Catechol-O-Methyltransferase (COMT) gene polymorphism and breast cancer risk in young women

Oestrogen exposure has long been considered to be a main risk factor of breast cancer. More recently, interest has also focused on the possible carcinogenic influence from oestrogen metabolites, such as catechol oestrogens. O-methylation, catalysed by Catechol-O-Methyltransferase (COMT), is one pathway by which the potentially carcinogenic catechol oestrogens can be inactivated. The gene coding for COMT protein contains a single-nucleotide polymorphism (SNP), resulting in an amino acid shift Val→Met, which has been shown to determine high- and low-activity configuration of the enzyme. We hypothesized that the low-activity allele, COMTMet, may be implicated in early onset breast cancer. In the present case–control study, including 126 young breast cancer patients (≤ 36 years) and 117 healthy female blood donors, we analysed the association between COMTMet genotype and risk of breast cancer. No significant difference in the frequency of low-/high-activity alleles was found between cases and controls, indicating that the polymorphism, as a single factor, may not contribute to breast carcinogenesis in young women. © 2001 Cancer Research Campaignhttp://www.bjcancer.co

Site-specific prolapse surgery. I. Reliability and durability of native tissue paravaginal repair

Introduction and hypothesis: This study aims to compare native tissue abdominal and vaginal paravaginal repair, and to investigate whether surgical outcome was independent of operative route. Methods: Retrospective comparison of 111 displacement cysto-urethrocoeles, repaired between 1997 and 2007. Treatment was by surgeon assignment, 52 women having abdominal (APVR) and 59 vaginal paravaginal repairs. Main outcome measures were same-site prolapse recurrence, time to failure and surgical complications. Initial reliability was evaluated by chi-square test, 10-year durability by Kaplan-Meier survival analysis and Cox proportional hazards model. Results: When examined in the Cox proportional hazards model, anatomic results of APVR were more durable than a mechanically analogous transvaginal operation done [95% CI=1.029-2.708 (p value=0.038)]. Kaplan-Meier curves plateaued within 38 months. Symptom resolution was broadly equivalent. Surgical complication rate was 3.6%. Conclusions: Site-specific re-suture of torn native tissue has genuine curative potential. Most of the long-term success was attributable to site-specific repair, rather than nonspecific scar formation.9 page(s

Multicentre phase II study of gemcitabine and cisplatin in malignant pleural mesothelioma

Malignant pleural mesothelioma is a notoriously chemoresistant tumour. However, a recent single institution study showed an impressive activity of gemcitabine and cisplatin. Our aim is to investigate the efficacy and toxicity of a gemcitabine and cisplatin combination in selected and chemo-naive patients with histologically proven malignant pleural mesothelioma. Method: Gemcitabine 1250 mg m−2 was administered on day 1 and day 8 and cisplatin 80 mg m−2 was administered on day 1 in a 3-week cycle with a maximum of six cycles. Response and toxicity evaluations were performed according to WHO and NCIC-CTC criteria. Pathology and radiology were centrally reviewed. Results show that in 25 evaluable patients, four PR were observed (ORR 16%, 95% CI 1–31%). Responses of seven patients were unevaluable. No unexpected toxicity occurred. Time to progression was 6 months (5–7 months) with a median survival from registration of 9.6 months (95% CI 8–12 months). In conclusion this trial excludes with 90% power a response rate of greater than 30% in patients with malignant pleural mesothelioma using a combination of gemcitabine and cisplatin at the proposed dose and schedule

HIV-Neutralizing Activity of Cationic Polypeptides in Cervicovaginal Secretions of Women in HIV-Serodiscordant Relationships

HIV exposed seronegative (HESN) women represent the population most in need of a prophylactic antiviral strategy. Mucosal cationic polypeptides can potentially be regulated for this purpose and we here aimed to determine their endogenous expression and HIV neutralizing activity in genital secretions of women at risk of HIV infection.Cervicovaginal secretions (CVS) of Kenyan women in HIV-serodiscordant relationships (HESN, n = 164; HIV seropositive, n = 60) and low-risk controls (n = 72) were assessed for the cationic polypeptides HNP1–3, LL-37 and SLPI by ELISA and for HIV neutralizing activity by a PBMC-based assay using an HIV primary isolate. Median levels of HNP1–3 and LL-37 in CVS were similar across study groups. Neither HSV-2 serostatus, nor presence of bacterial vaginosis, correlated with levels of HNP1–3 or LL-37 in the HESN women. However, an association with their partner's viral load was observed. High viral load (>10,000 HIV RNA copies/ml plasma) correlated with higher levels of HNP1–3 and LL-37 (p = 0.04 and 0.03, respectively). SLPI was most abundant in the low-risk group and did not correlate with male partner's viral load in the HESN women. HIV neutralizing activity was found in CVS of all study groups. In experimental studies, selective depletion of cationic polypeptides from CVS rendered the remaining CVS fraction non-neutralizing, whereas the cationic polypeptide fraction retained the activity. Furthermore, recombinant HNP1–3 and LL-37 could induce neutralizing activity when added to CVS lacking intrinsic activity.These findings show that CVS from HESN, low-risk, and HIV seropositive women contain HIV neutralizing activity. Although several innate immune proteins, including HNP1–3 and LL-37, contribute to this activity these molecules can also have inflammatory properties. This balance is influenced by hormonal and environmental factors and in the present HIV serodiscordant couple cohort study we show that a partner's viral load is associated with levels of such molecules

Understanding emotionally relevant situations in primary care dental practice: 1. Clinical situations and emotional responses

Background and aims. The stressful nature of dental practice is well established. Much less information is available on the coping strategies used by dentists and the emotions which underlie the stressful experience. Previous research has been almost exclusively questionnaire-based, limiting the range of emotions explored. This study used qualitative methods to explore the full extent of emotions and coping strategies associated with stressful events in primary dental practice. Method. Semi-structured interviews were conducted with 20 dentists in Lincoln and the surrounding area. Verbatim transcriptions were analysed using thematic analysis. Results. Participants reported a wide variety of stressful situations, consistent with the existing literature, which were associated with a diverse range of negative emotional responses including anxiety, anger and sadness. Dentists tended to have more difficulty identifying positive events and emotions. The designation of a situation as stressful or otherwise was dependent on the dentist's personal interpretation of the event. Data relating to the effects of stressors and the coping strategies used by dentists will be presented in subsequent papers. Conclusion. The situations which dentists find difficult are accompanied by a diverse set of emotions, rather than omnipresent 'stress.' This has implications for stress management programmes for those in dental practic

Do Dispersing Monkeys Follow Kin? Evidence from Gray-cheeked Mangabeys (Lophocebus albigena)

Among social vertebrates, immigrants may incur a substantial fitness cost when they attempt to join a new group. Dispersers could reduce that cost, or increase their probability of mating via coalition formation, by immigrating into groups containing first- or second-degree relatives. We here examine whether dispersing males tend to move into groups containing fathers or brothers in gray-cheeked mangabeys (Lophocebus albigena) in Kibale National Park, Uganda. We sampled blood from 21 subadult and adult male mangabeys in 7 social groups and genotyped them at 17 microsatellite loci. Twelve genotyped males dispersed to groups containing other genotyped adult males during the study; in only 1 case did the group contain a probable male relative. Contrary to the prediction that dispersing males would follow kin, relatively few adult male dyads were likely first- or second-degree relatives; opportunities for kin-biased dispersal by mangabeys appear to be rare. During 4 yr of observation, adult brothers shared a group only once, and for only 6 wk. Mean relatedness among adult males sharing a group was lower than that among males in different groups. Randomization tests indicate that closely related males share groups no more often than expected by chance, although these tests had limited power. We suggest that the demographic conditions that allow kin-biased dispersal to evolve do not occur in mangabeys, may be unusual among primates, and are worth further attention

A Polymorphism in a Gene Encoding Perilipin 4 Is Associated with Height but not with Bone Measures in Individuals from the Framingham Osteoporosis Study

There is increasing interest in identifying new pathways and candidate genes that confer susceptibility to osteoporosis. There is evidence that adipogenesis and osteogenesis may be related, including a common bone marrow progenitor cell for both adipocytes and osteoblasts. Perilipin 1 (PLIN1) and Perilipin 4 (PLIN4) are members of the PATS family of genes and are involved in lipolysis of intracellular lipid deposits. A previous study reported gender-specific associations between one polymorphism of PLIN1 and bone mineral density (BMD) in a Japanese population. We hypothesized that polymorphisms in PLIN1 and PLIN4 would be associated with bone measures in adult Caucasian participants of the Framingham Osteoporosis Study (FOS). We genotyped 1,206 male and 1,445 female participants of the FOS for four single-nucleotide polymorphism (SNPs) in PLIN1 and seven SNPs in PLIN4 and tested for associations with measures of BMD, bone ultrasound, hip geometry, and height. We found several gender-specific significant associations with the measured traits. The association of PLIN4 SNP rs8887, G>A with height in females trended toward significance after simulation testing (adjusted P = 0.07) and remained significant after simulation testing in the combined-sex model (adjusted P = 0.033). In a large study sample of men and women, we found a significant association between one SNP in PLIN4 and height but not with bone traits, suggesting that PATS family genes are not important in the regulation of bone. Identification of genes that influence human height may lead to a better understanding of the processes involved in growth and development

Timbre from Sound Synthesis and High-level Control Perspectives

International audienceExploring the many surprising facets of timbre through sound manipulations has been a common practice among composers and instrument makers of all times. The digital era radically changed the approach to sounds thanks to the unlimited possibilities offered by computers that made it possible to investigate sounds without physical constraints. In this chapter we describe investigations on timbre based on the analysis by synthesis approach that consists in using digital synthesis algorithms to reproduce sounds and further modify the parameters of the algorithms to investigate their perceptual relevance. In the first part of the chapter timbre is investigated in a musical context. An examination of the sound quality of different wood species for xylophone making is first presented. Then the influence of instrumental control on timbre is described in the case of clarinet and cello performances. In the second part of the chapter, we mainly focus on the identification of sound morphologies, so called invariant sound structures responsible for the evocations induced by environmental sounds by relating basic signal descriptors and timbre descriptors to evocations in the case of car door noises, motor noises, solid objects, and their interactions

Evolution of response dynamics underlying bacterial chemotaxis

© 2011 Soyer and Goldstein; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: The ability to predict the function and structure of complex molecular mechanisms underlying cellular behaviour is one of the main aims of systems biology. To achieve it, we need to understand the evolutionary routes leading to a specific response dynamics that can underlie a given function and how biophysical and environmental factors affect which route is taken. Here, we apply such an evolutionary approach to the bacterial chemotaxis pathway, which is documented to display considerable complexity and diversity.Results: We construct evolutionarily accessible response dynamics starting from a linear response to absolute levels of attractant, to those observed in current-day Escherichia coli. We explicitly consider bacterial movement as a two-state process composed of non-instantaneous tumbling and swimming modes. We find that a linear response to attractant results in significant chemotaxis when sensitivity to attractant is low and when time spent tumbling is large. More importantly, such linear response is optimal in a regime where signalling has low sensitivity. As sensitivity increases, an adaptive response as seen in Escherichia coli becomes optimal and leads to 'perfect' chemotaxis with a low tumbling time. We find that as tumbling time decreases and sensitivity increases, there exist a parameter regime where the chemotaxis performance of the linear and adaptive responses overlap, suggesting that evolution of chemotaxis responses might provide an example for the principle of functional change in structural continuity.Conclusions: Our findings explain several results from diverse bacteria and lead to testable predictions regarding chemotaxis responses evolved in bacteria living under different biophysical constraints and with specific motility machinery. Further, they shed light on the potential evolutionary paths for the evolution of complex behaviours from simpler ones in incremental fashion

Association of genetic variants of the histamine H1 and muscarinic M3 receptors with BMI and HbA1c values in patients on antipsychotic medication

Rationale: Antipsychotic affinity for the histamine H1 receptor and the muscarinic M3 receptor have been associated with the side effects weight gain, and development of diabetes, respectively. Objectives: We investigated polymorphisms of the histamine H1 (HRH1) and muscarinic acetylcholine receptor M3 (CHRM3) receptor genes for an association with body mass index (BMI) and glycated hemoglobin (HbA1c). Methods: We included 430 Caucasian patients with a non-affective psychotic disorder using antipsychotics for at least 3 months. Primary endpoints of the study were cross-sectionally measured BMI and HbA1c; secondary endpoints were obesity and hyperglycaemia. Two single-nucleotide polymorphisms (SNPs) in the HRH1 gene, rs346074 and rs346070, and one SNP in the CHRM3 gene, rs3738435, were genotyped. Our primary hypothesis in this study was an interaction between genotype on BMI and antipsychotic affinity for the H1 and M3 receptor. Results: A significant association of interaction between haplotype rs346074-rs346070 and BMI (p value 0.025) and obesity (p value 0.005) in patients using high-H1 affinity antipsychotics versus patients using low-H1 affinity antipsychotics was found. There was no association of CHRM3 gene variant rs3738435 with BMI, and we observed no association with HbA1c or hyperglycaemia in any of the variants. Conclusions: This study, for the first time, demonstrates a significant association between HRH1 variants and BMI in patients with a psychotic disorder using antipsychotics. In future, genotyping of HRH1 variants may help predicting weight gain in patients using antipsychotics