Steel ribbed dome structural performance with different node connections and bracing system.

The conventional design of steel structure objects relies on a first-order elastic analysis, where the entire object is treated as a set of individual structural elements requiring time-consuming, semi-empirical design calculations. Such an approach leads to inefficient design time and excessive material consumption and may additionally result in designing on the verge of structural safety. The AEC sector's technological and digitization advancement process forces designers to use advanced design methods. Hence, it is necessary to indicate the benefits of using effective optimization. The paper presents a comparative analysis of steel domes using two design approaches: traditional first-order analysis and an advanced second-order analysis. The latter method considers the influence of structural deformation on the magnitude of internal forces. Eight models were developed, varying in terms of the connection's stiffness. The work results identify the differences between the two selected design approaches and present opportunities for further structural performance of steel structures.

Relationship between Serum Angiopoietin-like Proteins 3 and 8 and Atherogenic Lipid Biomarkers in Non-Diabetic Adults Depends on Gender and Obesity.

Hypertriglyceridemia is an independent risk factor for coronary artery disease. Lipoprotein lipase (LPL) plays an essential role in the metabolism of triglyceride-rich lipoproteins (TRLs). Angiopoietin-like proteins ANGPTL3 and ANGPTL8 are shown to be important regulators of LPL activity. Increased concentrations of these proteins may reflect cardiovascular risk, and the treatment of patients with dyslipidemia with ANGPTLs inhibitors may decrease this risk. We assessed the gender-specific relationships of serum ANGPTL3 and ANGPTL8 with atherogenic lipid biomarkers and obesity in non-diabetic adults. The study comprised 238 participants aged 25-74 [122 with triglycerides (TG) <150 mg/dL (<1.7 mmol/L) and 116 with hypertriglyceridemia]. Total cholesterol, HDL-cholesterol, LDL-cholesterol, TG, C-reactive protein (CRP), glycated hemoglobin, apolipoprotein B, small dense LDL-C (sd-LDL-C), ANGPTL3, and ANGPTL8 were measured. Non-HDL-cholesterol, remnant cholesterol (remnant-C) concentrations, and body mass index (BMI) were calculated. Results: Women and men did not differ in terms of age, CRP levels, the percentage of obese subjects, and concentrations of atherogenic lipid biomarkers, except higher TG in males and higher ANGPTL3 concentrations in females. Positive correlations of both ANGPTLs with TG, remnant-C, and sdLDL-C levels were found in females. In males, only ANGPTL3 correlated positively with atherogenic biomarkers, but there were no correlations with ANGPTL8. Concentrations of ANGPTL3 were higher in obese men, whereas ANGPTL8 levels were higher in obese women. In women alone, ANGPTL8 showed very good discrimination power to identify subjects with hypertriglyceridemia (AUC = 0.83). Contrary to this, ANGPTL3 was a better discriminator of hypertriglyceridemia (AUC = 0.78) in male subjects. Regression models, adjusted for age, sex, and BMI showed a weak but significant effect of ANGPTL8 to increase the risk of hypertriglyceridemia. Conclusions: In females, ANGPTL8 is more strongly associated with TRLs metabolism, whereas in males, ANGPTL3 plays a more important role. We suggest sex differences be taken into consideration when applying new therapies with angiopoietin-like proteins inhibitors in the treatment of dyslipidemia.

Decreasing of Leaching and Improvement of Geopolymer Properties by Addition of Aluminum Calcium Cements and Titanium Oxide.

The article presents the latest results of the leaching of alkali from geopolymers depending on the introduced additions in the form of aluminum calcium cement and nanometric titanium oxide. Aluminum calcium cements were introduced in two variants: G40 (>40% Al2O3) and G70 (>70% Al2O3) in amounts of 0%, 2%, and 4% by weight. Titanium oxide was also incorporated in amounts of 2% and 4% by weight. The results of conductivity tests of solutions in which geopolymers were immersed were carried out. On this basis, it was found that geopolymers cured in the aquatic environment have a lower risk of efflorescence in the later periods of their use due to leaching of compounds at the stage of aquatic curing. In addition, it was found that the addition of calcium aluminum cements decreases the leaching of substances from geopolymers. It was also found that geopolymers based on an 8 M NaOH solution have greater leaching than when using a 10 M solution. The results of the compressive strength tests for the tested samples were also presented.

Secukinumab 150/300 mg Provides Sustained Improvements in the Signs and Symptoms of Active Ankylosing Spondylitis: 3-Year Results from the Phase 3 MEASURE 3 Study.

OBJECTIVE: Secukinumab 150 mg has demonstrated significant improvement in signs and symptoms of ankylosing spondylitis (AS), with response rates sustained for up to 5 years. Here, we report end-of-study 3-year efficacy and safety results of secukinumab 150 and 300 mg from the MEASURE 3 study. METHODS: A total of 226 patients was randomized to intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous (s.c.) secukinumab 300/150 mg every 4 weeks or a matched placebo. At week 16, placebo patients were re-randomized to s.c. secukinumab 300/150 mg. Analysis at week 156 included patients initially randomized to secukinumab and those who switched from placebo to secukinumab at week 16 (any secukinumab 300/150 mg). Outcome measures at week 156 included Assessment of Spondyloarthritis International Society (ASAS) 20/40, Bath Ankylosing Spondylitis Disease Activity Index, ASAS partial remission (PR), ASAS 5/6, and Ankylosing Spondylitis Disease Activity Score-C-reactive protein inactive disease. RESULTS: The retention rates from weeks 16 to 156 were 80.5% and 80.9% in secukinumab 300 and 150 mg, respectively. ASAS 20/40 response rates at week 156 were 75.0%/56.5% and 68.2%/47.7% for secukinumab 300 and 150 mg, respectively. At week 156, response rates on more stringent clinical end points (eg, ASAS 40, ASAS-PR) were higher with the 300-mg dose, particularly in tumor necrosis factor (TNF)-inadequate responder (IR) patients. No new safety findings were observed. CONCLUSION: Secukinumab (300 and 150 mg) provided sustained improvements through 3 years in the signs and symptoms of active AS. Improvements with secukinumab 300 mg were numerically higher compared with the 150-mg dose for some higher hurdle end points and in TNF-IR patients. The safety profile of secukinumab was consistent with previous reports.

5-year efficacy and safety of secukinumab in patients with ankylosing spondylitis: end-of-study results from the phase 3 MEASURE 2 trial.

BACKGROUND: Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin 17A, has shown significant and sustained improvement in the signs and symptoms of ankylosing spondylitis over 3 years in the MEASURE 2 study. We report the 5-year (end-of-study) results of subcutaneous secukinumab 150 mg in the MEASURE 2 study. METHODS: MEASURE 2 was a phase 3, double-blind, randomised, placebo-controlled, study done in 13 countries and 53 centres. Patients with ankylosing spondylitis who were 18 years of age or older and fulfilled the modified New York criteria were randomly assigned to receive secukinumab (150 mg or 75 mg) or placebo subcutaneously at baseline and weeks 1, 2, and 3, and then every 4 weeks from week 4. At week 16, patients initially given placebo were randomly assigned again (placebo switchers) to receive secukinumab 150 mg or 75 mg. Efficacy results are reported for patients initially randomised to secukinumab 150 mg and those who switched from placebo to secukinumab 150 mg at week 16. An optional dose escalation from secukinumab 75 mg to 150 mg was initiated beginning week 140. We assessed efficacy endpoints at week 260 (5 years), including Assessment of Spondyloarthritis International Society (ASAS) 20 and ASAS 40, inactive disease according to ankylosing spondylitis disease activity score with C-reactive protein (ASDAS-CRP), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BASDAI50, Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Functional Index, Short Form-36 Physical Component Summary, and ASAS partial remission. Analyses were stratified by anti-tumour necrosis factor (TNF) status (anti-TNF-naive and anti-TNF inadequate response). The safety analysis included all patients who received one dose or more of secukinumab. We report data as observed without accounting for missing data. The MEASURE 2 study was registered with ClinicalTrials.gov, NCT01649375. FINDINGS: 219 patients were randomly assigned during the trial and 150 (68%) completed 5 years of treatment, including 82 (77%) of 106 patients in the secukinumab 150 mg group and 68 (65%) of 105 in the secukinumab 75 mg group. Efficacy analysis in the secukinumab 150 mg group included 53 patients who completed the study and one additional patient who was assessed in the treatment period weeks 212-260, but did not complete the study. 134 (61%) of 219 patients were anti-TNF-naive and 85 (39%) were anti-TNF inadequate responders. ASAS responses at 5 years with secukinumab 150 mg were 36 (67%) of 54 patients (ASA20) and 27 (50%) patients (ASAS40). Sustained improvement was observed across other efficacy endpoints with secukinumab 150 mg at 5 years. At 5 years, the proportion of patients achieving efficacy endpoints of BASDAI 50 response was 53% (44/83); ASAS 5/6 response was 51% (42/83); ASDAS-CRP inactive disease was 21% (17/81); and ASAS partial remission was 25% (21/83). Exposure-adjusted incidence rates with any secukinumab dose for selected adverse events were 1·0 per 100 patient-years (95% CI 0·4-1·9) for Candida infections, 0·5 (0·1-1·2) for Crohn's disease, 0·4 (0·1-1·1) for ulcerative colitis, 0·6 (0·2-1·4) for major adverse cardiovascular events, 0·5 (0·1-1·2) for uveitis, and 0·6 (0·2-1·4) for malignant or unspecified tumours. INTERPRETATION: Secukinumab 150 mg provided sustained improvement in the signs, symptoms, and physical function in patients with ankylosing spondylitis after 5 years of treatment. The safety profile of secukinumab remained consistent with previous reports. FUNDING: Novartis Pharma.

Gonadotropins and Their Association with the Risk of Prediabetes and Type 2 Diabetes in Middle-Aged Postmenopausal Women.

Recent studies have suggested that a low concentration of follicle-stimulating hormone (FSH) is associated with a higher prevalence of metabolic disturbances in postmenopausal women. In this study, we aim to evaluate the association between FSH, luteinizing hormone (LH), and LH/FSH ratio values and the risk of insulin resistance (HOMA-IR >2.0), prediabetes (IFG), and type 2 diabetes in a 5-year prospective study in postmenopausal women. 114 postmenopausal women were divided into 4 groups: group 1 (baseline and follow-up normoglycemic women), group 2 (normoglycemic women at baseline progressing to IFG), group 3 (women with baseline and follow-up IFG), and group 4 (women with baseline IFG progressing to diabetes). Baseline and follow-up anthropometric measurements and blood collections were performed. Serum/plasma was assayed for glucose, HDL-C, TG, C-reactive protein (CRP), 17beta-estradiol, estrone, insulin, thyroid-stimulating hormone (TSH), FSH, and LH. Homeostatic model assessment of insulin resistance (HOMA-IR) and LH/FSH ratios were calculated. The baseline concentrations of FSH and LH statistically decreased across all four groups (the highest concentrations in group 1 and the lowest in group 4; p < 0.001). A logistic regression analysis showed that a 1 SD decrease in the z-score of FSH concentration is associated with a threefold increased risk of IFG and a fivefold increased risk of HOMA-IR of >2.0 and diabetes. The LH concentration had odds ratio (OR) values about two times lower than the FSH concentration. The ORs of the LH/FSH ratio were only significant for IFG. In conclusion, FSH concentration is strongly associated with insulin resistance, prediabetes, and diabetes in postmenopausal women with normal or impaired fasting glucose. LH and the LH/FSH ratio are also related to metabolic disturbances after menopause, yet to a lesser extent.

Aldosterone antagonist therapy and its relationship with inflammation, fibrosis, thrombosis, mineral-bone disorder and cardiovascular complications in peritoneal dialysis (PD) patients.

BACKGROUND: High aldosterone level may contribute to pathogenesis of hypertension, vessels damage and cardiovascular system deterioration in chronic kidney disease patients. Besides its classical action via mineralocorticoid receptor, aldosterone is also involved in cell growth, inflammation, oxidative stress, endothelial dysfunction and exerts fibroproliferative effects. The aim of the study was to assess whether aldosterone antagonist treatment may influence serum level of inflammatory, fibrosis, thrombosis and mineral-bone metabolism markers in peritoneal dialysis (PD) patients and blood pressure, aortic stiffness, echocardiographic indices after 12 months of treatment. METHODS: Twenty-two patients on PD were assigned to spironolactone treatment in dose of 50 mg daily during 12 months. Fifteen PD patients were assigned to control group. Echocardiographic indices, PVW, SBP, DBP (mean values from ABPM) and biochemical parameters such as: aldosterone, osteopontin, IL-6, selectin-P, TGF-ß, PTH, MMP-2 were performed at the beginning and after 12 months in spironolactone and control group. RESULTS: There were no statistically significant differences in echocardiographic indices, PWV, BP (ABPM readings) and biochemical markers: MMP-2, serum aldosterone, TGF-ß, IL-6, selectin-P, PTH level after 12 months of spironolactone treatment. There was statistically significant rise in osteopontin level after 12 months of spironolactone treatment. Episodes of life-threatening hyperkalemia were not reported. CONCLUSIONS: Aldosterone antagonists use in PD patients seems to be safe. Longer duration or higher dosage of spironolactone seems to be more effective in improving cardiovascular system status in PD patients. Further studies are required to determine relationship between mineralocorticoid receptor blockade and mineral-bone disturbances in PD patients.

Metabolic Syndrome and Menopause: Pathophysiology, Clinical and Diagnostic Significance.

Menopause is a risk factor for cardiometabolic diseases, including metabolic syndrome (MetS), type 2 diabetes, and cardiovascular diseases. MetS is a constellation of interdependent factors such as insulin resistance, abdominal obesity, dyslipidemia, and hypertension. The prevalence of MetS in postmenopause is due to loss of the protective role of estrogens and increased circulating androgens resulting in changes to body fat distribution and development of abdominal obesity. Excessive visceral adipose tissue plays an important role due to synthesis and secretion of bioactive substances such as adipocytokines, proinflammatory cytokines, reactive oxygen species, prothrombotic, and vasoconstrictor factors. MetS may also impact risk assessment of breast cancer, osteoporosis and chronic kidney disease, and quality of life during the menopausal transition. Increased MetS has stimulated the exploration of new laboratory tests for early detection and therapies.

Blocking retinoic acid receptor-α enhances the efficacy of a dendritic cell vaccine against tumours by suppressing the induction of regulatory T cells.

The immune system has evolved regulatory mechanisms to control immune responses to self-antigens. Regulatory T (Treg) cells play a pivotal role in maintaining immune tolerance, but tumour growth is associated with local immunosuppression, which can subvert effector immune responses. Indeed, the induction and recruitment of Treg cells by tumours is a major barrier in the development of effective immunotherapeutics and vaccines against cancer. Retinoic acid (RA) has been shown to promote conversion of naïve T cells into Treg cells. This study addresses the hypothesis that blocking RA receptor alpha (RARα) may enhance the efficacy of a tumour vaccine by inhibiting the induction of Treg cells. We found that RA significantly enhanced TGF-ß-induced expression of Foxp3 on naïve and committed T cells in vitro and that this was blocked by an antagonist of RARα (RARi). In addition, RARi significantly suppressed TGF-ß and IL-10 and enhanced IL-12 production by dendritic cells (DC) in response to killed tumour cells or TLR agonists. Furthermore, RARi augmented the efficacy of an antigen-pulsed and TLR-activated DC vaccine, significantly attenuating growth of B16 tumours in vivo and enhancing survival of mice. This protective effect was associated with significant reduction in tumour-infiltrating FoxP3(+) and IL-10(+) Treg cells and a corresponding increase in tumour-infiltrating CD4(+) and CD8(+) T cells that secreted IFN-γ. Our findings demonstrate that RARα is an important target for the development of effective anti-tumour immunotherapeutics and for improving the efficacy of cancer vaccines.

Decreased hypoxia-inducible factor-1α in gastrocnemius muscle in rats with chronic kidney disease.

BACKGROUND/AIMS: Hypoxia-inducible factor (HIF)-1α is responsible for increased expression of genes engaged in angiogenesis. Our previous study indicated capillary rarefaction and atrophy of glycolytic fibers, mainly in locomotor muscles of uremic animals. Perhaps these changes are secondary to disturbances of HIF-1α in skeletal muscles. METHODS: Expression of HIF-1α at mRNA and protein levels, as well as mRNA of vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor receptor (VEGFR)-1, VEGFR-2, endothelial nitric oxide synthase (eNOS) and inducible nitric oxide synthase (iNOS), in gastrocnemius muscle (MG) and longissimus thoracic muscle (ML) were measured by RT-PCR and Western blot. Rats were randomized to subtotal nephrectomy (CKD5/6), uninephrectomy (CKD1/2) or sham operation (controls). RESULTS: For CKD5/6 versus controls, mRNA levels for HIF-1α, VEGF-A, VEGFR-1 and VEGFR-2 were significantly reduced only in MG, while eNOS was significantly decreased and iNOS was significantly increased only in ML. Western blot analysis indicated significantly increased HIF-1α protein levels in MG and ML from CKD1/2 animals versus controls, whereas in the CKD5/6 group, the level of HIF-1α protein decreased significantly in MG and increased significantly in ML versus controls and CKD1/2. CONCLUSION: The reduced expression of HIF-1α mRNA and protein in locomotor muscle from CKD5/6 animals may be involved in the pathogenesis of uremic myopathy. Increased expression of iNOS in the postural muscles may act as a protective factor through HIF-1α stabilization.

Association of follicle-stimulating hormone and sex hormone binding globulin with the metabolic syndrome in postmenopausal women.

OBJECTIVES: We compared the association of follicle-stimulating hormone (FSH) and sex hormone binding globulin (SHBG) with metabolic syndrome (MetS). DESIGN AND METHODS: We examined 320 postmenopausal women (148 with MetS and 172 without MetS). RESULTS: FSH was more strongly associated with MetS probability in the logistic regression model compared to SHBG. Receiver operating characteristic (ROC) curves comparison showed greater areas under the curve for FSH than SHBG concentrations. CONCLUSIONS: FSH exhibited a stronger coherence to MetS than SHBG in postmenopausal women.

Heme oxygenase-1 inhibits myoblast differentiation by targeting myomirs.

AIMS: Heme oxygenase-1 (HMOX1) is a cytoprotective enzyme degrading heme to biliverdin, iron ions, and carbon monoxide, whose expression is induced in response to oxidative stress. Its overexpression has been suggested as a strategy improving survival of transplanted muscle precursors. RESULTS: Here we demonstrated that HMOX1 inhibits differentiation of myoblasts and modulates miRNA processing: downregulates Lin28 and DGCR8, lowers the total pool of cellular miRNAs, and specifically blocks induction of myomirs. Genetic or pharmacological activation of HMOX1 in C2C12 cells reduces the abundance of miR-1, miR-133a, miR-133b, and miR-206, which is accompanied by augmented production of SDF-1 and miR-146a, decreased expression of MyoD, myogenin, and myosin, and disturbed formation of myotubes. Similar relationships between HMOX1 and myomirs were demonstrated in murine primary satellite cells isolated from skeletal muscles of HMOX1(+/+), HMOX1(+/-), and HMOX1(-/-) mice or in human rhabdomyosarcoma cell lines. Inhibition of myogenic development is independent of antioxidative properties of HMOX1. Instead it is mediated by CO-dependent inhibition of c/EBPδ binding to myoD promoter, can be imitated by SDF-1, and partially reversed by enforced expression of miR-133b and miR-206. Control C2C12 myoblasts injected to gastrocnemius muscles of NOD-SCID mice contribute to formation of muscle fibers. In contrast, HMOX1 overexpressing C2C12 myoblasts form fast growing, hyperplastic tumors, infiltrating the surrounding tissues, and disseminating to the lungs. INNOVATION: We evidenced for the first time that HMOX1 inhibits differentiation of myoblasts, affects the miRNA processing enzymes, and modulates the miRNA transcriptome. CONCLUSION: HMOX1 improves the survival of myoblasts, but concurrently through regulation of myomirs, may act similarly to oncogenes, increasing the risk of hyperplastic growth of myogenic precursors.

Regulation of chemerin chemoattractant and antibacterial activity by human cysteine cathepsins.

Chemerin, a ligand for the G-protein coupled receptor chemokine-like receptor 1, requires C-terminal proteolytic processing to unleash its chemoattractant activity. Proteolytically processed chemerin selectively attracts specific subsets of immunoregulatory APCs, including chemokine-like receptor 1-positive immature plasmacytoid dendritic cells (pDC). Chemerin is predicted to belong to the structural cathelicidin/cystatin family of proteins composed of antibacterial polypeptide cathelicidins and inhibitors of cysteine proteinases (cystatins). We therefore hypothesized that chemerin may interact directly with cysteine proteases, and that it might also function as an antibacterial agent. In this article, we show that chemerin does not inhibit human cysteine proteases, but rather is a new substrate for cathepsin (cat) K and L. cat K- and L-cleaved chemerin triggered robust migration of human blood-derived pDC ex vivo. Furthermore, cat K- and L-truncated chemerin also displayed antibacterial activity against Enterobacteriaceae. Cathepsins may therefore contribute to host defense by activating chemerin to directly inhibit bacterial growth and to recruit pDC to sites of infection.

Chemerin and the recruitment of NK cells to diseased skin.

Natural killer (NK) cells play a major role in the initial control of many viral pathogens and in the rejection of tumors. Consistent with their roles as immune sentinels, NK cells are found in inflamed skin, including lichen planus, psoriasis and atopic dermatitis (AD) lesions. In oral lichen planus lesions, the recruitment as well as intradermal colocalization of NK cells and pDC (plasmacytoid dendritic cells) appear to be mediated by chemerin, a recently identified protein ligand for chemokine-like receptor 1 (CMKLR1), a chemoattractant receptor expressed by both cell types. Dendritic cells can regulate NK cell activity, and NK cells can regulate DC-mediated responses. Since chemerin was recently implicated in recruitment of pDC to psoriatic skin, in this work we determined whether chemerin facilitates interactions between NK and pDC in psoriatic plaques through controlling influx of NK cells to diseased skin. We demonstrate that circulating NK cells from normal donors as well as psoriasis and AD patients respond similarly in functional migration assays to chemerin. However, differences in the distribution of NK cells and pDC in skin lesions suggest that recruitment of both NK cells and pDC is unlikely to be controlled solely by chemerin.

Chronic obstructive pulmonary disease: evidence for an autoimmune component.

Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible limitation on pulmonary airflow associated with chronic inflammation and mucous hypersecretion (chronic bronchitis) and/or the pathological destruction of alveolar airspaces leading to emphysema. COPD, predominantly as a result of tobacco smoke exposure, represents the fourth leading cause of mortality worldwide and its prevalence is increasing. Despite this, much of the basic mechanisms which contribute to disease progression remain to be elucidated and current therapeutic approaches are, for the most part, based upon alleviating patient symptoms (bronchodilators) as opposed to treating the underlying pathological mechanisms triggered in response to cigarette smoke exposure. The classic disease paradigm suggests that an imbalance of pulmonary matrix proteases versus anti-proteases underlies the tissue destruction and inflammation associated with COPD. However, there is a growing appreciation of the complex and multifaceted nature of the pathological mechanisms associated with disease progression. Recently, there has been mounting evidence indicating that COPD patients exhibit many of the characteristics of a classical autoimmune response. We will discuss current evidence in support of this paradigm and outline how future therapeutic approaches may be tailored to address this.

Vascular endothelial growth factor-D transgenic mice show enhanced blood capillary density, improved postischemic muscle regeneration, and increased susceptibility to tumor formation.

Vascular endothelial growth factor-D (VEGF-D) has angiogenic and lymphangiogenic activity, but its biologic role has remained unclear because knockout mice showed no clear phenotype. Transgenic (TG) mice expressing the mature form of human VEGF-D (hVEGF-D) were produced by lentiviral (LV) transgenesis using the perivitelline injection method. Several viable founders showed a macroscopically normal phenotype and the transgene transmitted through germ line. Expression of hVEGF-D mRNA was high in skeletal muscles, skin, pancreas, heart, and spleen. A significant increase was found in capillary density of skeletal muscles and myocardium, whereas no changes were observed in lymphatic capillary density. After induction of hindlimb ischemia, the TG mice showed enhanced capacity for muscle regeneration. However, on aging the TG mice had significantly increased mortality from malignant tumors, of which half were breast adenocarcinomas characterized with the absence of periductal muscle cells. Some tumors metastasized into the lungs. In addition, lung and skin tumors were found, but no blood- or lymphatic vessel-derived malignancies were detected. We conclude that in mice hVEGF-D is an angiogenic factor associated with improved muscle regeneration after ischemic injury but also with increased incidence of tumor formation with a preference for mammary gland tumors.

Influence of different stages of experimental chronic kidney disease on rats locomotor and postural skeletal muscles microcirculation.

BACKGROUND: Chronic kidney disease (CKD) is associated with muscle excess fatigue and diminished maximal whole body oxygen consumption, which in part could be depended on poor muscle microcirculatory network. The aim of this study was to assume the influence of different stages of CKD on microcirculation vessels in functionally different skeletal muscles--locomotor, the gastrocnemius muscle, and postural, the longissimus thoracis muscle. METHODS: Male Wistar rats underwent sham operation (CON), uninephrectomy (CKD 1/2) and subtotal nephrectomy (CKD 5/6). Muscle samples were stained for an alkaline phosphatase to differentiate capillaries. The number of capillaries was estimated by a single observer in 10 microm transverse sections by point counting at a magnification of x 125 using an Image Analysis System Q 500 MC of Leica. Blood pressure and serum creatinine, haptoglobin, MCP-1, VEGF, and PDGF were measured. RESULTS: There were significant differences (p < 0.05) in CD (number of capillaries per 1 mm(2) of muscle tissue), C:F (capillary to fiber ratio), and CC/F (capillary contact per fiber). The CKD 1/2 group in gastrocnemius and longissimus muscle had 53% and 33% lower C:F; 56% and 33% lower CD; and 44% and 20% less CC/F than CON, respectively. The CKD 5/6 group in gastrocnemius and longissimus muscle had 46% and 20% lower C:F; 47% and 11% lower CD; and 48% and 25% less CC/F versus control, respectively. Blood pressure was higher in CKD 5/6 vs. CKD 1/2 and CON (145/95 vs. 107/87 and 119/77 mmHg, p < 0.05, respectively). CKD 5/6 had higher creatinine than CKD 1/2 and CON (1.22 vs. 0.83 and 0.74 mg/dL, p < 0.05, respectively). Haptoglobin was higher in CKD 1/2 and CKD 5/6 versus CON (1.68 and 1.63 vs. 0.70 mg/mL, p < 0.05, respectively). MCP-1 was higher in CKD 5/6 and CKD 1/2 versus CON (609 and 489 vs. 292 pg/mL, p < 0.05, respectively). There were no significant differences in serum growth factors concentration between groups. CONCLUSION: Capillary rarefaction is present in early stages of CKD. These changes are independent of blood pressure and progression of CKD. We suspected that muscle function has a big impact on microvasculature as capillaries rarefaction has been reduced more in locomotor than postural skeletal muscle.