Xanthohumol Requires the Intestinal Microbiota to Improve Glucose Metabolism in Diet-Induced Obese Mice.

SCOPE: The polyphenol xanthohumol (XN) improves dysfunctional glucose and lipid metabolism in diet-induced obesity animal models. Because XN changes intestinal microbiota composition, the study hypothesizes that XN requires the microbiota to mediate its benefits. METHODS AND RESULTS: To test the hypothesis, the study feeds conventional and germ-free male Swiss Webster mice either a low-fat diet (LFD, 10% fat derived calories), a high-fat diet (HFD, 60% fat derived calories), or a high-fat diet supplemented with XN at 60 mg kg-1 body weight per day (HXN) for 10 weeks, and measure parameters of glucose and lipid metabolism. In conventional mice, the study discovers XN supplementation decreases plasma insulin concentrations and improves Homeostatic Model Assessment of Insulin Resistance (HOMA-IR). In germ-free mice, XN supplementation fails to improve these outcomes. Fecal sample 16S rRNA gene sequencing analysis suggests XN supplementation changes microbial composition and dramatically alters the predicted functional capacity of the intestinal microbiota. Furthermore, the intestinal microbiota metabolizes XN into bioactive compounds, including dihydroxanthohumol (DXN), an anti-obesogenic compound with improved bioavailability. CONCLUSION: XN requires the intestinal microbiota to mediate its benefits, which involves complex diet-host-microbiota interactions with changes in both microbial composition and functional capacity. The study results warrant future metagenomic studies which will provide insight into complex microbe-microbe interactions and diet-host-microbiota interactions.

Searching for Gravitational Waves from Cosmological Phase Transitions with the NANOGrav 12.5-Year Dataset.

We search for a first-order phase transition gravitational wave signal in 45 pulsars from the NANOGrav 12.5-year dataset. We find that the data can be modeled in terms of a strong first order phase transition taking place at temperatures below the electroweak scale. However, we do not observe any strong preference for a phase-transition interpretation of the signal over the standard astrophysical interpretation in terms of supermassive black hole mergers; but we expect to gain additional discriminating power with future datasets, improving the signal to noise ratio and extending the sensitivity window to lower frequencies. An interesting open question is how well gravitational wave observatories could separate such signals.

Acute Glucose Load, Inflammation, Oxidative Stress, Nonenzymatic Glycation, and Screening for Gestational Diabetes.

AIMS: To investigate if oral glucose tolerance test (OGTT) associates with changes in maternal symptoms (ie, flushing, sweating), blood nonenzymatic advanced glycation end products (AGE), acute-phase reactive inflammatory markers, and oxidative stress. METHODS: Prospective case-control study of patients screened for gestational diabetes mellitus (GDM). One hundred nonfasting, second-trimester consecutive pregnant women allocated to either 50 g OGTT or water. Five women who had a 3-hour fasting 100 g OGTT also enrolled. Maternal serum glucose, AGE, soluble receptor for AGE (sRAGE), interleukin (IL)-6, and C-reactive protein (CRP) were immunoassayed. Total radical-trapping antioxidant parameter (TRAP) estimated with antioxidant capacityperoxyl assay. Data corrected for gestational age and maternal body mass index. RESULTS: During 50 g OGTT there was a decrease in systolic blood pressure not accompanied by the onset of adverse clinical symptoms. There was a decrease in serum glucose levels 1 hour after water (P = .019) but not glucose ingestion. Serum CRP (P = .001) but not IL-6 was increased. The AGE, sRAGE, and TRAP levels remained unchanged. Similar results were seen during 100 g OGTT, except serum glucose was significantly elevated after 1 hour. CONCLUSION: Results suggest screening tools for gestational diabetes are safe and clinically well tolerated during pregnancy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03029546.

Acute Glucose Load, Inflammation, Oxidative Stress, Nonenzymatic Glycation, and Screening for Gestational Diabetes.

AIMS:: To investigate if oral glucose tolerance test (OGTT) associates with changes in maternal symptoms (ie, flushing, sweating), blood nonenzymatic advanced glycation end products (AGE), acute-phase reactive inflammatory markers, and oxidative stress. METHODS:: Prospective case-control study of patients screened for gestational diabetes mellitus (GDM). One hundred nonfasting, second-trimester consecutive pregnant women allocated to either 50 g OGTT or water. Five women who had a 3-hour fasting 100 g OGTT also enrolled. Maternal serum glucose, AGE, soluble receptor for AGE (sRAGE), interleukin (IL)-6, and C-reactive protein (CRP) were immunoassayed. Total radical-trapping antioxidant parameter (TRAP) estimated with antioxidant capacity-peroxyl assay. Data corrected for gestational age and maternal body mass index. RESULTS:: During 50 g OGTT there was a decrease in systolic blood pressure not accompanied by the onset of adverse clinical symptoms. There was a decrease in serum glucose levels 1 hour after water ( P = .019) but not glucose ingestion. Serum CRP ( P = .001) but not IL-6 was increased. The AGE, sRAGE, and TRAP levels remained unchanged. Similar results were seen during 100 g OGTT, except serum glucose was significantly elevated after 1 hour. CONCLUSION:: Results suggest screening tools for gestational diabetes are safe and clinically well tolerated during pregnancy. Clinical Trial Registration: ClinicalTrials.gov NCT03029546.

Sport-related anxiety: current insights.

To date, much research has been devoted to understanding how anxiety can affect sport performance, both in practice and in competitive settings. It is well known that sport has the potential for high levels of stress and anxiety, and that practicing and employing a range of psychological strategies can be beneficial in anxiety management. Equally, growing evidence also suggests that anxiety can play a role in sport injury prevention, occurrence, rehabilitation, and the return to sport process. The purpose of this paper is to provide current insights into sport-related anxiety. More specifically, it will provide the reader with definitions and theoretical conceptualizations of sport-related anxiety. This will be followed by making a case for considering the term "performance" to be broader than activities associated with sport-related performance in practice and competition, by including performance activities associated with sport injury prevention, rehabilitation, and the return to sport process. The paper will then highlight the importance of recognizing early signs and symptoms of anxiety, and the potential need for referral. Finally, the conclusions will emphasize the need for appropriate, client-specific, and practitioner competent care for athletes experiencing sport-related anxiety.

Mortality associated with using medetomidine and ketamine for general anesthesia in pregnant and nonpregnant Wistar rats.

Medetomidine and ketamine are injectable drugs that can be used in combination to induce general anesthesia in rats. After noticing a high incidence of morbidity and mortality in pregnant Wistar rats given medetomidine and ketamine for anesthesia, the authors further investigated the effects of this combination of anesthetic drugs in both pregnant and nonpregnant Wistar rats. The time to recumbency and the duration of general anesthesia were similar between pregnant and nonpregnant rats. Pregnancy status did not affect the rats' pulse rate, respiratory rate, rectal temperature, oxygen saturation or perfusion index during 2 h of anesthesia. Pregnant rats had significantly lower blood glucose concentrations than nonpregnant rats at all time points, though blood glucose concentrations increased in both groups. The mortality rate was ∼15% both for nonpregnant rats and for pregnant rats. Researchers using medetomidine and ketamine to anesthetize Wistar rats should carefully monitor the rats in order to minimize mortality.

Maternal dietary omega-3 fatty acids and placental function.

The developing fetus requires substantial amounts of fatty acids to support rapid cellular growth and activity. Although the fatty acid composition delivered to the fetus is largely determined by maternal circulating levels, the placenta preferentially transfers physiologically important long-chain polyunsaturated fatty acids (LC-PUFAs), particularly omega-3 (n-3) PUFAs. Maternal dietary supplementation with n-3 PUFAs during pregnancy has been shown to increase gestation length, enhance fetal growth, and reduce the risk of pregnancy complications, although the precise mechanisms governing these effects remain uncertain. Omega-3 PUFAs are involved in several physiological pathways which could account for these effects, including anti-inflammatory, pro-resolving, and anti-oxidative pathways. Recent studies have shown that maternal dietary n-3 PUFA supplementation during rat pregnancy can reduce placental oxidative damage and increase placental levels of pro-resolving mediators, effects associated with enhanced fetal and placental growth. Because several placental disorders, such as intrauterine growth restriction, preeclampsia, and gestational diabetes mellitus, are associated with heightened placental inflammation and oxidative stress, there is considerable interest in the potential for dietary n-3 PUFAs as a therapeutic intervention for these disorders. In this study, we review the impact of dietary n-3 PUFAs on placental function, with particular focus on placental inflammation, inflammatory resolution, and oxidative stress.

Maternal omega-3 fatty acid intake increases placental labyrinthine antioxidant capacity but does not protect against fetal growth restriction induced by placental ischaemia-reperfusion injury.

Placental oxidative stress plays a key role in the pathophysiology of several placenta-related disorders. Oxidative stress occurs when excess reactive oxygen species (ROS) damages cellular components, an outcome limited by antioxidant enzymes; mitochondrial uncoupling protein 2 (UCP2) also limits ROS production. We recently reported that maternal dietary omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation reduced placental oxidative damage and enhanced fetal and placental growth in the rats. Here, we examined the effect of n-3 PUFAs on placental antioxidant defences and whether n-3 PUFA supplementation could prevent growth restriction induced by placental ischaemia-reperfusion (IR), a known inducer of oxidative stress. Rats were fed either standard or high-n-3 PUFA diets from day 1 of pregnancy. Placentas were collected on days 17 and 22 in untreated pregnancies (term=day 23) and at day 22 following IR treatment on day 17. Expression of several antioxidant enzyme genes (Sod1, Sod2, Sod3, Cat, Txn1 and Gpx3) and Ucp2 was measured by quantitative RT-PCR in the placental labyrinth zone (LZ) and junctional zone (JZ). Cytosolic superoxide dismutase (SOD), mitochondrial SOD and catalase (CAT) activities were also analyzed. Maternal n-3 PUFA supplementation increased LZ mRNA expression of Cat at both gestational days (2- and 1.5-fold respectively; P<0.01) and female Sod2 at day 22 (1.4-fold, P<0.01). Cytosolic SOD activity increased with n-3 PUFA supplementation at day 22 (1.3-fold, P<0.05). Sod1 and Txn1 expression decreased marginally (30 and 22%, P<0.05). JZ antioxidant defences were largely unaffected by diet. Despite increased LZ antioxidant defences, maternal n-3 PUFA supplementation did not protect against placental IR-induced growth restriction of the fetus and placental LZ.

Maternal dietary omega-3 fatty acid intake increases resolvin and protectin levels in the rat placenta.

Placental inflammation is associated with several pregnancy disorders. Inflammation is limited by anti-inflammatory and proresolving mechanisms, the latter partly mediated by resolvins and protectins derived from omega-3 polyunsaturated fatty acids (n-3PUFA). We examined effects of dietary n-3PUFAs on levels of resolvins, protectins, and lipoxygenase (ALOX) enzymes in the rat placenta. Rats consumed standard (Std) or high n-3PUFA (Hn3) diets from day 1 of pregnancy; tissues were collected on day 17 or 22 (term = day 23). Maternal Hn3 diet increased resolvin and protectin precursors, 18R/S-HEPE (P < 0.001), and 17R/S-HDHA (P < 0.01) at both days. Resolvins (17R-RvD1 and RvD1) increased at day 22 (P < 0.001) after Hn3 consumption, coincident with higher Alox15b and Alox5 mRNA expression, while RvD2 increased at both days (P < 0.05). Protectins, PD1, and 10S,17S-DiHDHA increased over late gestation (P < 0.001), coincident with higher Alox15 mRNA expression (P < 0.001) and further increased with Hn3 diet (P < 0.05). Maternal systemic and placental proinflammatory mediators were not suppressed by Hn3 diet; systemic IL1ß, placental Il1ß, and Il6 mRNA expression increased marginally with Hn3 at day 22 (P < 0.001), while Ptgs1 (Cox1) expression increased both days (P < 0.05). Our data indicate that maternal n-3PUFA supplementation enhances expression of enzymes in the n-3PUFA metabolic pathway and increases placental levels of resolvins and protectins.

Maternal dietary omega-3 fatty acid supplementation reduces placental oxidative stress and increases fetal and placental growth in the rat.

Placental oxidative stress plays a key role in the pathophysiology of several placenta-related disorders including intrauterine growth restriction. Oxidative stress occurs when accumulation of reactive oxygen species damages DNA, proteins, and lipids, an outcome normally limited by antioxidant defenses. Dietary supplementation with omega-3 polyunsaturated fatty acids (n-3 PUFAs) may limit oxidative stress by increasing antioxidant capacity, but n-3 PUFAs are also highly susceptible to lipid peroxidation; so n-3 PUFA supplementation is potentially harmful. Here we examined the effect of n-3 PUFAs on placental oxidative stress and on placental and fetal growth in the rat. We also investigated whether diet-induced changes in maternal plasma fatty acid profiles are associated with comparable changes in placental and fetal tissues. Rats were fed either standard or high n-3 PUFA diets from Day 1 of pregnancy, and tissues were collected on Day 17 or 22 (term = Day 23). Dietary supplementation with n-3 PUFAs increased fetal (6%) and placental (12%) weights at Day 22, the latter attributable primarily to growth of the labyrinth zone (LZ). Increased LZ weight was accompanied by reduced LZ F(2)-isoprostanes (by 31% and 11% at Days 17 and 22, respectively), a marker of oxidative damage. Maternal plasma PUFA profiles were altered by dietary fatty acid intake and were strongly predictive of corresponding profiles in placental and fetal tissues. Our data indicate that n-3 PUFA supplementation reduces placental oxidative stress and enhances placental and fetal growth. Moreover, fatty acid profiles in the mother, placenta, and fetus are highly dependent on dietary fatty acid intake.

Antioxidant defenses in the rat placenta in late gestation: increased labyrinthine expression of superoxide dismutases, glutathione peroxidase 3, and uncoupling protein 2.

Placental oxidative stress plays a key role in the pathophysiology of placenta-related disorders, most notably preeclampsia (PE) and intrauterine growth restriction (IUGR). Oxidative stress occurs when accumulation of reactive oxygen species (ROS) damages DNA, proteins and lipids, an outcome that is limited by antioxidant enzymes; mitochondrial uncoupling protein 2 (UCP2) may also limit oxidative stress by reducing ROS production. Here we characterized placental antioxidant defenses during normal gestation and following glucocorticoid-induced IUGR. Placentas were collected on Days 16 and 22 of normal rat pregnancy (term = Day 23) and at Day 22 after dexamethasone treatment from Day 13. Expression of several genes encoding antioxidant enzymes (Sod1, Sod2, Sod3, Cat, Gpx3, Txn1, Txnrd1, Txnrd2, and Txnrd3) and Ucp2 was measured by quantitative RT-PCR in the labyrinth (LZ) and junctional zones (JZ) of the placenta. Expression of Sod1 and Ucp2 mRNAs and the activity of xanthine oxidase, a source of ROS, all increased from Days 16 to 22 in both placental zones, whereas Sod2 and Gpx3 increased only in the rapidly growing LZ. In contrast, Sod3 and Txnrd1 expression fell in the LZ over this period, whereas total superoxide dismutase activity remained stable. Dexamethasone treatment reduced fetal-placental growth and LZ expression of Ucp2 but increased JZ expression of Txn1. Indices of placental oxidative damage (TBARS, F(2)-isoprostanes, and 8-OHdG) did not change with gestational age or dexamethasone, indicative of adequate antioxidant protection. Overall, our data suggest that the rat placenta is protected from oxidative stress by the dynamic zone- and stage-dependent expression of antioxidant defense genes.

In search of pharmacoeconomic evaluations for fibromyalgia treatments: a review.

Fibromyalgia is characterised by chronic widespread pain of unknown aetiology and affects approximately 2% of the population. It can cause significant patient disability, sizeable economic costs, complex management decisions and controversy for healthcare providers. In lieu of uniformly approved treatments for fibromyalgia, patients may try multiple pharmacological and non-pharmacological therapies with questionable efficacy. The literature lacks pharmacoeconomic studies that balance the cost and benefit of interventions. In the absence of this work, cost outcomes are reviewed in this paper. Due to inconclusive results, further study is needed on fibromyalgia treatment cost-effectiveness. These analyses could provide useful information for policy and evidence-based practice guidelines toward optimal disease management. Medical professionals should be a driving force in understanding the clinical and economic challenges of fibromyalgia.