Dietary inflammatory index scores are associated with atherogenic risk in Brazilian schoolchildren.

OBJECTIVE: To investigate the association between the Children's Dietary Inflammatory Index (C-DIITM) scores and atherogenic risk in Brazilian schoolchildren. DESIGN: A cross-sectional representative study. Three 24-h dietary recalls were performed to evaluate food consumption and to calculate C-DII scores. Blood samples were collected for the lipid profile analysis (serum total cholesterol (TC), HDL-cholesterol, LDL-cholesterol, VLDL-cholesterol and triglycerides (TAG)) and to determine atherogenic indexes (Castelli risk indexes I and II, lipoprotein combined index (LCI), and atherogenic index of plasma and atherogenic coefficient (AC)). A semi-structured questionnaire was used to obtain sociodemographic characteristics and screen time. Body fat was assessed by dual-energy X-ray absorptiometry. We compared the distributions of outcomes by C-DII categories using multivariable linear regression. SETTING: Viçosa, Minas Gerais, Brazil. PARTICIPANTS: Three hundred seventy-eight children between the ages of 8 and 9 years. RESULTS: The mean C-DII score was 0·60 ± 0·94, and the prevalence of dyslipidaemia was 70 %. Children with hypercholesterolaemia and hypertriglyceridaemia had higher C-DII scores. The C-DII was directly associated with atherogenic risk. Every 1 sd of C-DII was associated with a 0·07 (0·01, 0·13), 1·94 (0·20, 3·67), 0·06 (0·002, 0·12) and 0·12 (0·02, 0·22) units higher TC:HDL cholesterol ratio, LCI, AC and accumulation of altered dyslipidaemia markers (high TC + high LDL-cholesterol + high TAG + low HDL-cholesterol), respectively. CONCLUSIONS: Dietary inflammatory potential, as estimated by the C-DII, is directly associated with atherogenic risk in Brazilian schoolchildren. This results reinforce the importance of effective nutritional policies to promote healthy eating habits and improve children's lipid profiles.

Effect of Uncaria tomentosa extract on purinergic enzyme activities in lymphocytes of rats submitted to experimental adjuvant arthritis model.

BACKGROUND: Considering that adjuvant arthritis is an experimental model of arthritis widely used for preclinical testing of numerous anti-arthritic agents, which were taken by a large number of patients worldwide, it is of great interest to investigate the therapeutic action of compounds with anti-inflammatory properties, such as Uncaria tomentosa extract. Moreover, there are no studies demonstrating the effect of U. tomentosa on the metabolism of adenine nucleotides published so far. Thus, the purpose of the present study is to investigate the effects of U. tomentosa extract on E-NTPDase and E-ADA activities in lymphocytes of Complete Freund's Adjuvant (CFA) arthritis induced rats. METHODS: To evaluate the effect of U. tomentosa extract on the activity of E-NTPDase and ADA in lymphocytes, the rats were submitted to an experimental adjuvant arthritis model. Peripheral lymphocytes were isolated and E-NTPDase and E-ADA activities were determined. Data were analyzed by a one- or two-way ANOVA. Post hoc analyses were carried out by the Student-Newman-Keuls (SNK) Multiple Comparison Test. RESULTS: E-NTPDase activity was increased in arthritic untreated. Arthritic rats which received U. tomentosa extract, presented similar results to the control group. However, results obtained for adenosine hydrolysis by E-ADA were not altered in arthritic rats. U. tomentosa extract did not alter E-NTPDase and E-ADA activity in healthy animals. CONCLUSIONS: The present investigation supports the hypothesis that the increased E-NTPDase activity verified in arthritic rats might be an attempt to maintain basal levels of ATP and ADP in the extracellular medium, since the arthritis induction causes tissue damage and, consequently, large amounts of ATP are released into this milieu. Also, it highlights the possibility to use U. tomentosa extract as an adjuvant to treat arthritis.

Transient receptor potential ankyrin 1 receptor stimulation by hydrogen peroxide is critical to trigger pain during monosodium urate-induced inflammation in rodents.

OBJECTIVE: Gout is a common cause of inflammatory arthritis and is provoked by the accumulation of monosodium urate (MSU) crystals. However, the underlying mechanisms of the pain associated with acute attacks of gout are poorly understood. The aim of this study was to evaluate the role of transient receptor potential ankyrin 1 (TRPA-1) and TRPA-1 stimulants, such as H2 O2 , in a rodent model of MSU-induced inflammation. METHODS: MSU or H2 O2 was injected into the hind paws of rodents or applied in cultured sensory neurons, and the intracellular calcium response was measured in vitro. Inflammatory or nociceptive responses in vivo were evaluated using pharmacologic, genetic, or biochemical tools and methods. RESULTS: TRPA-1 antagonism, TRPA-1 gene deletion, or pretreatment of peptidergic TRP-expressing primary sensory neurons with capsaicin markedly decreased MSU-induced nociception and edema. In addition to these neurogenic effects, MSU increased H2 O2 levels in the injected tissue, an effect that was abolished by the H2 O2 -detoxifying enzyme catalase. H2 O2 , but not MSU, directly stimulated sensory neurons through the activation of TRPA-1. The nociceptive responses evoked by MSU or H2 O2 injection were attenuated by the reducing agent dithiothreitol. In addition, MSU injection increased the expression of TRPA-1 and TRP vanilloid channel 1 (TRPV-1) and also enhanced cellular infiltration and interleukin-1ß levels, and these effects were blocked by TRPA-1 antagonism. CONCLUSION: Our results suggest that MSU injection increases tissue H2 O2 , thereby stimulating TRPA-1 on sensory nerve endings to produce inflammation and nociception. TRPV-1, by a previously unknown mechanism, also contributes to these responses.

Modulation of gene expression and influence of gene polymorphisms related to genotoxicity and redox status on occupational exposure to inhaled anesthetics.

The extensive use of inhalational anesthetics contributes to both indoor and outdoor (environmental) pollution. The influence of genetic susceptibility on DNA damage and oxidative stress and the possible modulation of gene expression have not yet been investigated upon occupational exposure to waste anesthetic gases (WAGs). This study assessed 8-oxoguanine DNA glycosylase 1 (OGG1) and superoxide dismutase 2 (SOD2) gene expression, which are related to oxidized DNA repair and antioxidant capacity, respectively, and the influence of their polymorphisms (OGG1 rs1052133 and SOD2 rs4880) in 100 professionals highly exposed to WAGs and 93 unexposed volunteers (control group). Additionally, X-ray repair cross complementing 1 (XRCC1 rs25487 and rs1799782) and ataxia telangiectasia mutated (ATM rs600931) gene polymorphisms as well as genetic instability (micronucleus-MN and nuclear bud-NBUD) and oxidative stress (malondialdehyde-MDA and ferric reducing antioxidant power-FRAP) biomarkers were assessed in the groups (control and exposed) and in the subgroups of the exposed group according to job occupation (anesthesiologists versus surgeons/technicians). Except for the ATM TT controls (associated with increased FRAP), there were no influences of OGG1, XRCC1, ATM, and SOD2 polymorphisms on MN, NBUD, MDA, and FRAP values in exposed or control subjects. No significant difference in the expression of either gene evaluated (OGG1 and SOD2) was found between the exposed and control groups. Increased OGG1 expression was observed among OGG1 -/Cys individuals only in the control group. Among the exposed group, anesthesiologists had a greater duration of WAG exposure (both h/week and years) than surgeons/technicians, which was associated with increased MDA and decreased antioxidant capacity (FRAP) and SOD2 expression (redox status). Higher expression of OGG1 was found in -/Cys surgeons/technicians than in anesthesiologists with the same genotype. Increased antioxidant capacity was noted in the surgeons/technicians carrying the ATM T allele and in those carrying XRCC1 -/Gln. Increased MN was influenced by OGG1 -/Cys in surgeons/technicians. Anesthesiologists with ATM CC exhibited increased MN, and those carrying the C allele (CC/CT genotype) exhibited increased NBUD. SOD2 polymorphism did not seem to be relevant for WAG exposure. These findings contribute to advancing the knowledge on genetic susceptibility/gene expression/genetic instability/oxidative stress, including differences in job occupation considering the workload, in response to occupational exposure to WAGs.

Comparison between inhalational anesthetics in terms of DNA damage and immunological markers.

This study compared genetic damage and immunological markers between surgical patients who underwent inhalational anesthesia with isoflurane or sevoflurane. Blood samples were collected from surgical patients (n = 18 in the isoflurane group and n = 17 in the sevoflurane group) at baseline (before the anesthesia procedure) and the day after anesthesia. DNA damage was detected using an alkaline comet assay; proinflammatory interleukin (IL)-6 was detected by flow cytometry, and white blood cells were detected via an automatic hematology analyzer. The characteristics of both groups were similar, and neither of the two anesthetics induced DNA damage. Similarly, mild neutrophilia was observed after anesthesia in both groups. Increased IL-6 levels were observed 1 day after anesthesia regardless of the type of anesthetic, but this increase was greater in the isoflurane group. Our study suggested that isoflurane and sevoflurane administration may contribute to changes in the immune parameters measured, though no genotoxic hazard was identified, in healthy adult patients who undergo low-stress surgery.

Modulation of gene expression and inflammation but not DNA damage after sevoflurane anesthesia.

This study assessed, for the first time, the expression of the genes hOGG1, TP53, and IL-6 in leukocytes by real-time quantitative polymerase chain reaction in surgical patients before (baseline), during (2 h of anesthesia) and 1 day after sevoflurane anesthesia. Additionally, DNA damage was detected by the comet assay, serum interleukin (IL)-6 was detected by flow cytometry, and differential leukocyte counting was also performed. TP53 and hOGG1 expression was downregulated on the day after anesthesia compared to before anesthesia. However, IL-6 expression did not change, and no DNA damage induction was observed during or after anesthesia. At the systemic level, mild neutrophilia and an increase in IL-6 levels occurred after anesthesia. Our findings suggest that sevoflurane anesthesia downregulates gene expression (hOGG1 and TP53) and contributes to an inflammatory status (increased systemic IL-6 and mild neutrophilia) but is not associated with DNA damage in patients without comorbidities who undergo minor elective surgery.

Evaluation of genetic instability, oxidative stress, and metabolism-related gene polymorphisms in workers exposed to waste anesthetic gases.

Professionals who work in operating rooms (ORs) may be exposed daily to waste anesthetic gases (WAGs) due to the use of inhalational anesthetics. Considering the controversial findings related to genetic damage and redox status in addition to a lack of knowledge about the effect of polymorphisms in genes related to phase I and II detoxification upon occupational exposure to WAGs, this cross-sectional study is the first to jointly evaluate biomarkers of genetic instability, oxidative stress, and susceptibility genes in professionals occupationally exposed to high trace amounts of halogenated (≥ 7 ppm) and nitrous oxide (165 ppm) anesthetics in ORs and in individuals not exposed to WAGs (control group). Elevated rates of buccal micronucleus (MN) and nuclear bud (NBUD) were observed in the exposure group and in professionals exposed aged more than 30 years. Exposed males showed a higher antioxidant capacity, as determined by the ferric reducing antioxidant power (FRAP), than exposed females; exposed females had higher frequencies of MN and NBUD than nonexposed females. Genetic instability (MN) was observed in professionals with greater weekly WAG exposure, and those exposed for longer durations (years) exhibited oxidative stress (increased lipid peroxidation and decreased FRAP). Polymorphisms in metabolic genes (cytochrome P450 2E1 (CYP2E1) and glutathione S-transferases (GSTs)) did not exert an effect, except for the effects of the GSTP1 (rs1695) AG/GG polymorphism on FRAP (both groups) and GSTP1 AG/GG and GSTT1 null polymorphisms, which were associated with greater FRAP values in exposed males. Minimizing WAG exposure is necessary to reduce impacts on healthcare workers.

High anesthetic exposure leads to oxidative damage and gene expression changes in physicians during medical residency: a cohort study.

Evaluation of the possible toxic effects of occupational exposure to anesthetics is of great importance, and the literature is limited in assessing the possible association between occupational exposure to anesthetics and oxidative stress and genetic damage. To contribute to the gap of knowledge in relation to cause-effect, this cohort study was the first to monitor exposure assessment and to evaluate oxidative stress, DNA damage, and gene expression (OGG1, NRF2, HO-1, and TP53) in young adult physicians occupationally exposed to the most modern halogenated anesthetics (currently the commonly used inhalational anesthetics worldwide) in addition to nitrous oxide gas during the medical residency period. Therefore, the physicians were evaluated before the beginning of the medical residency (before the exposure to anesthetics-baseline), during (1 1/2 year) and at the end (2 1/2 years) of the medical residency. Anesthetic air monitoring was performed in operating rooms without adequate ventilation/scavenging systems, and biological samples were analyzed for lipid peroxidation, protein carbonyl content, primary and oxidative DNA damage, antioxidant enzymes and plasma antioxidant capacity, and expression of some key genes. The results showed induction of lipid peroxidation, DNA damage, glutathione peroxidase activity, and NRF2 and OGG1 expression up to the end of medical residency. Plasma antioxidant capacity progressively increased throughout medical residency; oxidative DNA damage levels started to increase during medical residency and were higher at the end of residency than at baseline. Protein carbonyls increased during but not at the end of medical residency compared to baseline. The antioxidant enzyme superoxide dismutase activity remained lower than baseline during and at the end of medical residency, and HO-1 (related to antioxidant defense) expression was downregulated at the end of medical residency. Additionally, anesthetic concentrations were above international recommendations. In conclusion, high concentrations of anesthetic in the workplace induce oxidative stress, gene expression modulation, and genotoxicity in physicians during their specialization period.

High anesthetic (isoflurane) indoor pollution is associated with genetic instability, cytotoxicity, and proliferative alterations in professionals working in a veterinary hospital.

This is the first study to monitor anesthetic pollution in veterinary operating rooms (VOR) and assess the toxicological impact of the inhalational anesthetic isoflurane (exposed group) compared to matched volunteers (control group). DNA damage was evaluated in mononuclear cells by the comet assay while genetic instability (including micronucleus-MN), cell proliferation, and cell death markers were assessed by the buccal MN cytome assay. Residual isoflurane concentrations in VOR (air monitoring) lacking the scavenging system were assessed by infrared spectrophotometry; the mean concentration was 11 ppm (≥ 5 times above the international recommended threshold). Comet assay results did not differ between groups; however, both younger exposed professionals (with higher week workload) compared to older individuals exposed for the same period and older professionals with greater time of exposure (years) compared to those in the same age group with fewer years of exposure presented higher DNA damage. The exposed group had a higher frequency of MN, nuclear buds, binucleated cells, karyorrhexis, and karyolysis and a lower frequency of basal cells than the control group. Exposed women were more vulnerable to genetic instability and proliferative index; exposed men presented more cytotoxicity. High WAG exposure has deleterious effects on exposed professionals.

Hepatotoxic and neuroendocrine effects in physicians occupationally exposed to most modern halogenated anesthetics and nitrous oxide.

The lack of data on hepatic and hormonal markers for occupational exposure to most modern halogenated anesthetics has stimulated our research, which assessed liver enzymes, high-sensitivity C-reactive protein (hs-CRP) and neuroendocrine response. The study investigated 106 physicians who were categorized in an exposed group (primarily exposed to isoflurane and sevoflurane and less to desflurane and nitrous oxide) as well as as a control group. Anesthetic air monitoring was performed, and biological samples were analyzed for the most important liver enzymes, hs-CRP, adrenocorticotrophic hormone, cortisol and prolactin. No biomarkers were significantly different between the groups. Exposed males showed significant increases in cortisol and prolactin compared to unexposed males. However, values were within the reference ranges, and 22 % of exposed males versus 5 % of unexposed males exhibited higher prolactin values above the reference range. This study suggests that occupational exposure to the most commonly used inhalational anesthetics is not associated with hepatotoxicity or neurohormonal changes.

Genetic instability assessed by telomere length and micronucleus in physicians exposed to anesthetics.

This study evaluated both telomere length (TL) and micronucleus (MN) as indicators of genome instability in 40 anesthesiologists occupationally exposed to anesthetics and in 40 physicians without occupational exposure to anesthetics who were matched by age, sex, and lifestyle. Blood and buccal samples were collected from both groups at the same period. Anesthetic exposure assessment was performed. The studied groups were assessed regarding relative TL by quantitative polymerase chain reaction and MN by buccal MN assay. Mean trace concentrations of anesthetics were below two parts per million. No significant differences between groups were found for both biomarkers. However, MN frequency was slightly increased (1.9-fold; p = .094) in the exposed group compared to the control group and in the exposed males (2.4-fold; p = .090) compared to unexposed males. TL and age showed a significant negative correlation. Anesthetic occupational exposure below recommended levels is not associated with changes in TL and MN in anesthesiologists.

Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial.

BACKGROUND: Methadone and ketamine are used in neuropathic pain management. However, the benefits of both drugs association are uncertain in the treatment of neuropathic pain. OBJECTIVE: Our primary objective was test the hypothesis that oral methadone combined with oral ketamine is more effective than oral methadone or ketamine alone in reducing neuropathic pain. STUDY DESIGN: We conducted a randomized, double blind, active-controlled parallel-group clinical trial. METHODS: Forty-two patients with neuropathic pain refractory to conventional therapy were randomly assigned to receive oral methadone (n = 14), ketamine (n = 14), or methadone plus ketamine (n = 14) over a 3-month period. RESULTS: During these 90 days, we observed pain scores using a visual analogical scale (VAS), allodynia, burning/shooting pain, and some side effects. All treatments were effective in reducing pain scores by at least 40%. However, a significant improvement in pain was observed only in the ketamine alone group compared with both the methadone or methadone/ketamine groups. No significant differences were observed among the treatment groups for the reduction of burning or shooting pain, while ketamine alone was more effective than methadone or methadone/ketamine for the reduction of allodynia. LIMITATIONS: Formal assessment for awareness of the allocation was not performed, some co-intervention bias may have occurred, our results could be only relevant to the patient population investigated and the use of VAS as the primary outcome detect changes in pain intensity but not to assess neuropathic pain symptoms. CONCLUSION: This study indicates that ketamine was better than methadone or methadone/ketamine for treating neuropathic pain.Key words: Multimodal analgesia, refractory pain, NMDA receptor, opioid.

Effect of ω-conotoxin MVIIA and Phα1ß on paclitaxel-induced acute and chronic pain.

The treatment with the chemotherapeutic agent paclitaxel produces a painful peripheral neuropathy, and is associated with an acute pain syndrome in a clinically significant number of patients. However, no standard therapy has been established to manage the acute pain or the chronic neuropathic pain related to paclitaxel. In the present study, we evaluated the analgesic potential of two N-type voltage-gated calcium channel (VGCC) blockers, ω-conotoxin MVIIA and Phα1ß, on acute and chronic pain induced by paclitaxel. Adult male rats were treated with four intraperitoneal injections of paclitaxel (1+1+1+1mg/kg, in alternate days) and the development of mechanical hyperalgesia was evaluated 24h (acute painful stage) or 15days (chronic painful stage) after the first paclitaxel injection. Not all animals showed mechanical hyperalgesia 24h after the first paclitaxel injection, but those that showed developed a more intense mechanical hyperalgesia at the chronic painful stage. Intrathecal administration (i.t.) of ω-conotoxin MVIIA (3-300pmol/site) or Phα1ß (10-300pmol/site) reduced the mechanical hyperalgesia either at the acute or at the chronic painful stage induced by paclitaxel. When administered at the acute painful stage, ω-conotoxin MVIIA (300pmol/site, i.t.) and Phα1ß (300pmol/site, i.t.) prevented the worsening of chronic mechanical hyperalgesia. Furthermore, Phα1ß (30-300pmol/site, i.t.) elicited less adverse effects than ω-conotoxin MVIIA (10-300 pmol/site, i.t.). Taken together, our data evidence the involvement of N-type VGCC in pain sensitization induced by paclitaxel and point out the potential of Phα1ß as a safer alternative than ω-conotoxin MVIIA to treat the pain related to paclitaxel.

Role of peripheral polyamines in the development of inflammatory pain.

Polyamines (putrescine, spermidine and spermine) are aliphatic amines that are produced by the action of ornithine decarboxylase (ODC) in a rate-limiting and protein kinase C (PKC)-regulated step. Because high levels of polyamines are found in the synovial fluid of arthritic patients, the aim of the present study was to identify the role of peripherally produced polyamines in a model of inflammatory pain induced by adjuvant. The subcutaneous injection of Complete Freund's adjuvant (CFA, 50 µL/paw) caused the development of mechanical allodynia and edema. Moreover, it increased ODC expression and activity and PKC activation. Administration of the selective ODC inhibitor DFMO (10 µmol/paw) attenuated the development of allodynia and edema and decreased ODC activity in both control and CFA-treated animals. Furthermore, administration of the PKC inhibitor GF109203X (1 nmol/paw) reduced allodynia and ODC activity in animals injected with CFA. A subcutaneous injection of putrescine (10 µmol/paw), spermidine (3-10 µmol/paw) or spermine (0.3-3 µmol/paw) into the rat paw also caused mechanical allodynia and edema. The present results suggest that endogenously synthesized polyamines are involved in the development of nociception and edema caused by an adjuvant. Moreover, polyamine production in inflammatory sites seems to be related to an increase in ODC activity stimulated by PKC activation. Thus, controlling polyamine synthesis and action could be a method of controlling inflammatory pain.