Discovery of Novel Reductive Elimination Pathway for 10-Hydroxywarfarin

Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend on a diversity of metabolic pathways. Cytochromes P450 play a major role in oxidizing R- and S-warfarin to 6-, 7-, 8-, 10-, and 4′-hydroxywarfarin, and warfarin alcohols form through a minor metabolic pathway involving reduction at the C11 position. We hypothesized that due to structural similarities with warfarin, hydroxywarfarins undergo reduction, possibly impacting their pharmacological activity and elimination. We modeled reduction reactions and carried out experimental steady-state reactions with human liver cytosol for conversion of rac-6-, 7-, 8-, 4′-hydroxywarfarin and 10-hydroxywarfarin isomers to the corresponding alcohols. The modeling correctly predicted the more efficient reduction of 10-hydroxywarfarin over warfarin but not the order of the remaining hydroxywarfarins. Experimental studies did not indicate any clear trends in the reduction for rac-hydroxywarfarins or 10-hydroxywarfarin into alcohol 1 and 2. The collective findings indicated the location of the hydroxyl group significantly impacted reduction selectivity among the hydroxywarfarins, as well as the specificity for the resulting metabolites. Based on studies with R- and S-7-hydroxywarfarin, we predicted that all hydroxywarfarin reductions are enantioselective toward R substrates and enantiospecific for S alcohol metabolites. CBR1 and to a lesser extent AKR1C3 reductases are responsible for those reactions. Due to the inefficiency of reactions, only reduction of 10-hydroxywarfarin is likely to be important in clearance of the metabolite. This pathway for 10-hydroxywarfarin may have clinical relevance as well given its anticoagulant activity and capacity to inhibit S-warfarin metabolism.

Brain 5-HT2A receptor binding and its neural network related to behavioral inhibition system

The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. To clarify the association between individual variations in behavioral inhibition system and brain 5-HT2A receptor availability and specify which brain networks were involved in healthy male subjects, using [18F]altanserin positron emission tomography and resting-state functional magnetic resonance imaging. Behavioral inhibition system score negatively correlated with 5-HT2A receptor availability in anterior cingulate cortex. A statistical model indicated that the behavioral inhibition system score was associated with 5-HT2A receptor availability, which was mediated by the functional connectivity between anterior cingulate cortex and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Individuals with high behavioral inhibition system displays low 5-HT2A receptor availability in anterior cingulate cortex and this cognitive control network links with prefrontal-cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.

Simulated proximity enhances perceptual and physiological responses to emotional facial expressions

Physical proximity is important in social interactions. Here, we assessed whether simulated physical proximity modulates the perceived intensity of facial emotional expressions and their associated physiological signatures during observation or imitation of these expressions. Forty-four healthy volunteers rated intensities of dynamic angry or happy facial expressions, presented at two simulated locations, proximal (0.5 m) and distant (3 m) from the participants. We tested whether simulated physical proximity affected the spontaneous (in the observation task) and voluntary (in the imitation task) physiological responses (activity of the corrugator supercilii face muscle and pupil diameter) as well as subsequent ratings of emotional intensity. Angry expressions provoked relative activation of the corrugator supercilii muscle and pupil dilation, whereas happy expressions induced a decrease in corrugator supercilii muscle activity. In proximal condition, these responses were enhanced during both observation and imitation of the facial expressions, and were accompanied by an increase in subsequent affective ratings. In addition, individual variations in condition related EMG activation during imitation of angry expressions predicted increase in subsequent emotional ratings. In sum, our results reveal novel insights about the impact of physical proximity in the perception of emotional expressions, with early proximity-induced enhancements of physiological responses followed by an increased intensity rating of facial emotional expressions.

Risk perception and behaviour during the COVID-19 pandemic: Predicting variables of compliance with lockdown measures

The COVID-19 pandemic and the measures to counteract it have highlighted the role of individual differences in evaluating and reacting to emergencies, and the challenges inherent in promoting precautionary behaviours. We aimed to explore the psychological and cognitive factors modulating behaviour and intentions during the national lockdown in Italy. We administered an online questionnaire (N = 244) that included tests for assessing personality traits (Temperament and Character Inventory; Locus of Control of Behaviour) and moral judgment (Moral Foundations Questionnaire), alongside behavioural economics tasks addressing different facets of risk attitude (loss aversion, risk aversion and delay discounting). We then assessed the extent to which individual variations in these dimensions modulated participants’ compliance with the lockdown norms. When assessing their joint contribution via multiple regressions, lockdown adherence was mostly predicted by internal locus of control, psycho-economic dimensions suggestive of long-sighted and loss-averse attitudes, as well as personality traits related to cautionary behaviour, such as harm avoidance, and the authority moral concern. These findings show that a multi-domain assessment of the factors underlying personal intentions, and thus driving compliance with government measures, can help predict individuals’ actions during health emergencies. This evidence points to factors that should be considered when developing interventions and communication strategies to promote precautionary behaviours.

Weaning among Colonists from Montreal and Environs

This paleochemical study explores the differences and similarities in weaning practices between two colonist populations buried in Montreal and its environs: the rural village cemetery of Pointe-aux-Trembles (PT, 1709–1843) and the urban Notre-Dame cemetery (ND, 1691–1796). Forty-six teeth (or individuals) were microsampled in both crown and root parts of the dentine (one to four and four to six sampling sites for deciduous and permanent teeth, respectively), totaling 56 microsamples for PT (seven M1, seven m1, and three m2) and 102 for ND (22 M1 and seven m1). For both sites, a general decrease of 1.3‰ in δ15N (ranging from 0.5‰ to 2.6‰) was observed between the first and last samples for permanent teeth (PT: five out of seven individuals; ND: 14 out of 22), and weaning seems to end around 2 years of age. As expected, in both parishes, weaning was mainly gradual (80%: PT; 86%: ND). An introduction of complementary food was also identified after 6 months of age (73%: PT; 81%: ND). The variation in δ15N profiles suggested other scenarios such as introduction of complementary foods just after birth (four PT and four ND), absence of breastfeeding (three PT and nine ND), and abrupt weaning (three ND). Environmental and socioeconomic factors might explain these individual variations, as infant feeding practices might have changed over time in these two growing and closely related parishes. Cette étude paléochimique explore les différences et les similitudes dans les pratiques de sevrage entre deux populations de colons enterrées à Montréal et ses environs : le cimetière rural du village de Pointe-aux-Trembles (PT, 1709–1843) et le cimetière urbain de Notre-Dame (ND, 1691–1796). Quarante-six dents (ou individus) ont été micro-échantillonnées dans la dentine de la couronne et des racines (1 à 4 et 4 à 6 sites d'échantillonnage pour les dents de lait et les dents permanentes respectivement), totalisant 56 micro-échantillons pour PT (7 M1, 7 m1 et 3 m2) et 102 pour ND (22 M1 et 7 m1). Pour les deux sites, une diminution du d 15N d’une moyenne de 1,3‰ (allant de 0,5 à 2,6‰) a été observé entre le premier et le dernier micro-échantillon pour les dents permanentes (PT : 5 sur 7 individus ; ND : 14 sur 22), et le sevrage semble se terminer vers l'âge de deux ans. Comme attendu, dans les deux paroisses, le sevrage a été principalement progressif (80 % : PT ; 86 % : ND). Une introduction d'aliments complémentaires a également été identifiée après l'âge de six mois (73 % : PT ; 81 % : ND). La variation des profils des valeurs de δ15N permet également de suggérer d'autres scénarios tels que : l'introduction d'aliments complémentaires juste après la naissance (4 PT et 4 ND), l'absence d'allaitement (3 PT et 9 ND) et un sevrage abrupt (3 ND). Des facteurs environnementaux et socio-économiques pourraient expliquer ces variations individuelles, car les pratiques d'alimentation des nourrissons pourraient avoir changé au fil du temps dans ces deux paroisses en pleine croissance et étroitement liées.

Cemeteries of the Great War by Sir Edwin Lutyens

En 1917 se le encargó al arquitecto británico sir Edwin Lutyens que hiciera diseños para los cementerios de guerra en el continente. El resultado fue casi 1000 cementerios y monumentos diseñados por Lutyens y otros arquitectos en Bélgica, norte de Francia y varios lugares de Asia. Bajo el liderazgo del director del Museo Británico, los arquitectos optaron por un estilo común, con la libertad de hacer variaciones individuales para cada cementerio relacionado con su contexto. Como resultado de estas dos ideas opuestas, hay dos elementos principales en cada cementerio, la ‘Piedra de Guerra’ diseñada por Lutyens y la Cruz del Sacrificio de Blomfield. Para los soldados desaparecidos, se erigieron enormes monumentos con sus nom- bres en las paredes como único recuerdo. Los cementerios más pequeños fueron diseñados por jóvenes arquitectos que estuvieron en el ejército durante la guerra. Hay lápidas en lugar de cruces para cada tumba según las diferentes condiciones religiosas de los soldados. Para Lutyens, el concepto de cementerio se basaba en la idea de una catedral verde, una iglesia al aire libre, rodeada de árboles como columnas. Esta idea se inspiró en la conocida arquitecta paisajista Getrude Jekyll. Gracias al mantenimiento por parte de la Commonwealth War Graves Commission, los cementerios todavía están en perfecto estado y juegan un papel importante en el recuerdo de la Primera Guerra Mundial. Already in 1917, the British architect sir Edwin Lutyens was asked to make designs for warcemeteries on the continent. In the end this resulted in almost 1000 cemeteries and monuments designed by Lutyens and other architects in Belgium, Northern France and other locations in Asia. Under leadership of the director of the British Museum, the architects have chosen for a common style, with the freedom to make individual variations for each cemetery related to the site. As a result of two opposing ideas there are two main elements on each cemetery, the War Stone designed by Lutyens and the Cross of Sacrifice by Blomfield. For the soldiers which were not found huge monuments were erected with their names on walls as their only surviving memory. The smaller cemeteries were designed by young architects who were in the army during the war. There are headstones instead of crosses for each grave due to the different religious background of the soldiers. For Lutyens the concept of a cemetery was based on the idea of green cathedral, a church in the open air, surrounded by trees as columns. For this idea he took advice from the well-known landscape architect Getrude Jekyll. Because of the maintenance by de Commonwealth War Graves Commission Still the cemeteries are still in perfect state and play an important role in the remembrance of the First World War.

Determining Risk Factors for Triple Whammy Acute Kidney Injury

Concurrent use of a diuretic, a renin-angiotensin system (RAS) inhibitor, and a non-steroidal anti-inflammatory drug (NSAID) significantly increases the risk of acute kidney injury (AKI). This phenomenon is known as "triple whammy". Diuretics and RAS inhibitors, such as an angiotensin converting enzyme inhibitor or angiotensin receptor blocker, are often prescribed in tandem for the treatment of hypertension, whereas some NSAIDs, such as ibuprofen, are available over the counter. As such, concurrent treatment with all three drugs is common. The goals of this study are to better understand the mechanisms underlying the development of triple whammy AKI and to identify physiological factors that may increase an individual's susceptibility. To accomplish these goals, we utilize computational models of long-term blood pressure regulation. These models include variables describing the heart and circulation, kidney function, sodium and water reabsorption in the nephron and the RAS and are parameterized separately for men and women. Hypertension is modeled as overactive renal sympathetic nervous activity. Model simulations suggest that individual variations in water intake, the myogenic response, and drug sensitivity may predispose patients with hypertension to develop triple whammy-induced AKI.

Evaluation of Antioxidant and Protease-inhibitory Potential of Ethanolic Extract of Myristica fragrans (Nutmeg)

Introduction: Myristica fragrans is an important commercial plant used for spices. The plant has been traditionally used as an anticancer, anti inflammatory, antioxidant, sedative hypnotics and antimicrobial agent. Plants have played an important role in maintaining human health & improving the quality of human life for thousands of years and have served humans well as valuable components of medicines. Methods: Ethanolic extract of myristica fragrans was obtained by hot percolation method. Preliminary Phytochemical screening of the extract was done .Antioxidant and anti inflammatory potential of ethanolic extract of myristica fragrans was analysed. The data were analysed statistically using two – way analysis of variance (ANOVA) and Tukey’s multiple range test to assess the significance of individual variations between the groups. In Tukey’s test, significance was considered at the level of p<0.05. Results: Ethanolic extract of Myristica fragrans (Nutmeg) was rich in the phytoconstituents such as alkaloids, flavonoids, terpenoids and saponins. IC50 of antioxidant activity of ethanolic extract of Myristica fragrans was found to be 300 µg/ml. IC50 of anti-inflammatory potential of the ethanolic extract of Myristica fragrans was found to be 360 µg/ml. Conclusion: From the study, it was evident that the ethanolic extract of myristica fragrans has significant antioxidant and anti-inflammatory potential. In future, the extract can be validated as a drug formulation.

POSTERIOR AURICULAR NERVE – A NOVEL LANDMARK FOR IDENTIFICATION OF THE FACIAL NERVE IN SUPERFICIAL PAROTIDECTOMY

ABSTRACT Background-Facial nerve identification and preservation is the most critical step in parotid surgery. Though there are described landmarks to locate the facial nerve trunk, they have individual variations. The posterior auricular nerve (PAN) is a branch of the facial nerve and is always present, it can be followed to reach the facial nerve trunk. MATERIALS AND METHODS A retrospective cohort study in which analysis of parotidectomy performed from January 2017 to November 2018 at our tertiary referral center was done. RESULTS A total of 23 parotidectomies were performed, of which 18 cases were pleomorphic adenoma. In four cases of pleomorphic adenoma we could clearly identify and preserve the PAN. Using PAN as the landmark the facial nerve trunk was located, all its peripheral branches were dissected and preserved. PAN identification narrows down the target area of dissection to identify the facial nerve trunk. CONCLUSION The posterior auricular branch of the facial nerve can be used as a standard landmark in parotid surgeries, that almost always leads to the facial nerve trunk. CLINICAL SIGNIFICANCE Though identification of PAN may be difficult in all cases, effort must be made to identify it under magnification. If done meticulously PAN can be an ideal landmark to identify facial nerve in parotid surgery. KEYWORDS Parotid surgery, Superficial Parotidectomy, Posterior auricular nerve, Facial nerve.