Therapeutic effects of inorganic nitrate and nitrite in cardiovascular and metabolic diseases

Abstract

Nitric oxide (NO) is generated endogenously by NO synthases to regulate a number of physiological processes including cardiovascular and metabolic functions. A decrease in the production and bioavailability of NO is a hallmark of many major chronic diseases including hypertension, ischaemia–reperfusion injury, atherosclerosis and diabetes. This NO deficiency is mainly caused by dysfunctional NO synthases and increased scavenging of NO by the formation of reactive oxygen species. Inorganic nitrate and nitrite are emerging as substrates for in vivo NO synthase-independent formation of NO bioactivity. These anions are oxidation products of endogenous NO generation and are also present in the diet, with green leafy vegetables having a high nitrate content. The effects of nitrate and nitrite are diverse and include vasodilatation, improved endothelial function, enhanced mitochondrial efficiency and reduced generation of reactive oxygen species. Administration of nitrate or nitrite in animal models of cardiovascular disease shows promising results, and clinical trials are currently ongoing to investigate the therapeutic potential of nitrate and nitrite in hypertension, pulmonary hypertension, peripheral artery disease and myocardial infarction. In addition, the nutritional aspects of the nitrate–nitrite–NO pathway are interesting as diets suggested to protect against cardiovascular disease, such as the Mediterranean diet, are especially high in nitrate. Here, we discuss the potential therapeutic opportunities for nitrate and nitrite in prevention and treatment of cardiovascular and metabolic diseases.

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Intake of Meals Containing High Levels of Carbohydrates or High Levels of Unsaturated Fatty Acids Induces Postprandial Dysmetabolism in Young Overweight/Obese Men

Postprandial metabolic response depends on the meals' components and can be different in normal weight and obese people. However, there are some discrepancies between various reports. The aim of this study was to determine the metabolic response after intake of standardised meals with various fat and carbohydrate contents and to determine the differences among normal weight and overweight/obese individuals. The study group comprised 46 healthy men. The participants were divided into two groups and study was carried out using a crossover method. Group I received high- and normal-carbohydrate meals, whereas group II received high-carbohydrate and high-fat meals. Glucose, insulin, triglyceride, and free fatty acids levels were measured at fasting state and at 30, 60, 120, 180, and 240 minutes after meal intake. Despite the lack of differences in glucose levels, insulin levels were higher among overweight/obese individuals after each meal. TG and FFA levels were higher after normal-carbohydrate and high-fat meals. Moreover, in overweight/obese young men after high-fat meal intake postprandial hypertriglyceridemia was observed, even if meals contained predominantly unsaturated fatty acids, and fasting triglycerides levels were in normal range. The conducted study showed that postprandial metabolic response depends not only on the meal macronutrient content but also on the current body mass index (BMI).

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Production of high titer attenuated poliovirus strains on the serum-free PER.C6® cell culture platform for the generation of safe and affordable next generation IPV

Publication date: Available online 1 November 2015
Source:Vaccine
Author(s): Barbara P. Sanders, Isabel de los Rios Oakes, Vladimir van Hoek, Ying Liu, Wilfred Marissen, Philip D. Minor, Eckard Wimmer, Hanneke Schuitemaker, Jerome H.H.V. Custers, Andrew Macadam, Jeronimo Cello, Diana Edo-Matas
BackgroundAs poliovirus eradication draws closer, alternative Inactivated Poliovirus Vaccines (IPV) are needed to overcome the risks associated with continued use of the Oral Poliovirus Vaccine and of neurovirulent strains used during manufacture of conventional (c) IPV. We have previously demonstrated the susceptibility of the PER.C6^® cell line to cIPV strains; here we investigated the suspension cell culture platform for growth of attenuated poliovirus strains.MethodsWe examined attenuated Sabin strain productivity on the PER.C6^® cell platform compared to the conventional Vero cell platform. The suitability of the suspension cell platform for propagation of rationally-attenuated poliovirus strains (stabilized Sabin type 3 S19 derivatives and genetically attenuated and stabilized MonoCre(X) strains), was also assessed. Yields were quantified by infectious titer determination and D-antigen ELISA using either serotype-specific polyclonal rabbit sera for Sabin strains or monoclonal cIPV-strain-specific antibodies for cIPV, S19 and MonoCre(X) strains.ResultsPER.C6^® cells supported the replication of Sabin strains to yields of infectious titers that were in the range of cIPV strains at 32.5°C. Sabin strains achieved 30-fold higher yields (p<0.0001) on the PER.C6^® cell platform as compared to the Vero cell platform in infectious titer and D-antigen content. Furthermore, Sabin strain productivity on the PER.C6^® cell platform was maintained at 10l scale. Yields of infectious titers of S19 and MonoCre(X) strains were 0.5–1 log10 lower than seen for cIPV strains, whereas D-antigen yield and productivities in doses/ml using rationally-attenuated strains were in line with yields reported for cIPV strains.ConclusionsSabin and rationally-attenuated polioviruses can be grown to high infectious titers and D-antigen yields. Sabin strain infection shows increased productivity on the PER.C6^® cell platform as compared to the conventional Vero cell platform. Novel cell platforms with the potential for higher yields could contribute to increased affordability of a next generation of IPV vaccines needed for achieving and maintaining poliovirus eradication.



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Pediatric provider vaccine hesitancy: An under-recognized obstacle to immunizing children

Publication date: Available online 1 November 2015
Source:Vaccine
Author(s): Manika Suryadevara, Andrew Handel, Cynthia A. Bonville, Donald A. Cibula, Joseph B. Domachowske
ObjectiveTo describe vaccine attitudes among pediatric healthcare providers attending immunization conferences.Study designAttendees of 5 American Academy of Pediatrics (AAP)-sponsored vaccine conferences held between June and November 2013 anonymously completed a questionnaire assessing vaccine attitudes and practices prior to the opening of educational sessions. Pearson's chi-square tests and Fisher's exact tests were used to analyze associations between vaccine attitudes, vaccine practices and provider characteristics.Results680 providers attending AAP-sponsored vaccine conferences were included. 661/666 (99%) enrolled providers state they routinely recommend standard pediatric vaccines, yet, 30 (5%) state that they do not routinely recommend influenza and/or human papillomavirus (HPV) vaccines. These providers expressed vaccine safety (87/680 (13%)) and efficacy (21/680 (31%)) concerns and stated belief in vaccine misperceptions: vaccine causes autism (34/668, 5%), multiple vaccines at a single visit reduces vaccine efficacy (43/680, 6%) or overwhelms the immune system (63/680, 9%), and administering HPV vaccine will increase the likelihood of unprotected adolescent sexual activity (29/680, 4%). Six percent of providers who do not routinely recommend all pediatric vaccines correctly identified themselves as vaccine hesitant.ConclusionVaccine hesitancy is under-recognized among pediatric providers attending AAP-sponsored immunization conferences. Educational interventions tailored to address provider vaccine concerns are needed to improve provider vaccine confidence.



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Non-thermal plasma for inactivated-vaccine preparation

Publication date: Available online 1 November 2015
Source:Vaccine
Author(s): Guomin Wang, Ruihao Zhu, Licong Yang, Kaile Wang, Qian Zhang, Xia Su, Bing Yang, Jue Zhang, Jing Fang
Vaccines are of great importance in controlling the spread of infectious diseases in poultry farming. The safety and efficacy of vaccines are also essential. To explore the feasibility of a novel technology (non-thermal plasma) in inactivated vaccine preparation, an alternating current atmospheric pressure non-thermal plasma (NTP) jet with Ar/O2/N2 as the operating gas was used to inactivate a Newcastle disease virus (NDV, LaSota) strain and H9N2 avian influenza virus (AIV, A/Chicken/Hebei/WD/98) for vaccine preparation. The results showed that complete inactivation could be achieved with 2min of NTP treatment for both NDV and AIV. Moreover, a proper NTP treatment time is needed for inactivation of a virus without destruction of the antigenic determinants. Compared to traditional formaldehyde-inactivated vaccine, the vaccine made from NDV treated by NTP for 2min (NTP-2min-NDV-vaccine) could induce a higher NDV-specific antibody titer in specific pathogen-free (SPF) chickens, and the results of a chicken challenge experiment showed that NTP-2min-NDV-vaccine could protect SPF chickens from a lethal NDV challenge. Vaccines made from AIV treated by NTP for 2min (NTP-2min-AIV-vaccine) also showed a similar AIV-specific antibody titer compared with traditional AIV vaccines prepared using formaldehyde inactivation. Studies of the morphological changes of the virus, chemical analysis of NDV allantoic fluid and optical emission spectrum analysis of NTP suggested that reactive oxygen species and reactive nitrogen species produced by NTP played an important role in the virus inactivation process. All of these results demonstrated that it could be feasible to use non-thermal NTP as an alternative strategy to prepare inactivated vaccines for Newcastle disease and avian influenza.



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Assessment of the enhancement of PLGA nanoparticle uptake by dendritic cells through the addition of natural receptor ligands and monoclonal antibody

Publication date: Available online 1 November 2015
Source:Vaccine
Author(s): Adam A. Walters, Satyanarayana Somaravarapu, Victor Riitho, Graham R. Stewart, Bryan Charleston, Falko Steinbach, Simon P. Graham
Targeting of specific receptors on antigen-presenting cells is an appealing prospect in the production of novel nanoparticulate vaccines. In particular, the targeting of vaccines to dendritic cell (DC) subsets has been shown in models to significantly improve the induction of immune responses. This paper describes the evaluation of natural ligands, mannan and chitosan, and monoclonal antibodies as targeting motifs to enhance uptake of PLGA nanoparticle carriers by bovine DCs. To assess enhancement of uptake after the addition of natural ligands a bovine monocyte derived DC (MoDC) model was used. For the assessment of monoclonal antibody targeting, the model was expanded to include afferent lymph DCs (ALDCs) in a competitive uptake assay. Mannan, proved unsuccessful at enhancing uptake or targeting by MoDCs. Chitosan coated particle uptake could be impeded by the addition of mannan suggesting uptake may be mediated through sugar receptors. Inclusion of monoclonal antibodies specific for the DEC-205 (CD205) receptor increased the number of receptor expressing DCs associated with particles as well as the number of particles taken up by individual cells. These results support the further evaluation of active targeting of nanovaccines to DCs to enhance their immunogenicity in cattle and other large mammalian species including humans.



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Intranasal immunisation with recombinant adenovirus vaccines protects against a lethal challenge with pneumonia virus of mice

Publication date: Available online 1 November 2015
Source:Vaccine
Author(s): Helen E. Maunder, Geraldine Taylor, Keith N. Leppard, Andrew J. Easton
Pneumonia virus of mice (PVM) infection of BALB/c mice induces bronchiolitis leading to a fatal pneumonia in a dose-dependent manner, closely paralleling the development of severe disease during human respiratory syncytial virus infection in man, and is thus a recognised model in which to study the pathogenesis of pneumoviruses. This model system was used to investigate delivery of the internal structural proteins of PVM as a potential vaccination strategy to protect against pneumovirus disease. Replication-deficient recombinant human adenovirus serotype 5 (rAd5) vectors were constructed that expressed the M or N gene of PVM pathogenic strain J3666. Intranasal delivery of these rAd5 vectors gave protection against a lethal challenge dose of PVM in three different mouse strains, and protection lasted for at least 20 weeks post-immunisation. Whilst the PVM-specific antibody response in such animals was weak and inconsistent, rAd5N primed a strong PVM-specific CD8⁺ T cell response and, to a lesser extent, a CD4⁺ T cell response. These findings suggest that T-cell responses may be more important than serum IgG in the observed protection induced by rAd5N.



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Randomized comparison of the safety of Flublok® versus licensed inactivated influenza vaccine in healthy, medically stable adults ≥50 years of age

Publication date: Available online 1 November 2015
Source:Vaccine
Author(s): Ruvim Izikson, David J. Leffell, S. Allan Bock, Peter A. Patriarca, Penny Post, Lisa M. Dunkle, Manon M.J. Cox
BackgroundThe safety and tolerability of Flublok^®, a purified recombinant hemagglutinin seasonal influenza vaccine, was compared to AFLURIA^® in a randomized, blinded clinical trial in adults ≥50 years of age with attention to hypersensitivity reactions.MethodsThis blinded, randomized trial of healthy adults ≥50 years of age compared safety of Flublok vs. AFLURIA with respect to pre-specified possible hypersensitivity: "rash," "urticaria," "swelling" and "non-dependent edema;" solicited reactogenicity and unsolicited adverse events. Subject-reported outcomes were collected for 30 days after vaccination. All adverse event terms were reviewed by physicians blinded to vaccine group, who added other terms possibly reflecting hypersensitivity. Case records of subjects with possible hypersensitivity were adjudicated by independent experts blinded to treatment assignment to identify likely hypersensitivity reactions. Non-inferiority of the incidence of hypersensitivity in the two vaccine groups was pre-defined as an absolute difference with an upper bound of 2-sided 95% confidence limits ≤0.015.ResultsA total of 2640 subjects were enrolled, evenly split in age cohorts of 50–64 and ≥65 years. Fifty-two subjects reported at least one term possibly representing hypersensitivity, with a slight imbalance of 31 on Flublok and 21 on AFLURIA. The adjudicators determined that six and four subjects on Flublok and AFLURIA, respectively, likely met clinical criteria for hypersensitivity, yielding a difference in incidence between the two vaccine groups of 0.15% (upper bound of 2-sided 95% CI=0.9%). Reactogenicity and overall adverse event profiles were similar across both vaccines.ConclusionsFlublok was non-inferior to AFLURIA in adults ≥50 years of age with respect to expert-adjudicated events of likely hypersensitivity during 30 days following vaccination (Sponsored by Protein Sciences Corporation; ClinicalTrials.gov number NCT01825200).



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Incidence of invasive pneumococcal disease in 5–15 year old children with and without comorbidities in Germany after the introduction of PCV13: Implications for vaccinating children with comorbidities

Publication date: Available online 1 November 2015
Source:Vaccine
Author(s): Raphael Weinberger, Gerhard Falkenhorst, Christian Bogdan, Mark van der Linden, Matthias Imöhl, Rüdiger von Kries
ObjectiveTo describe the burden of suffering from IPD in children aged 5–15 years with and without comorbidities up to 5 years after the introduction of PCV13 in Germany and to identify the potential benefit for PCV13 and PPV23 vaccination.MethodsThe surveillance of IPD for children <16 years was based on two independently reporting sources: active surveillance in pediatric hospitals and a laboratory-based sentinel surveillance system. Case definition: IPD with cultural detection of pneumococci at a physiologically sterile site in children from 2010 to 2014 in Germany. Incidence was estimated by capture–recapture analysis with stratification by absence/presence of comorbidities. Coverage of the observed serotypes by different vaccines was assessed.Results142 (Capture recapture-corrected: 437) cases were reported: 72.5% were healthy children and 27.5% had a comorbidity. The incidence of IPD related to children with comorbidities was 0.2 per 100,000. One third of these cases had serotypes not included in either vaccine. The remaining cases might benefit from pneumococcal vaccination but one third of all cases was not vaccinated. The additional potential benefit of PPV23 compared to PCV13 with respect to coverage was 10%.ConclusionThe incidence of IPD in children with comorbidities in Germany is low. Pneumococcal vaccination uptake in children with comorbidities should be increased, although only about two-thirds of the cases might be preventable by presently available vaccines.



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The bm12 Inducible Model of Systemic Lupus Erythematosus (SLE) in C57BL/6 Mice

The transfer of bm12 lymphocytes into a C57BL/6 recipient is an established model of systemic lupus erythematosus. Here we describe how to initiate disease using this model and how to characterize T follicular helper cells, germinal center B cells and plasma cells by flow cytometry.

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Strength training, but not endurance training, reduces motor unit discharge rate variability

Publication date: Available online 31 October 2015
Source:Journal of Electromyography and Kinesiology
Author(s): Carolina Vila-Chã, Deborah Falla
This study evaluates and compares the effects of strength and endurance training on motor unit discharge rate variability and force steadiness of knee extensor muscles. Thirty sedentary healthy men (age, 26.0 ± 3.8 yrs) were randomly assigned to strength training, endurance training or a control group. Conventional endurance and strength training was performed 3 days per week, over a period of 6 weeks. Maximum voluntary contraction (MVC), time to task failure (at 30% MVC), coefficient of variation (CoV) of force and of the discharges rates of motor units from the vastus medialis obliquus and vastus lateralis were determined as subjects performed 20 and 30% MVC knee extension contractions before and after training. CoV of motor unit discharges rates was significantly reduced for both muscles following strength training (P<0.001), but did not change in the endurance (P=0.875) or control groups (P=0.995). CoV of force was reduced after the strength training intervention only (P<0.01). Strength training, but not endurance training, reduces motor unit discharge rate variability and enhances force steadiness of the knee extensors. These results provide new insights into the neuromuscular adaptations that occur with different training methods.



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Factors to consider in identifying critical points in lumbar spine flexion relaxation

Publication date: Available online 31 October 2015
Source:Journal of Electromyography and Kinesiology
Author(s): Derek P. Zwambag, Stephen H.M. Brown
Flexion relaxation (FR), a myoelectric silence of extensor muscles near end range of lumbar flexion, is commonly reported as the lumbar flexion angle at the instant the extensor muscles become silent. However, lumbar flexion angle alone is insufficient to characterize mechanisms that modulate FR. As FR requires the moment generated by passive lumbar extensor tissues to equilibrate the moment due to gravity, the inter-relationships between lumbar moment, flexion angle, and myoelectrical silence will provide added information in the understanding of FR. The purpose of this study was to examine the relationship between lumbar moment and flexion angle throughout various flexion manoeuvres. It was hypothesized that lumbar moment and flexion angle would not be linearly related and would be affected by lower limb position, range of motion, and the addition of mass to the torso. Eleven participants performed four different lumbar flexion trials. Results showed that lumbar flexion was correlated with the lumbar moment (r=0.92); however an analysis of residuals found that these measures were not linearly related. The moment was, however, correlated (r=0.99) and linearly related to the sine of trunk inclination (T12 rigid body with respect to global horizontal). Future studies of FR could use trunk inclination as a simple kinematic measure to predict relative changes in lumbar moment with flexion.



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Nanoparticle Probes for Structural and Functional Photoacoustic Molecular Tomography

Nowadays, nanoparticle probes have received extensive attention largely due to its potential biomedical applications in structural, functional, and molecular imaging. In addition, photoacoustic tomography (PAT), a method based on the photoacoustic effect, is widely recognized as a robust modality to evaluate the structure and function of biological tissues with high optical contrast and high acoustic resolution. The combination of PAT with nanoparticle probes holds promises for detecting and imaging diseased tissues or monitoring their treatments with high sensitivity. This review will introduce the recent advances in the emerging field of nanoparticle probes and their preclinical applications in PAT, as well as relevant perspectives on future development.

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Reducing sitting time after stroke. A Phase II safety and feasibility randomised controlled trial

Publication date: Available online 31 October 2015
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Coralie English, Genevieve N. Healy, Tim Olds, Gaynor Parfitt, Erika Borkoles, Alison Coates, Sharon Kramer, Julie Bernhardt
ObjectiveTo test the safety, feasibility and effectiveness of reducing sitting time in stroke survivors.DesignRandomised controlled trial with attention-matched control and blinded assessments.SettingCommunityParticipantsThirty-five stroke survivors (22 male, mean age 66.9 ± 12.7 years).InterventionsFour counselling sessions over seven weeks with a message of 'sit less, move more' (intervention group) or 'calcium for bone health' (attention-matched control group).Main outcome measuresSafety (adverse events, increases in pain, spasticity or fatigue) and feasibility (adherence to trial protocol). Secondary measures included time spent sitting (including in prolonged bouts ≥30mins), standing, and stepping as measured by the thigh-worn activPAL3 activity monitor (7 days, 24hrs/day protocol) and time spent in physical activity of at least moderate intensity as measured by the actigraph GT3x+. The Multi-Media Activity Recall for Children and Adults (MARCA) was used to describe changes in use-of-time.ResultsThirty-three participants completed the full protocol. Four participants reported falls during the intervention period with no other adverse events. From a baseline average of 640.7 (SD 99.6) min/day, daily sitting time reduced on average by 30.0 (SD 50.6) min/day (95% CI 5.8 to 54.6) in the intervention group and 40.4 (SD 92.5) min/day in the control group (95% CI 13.0 to 93.8). Participants in both groups also reduced their time spent in prolonged sitting bouts (≥30 minutes) and increased time spent standing and stepping.ConclusionsOur protocol was both safe and feasible. Participants in both groups spent less time sitting and more time standing and stepping post-intervention, but outcomes were not superior for intervention participants. Attention-matching is desirable in clinical trials, and may have contributed to the positive outcomes for control participants.



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A Cross-Sectional Examination of the Associations Between Symptoms, Community Integration, and Mental Health in Multiple Sclerosis

Publication date: Available online 31 October 2015
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Anna L. Kratz, Dawn M. Ehde, Marisol A. Hanley, Mark P. Jensen, Travis L. Osborne, George H. Kraft
ObjectiveTo determine the frequency and severity of eight symptoms in persons with multiple sclerosis (MS) and to examine the association between these symptoms and community integration and mental health.DesignA cross-sectional survey that assessed eight symptoms (pain, fatigue, imbalance, numbness, weakness, shortness of breath, vision loss, and memory loss), disease progression (the self-report version of the Expanded Disability Status Scale; EDSS), community integration, and mental health.SettingCommunity.Participants180 adults with self-reported MS who responded to a mailed survey.InterventionsNot applicable.Main Outcome MeasuresThe presence and intensity of symptoms were measured with a symptoms checklist. Community integration was assessed with the Community Integration Questionnaire and mental health was measured by the Mental Health Index of the Short Form Health Survey-36.ResultsThe average number of symptoms reported was 5.07 (SD = 2.18). The most common symptoms - fatigue, weakness, and imbalance - were also rated as most severe. Not all symptoms were associated with level of disease progression or with MS subtype. Symptoms related to mobility were more likely to be associated with these variables. The eight symptoms as a whole accounted for significant amounts of variance (ranging from 13% to 21%) in measures of community integration and mental health, with specific symptoms made differential independent contributions to these measures.ConclusionsThis study demonstrates that most individuals with MS report a number of bothersome symptoms. Type of MS or level of progression does not tell the whole story regarding the impact of symptoms.



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Isoflurane Damages the Developing Brain of Mice and Induces Subsequent Learning and Memory Deficits through FASL-FAS Signaling

Background. Isoflurane disrupts brain development of neonatal mice, but its mechanism is unclear. We explored whether isoflurane damaged developing hippocampi through FASL-FAS signaling pathway, which is a well-known pathway of apoptosis. Method. Wild type and FAS- or FASL-gene-knockout mice aged 7 days were exposed to either isoflurane or pure oxygen. We used western blotting to study expressions of caspase-3, FAS (CD95), and FAS ligand (FASL or CD95L) proteins, TUNEL staining to count apoptotic cells in hippocampus, and Morris water maze (MWM) to evaluate learning and memory. Result. Isoflurane increased expression of FAS and FASL proteins in wild type mice. Compared to isoflurane-treated FAS- and FASL-knockout mice, isoflurane-treated wild type mice had higher expression of caspase-3 and more TUNEL-positive hippocampal cells. Expression of caspase-3 in wild isoflurane group, wild control group, FAS/FASL-gene-knockout control group, and FAS/FASL-gene-knockout isoflurane group showed FAS or FASL gene knockout might attenuate increase of caspase-3 caused by isoflurane. MWM showed isoflurane treatment of wild type mice significantly prolonged escape latency and reduced platform crossing times compared with gene-knockout isoflurane-treated groups. Conclusion. Isoflurane induces apoptosis in developing hippocampi of wild type mice but not in FAS- and FASL-knockout mice and damages brain development through FASL-FAS signaling.

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Prognostic Significance of the Tumor-Stroma Ratio in Epithelial Ovarian Cancer

Tumor-stroma ratio (TSR) has recently been identified as a promising prognostic parameter for several solid tumors. This study aimed to evaluate the prognostic role of TSR in epithelial ovarian cancer (EOC) and 838 EOC patients were enrolled in this study. TSR was estimated on hematoxylin-and-eosin-stained tissue sections from the most invasive part of the primary tumor. Patients were classified as stroma-rich or stroma-poor according to the proportion of stroma ≥50% or

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Effectiveness and Safety of Manufactured Chinese Herbal Formula for Knee Osteoarthritis: Insights from a Systematic Review

Objective. To assess the current clinical evidence of manufactured Chinese herbal formulae (MCHF) for knee osteoarthritis (KOA). Methods. Seven databases were searched from inception to May 2015. Eligible randomized controlled trials investigating the effectiveness of MCHF for KOA were included. Data extraction, methodological assessment, and meta-analyses were conducted according to the Cochrane standards. Results. A total of 17 kinds of MCHF were identified from the twenty-six included trials. Meta-analyses showed that MCHF significantly relieved the global pain of knee joints, either used alone or combined with routine treatments. Additionally, MCHF plus routine treatments significantly decreased the scores of WOMAC and Lequesne index. However, there were no statistical differences between MCHF group and routine treatment group in walk-related pain and WOMAC scores. No significant differences were found in Lysholm scores. There were twenty-one trials that mentioned adverse events. A pooled analysis showed that adverse events occurred more frequently in control group compared with MCHF group. Conclusions. Our results indicated that MCHF showed some potential benefits for KOA. However, we still cannot draw firm conclusions due to the poor methodological quality of included trials. More high-quality RCTs would help to confirm the evidence.

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The Combination of Resveratrol and Quercetin Attenuates Metabolic Syndrome in Rats by Modifying the Serum Fatty Acid Composition and by Upregulating SIRT 1 and SIRT 2 Expression in White Adipose Tissue

Resveratrol (RSV) and quercetin (QRC) modify energy metabolism and reduce cardiovascular risk factors included in the metabolic syndrome (MetS). These natural compounds upregulate and activate sirtuins (SIRTs), a family of NAD-dependent histone deacetylases. We analyzed the effect of two doses of a commercial combination of RSV and QRC on serum fatty acid composition and their regulation of SIRTs 1–3 and PPAR-γ expression in white adipose tissue. MetS was induced in Wistar rats by adding 30% sucrose to drinking water for five months. Rats were divided into control and two groups receiving the two different doses of RSV and QRC in drinking water daily for 4 weeks following the 5 months of sucrose treatment. Commercial kits were used to determine serum parameters and the expressions of SIRTs in WAT were analysed by western blot. In MetS rats body mass, central adiposity, insulin, triglycerides, non-HDL-C, leptin, adiponectin, monounsaturated fatty acids (MUFAs), and nonesterified fatty acids (NEFAs) were increased, while polyunsaturated fatty acids (PUFAs) and HDL-C were decreased. SIRT 1 and SIRT 2 were downregulated, while PPAR-γ was increased. RSV + QRC administration improved the serum health parameters modified by MetS and upregulate SIRT 1 and SIRT 2 expression in white abdominal tissue in MetS animals.

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MR Prediction of Liver Function and Pathology Using Gd-EOB-DTPA: Effect of Liver Volume Consideration

Purpose. To evaluate whether the diagnostic performance of Gd-EOB-DTPA-enhanced MRI in evaluating liver function and pathology is improved by considering liver volume (LV). Methods. This retrospective study included 104 patients who underwent Gd-EOB-DTPA-enhanced MRI before liver surgery. For each patient, using the precontrast and hepatobiliary phase images, we calculated the increase rate of the liver-to-spleen signal intensity ratio (LSR), that is, the "ΔLSR," and the increase rate of the liver-to-muscle signal intensity ratio (LMR), that is, the "ΔLMR." ΔLSR × LV and ΔLMR × LV were also calculated. The correlation of each MR parameter with liver function data or liver pathology was assessed. The correlation coefficients were compared between ΔLSR (ΔLMR) and ΔLSR (ΔLMR) × LV. Results. The correlation coefficient between ΔLSR (ΔLMR) × LV and cholinesterase was significantly higher than that between ΔLSR (ΔLMR) and cholinesterase. The correlation coefficient between ΔLSR (ΔLMR) × LV and the degree of fibrosis or necroinflammatory activity was significantly lower than that between ΔLSR (ΔLMR) and the degree of fibrosis or necroinflammatory activity. Conclusion. The inclusion of liver volume may improve Gd-EOB-DTPA-based predictions of liver function, but not in predictions of liver pathology.

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Magnetic Resonance Imaging as a Biomarker for Renal Cell Carcinoma

As the most common neoplasm arising from the kidney, renal cell carcinoma (RCC) continues to have a significant impact on global health. Conventional cross-sectional imaging has always served an important role in the staging of RCC. However, with recent advances in imaging techniques and postprocessing analysis, magnetic resonance imaging (MRI) now has the capability to function as a diagnostic, therapeutic, and prognostic biomarker for RCC. For this narrative literature review, a PubMed search was conducted to collect the most relevant and impactful studies from our perspectives as urologic oncologists, radiologists, and computational imaging specialists. We seek to cover advanced MR imaging and image analysis techniques that may improve the management of patients with small renal mass or metastatic renal cell carcinoma.

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Endogenous Ouabain: An Old Cardiotonic Steroid as a New Biomarker of Heart Failure and a Predictor of Mortality after Cardiac Surgery

Cardiovascular diseases remain the main cause of mortality and morbidity worldwide; primary prevention is a priority for physicians. Biomarkers are useful tools able to identify high-risk individuals, guide treatments, and determine prognosis. Our aim is to investigate Endogenous Ouabain (EO), an adrenal stress hormone with hemodynamic effects, as a valuable biomarker of heart failure. In a population of 845 patients undergoing elective cardiac surgery, we have investigated the relationships between EO and echocardiography parameters/plasmatic biomarker of cardiac function. EO was found to be correlated negatively with left ventricular EF (), positively with Cardiac End-Diastolic Diameter (), and positively with plasmatic NT-proBNP level (). Moreover, a different plasmatic EO level (both preoperative and postoperative) was found according to NYHA class (). All these results have been replicated on an independent cohort of patients (147 subjects from US). Finally, a higher EO level in the immediate postoperative time was indicative of a more severe cardiological condition and it was associated with increased perioperative mortality risk ( for 30-day morality). Our data suggest that preoperative and postoperative plasmatic EO level identifies patients with a more severe cardiovascular presentation at baseline. These patients have a higher risk of morbidity and mortality after cardiac surgery.

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Novel Sensor-Enabled Ex Vivo Bioreactor: A New Approach towards Physiological Parameters and Porcine Artery Viability

The aim of the present work is to design and construct an ex vivo bioreactor system to assess the real time viability of vascular tissue. Porcine carotid artery as a model tissue was used in the ex vivo bioreactor setup to monitor its viability under physiological conditions such as oxygen, pressure, temperature, and flow. The real time tissue viability was evaluated by monitoring tissue metabolism through a fluorescent indicator "resorufin." Our ex vivo bioreactor allows real time monitoring of tissue responses along with physiological conditions. These ex vivo parameters were vital in determining the tissue viability in sensor-enabled bioreactor and our initial investigations suggest that, porcine tissue viability is considerably affected by high shear forces and low oxygen levels. Histological evaluations with hematoxylin and eosin and Masson's trichrome staining show intact endothelium with fresh porcine tissue whereas tissues after incubation in ex vivo bioreactor studies indicate denuded endothelium supporting the viability results from real time measurements. Hence, this novel viability sensor-enabled ex vivo bioreactor acts as model to mimic in vivo system and record vascular responses to biopharmaceutical molecules and biomedical devices.

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Coevolution between Cancer Activities and Food Structure of Human Being from Southwest China

Yunnan and Tibet are the lowest cancer mortality and the largest producer for anticancer crops (brown rice, barley, buckwheat, tea, walnut, mushrooms, and so forth). Shanghai and Jiangsu province in China have the highest mortality of cancers, which are associated with the sharp decline of barley.

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Upconversion nanosensor for sensitive fluorescence detection of Sudan I–IV based on inner filter effect

Publication date: 1 February 2016
Source:Talanta, Volume 148
Author(s): Aijin Fang, Qian Long, Qiongqiong Wu, Haitao Li, Youyu Zhang, Shouzhuo Yao
Sudan dyes are banned as food additives due to the carcinogenicity of their metabolites in the human body. Therefore, it is of great significance for sensitive detection of Sudan dyes. This paper reports a novel nanosensor for Sudan dyes detection based on fluorescence (FL) quenching of hexadecyl trimethyl ammonium bromide (CTAB) stabilized upconversion nanoparticles (UCNPs) through the inner filter effect (IFE). In the presence of Sudan I–IV, the fluorescence emission of UCNPs was effectively quenched due to the absorption bands of Sudan I–IV largely covered the emission bands of UCNPs. Under the optimized conditions, the FL was quenched with Sudan concentration over the range of 0.05–40, 0.01–20, 0.01–40 and 0.05–40μg/mL for Sudan I–IV, respectively. The corresponding limit of detection is 15.1, 2.83, 3.52 and 16.7ng/mL (at 3σ/slope) respectively. Meanwhile, the nanosensor shows good selectivity, sensitivity and can be successfully applied to detection of Sudan in chili powder samples.

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Metabolomic profile related to cardiovascular disease in patients with type 2 diabetes mellitus: A pilot study

Publication date: 1 February 2016
Source:Talanta, Volume 148
Author(s): Beatriz García-Fontana, Sonia Morales-Santana, Caridad Díaz Navarro, Pedro Rozas-Moreno, Olga Genilloud, Francisca Vicente Pérez, José Pérez del Palacio, Mnuel Muñoz-Torres
Type 2 diabetes mellitus (T2DM) patients have an increased risk of cardiovascular disease (CVD) that represents one of the main causes of mortality in this population. The knowledge of the underlie factors involved in the development of CVD and the discovery of new biomarkers of the disease could help to early identification of high-risk patients.Using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS) we analyzed the serum metabolomic profile of 30 subject distributed according three groups: (i) T2DM patients with CVD; (ii) T2DM patients without CVD; (iii) non-diabetic subjects as controls (C) in order to identify potential biomarkers of the CVD related to T2DM.A partial least squares discriminant analysis (PLS-DA) and one-way analysis of variance (ANOVA) were applied to identify differential metabolites between different groups.Four glycerophospholipids were further identified as potential biomarkers of CVD in T2DM patients. Specifically, a reduction in phosphatidylcholine, lysophosphatidylcholine and lysophosphatidylethanolamine (LPE) serum levels were found in T2DM patients compared to controls, presenting the patients with CVD the lowest serum levels of these metabolites.These results show a generalized reduction of circulating phospholipids species in T2DM patients which is more pronounced in those with CVD providing information of the pathways involved in the pathogenesis and progression of CVD associated to T2DM.

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Synthesis and Biological Profiling of 6- or 7-(Het)aryl-7-deazapurine 4’-C-Methylribonucleosides

Publication date: Available online 31 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Petr Nauš, Olga Caletková, Pavla Perlíková, Lenka Poštová Slavětínská, Eva Tloušťová, Jan Hodek, Jan Weber, Petr Džubák, Marián Hajdúch, Michal Hocek
The synthesis and biological activity profiling of a large series of diverse pyrrolo[2,3-d]pyrimidine 4'-C-methylribonucleosides bearing an (het)aryl group at position 4 or 5 is reported as well as the synthesis of several phosphoramidate prodrugs. These compounds are 4'-C-methyl derivatives of previously reported cytostatic hetaryl-7-deazapurine ribonucleosides. The synthesis is based on glycosylation of halogenated 7-deazapurine bases with 1,2-di-O-acetyl-3,5-di-O-benzyl-4-C-methyl-β-d-ribofuranose followed by cross-coupling and nucleophilic substitution reactions. The final compounds showed low cytotoxicity and several derivatives exerted antiviral activity against HCV or Dengue viruses at micromolar concentrations.

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Synthesis and Evaluation of 3-Hydroxy-3-phenylpropanoate Ester-AZT Conjugates as Potential Dual-action HIV-1 Integrase and Reverse Transcriptase Inhibitors

Publication date: Available online 31 October 2015
Source:Bioorganic & Medicinal Chemistry
Author(s): Meloddy H. Manyeruke, Temitope O. Olomola, Swarup Majumder, Shaakira Abrahams, Michelle Isaacs, Nicodemus Mautsa, Salerwe Mosebi, Dumisani Mnkandhla, Raymond Hewer, Heinrich C. Hoppe, Rosalyn Klein, Perry T. Kaye
Novel 3-hydroxy-3-phenylpropanoate ester-azidothymidine (AZT) conjugates have been prepared using Baylis-Hillman methodology, and their potential as dual-action HIV-1 Integrase and Reverse Transcriptase inhibitors has been explored using enzyme inhibition and computer modelling techniques; their activity and HeLa cell toxicity have been compared with those of their cinnamate ester analogues.

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Big Data and Network Biology 2015

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Synergistic Effects of BMP9 and miR-548d-5p on Promoting Osteogenic Differentiation of Mesenchymal Stem Cells

Various stimulators have been reported to promote MSC osteogenic differentiation via different pathways such as bone morphogenetic protein 9 (BMP9) through influencing COX-2 and miR-548d-5p through targeting peroxisome proliferator-activated receptor-γ (PPARγ). Whether synergistic effects between BMP9 and miR-548d-5p existed in promoting osteogenesis from MSCs was unclear. In the study, the potential synergistic effects of BMP9 and miR-548d-5p on human MSC differentiation were investigated. Osteogenic differentiation of MSCs treated with BMP9 or miR-548d-5p was detected with multimodality of methods. The results demonstrated that BMP9 and miR-548d-5p significantly influenced COX-2 and PPARγ, respectively. BMP9 also influenced the expression of PPARγ, but no significant effect of miR-548d-5p on COX-2 was observed. When BMP9 and miR-548d-5p were combined, more potent effects on both COX-2 and PPARγ were observed than BMP9 or miR-548d-5p alone. Consistently, osteogenic analysis at different timepoints demonstrated that osteogenic genes, ALP activity, calcium deposition, OPN protein, and matrix mineralization were remarkably upregulated by BMP9/miR-548d-5p compared with BMP9 or miR-548d-5p alone, indicating the synergetic effects of BMP9 and miR-548d-5p on osteogenic differentiation of MSCs. Our study demonstrated that regulating different osteogenic regulators may be an effective strategy to promote bone tissue regeneration for bone defects.

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Interoceptive awareness in patients with functional neurological symptoms

Publication date: Available online 31 October 2015
Source:Biological Psychology
Author(s): Lucia Ricciardi, Benedetta Demartini, Laura Crucianelli, Charlotte Krahé, Mark J. Edwards, Aikaterini Fotopoulou
Historically, emotional factors, such as trauma or psychological conflict, have been suggested as causal factors of functional motor disorders (FMD). More recent approaches have instead stressed potential neural and cognitive abnormalities in the allocation and maintenance of attention. Yet these studies have mostly focused on how attention is allocated to exteroceptive signals about the state of the body. Given the proposed important role of interoception for emotion, the study of FMD patients' ability to monitor their interoceptive signals may serve as a useful, mechanistic link between studies that aim to identify key emotional factors in FMD, and those that examine specific sensorimotor or cognitive abnormalities.In the current study, we compared the interoceptive awareness of a group of individuals with FMD (N = 16) with a group of healthy controls (N =17). We employed a commonly used heartbeat detection task which tracks the level of concordance between one's heart rate and its subjective perception, as a proxy for interoceptive awareness more generally.We found that FMD patients have lower interoceptive accuracy than healthy subjects, and such reduced interoceptive accuracy was predictive of their depressive symptoms, as well as their tendency to focus on the external features of their body (self-objectification). Contary to our predictions, interoceptive accuracy was not predictive of alexithymia. These results suggest a potental trade-off between the allocation of attention to internal versus external aspects of the body in FMD. More generally, they warrant further investigation of interoceptive awareness in this population, as a means to understand their emotional abnormalities at a more mechanistic level than studies concentrating on traumatic life events and related risk factors.



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