Associations of accumulated persistent organic pollutants in breast adipose tissue with the evolution of breast cancer after surgery.

Chronic exposure to persistent organic pollutants (POPs) is suspected to contribute to the onset of breast cancer, but the impact on the evolution of patients after diagnosis is unclear. We aimed to analyze the contribution of long-term exposure to five POPs to overall mortality, cancer recurrence, metastasis, and development of second primary tumors over a global follow-up of 10 years after surgery in breast cancer patients in a cohort study. Between 2012 and 2014, a total of 112 newly diagnosed breast cancer patients were recruited from a public hospital in Granada, Southern Spain. Historical exposure to POPs was estimated by analyzing their concentrations in breast adipose tissue samples. Sociodemographic data were collected through face-to-face interviews, while data on evolution tumor were retrieved from clinical records. Statistical analyses were performed using Cox regression (overall survival, breast cancer recurrence or metastasis) and binary logistic regression models (joint outcome variable). We also tested for statistical interactions of POPs with age, residence, and prognostic markers. The third vs first tertile of hexachlorobenzene concentrations was associated with a lower risk of all-cause mortality (Hazard Ratio, HR = 0.26; 95 % Confidence Interval, CI = 0.07-0.92) and of the appearance of any of the four events (Odds Ratio = 0.37; 95 % CI = 0.14-1.03). Polychlorinated biphenyl 138 concentrations were significantly and inversely associated with risk of metastasis (HR = 0.65; 95 % CI = 0.44-0.97) and tumor recurrence (HR = 0.69; 95 % CI = 0.49-0.98). Additionally, p,p'-dichlorodiphenyldichloroethylene showed inverse associations with risk of metastasis in women with ER-positive tumors (HR = 0.49; 95 % CI = 0.25-0.93) and in those with a tumor size <2.0 cm (HR = 0.39; 95 % CI = 0.18-0.87). The observed paradoxical inverse associations of POP exposure with breast cancer evolution might be related to either a better prognosis of hormone-dependent tumors, which have an approachable pharmacological target, or an effect of sequestration of circulating POPs by adipose tissue.

The Absence of Caspase-8 in the Dopaminergic System Leads to Mild Autism-like Behavior.

In the last decade, new non-apoptotic roles have been ascribed to apoptotic caspases. This family of proteins plays an important role in the sculpting of the brain in the early stages of development by eliminating excessive and nonfunctional synapses and extra cells. Consequently, impairments in this process can underlie many neurological and mental illnesses. This view is particularly relevant to dopamine because it plays a pleiotropic role in motor control, motivation, and reward processing. In this study, we analyze the effects of the elimination of caspase-8 (CASP8) on the development of catecholaminergic neurons using neurochemical, ultrastructural, and behavioral tests. To do this, we selectively delete the CASP8 gene in cells that express tyrosine hydroxylase with the help of recombination through the Cre-loxP system. Our results show that the number of dopaminergic neurons increases in the substantia nigra. In the striatum, the basal extracellular level of dopamine and potassium-evoked dopamine release decreased significantly in mice lacking CASP8, clearly showing the low dopamine functioning in tissues innervated by this neurotransmitter. This view is supported by electron microscopy analysis of striatal synapses. Interestingly, behavioral analysis demonstrates that mice lacking CASP8 show changes reminiscent of autism spectrum disorders (ASD). Our research reactivates the possible role of dopamine transmission in the pathogenesis of ASD and provides a mild model of autism.

Social mobility and healthy behaviours from a gender perspective in the Spanish multicase-control study (MCC-Spain).

There is evidence for the influence of socioeconomic status (SES) on healthy behaviours but the effect of social mobility (SM) is not yet well known. This study aims to analyse the influence of origin and destination SES (O-SES and D-SES) and SM on healthy behaviours and co-occurrence, from an integrated gender and age perspective. Data were obtained from the controls of MCC-Spain between 2008-2013 (3,606 participants). Healthy behaviours considered: healthy diet, moderate alcohol consumption, non-smoking and physical activity. SM was categorized as stable high, upward, stable medium, downward or stable low. Binary and multinomial logistic regression models were adjusted. Those aged <65, with a low O-SES, D-SES and stable low SM are less likely to have healthy behaviours in the case of both women (physically active: OR = 0.65 CI = 0.45-0.94, OR = 0.71 CI = 0.52-0.98, OR = 0.61 CI = 0.41-0.91) and men (non-smokers: OR = 0.44 CI = 0.26-0.76, OR = 0.54 CI = 0.35-0.83, OR = 0.41 CI 0.24-0.72; physically active: OR = 0.57 CI = 0.35-0.92, OR = 0.64 CI = 0.44-0.95, OR = 0.53 CI = 0.23-0.87). However, for those aged ≥65, this probability is higher in women with a low O-SES and D-SES (non-smoker: OR = 8.09 CI = 4.18-15.67, OR = 4.14 CI = 2.28-7.52; moderate alcohol consumption: OR = 3.00 CI = 1.45-6.24, OR = 2.83 CI = 1.49-5.37) and in men with a stable low SM (physically active: OR = 1.52 CI = 1.02-1.26). In the case of men, the same behaviour pattern is observed in those with a low O-SES as those with upward mobility, with a higher probability of co-occurring behaviours (three-to-four behaviours: OR = 2.00 CI = 1.22-3.29; OR = 3.13 CI = 1.31-7.48). The relationship of O-SES, D-SES and SM with healthy behaviours is complex and differs according to age and gender.

Alcohol consumption during pregnancy and risk of small-for-gestational-age newborn.

BACKGROUND: Contradictory results have been published on the association of alcohol consumption during pregnancy with perinatal outcomes, including the risk of small for gestational age newborn. AIM: To determine whether alcohol consumption during pregnancy is associated with the risk of small for gestational age newborn. METHOD: A case-control study with 518 pairs of pregnant Spanish women in five hospitals was conducted; cases were women with small for gestational age newborn and age-matched (±2years) controls were women with non-small for gestational age newborn. Data were gathered on demographic characteristics, socioeconomic status, toxic habits, and diet. Alcohol intake was recorded with a self-administered 137 food frequency questionnaire and with a personal interview, Alcohol intake was categorized -. Agreement in alcohol intake results between direct interview and frequency food questionnaire was evaluated with the Kappa index. Crude and adjusted odds ratios and their 95% confidence intervals were estimated by conditional logistic regression. FINDINGS: Poor agreement was observed between food frequency questionnaire and personal interview results for both cases (κ=0.23) and controls (κ=0.14). A food frequency questionnaire-recorded intake of less than 4g/day was associated with a significantly lower odds ratios for small for gestational age newborn (odds ratios=0.62, 95% confidence intervals, 0.43-0.88), whereas an interview-recorded intake of <4g/day was not related to small for gestational age newborn (odds ratios=0.86, 95% confidence intervals, 0.49-1.54). CONCLUSIONS: A very moderate alcohol intake during pregnancy may have a negative association with the risk of having a small for gestational age newborn.

Factors associated with insomnia in pregnancy: A prospective Cohort Study.

OBJECTIVE: To quantify insomnia and their components in a longitudinal cohort of pregnant women and factors associated with insomnia. STUDY DESIGN: A prospective cohort of 486 healthy singleton pregnancies assembled before the 14th gestational week (February 2013 to March 2016). Insomnia data were collected pre-gestationally, in each trimester and six months post-partum, analysing five different moments. Multiple logistic regression analysis was performed to generate adjusted Odds Ratios (aOR) with 95% confidence intervals (CI) of determinants of insomnia in each trimester, defined using Athens Insomnia Scale (AIS) as score ≥8. RESULTS: Insomnia prevalence was 6.1% (3.9-8.9) pre-gestational, 44.2% (39.3-49.6) in first trimester (T1), 46.3% (41.9-51.3) in second (T2) and 63.7% (57.7-67.8) in third trimester (T3). Post-gestational insomnia was 33.2% (28.2-37.9) (p < 0.001 pre-gestational vs T1, T2 vs T3 and T3 vs after pregnancy). There was worsening mean AIS score, from: 2.34 before pregnancy to 9.87 in T3 because the deterioration of nighttime sleep, in absolute terms, but daytime impact was higher in T1. Previous trimester insomnia was associated with insomnia in T2 (aOR = 4.21, 95% CI 2.78-6.37) and T3 (aOR = 4.43, 95% CI 2.77-7.08). Pre-gestational insomnia was determinant of insomnia in T1 (aOR 12.50, 95% CI 3.58-43.60) and obesity was associated with insomnia in T3 (aOR = 2.30, 95% CI 0.99-5.32). On the contrary, moderate physical activity reduced the odds of insomnia in T3 (aOR 0.65, 95% CI 0.40-1.03). CONCLUSIONS: Insomnia prevalence was high from the beginning of pregnancy, associated with pre-gestational insomnia. In late pregnancy, two out of three pregnant women suffering insomnia. Insomnia prevention should be targeted particularly to those with high body mass index and pre-gestational insomnia.

Bacterial viability on chemically modified silicon nanowire arrays.

The global threat of antimicrobial resistance is driving an urgent need for novel antimicrobial strategies. Functional surfaces are essential to prevent spreading of infection and reduce surface contamination. In this study we have fabricated and characterized multiscale-functional nanotopographies with three levels of functionalization: (1) nanostructure topography in the form of silicon nanowires, (2) covalent chemical modification with (3-aminopropyl)triethoxysilane, and (3) incorporation of chlorhexidine digluconate. Cell viability assays were carried out on two model microorganisms E. coli and S. aureus over these nanotopographic surfaces. Using SEM we have identified two growth modes producing distinctive multicellular structures, i.e. in plane growth for E. coli and out of plane growth for S. aureus. We have also shown that these chemically modified SiNWs arrays are effective in reducing the number of planktonic and surface-attached microorganisms.

Galanin-(1-16) modulates 5-HT1A receptors in the ventral limbic cortex of the rat.

The aim of the present study was to evaluate whether galanin-(1-16) of the rat and porcine type and rat galanin-(1-29) can modulate the 5-HT1A receptors, using [3H]8-OH-DPAT as a radioligand, in membrane preparations from the ventral limbic cortex of the rat. Galanin-(1-16) produced a concentration dependent increase in the Kd value of [3H]8-OH-DPAT binding sites with a maximal effect of approximately 61% at 30 nM without changing the Bmax values. The galanin antagonist M35 blocked these effects. Rat galanin produced the same pattern of response but was less potent and effective. These results indicate the existence of a galanin receptor subtype in the ventral limbic cortex mainly recognizing N-terminal galanin fragments and capable of more strongly modulating 5-HT1A receptors than cloned galanin receptors.

Atropine and glycopyrronium show similar binding patterns to M2 (cardiac) and M3 (submandibular gland) muscarinic receptor subtypes in the rat.

Atropine and glycopyrronium are frequently used for premedication to reduce oral and respiratory secretions and prevent bradycardia. Glycopyrronium is said to have similar antisialagogue effects, but is less likely to cause significant tachycardia than atropine. Different antimuscarinic receptor selectivity patterns could explain the differences. The aim of this investigation was to determine the possible selectivity of glycopyrronium for M2 and M3 muscarinic receptor subtypes. Muscarinic receptor subtypes in Wistar rat ventricle and submandibular gland homogenates were characterized with [3H]-N-methylscopolamine ([3H]-NMS) by ligand binding studies. Inhibition of [3H]-NMS binding by non-labelled compounds showed the following order: in rat ventricle: glycopyrronium > atropine >> otenzepad > hexahydrosiladiphenidol (HHSiD) > pirenzepine; in rat submandibular gland: glycopyrronium > atropine >> HHSiD >> pirenzepine > otenzepad. These were similar to the expected order of frequency of M2 and M3 subtypes, respectively. Glycopyrronium showed similarly high affinities for both M2 (Ki = 1.889 (SEM 0.049) nmol litre-1) and M3 (Ki = 1.686 (0.184) nmol litre-1) subtypes. Glycopyrronium bound to a homogeneous population of binding sites in both tissues and showed no selectivity for M2 or M3 muscarinic receptor subtypes.

Otenzepad shows two populations of binding sites in human gastric smooth muscle.

Cholinergic agonists and antagonists frequently used for gastrointestinal motility disorders often produce adverse effects. A possible explanation for this is the presence of similar muscarinic receptor subtypes on smooth muscle from different gastrointestinal organs. The aim of this study was to characterize muscarinic receptor subtypes in human gastric smooth muscle with receptor binding methods. N-[3H]Methylscopolamine ([3H]NMS) saturation experiments showed a homogeneous population of noninteracting binding sites (KD = 0.76 +/- 0.07 nM, Bmax = 46.94 +/- 3.69 fmol/mg of tissue protein, nH = 0.99 +/- 0.01). The rank order of inhibition of [3H]NMS binding by nonlabelled compounds was atropine >> otenzepad >> pirenzepine. Atropine and pirenzepine bound to a homogeneous population of binding sites. The inhibition of [3H]NMS binding by otenzepad showed two populations of receptors (nH < 1, p < 0.01), whose apparent Ki1 of 298 +/- 40 nM and apparent Ki2 of 3.463 +/- 0.62 mM were similar to those reported for the M2 and M3 muscarinic receptor subtypes. The M2 subtype was the more abundant of the two, representing 79.12 +/- 5.48% of the total population. We conclude that two muscarinic receptor subpopulations similar to the M2 and M3 subtypes are present in human gastric smooth muscle and that the M2-like receptor is the more abundant of the two.

Muscarinic receptor subtypes in human and rat colon smooth muscle.

Muscarinic receptor subtypes in human and rat colon smooth muscle homogenates were characterized with [3H]N-methylscopolamine ([3H]NMS) by ligand binding studies. [3H]NMS saturation experiments show the existence of a homogeneous population of non-interacting binding sites with similar affinity (KD values of 1.38 +/- 0.20 nM in human colon smooth muscle and 1.48 +/- 0.47 nM in rat colon smooth muscle) and with Hill slopes close to unity in both samples of tissue. However, a significant (P less than 0.01) increase in muscarinic receptor density (Bmax) is found in human colon (29.9 +/- 2.9 fmol/mg protein) compared with rat colon (17.2 +/- 1.5 fmol/mg protein). Inhibition of [3H]NMS binding by non-labelled compounds shows the following order in human colon: atropine greater than AF-DX 116 greater than pirenzepine. Whereas in rat colon the rank order obtained is atropine greater than pirenzepine greater than AF-DX 116. Atropine and pirenzepine bind to a homogeneous population of binding sites, although pirenzepine shows higher affinity to bind to the sites present in rat colon (Ki = 1.08 +/- 0.08 microM) than those in human colon (Ki = 1.74 +/- 0.02 microM) (P less than 0.05). Similarly, IC50 values obtained in AF-DX 116 competition experiments were significantly different (P less than 0.01) in human colon (IC50 = 1.69 +/- 0.37 microM) than in rat colon (IC50 = 3.78 +/- 0.75 microM). Unlike atropine and pirenzepine, the inhibition of [3H]NMS binding by AF-DX 116 did not yield a simple mass-action binding curve (nH less than 1, P less than 0.01) suggesting the presence of more than one subtype of muscarinic receptor in both species. Computer analysis of these curves with a two binding site model suggests the presence of two populations of receptor. The apparent Ki1 value for the high affinity binding site is 0.49 +/- 0.07 microM for human colon smooth muscle and 0.33 +/- 0.05 microM for rat colon smooth muscle. The apparent Ki2 for the low affinity binding site is 8.01 +/- 1.0 microM for human samples and 6.07 +/- 1.1 microM for rat samples. These values are close enough to suggest that the first subtype of muscarinic receptor may be considered cardiac (M2) and the second subtype glandular (M3). The relative densities of the receptor subtypes are significantly different for both species. Human colon samples show the major densities of subtype M2, 22.62 +/- 1.11 fmol/mg protein, this represents 75.66 +/- 3.73% of the total receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

The pyrimido-pyrimidine derivative RA-642: a potent inhibitor of ferrous-induced lipid peroxidation in cell membranes.

The effects of three pyrimido-pyrimidine derivatives (RA-642, dipyridamole and mopidamol) on hydroxyl anion-induced lipid peroxidation in cell membranes from liver, brain, kidney, lung and heart rat tissue were studied using d-alpha-tocopherol as standard for lipid peroxidation. Ferrous sulfate and ascorbic acid (FeAs) were used to induce lipid peroxidation via the formation of hydroxyl anions. The products resulting from the reaction with thiobarbituric acid were taken to be indicators of lipid peroxidation. Thiobarbituric acid reactive substances (TBARS) were produced by different rat tissues in the following sequence: brain greater than liver greater than kidney greater than heart greater than lung. Dose-response and time-response curves were plotted for all compounds. Inhibiting concentrations, 50% (IC50), ranged from 0.3-1.4 microM for RA-642, and 2.5 and 4.6 microM for dipyridamole. In liver mitochondrial membranes, IC50s of these compounds were 0.4 +/- 0.2 and 5.8 +/- 1.2 microM, respectively. At 15 min after beginning TBARS production, dipyridamole and RA-642 did not exert any inhibitory effect.

Effect of triflusal and acetylsalicylic acid on platelet aggregation in human whole blood: influence of red blood cells and leukocytes.

A study has been made on the in vitro effect of triflusal, acetylsalicylic acid (ASA and their major metabolite, 2-hydroxy-4-trifluoromethylbenzoic acid (HTB), and salicylic acid (SA), on platelet aggregation in human whole blood. SA exhibited no significant antiplatelet effects (IC50 greater than 2mM) against several inducers; the IC50 values for the other compounds were: triflusal, 140 microM against ADP and 63.2 microM against collagen; HTB, 100 microM against ADP and 260 microM against collagen; ASA 687 microM against ADP and 9.3 microM against collagen. Red blood cells potentiate the antiaggregant effect of HTB and of triflusal, and to a lesser extent, that of ASA; leukocytes primarily potentiate the effect of ASA and, to a lesser extent, that of triflusal.

Platelet antiaggregatory effect of triflusal in human whole blood.

An in vitro and ex vivo study has been made to determine the inhibition of platelet aggregation in human whole blood (WB) and platelet rich plasma by triflusal and its main metabolite HTB (2-hydroxy-4-trifluoromethylbenzoic acid). Triflusal was administered orally at 300 mg x 2/day, for 15 days, to 13 healthy volunteers (ex vivo tests). Triflusal and HTB, at concentrations lower than 1 mM, produced a significant inhibition of platelet aggregation induced by ADP (2.5 microM, final) and collagen (1 microgram/ml, final) in PRP, while about 50% inhibition was induced in WB samples at 0.12 mM. Ex vivo studies also revealed a stronger inhibitory effect of triflusal in WB samples against several inducers; differences were particularly pronounced against ADP (10.6 times more potent in WB). These results suggest an important role of red blood cells and/or leukocytes in the mechanism of action of triflusal. The antiplatelet effect of triflusal in WB was modified when incubated with HTB at therapeutic concentrations. The IC50 value against collagen increased from 82 to 140 microM with 37.5 microM HTB, but decreased in a dose-dependent manner when incubated with higher concentrations of HTB, suggesting that inhibition of platelet cyclooxygenase by HTB masks its negative interaction with triflusal.

Platelet aggregation in human whole blood after chronic administration of aspirin.

We have used the impedance aggregometer to study the "ex vivo" effect of acetylsalicylic acid (ASA) in whole blood (WB) versus platelet-rich plasma (PRP) in 35 male healthy volunteers after 10 days of treatment with 25, 50, 125, 250, and 500 mg/day of ASA. Percent of inhibition of platelet aggregation was determinated at the end of treatment. A greater inhibition of platelet aggregation was observed in WB than in PRP when ASA was administrated at almost all doses. Maximal differences were at 25, 50, and 125 mg/day of ASA on adrenaline, collagen and arachidonic acid induced aggregation, and with 250 and 500 mg/day of ASA when ADP was used as aggregating agent. In the "in vitro" trials, IC-50 values of ASA on ADP and collagen induced aggregation were determined in platelet aggregation by the impedance method in both WB and PRP. ASA shows a lower IC-50 in WB than in PRP. When leucocytes were incubated in PRP samples, it effect was similar to the percent of inhibition in WB.

Effects of acetylsalicylic acid on platelet aggregation in male and female whole blood: an in vitro study.

We have used the impedance aggregometer to study the in vitro effect of acetylsalicylic acid (ASA) in whole blood (WB) versus platelet-rich plasma (PRP) using blood samples from 24 male and 24 female healthy volunteers. IC50 was calculated from dose-response curves of ADP-, adrenaline-, collagen- and arachidonic acid-induced aggregation. ASA inhibited platelet aggregation in WB with a lower IC50 than PRP in male and female samples; the greater differences between WB and PRP inhibitory effect of ASA were in collagen- and archidonic acid-induced aggregation. A higher ASA concentration was needed in order to produce half maximal inhibition of platelet aggregation in female than in male samples with both WB and PRP method, except when ADP was used as the aggregating agent in PRP.

Flavonoids from Inula viscosa.

Phytochemical study of the aerial parts of INULA VISCOSA resulted in the isolation of sixteen flavonoids. One of them, 3- O-acetylpadmatin [(2 R,3 R)-3-acetoxy-5,3',4'-trihydroxy-7-methoxyflavanone], was isolated for the first time as a natural compound. Ferulic aldehyde, 2-methylphloroacetophenone, inuviscolide and 2-deacetoxyxanthinin were also isolated.

Flavonoids from Chenopodium botrys.

From Chenopodium botrys, five flavonoids have been isolated: hispidulin, 1, salvigenin 2, 5-methylsalvigenin, 3, 7-methyleupatulin, 4 and sinensetin, 5. None of them have been previously reported from Ch. botrys.