free magnesium rises. The fungi were found to contain a novel form of bound magnesium, a polymeric magnesium orthophosphate (PO Mg), which appears to take part in the control of free magnesium level in Penicillium chrysogenum Q-176. The level of free magnesium is proportional to the growth rate of Endomyces magnusii and Penicillium chrysogenum Q-176 and 140A. Total, as well as free, magnesium changes less than three-fold as external Mg concentration is changed 13,000-fold. The magnesium is taken up against concentration gradients of 1 : 25 to 1 : 1300, the metal being distributed non-uniformly in the cells of Saccharomyces cerevisiae.