The c.-1639G > A polymorphism of the VKORC1 gene is a major determinant of the response to acenocoumarol in anticoagulated patients

Much of the variability in the sensitivity to warfarin in anticoagulated patients is associated with the c.-1639G > A polymorphism of the vitamin K-epoxide reductase (VKORC1) gene. However, its association with the acenocoumarol dose in patients under anticoagulant therapy has not been studied. The c.-1639G > A genotype of VKORC1 was determined in 113 patients on stable anticoagulation requiring low (n = 42), medium (n = 42) or high (n = 21) acenocoumarol doses. To evaluate the association between acenocoumarol requirements and the c.-1639G > A variant, multivariate logistic regression models were fitted, adjusting for age, gender, and the c.430C > T and c.1075A > C variants of cytochrome P450 2C9 (CYP2C9). A total of 90.5% of the patients in the low acenocoumarol dose group carried the A allele of VKORC1:c.-1639G > A. The A allele independently increased the odds of requiring a low acenocoumarol dose [odds ratio (OR) 9.4; 95% confidence interval (CI) 1.9-46.4; P = 0.006], especially when the homozygous form was present (OR 44.2; 95% CI 5.5-354.6; P < 0.001). The A allele was less frequent in the high dose group showing an inverse association with the requirement for high doses (OR 0.04; 95% CI 0.01-0.22; P < 0.001). The A allele of the c.-1639G > A polymorphism of VKORC1 is therefore associated with a low-dose requirement for acenocoumarol in patients receiving anticoagulant therapy.     

Structural insights into monoamine oxidase inhibitory potency and selectivity of 7-substituted coumarins from ligand- and target-based approaches

A new series of 3-, 4-, 7-polysubstituted coumarins have been designed and evaluated for their monoamine oxidase A and monoamine oxidase B (MAO-A and MAO-B) inhibitory potency. Substituents at position 7 consisted of a bridge of different physicochemical nature linking a phenyl ring to the coumarin scaffold. Structure-affinity and structure-selectivity relationships, derived through CoMFA-GOLPE and docking studies, revealed the key physicochemical interactions responsible for the observed MAO-B and MAO-A inhibitory potency and suggested the main structural determinants for high selectivity toward one of the two enzymatic isoforms. The predictive power of our models was proved with the design of a new inhibitor demonstrating an outstanding MAO-B affinity (pIC50 = 8.29) and the highest MAO-B selectivity (DeltapIC50 = 3.39) within the entire series of ligands examined herein.     

Principles and strategies for teaching therapeutic responses to self-harm

This paper explains the educational principles and strategies underpinning a nursing course offered at an Australian university. The course is entitled 'Self-harm and therapeutic responses' and explores contemporary theories and practices to improve understanding and responses to people who self-harm. The course aims to shape the practices of nurses in developing healthier clinical and social environments for people who self-harm.     

Functional neuroanatomy of the endocannabinoid system

Several components of the endocannabinoid system have been fully characterized. Among them are two types of cannabinoid receptors (termed CB1 and CB2), endogenous ligands for those receptors (referred to as "endocannabinoids"), and specific enzymes responsible for their degradation and inactivation. The study of the distribution and abundance of these elements in the central nervous system has provided the basis for the well-known effects of exogenous (both natural and synthetic) and endogenous cannabinoids. In addition, recent developments also support the idea that the endocannabinoid system plays a critical neuromodulatory role in the central nervous system. For instance, cannabinoid CB1 receptor activation is known to modify the release of several neurotransmitters, such as glutamate and gamma-aminobutyric acid. However, we still lack knowledge on fundamental aspects of the physiological roles of this system. Interestingly, changes in the distribution and activity of some of these components of the endocannabinoid system have been reported under different pathological conditions, suggesting their possible involvement in the pathogenesis of these diseases. As comprehensive excellent reviews have been recently published, the present review will focus only on the most recent advances in the field, considering a new perspective of the endocannabinoid system as composed of both neuronal and glial divisions.     

Hemiphiltrum rotated flap

In three patients of different ages, large resections of the philtrum have been repaired by rotating island flaps from the residual philtrum, leaving inconspicuous scars and no contour deformity. The rotated hemiphiltrum flap described here is an easy and safe procedure performed with local anesthesia that may be an effective cosmetic and functional repair of selected difficult surgical defects of the central upper lip involving the philtrum.     

Ethnographic reflections on communicative inequities,global health relationships,and two decades of HIV in the Bolivian press

ABSTRACT

This article draws on two decades of media representations of HIV, ethnographic research among people living with HIV, and an analysis of global health programms in Bolivia. In doing so, we chart the evolution of media representations in relation to the global health context and the implications of these representations for people living with HIV. Our overarching argument is that media discourses on HIV in Bolivia have consistently been produced in a context of an unequal balance of power between global health bodies and local actors. This power imbalance has enabled global health bodies operating in Bolivia to maintain authority in producing local narratives about HIV, even when these narratives do not adequately capture the particularities of the Bolivian context. The mismatch between dominant global health narratives that have infiltrated the Bolivian media and ethnographic realities can have deleterious effects on people living with HIV. We draw on the concept communicative inequities to highlight how global health bodies shape dominant media narratives and the ways these dominant narratives at times misrepresent ethnographic realities. Thus, a media analysis informed by ethnographic experiences offers a unique lens for interrogating the implications of global health interventions.     

Acromegalic features in growth hormone (GH)-deficient patients after long-term GH therapy

BACKGROUND: Craniofacial, hand, foot and somatic growth depend on normal GH secretion. Acromegalic features have been described in children with GH insensitivity after IGF-I treatment. We observed patients with acromegalic features such as increase of foot size, nose and jaw enlargement among our cases with GH deficiency, treated with standard recombinant (rh)GH doses. The aim of our study was to analyse the possible factors involved in the development of acromegalic features in these patients. PATIENTS: We evaluated 21 patients, 17 with combined pituitary hormone deficiency and four with isolated GH deficiency treated with rhGH (0.05-0.15 U/kg/day, sc, at night) for 2-12 years who achieved final height. IGF-I and IGFBP-3 were measured before and every 6 months during therapy and bone age was evaluated yearly. At the end of therapy, patients' hand and foot sizes and height were measured and plotted on nomograms for hand according to height and age, and foot size according to height. Lateral radiographs of the face were performed to obtain the linear measurement of the lower jaw length. RESULTS: Foot size was greater than 97th percentile in 8/21 patients and lower jaw length was greater than +2SD in 4/21 patients. Patients were classified in two groups: group 1 (with foot size greater than 97th percentile and/or lower jaw length greater than +2SD) consisted of 11 patients (six females); nine had combined pituitary hormone deficiency (six associated to hypogonadotrophic hypogonadism) and three had isolated GH deficiency; group 2 (with foot size smaller than 97th percentile and lower jaw length less than +2SD) consisted of 10 patients (seven boys); nine had combined pituitary hormone deficiency (six associated to hypogonadotrophic hypogonadism) and one with isolated GH deficiency. During treatment, IGF-I levels ranged from < or = 3 to +2SD and IGFBP-3 levels ranged from -3 to +2SD, in both groups. We observed no statistically significant differences between the two groups regarding chronological age, bone age, height at the beginning and at the end of therapy, pubertal development, duration of rhGH treatment and IGF-I and IGFBP-3 levels (P > 0.05). Foot size percentile exceeded final height percentile in 11/21 patients (seven girls). CONCLUSION: Long-term rhGH treatment with standard doses might be associated with acromegalic features (increased foot size and lower jaw measurements) in patients with GH deficiency who achieved final height, especially in girls. Neither the clinical nor the hormonal parameters, IGF-I and IGFBP-3 levels, were useful to predict the development of these features. Further studies are necessary to analyse the frequency of this side-effect and how to prevent it.