Effect of dimethyl fumarate on mitochondrial metabolism in a pediatric porcine model of asphyxia-induced in-hospital cardiac arrest.

Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p < 0.001). Despite alterations in mitochondrial content and morphology in the myocardium, as assessed per transmission electron microscopy, mitochondrial function was unchanged. DMF treatment counteracted 25% of the proteomic changes induced by CA in the brain, and preserved mitochondrial structure in the myocardium. DMF demonstrates a potential therapeutic benefit in preserving mitochondrial integrity following asphyxia-induced IHCA. Further investigation is warranted to fully elucidate DMF's protective mechanisms and optimize its therapeutic application in post-arrest care.

Succinate prodrugs as treatment for acute metabolic crisis during fluoroacetate intoxication in the rat.

Sodium fluoroacetate (FA) is a metabolic poison that systemically inhibits the tricarboxylic acid (TCA) cycle, causing energy deficiency and ultimately multi-organ failure. It poses a significant threat to society because of its high toxicity, potential use as a chemical weapon and lack of effective antidotal therapy. In this study, we investigated cell-permeable succinate prodrugs as potential treatment for acute FA intoxication. We hypothesized that succinate prodrugs would bypass FA-induced mitochondrial dysfunction, provide metabolic support, and prevent metabolic crisis during acute FA intoxication. To test this hypothesis, rats were exposed to FA (0.75 mg/kg) and treated with the succinate prodrug candidate NV354. Treatment efficacy was evaluated based on cardiac and cerebral mitochondrial respiration, mitochondrial content, metabolic profiles and tissue pathology. In the heart, FA increased concentrations of the TCA metabolite citrate (+ 4.2-fold, p < 0.01) and lowered ATP levels (- 1.9-fold, p < 0.001), confirming the inhibition of the TCA cycle by FA. High-resolution respirometry of cardiac mitochondria further revealed an impairment of mitochondrial complex V (CV)-linked metabolism, as evident by a reduced phosphorylation system control ratio (- 41%, p < 0.05). The inhibition of CV-linked metabolism is a novel mechanism of FA cardiac toxicity, which has implications for drug development and which NV354 was unable to counteract at the given dose. In the brain, FA induced the accumulation of ß-hydroxybutyrate (+ 1.4-fold, p < 0.05) and the reduction of mitochondrial complex I (CI)-linked oxidative phosphorylation (OXPHOSCI) (- 20%, p < 0.01), the latter of which was successfully alleviated by NV354. This promising effect of NV354 warrants further investigations to determine its potential neuroprotective effects.

Succinate prodrugs in combination with atropine and pralidoxime protect cerebral mitochondrial function in a rodent model of acute organophosphate poisoning.

Pesticides account for hundreds of millions of cases of acute poisoning worldwide each year, with organophosphates (OPs) being responsible for the majority of all pesticide-related deaths. OPs inhibit the enzyme acetylcholinesterase (AChE), which leads to impairment of the central- and peripheral nervous system. Current standard of care (SOC) alleviates acute neurologic-, cardiovascular- and respiratory symptoms and reduces short term mortality. However, survivors often demonstrate significant neurologic sequelae. This highlights the critical need for further development of adjunctive therapies with novel targets. While the inhibition of AChE is thought to be the main mechanism of injury, mitochondrial dysfunction and resulting metabolic crisis may contribute to the overall toxicity of these agents. We hypothesized that the mitochondrially targeted succinate prodrug NV354 would support mitochondrial function and reduce brain injury during acute intoxication with the OP diisopropylfluorophosphate (DFP). To this end, we developed a rat model of acute DFP intoxication and evaluated the efficacy of NV354 as adjunctive therapy to SOC treatment with atropine and pralidoxime. We demonstrate that NV354, in combination with atropine and pralidoxime therapy, significantly improved cerebral mitochondrial complex IV-linked respiration and reduced signs of brain injury in a rodent model of acute DFP exposure.

Analysis of Mutational Profile of Hypopharyngeal and Laryngeal Head and Neck Squamous Cell Carcinomas Identifies KMT2C as a Potential Tumor Suppressor.

Hypopharyngeal cancer is a poorly characterized type of head and neck squamous cell carcinoma (HNSCC) with bleak prognosis and only few studies focusing specifically on the genomic profile of this type of cancer. We performed molecular profiling of 48 HPV (Human Papilloma Virus)-negative tumor samples including 23 originating from the hypopharynx and 25 from the larynx using a targeted next-generation sequencing approach. Among genes previously described as significantly mutated, TP53, FAT1, NOTCH1, KMT2C, and CDKN2A were found to be most frequently mutated. We also found that more than three-quarters of our patients harbored candidate actionable or prognostic alterations in genes belonging to RTK/ERK/PI3K, cell-cycle, and DNA-damage repair pathways. Using previously published data we compared 67 hypopharyngeal cancers to 595 HNSCC from other sites and found no prominent differences in mutational frequency except for CASP8 and HRAS genes. Since we observed relatively frequent mutations of KTM2C (MLL3) in our dataset, we analyzed their role, in vitro, by generating a KMT2C-mutant hypopharyngeal cancer cell line FaDu with CRISPR-Cas9. We demonstrated that KMT2C loss-of-function mutations resulted in increased colony formation and proliferation, in concordance with previously published results. In summary, our results show that the mutational profile of hypopharyngeal cancers might be similar to the one observed for other head and neck cancers with respect to minor differences and includes multiple candidate actionable and prognostic genetic alterations. We also demonstrated, for the first time, that the KMT2C gene may play a role of tumor suppressor in HNSCC, which opens new possibilities in the search for new targeted treatment approaches.

In vitro comparison of hydroxocobalamin (B12a) and the mitochondrial directed therapy by a succinate prodrug in a cellular model of cyanide poisoning.

The objective of this study was to compare the use of hydroxocobalamin (B12a) and a succinate prodrug to evaluate for improvement in mitochondrial function in an in vitro model of cyanide poisoning. Peripheral blood mononuclear cells (PBMC) and human aortic smooth muscle cells (HASMC) incubated with 50 mM of sodium cyanide (CN) for five minutes serving as the CN group compared to controls. We investigated the following: (1) Mitochondrial respiration; (2) Superoxide and mitochondrial membrane potential with microscopy; (3) Citrate synthase protein expression. All experiments were performed with a cell concentration of 2-3 × 106 cells/ml for both PBMC and HASMC. There were four conditions: (1) Control (no exposure); (2) Cyanide (exposure only); (3) B12a (cyanide exposure followed by B12a treatment); (4) NV118 (cyanide followed by NV118 treatment). In this study the key findings include: (1) Improvement in key mitochondrial respiratory states with the succinate prodrug (NV118) but not B12a; (2) Attenuation of superoxide production with treatment of NV118 but not with B12a treatment; (3) The changes in respiration were not secondary to increased mitochondrial content as measured by citrate synthase; (4) The use of easily accessible human blood cells showed similar mitochondrial response to both cyanide and treatment to HASMC. The use of a succinate prodrug to circumvent partial CIV inhibition by cyanide with clear reversal of cellular respiration and superoxide production that was not attributed to changes in mitochondrial content not seen by the use of B12a.

C1q/TNF-related Protein 1, a Multifunctional Adipokine: An Overview of Current Data.

The present review aimed to present the research highlights on C1q/TNF-related protein 1 (CTRP1), a member of the recently discovered family of highly conserved adiponectin paralog proteins, C1q tumor necrosis factor-related proteins. CTRP1 plays an important role in regulating body energy homeostasis and sensitivity to insulin. Studies on animal models have shown that it lowers the concentration of glucose. Elevated concentrations of CTRP1 reduce weight gain and diet-induced insulin resistance. CTRP1 limits the extent of ischemia-reperfusion injury in acute myocardial infarction. It inhibits platelet aggregation by blocking von Willebrand factor binding to collagen. In patients with chronic kidney disease, an increase in CTRP1 levels is associated with a lesser degree of disease progression. CTRP1 stimulates aldosterone synthesis in the adrenal cortex by affecting aldosterone synthase expression. In dehydration, an increase in CTRP1 concentration helps to maintain normotension. It participates in processes related to the proliferation and maturation of chondrocytes. It also promotes atherosclerosis, and a surge in its concentration is correlated with a higher cardiovascular risk in patients with coronary atherosclerosis. In vascular smooth muscle cells, it induces the expression of proinflammatory cytokines. An increase in CTRP1 levels is correlated with the progression of the neoplastic process in patients with glioblastoma.

Mitochondrial respiratory chain complex I dysfunction induced by N-methyl carbamate ex vivo can be alleviated with a cell-permeable succinate prodrug.

Human exposure to carbamates and organophosphates poses a serious threat to society and current pharmacological treatment is solely targeting the compounds' inhibitory effect on acetylcholinesterase. This toxicological pathway, responsible for acute symptom presentation, can be counteracted with currently available therapies such as atropine and oximes. However, there is still significant long-term morbidity and mortality. We propose mitochondrial dysfunction as an additional cellular mechanism of carbamate toxicity and suggest pharmacological targeting of mitochondria to overcome acute metabolic decompensation. Here, we investigated the effects on mitochondrial respiratory function of N-succinimidyl N-methylcarbamate (NSNM), a surrogate for carbamate insecticides, ex vivo in human platelets. Characterization of the mitochondrial toxicity of NSNM in platelets revealed a dose-dependent decrease in mitochondral oxygen consumption linked to respiratory chain complex I while the pathway through complex II was unaffected. In intact platelets, an increase in lactate production was seen, due to a compensatory shift towards anaerobic metabolism. Treatment with a cell-permeable succinate prodrug restored the NSNM-induced (100 µM) decrease in mitochondrial oxygen consumption and normalized lactate production to the level of control. We have demonstrated that carbamate-induced mitochondrial complex I dysfunction can be alleviated with a mitochondrial targeted countermeasure: a cell-permeable prodrug of the mitochondrial complex II substrate succinate.

Potential beneficial effect of some adipokines positively correlated with the adipose tissue content on the cardiovascular system.

Obesity is a risk factor of cardiovascular diseases. However, in the case of heart failure, obese and overweight patients have a more favourable prognosis compared to patients who have a normal body weight. This phenomenon is referred to as the "obesity paradox," and it is explained by, among others, a positive effect of adipokines produced by adipose tissue, particularly by the tissue located in the direct vicinity of the heart and blood vessels. The favourable effect on the cardiovascular system is mostly associated with adiponectin and omentin, but the levels of these substances are reduced in obese patients. Among the adipokines which levels are positively correlated with the adipose tissue content, favourable activity is demonstrated by apelin, progranulin, chemerin, TNF-α (tumour necrosis factor-)α, CTRP-3 (C1q/tumour necrosis factor (TNF) related protein), leptin, visfatin and vaspin. This activity is associated with the promotion of regeneration processes in the damaged myocardium, formation of new blood vessels, reduction of the afterload, improvement of metabolic processes in cardiomyocytes and myocardial contractile function, inhibition of apoptosis and fibrosis of the myocardium, as well as anti-inflammatory and anti-atheromatous effects. The potential use of these properties in the treatment of heart failure and ischaemic heart disease, as well as in pulmonary hypertension, arterial hypertension and the limitation of the loss of cardiomyocytes during cardioplegia-requiring cardiosurgical procedures, is studied. The most advanced studies focus on analogues of apelin and progranulin.

Interdependencies among Selected Pro-Inflammatory Markers of Endothelial Dysfunction, C-Peptide, Anti-Inflammatory Interleukin-10 and Glucose Metabolism Disturbance in Obese Women.

BACKGROUND: Currently increasing importance is attributed to the inflammatory process as a crucial factor responsible for the progressive damage to vascular walls and progression of atherosclerosis in obese people. We have studied the relationship between clinical and biochemical parameters and C-peptide and anti-inflammatory IL-10, as well as selected markers of inflammation and endothelial dysfunction such as: CCL2, CRP, sICAM-1, sVCAM-1 and E-selectin in obese women with various degree of glucose metabolism disturbance. MATERIAL AND METHODS: The studied group consisted of 61 obese women, and 20 normal weight, healthy volunteers. Obese patients were spited in subgroups based on the degree of glucose metabolism disorder. Serum samples were analyzed using ELISA kits. RESULTS: Increased concentrations of sICAM-1, sVCAM-1, E-selectin, CCL2 and CRP were found in all obese groups compared to the normal weight subjects. In patients with Type 2 diabetes mellitus (T2DM) parameters characterizing the degree of obesity significantly positively correlated with levels of CRP and CCL2. Significant relationships were found between levels of glucose and sICAM-1and also E-selectin and HOMA-IR. C-peptide levels are positively associated with CCL2, E-selectin, triglycerides levels, and inversely with IL-10 levels in newly diagnosed T2DM group (p<0.05). Concentrations of IL-10 correlated negatively with E-selectin, CCL2, C-peptide levels, and HOMA-IR in T2DM group (p<0.05). CONCLUSION: Disturbed lipid and carbohydrate metabolism are manifested by enhanced inflammation and endothelial dysfunction in patients with simply obesity. These disturbances are associates with an increase of adhesion molecules. The results suggest the probable active participation of higher concentrations of C-peptide in the intensification of inflammatory and atherogenic processes in obese patients with type 2 diabetes. In patients with obesity and type 2 diabetes, altered serum concentrations of Il-10 seems to be dependent on the degree of insulin resistance and proinflammatory status.

Solid Cancers in the Premature and the Newborn: Report of Three National Referral Centers.

BACKGROUND: Advances in multidisciplinary care for pediatric cancer have resulted in significant improvement in cure rates over the last decades; however, these advances have not been uniform across all age groups. Cancer is an important cause of perinatal mortality, yet the full spectrum of malignant neoplasms in newborns is not well defined. METHODS: The authors have reviewed the clinical features and outcomes of 37 newborns with congenital malignant tumors treated at three referral centers in North, Central, and South Poland between 1980 and 2014. Event-free survival (EFS) and overall survival (OS) rates were estimated by Kaplan-Meier methods and compared using long-rank test and Cox models. RESULTS: Twenty-two patients were diagnosed prenatally. The most common diagnoses were neuroblastoma (48.7%), followed by malignant germ-cell tumor (16.2%), and Wilms' tumor (8.1%). Neuroblastoma was the most common malignancy among full-term infants, and malignant sacrococcygeal teratoma was the most common malignancy in premature infants. Thirty patients (81%) are alive with a median follow-up of 4.8 years from diagnosis. Patients with Wilms' tumor and malignant germ-cell tumors had the best outcomes (5-year OS 100% for both), whereas the worst prognosis was observed for sarcoma patients (5-year OS 72.92%). Premature infants had better outcome than full-term infants (5-year OS 92.8% vs. 72.58%, respectively). CONCLUSION: Although rare, neonatal cancers can present with an aggressive clinical behavior, but they have a generally good outcome. Early diagnosis and management by expert multidisciplinary teams that integrate perinatal medicine experts with pediatric and surgical oncologists are critical. Centralized care with clear referral pathways that facilitate early initiation of specialized treatment should be prioritized.

Intraluminal thrombus thickness is not related to lower concentrations of trace elements in the wall of infrarenal abdominal aortic aneurysms.

BACKGROUND: Intraluminal thrombus (ILT) formation plays a significant role in the progression of infrarenal abdominal aortic aneurysms (AAA). Potentially, as ILT thickness increases the availability of trace elements in the aneurysm wall could decrease thereby leading to oxidative stress and intensifying pro-inflammatory cytokine generation. AIM: To determine if thrombus thickness is related to the concentration of trace elements in the wall of infrarenal AAA. PATIENTS AND METHODS: The concentrations of trace elements in the wall of the aneurysm sack and ILT obtained from 19 consecutive patients during surgery for infrarenal AAA were determined using emission spectrometry. RESULTS: The concentrations of magnesium, zinc, manganese, and lead in the wall of AAA were significantly greater than in the ILT. Only the concentration of copper was lower in the AAA wall compared with the thrombus. The concentration of calcium, phosphorus, zinc, lead, copper, and magnesium increased with ILT thickness. The concentrations of no other trace elements in the wall of AAA were found to be related to the ILT thickness. CONCLUSIONS: Intraluminal thrombus thickness is not associated with a lower concentration of trace elements in the wall of the infrarenal AAA. Thus, the intraluminal thrombus participates in the progression of AAA by mechanisms independent of trace element supply to the wall of the aneurysm sack.

Long-term inhibition of intestinal lipase by orlistat improves release of gut hormones increasing satiety in obese women.

BACKGROUND: Reduced postprandial secretion of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), cholecystokinin, and increased hunger was reported after a single dose of orlistat, an inhibitor of intestinal lipase. As yet, the influence of long-term therapy with orlistat on PYYand GLP-1 release has not been studied. Our study was aimed at assessing the influence of 8-week therapy with orlistat as a component of a weight loss program on pre-prandial circulating PYY and GLP-1 levels. METHODS: Forty obese women, without concomitant diseases, were randomly allocated to groups receiving orlistat or placebo during an 8-week weight management program. Body mass, body composition and plasma levels of PYY, GLP-1 and insulin (for QUICKI calculation) were determined prior to and at the end of therapy. RESULTS: Women treated with orlistat obtained significantly greater body and fat mass loss than those receiving placebo (9.0 ± 3.1 vs. 5.9 ± 3.2% and 21.9 ± 10.9 vs. 7.4 ± 15.6%, respectively). Only in those treated with orlistat a slight, but significant increase of the QUICKI was found (8.0 ± 16.5 vs. -0.1 ± 12.7 %, respectively). Weight loss was followed by a significant increase of plasma levels of PYY and GLP-1 in group treated with orlistat, and was about 2-times greater than receiving placebo. The increase was independent of body mass changes. CONCLUSION: The long-term inhibition of intestinal lipase by orlistat increases the pre-prandial levels of GLP-1 and PYY, independent of body mass changes. Therefore, it seems that long-term treatment with orlistat may exert hunger suppressing and insulin sensitizing incretin effect beyond weight reduction.

Plasma visfatin and tumor necrosis factor-alpha (TNF-α) levels in metabolic syndrome.

BACKGROUND: Experimental studies have shown that tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) downregulate visfatin gene expression in adipocytes. On the other hand, the induction of cytokine production by visfatin in leucocytes and monocytes has also been described. AIM: To assess the possible interrelation between plasma concentrations of visfatin and TNF-α and TNF soluble receptor in obese women fulfilling, or not, the criteria of metabolic syndrome (MS). METHODS: Ninety two obese women were included in the study. Metabolic syndrome, based on IDF criteria (2005) was diagnosed in 71 subjects (mean age 53 ± 9 years; body mass index 39.1 ± 5.6 kg/m(2), waist circumference 109.6 ± 11.4 cm). The remaining 21 formed the non-MS subgroup (mean age 52 ± 9 years, body mass index 36.3 ± 5.2 kg/m(2), waist circumference 104.7 ± 11.0 cm). Fourteen healthy normal weight women served as controls. In all subjects, body composition was assessed by the bioimpedance method. RESULTS: In the MS subgroup, but not in the non-MS subgroup, visfatin levels were significantly higher than in controls. We did not observe any significant difference in plasma concentrations of visfatin, TNF-α or sTNFRs between the MS subgroup and the non-MS subgroup. Only in the MS subgroup and in the combined analysis of all study subgroups did plasma visfatin concentrations correlate significantly with TNF-α levels (R = 0.31, p = 0.01, R = 0.21, p = 0.03; respectively). Additionally, in the MS subgroup there was a positive correlation between visfatin levels and insulin resistance (R = 0.53, p = 0.01). CONCLUSIONS: Our findings suggest that visfatin in metabolic syndrome should be regarded as a proinflammatory factor indirectly favouring the development of insulin resistance.

N-3 polyunsaturated fatty acids early supplementation improves ultrasound indices of endothelial function, but not through NO inhibitors in patients with acute myocardial infarction: N-3 PUFA supplementation in acute myocardial infarction.

BACKGROUND & AIMS: Our aim was to evaluate early initiated one month n-3 polyunsaturated fatty acids (PUFA) supplementation effects on ultrasound indices of endothelial function and serum asymmetric dimethylarginine (ADMA) levels in patients with acute myocardial infarction (AMI). METHODS: Forty patients with AMI and successful percutaneous coronary intervention (PCI) were recruited into the study and randomized to the study group (group P; n = 20; standard therapy + n-3 PUFA 1 g daily) or the control group (group C; n = 20; standard therapy). Ultrasound indices of endothelial function: flow-mediated dilatation (FMD), nitroglycerin-mediated dilatation (NMD) and serum ADMA concentrations (ELISA) were obtained before and after one month (30 ± 1 days) therapy (presented as means ± standard deviations). RESULTS: There was a significant difference between both groups in mean delta (baseline/after one month) FMD (P: 8.1 ± 12.6% vs C: -2.2 ± 11.8%; p = 0.02) with no difference in mean delta NMD (P: 3.3 ± 11.9% vs 0.66 ± 14.3%; p = 0.53). We found also a significant increase in mean FMD (7.4 ± 6.4 to 15.5 ± 10.5%; p = 0.02) with a nonsignificant change in mean NMD values (26.9 ± 12.1 to 30.2 ± 14.0%; p = 0.24) after 1-month therapy with n-3 PUFA. FMD and NMD mean values did not change in control patients (FMD: 11.6 ± 6.1% to 9.4 ± 8.0%; p = 0.5 NMD: 25.1 ± 11.4% to 25.8 ± 14.0%; p = 0.84). The comparison of mean delta ADMA values for both groups revealed no differences (P: 6.2 ± 9.7 µmol/l vs C: 3.6 ± 9.5 µmol/l; p = 0.43). Mean serum ADMA concentrations were significantly increased after 1-month therapy in the group P (P: 2.1 ± 1.8 to 8.3 ± 9.7 µmol/l; p = 0.001; C: 4.5 ± 7.1 to 8.1 ± 9.5 µmol/l; p = 0.09). However, there was a nonsignificant difference in mean baseline serum ADMA levels between both groups (P: 2.1 ± 1.8 µmol/l vs C: 4.5 ± 7.1 µmol/l; p = 0.32). There were no significant correlations between FMD, NMD, ADMA levels and demographic, clinical or biochemical parameters. CONCLUSIONS: Early and short-term n-3 PUFA supplementation improved ultrasound indices of endothelial function without affecting serum ADMA levels in patients with AMI and successful primary PCI.

N-3 Polyunsaturated fatty acid therapy improves endothelial function and affects adiponectin and resistin balance in the first month after myocardial infarction.

INTRODUCTION: N-3 Polyunsaturated fatty acids (n-3 PUFA) exert clinical beneficial effects in patients after acute myocardial infarction (AMI). However, their exact mechanisms of action are not well recognized yet. Our aim was to evaluate effects of early introduced n-3 PUFA supplementation on endothelial function and serum adipokine concentrations in patients with AMI. MATERIAL AND METHODS: Thirty-eight patients with AMI and successful coronary stent implantation were randomized to the study group (PUFA group: n = 19; standard therapy + PUFA 1 g daily) and the control group (control group: n = 19; standard therapy). The study group patients were given n-3 PUFA (Omacor 1 g daily) starting from the 3(rd) day of AMI. Ultrasound vascular indexes (flow-mediated dilatation [FMD], nitroglycerine-mediated dilation [NMD]) and serum concentrations of adiponectin and resistin (ELISA) were evaluated before and after 30 days of pharmacotherapy. RESULTS: Comparison of the mean delta values (baseline/after 30 days of therapy) between groups revealed significant differences for delta FMD (PUFA 7.6 ±12.4% vs. control -1.7 ±10.5%, p = 0.019) and delta resistin concentrations (PUFA 1.0 ±3.8pg/ml vs. control -1.6 ±2.9pg/ml, p = 0.028). Multiple linear regression analysis for all subjects revealed the n-3 PUFA supplementation (r = 10.933, p = 0.004) and waist circumference (r = -0.467, p = 0.01) as independent factors associated with delta FMD values (R-adjusted 0.29; p = 0.002). CONCLUSIONS: Early and short-term n-3 PUFA supplementation in AMI with successful primary PCI and optimal pharmacotherapy improves endothelial function. However, increased resistin serum levels observed after 1-month n-3 PUFA supplementation merits further investigations.

Proangiogenic cytokines vascular-endothelial growth factor and basic fibroblst growth factor in childhood lymphadenopathy.

Increased angiogenesis is observed both in the inflammatory and in the neoplasmatic tissue. The aim of the study was to assess the diagnostic significance of serum concentration of vascular-endothelial growth factor (sVEGF) and basic fibroblast growth factor (sbFGF) in the various forms of lymphadenopathy in children. Ninety-four children with lymphadenopathy were studied: group A, 52 patients with lymphadenitis; group B, 42 patients with lymphomas. Group B was divided into subgroups: B(P), children with lymphomas in peripheral lymph nodes and B(M), children with lymphomas in peripheral lymph nodes and mediastinal tumor. The healthy control group was 20 children. Using enzyme-linked immunosorbent assays the authors quantified VEGF and bFGF in serum of healthy children and of children with lymphadenopathy. The sVEGF in group A was significantly higher than controls (313.8 versus 44.6 pg/mL; P <.05) and in group B was 633.4 pg/mL and was significantly higher than controls (P <.0001). The sVEGF and bFGF in group A versus subgroup B(P) were significantly lower (P(VEGF) <.05, P(bFGF) <.05), and sVEGF in subgroup B(P) versus B(M) was significantly lower (P <.05). These results show that the evaluation of serum VEGF concentration might be useful as noninvasive diagnosis of some chronic peripheral lymphadenopathies in children.

Serum ADMA concentration-- an independent factor determining FMD impairment in cardiac syndrome X.

UNLABELLED: Mechanisms of decreased endogenous vascular reactivity in individuals with cardiac syndrome X (CSX) are not fully understood. AIM: To evaluate the following serum markers: total nitric oxide (NO), asymmetric dimethylarginine (ADMA), platelet-derived growth factor (PDGF), and to establish their relation to ultrasound indexes of endothelial function and structural remodeling in CSX patients. METHOD: The study group consisted of 43 CSX patients (mean age: 56.3 +/- 9 years), while the control group included 21 healthy subjects (mean age: 54.86 +/- 6.9 years). The high-resolution ultrasound was performed to measure: flow-mediated vasodilatation (FMD), nitroglycerine-mediated vasodilatation (NMD) and intima-media thickness (IMT) of carotid arteries. RESULTS: In CSX patients, significantly lower FMD (9.06 +/- 3.2%) and significantly higher IMT (0.667 +/- 0.14 mm) values were observed compared to healthy individuals (17.42 +/- 8.4%, 0.571 +/- 0.2 mm; P < 0.05). Mean total NO serum concentration was significantly higher in the CSX group (48.2 +/- 18.2 micromol/L) as compared to controls (32.1 +/- 1.4 micromol/L; P < 0.0001). There were no differences in serum ADMA and PDGF levels. In CSX patients, FMD values correlated with NO (r = 0.323; P = 0.039) and ADMA (r = -0.387; P = 0.012) serum levels; however, there were no significant correlations between NO and ADMA concentrations. CONCLUSION: Serum ADMA concentration is the only independent factor determining FMD impairment.

Selected angiogenic cytokines in systemic lupus erythematosus patients.

The objective of this study was to determine the serum concentration of angiogenic factors (vascular endothelial growth factor, VEGF; transforming growth factor beta, TGF-beta1; hepatic growth factor, HGF; basic fibroblast growth factor, bFGF; tumor necrosis factor alpha, TNF-alpha; soluble vascular endothelial growth factor receptor 1, sVEGF-R1; soluble vascular endothelial growth factor receptor 2, sVEGF-R2), the relationships among them and to assess the relation of their levels with the applied therapy in 48 females with systemic lupus erythematosus (SLE; 37 long-term treated +11 newly diagnosed). The control group consisted of 24 healthy women. A statistically significant increase of sVEGF-R2 and significant decrease of sVEGF-R1 were observed in the subgroup of newly diagnosed SLE patients as compared to the control subjects. No significant differences were found between serum angiogenic factors in the long-term treated subgroup and the control, the long-term treated subgroup and the newly diagnosed SLE patients after a 3-month treatment, and the subgroup of newly diagnosed SLE patients before therapy and after a 3-month treatment. The significant decrease in the serum of sVEGF-R2 was revealed in the subgroup treated for a long-time as compared to the subgroup of newly diagnosed untreated SLE patients. The analysis of relationships between serum concentration of sVEGF-R1 and other cytokines levels revealed positive correlation with concentration of VEGF and TNF-alpha in the total group of patients. In the newly diagnosed untreated subgroup, a strong positive correlation between concentration of sVEGF-R1 and bFGF was observed. Furthermore, a moderate positive correlation between concentration of sVEGF-R1 and the level of VEGF was revealed in the long-term treated patients. The association between sVEGF-R2 and HGF was also noted in this subgroup. The obtained data suggest the necessity of further investigations to determine the importance of angiogenic factors in pathogenesis and therapy of SLE.

Is chronic inflammation a possible cause of obesity-related depression?

Adult obesity has been associated with depression, especially in women. Whether depression leads to obesity or obesity causes depression is unclear. Chronic inflammation is observed in obesity and depression. In 63 obese women without additional diseases depression level was assessed with the Beck's questionnaire. After evaluation of depression level study group was divided into groups according to the mood status (A--without depression, B-mild depression, and C--severe depression), and serum concentration of TNF-alpha, sTNFs, leptin, and IL-6 were measured by ELISA. No differences in age, body mass, BMI, and body composition were observed in study groups. We did not observe differences of serum concentrations of TNF-alpha, sTNFRs, leptin, and IL-6 between subgroup A and subgroups B and C. It seems that circulating adipokines did not exert influence on depression levels in obese women.

Prognostic value of proangiogenic cytokines in children with lymphomas.

BACKGROUND: Angiogenesis and proangiogenic cytokines are involved in neoplastic development. The role of these processes in lymphoma formation has not been established. The aim of the study was to assess angiogenesis on the basis of serum levels of vascular-endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in childhood lymphomas. The prognostic value of these parameters was determined in the examined children. PROCEDURE: Forty-two children with lymphomas (Hodgkin and non-Hodgkin Lymphomas) were studied (group A). Group A was divided into two subgroups: A(CR)-30 children with complete remission (CR) and A(PR+P+ER)-12 children with partial remission (PR), progressive disease (P), and early relapse (ER). The control group (group C) consisted of healthy 20 children. Using enzyme-linked immunosorbent assays we quantified VEGF and bFGF in serum of the healthy children and of the children with lymphomas. RESULTS: The serum VEGF concentration in group A was 633.4 pg/ml (24.0-1,210.5) and was significantly higher (P = 0.0001) in comparison with group C (144.6 pg/ml; 32.3-734.8). In subgroup A(PR+P+ER), the baseline serum VEGF concentration was 865.0 pg/ml (205.8-1,209.2) and was significantly higher (P = 0.02) than in subgroup A(CR) (564.0 pg/ml; 24.0-1,210.5). The high serum VEGF concentration in children with lymphomas was the only independent risk factor for treatment failure (OR = 8.64; 95 CI: 1.51-49.34; P = 0.01). The cutoff point for the serum VEGF level >or=633.4 pg/ml as a parameter predicting treatment failure was established (P = 0.01). CONCLUSION: Baseline serum VEGF concentration constitutes a prognostic marker for the progression of Hodgkin and non-Hodgkin Lymphomas in children.