Improving effective contraception uptake through provision of bridging contraception within community pharmacies: findings from the Bridge-it Study process evaluation.

OBJECTIVE: To present process evaluation results from the Bridge-it Study, a pragmatic cluster randomised cross-over trial to improve effective contraception uptake through provision of the progestogen only pill (POP) plus sexual and reproductive health (SRH) clinic rapid-access to women presenting to community pharmacies for emergency contraception (EC). RESEARCH DESIGN AND METHODS: A multimethod process evaluation was conducted to assess intervention implementation, mechanisms of change and contextual factors. Data were gathered from screening logs (n=599), observations of pharmacist training, analysis of data from 4-month follow-up questionnaires (n=406), monitoring of contemporaneous events and qualitative interviews with 22 pharmacists, 5 SRH clinical staff and 36 study participants in three participating UK sites in Lothian, Tayside and London. RESULTS: The intervention was largely delivered as intended and was acceptable. Pharmacists', SRH clinical staff and participants' accounts highlighted that providing a supply of POP with EC from the pharmacy as routine practice may have positive impacts on contraceptive practices in the short term, and potentially longer term. Key mechanisms of change included ease of access, increased awareness of contraception and services, and greater motivation and perceptions of self-efficacy. Few participants took up the offer to attend an SRH service (rapid-access component), and existing barriers within the SRH context were apparent (eg, lack of staff). Participant accounts highlight persistent barriers to accessing and using routine effective contraception remain. CONCLUSIONS: Implementation appeared to be acceptable and feasible, highlighting the potential for provision of POP within EC consultations as routine practice in community pharmacies. However, lack of engagement with the rapid access component of the intervention and existing barriers within the SRH context suggest that signposting to SRH services may be sufficient. Wider implementation should consider ways to address key implementation challenges to increase effectiveness and sustainability, and to overcome persistent barriers to accessing and using effective contraception. TRIAL REGISTRATION NUMBER: ISRCTN70616901.

Pragmatic cluster randomised cohort cross-over trial to determine the effectiveness of bridging from emergency to regular contraception: the Bridge-It study protocol.

INTRODUCTION: Oral emergency contraception (EC) can prevent unintended pregnancy but it is important to start a regular method of contraception. Women in the UK usually access EC from a pharmacy but then need a subsequent appointment with a general practitioner or a sexual and reproductive health (SRH) service to access regular contraception. Unintended pregnancies can occur during this time. METHODS AND ANALYSIS: Bridge-It is a pragmatic cluster randomised cohort cross-over trial designed to determine whether pharmacist provision of a bridging supply of a progestogen-only pill (POP) plus rapid access to a local SRH clinic, results in increased uptake of effective contraception and prevents more unintended pregnancies than provision of EC alone. Bridge-It involves 31 pharmacies in three UK regions (London, Lothian and Tayside) aiming to recruit 626-737 women. Pharmacies will give EC (levonorgestrel) according to normal practice and recruit women to both intervention and the control phases of the study. In the intervention phase, pharmacists will provide the POP (desogestrel) and offer rapid access to an SRH clinic. In the control phase, pharmacists will advise women to attend a contraceptive provider for contraception (standard care).Women will be asked 4 months later about contraceptive use. Data linkage to abortion registries will provide abortion rates over 12 months. The sample size is calculated on the primary outcome of effective contraception use at 4 months (yes/no) with 90% power and a 5% level of significance. Abortion rates will be an exploratory secondary analysis. Process evaluation includes interviews with pharmacists, SRH clinicians and women. Cost-effectiveness analysis will use a healthcare system perspective and be expressed as incremental cost-effectiveness ratio. ETHICS AND DISSEMINATION: Ethical approval was received from South East Scotland REC June 2017. Results will be published in peer-reviewed journals and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN70616901.

Clinical characteristics in subjects with NLRP3 V198M diagnosed at a single UK center and a review of the literature.

INTRODUCTION: Mutations in the NLRP3 gene are associated with the dominantly inherited cryopyrin-associated periodic syndrome (CAPS). The significance of the V198M variant is unclear; it has been reported in association with various CAPS phenotypes and as a variant of uncertain consequence. The aim of this study was to characterize the clinical phenotypes and treatments in individuals with V198M assessed in a single UK center. METHODS: DNA samples from 830 subjects with fever syndromes or a family history of CAPS were screened for mutations in the NLRP3 gene with polymerase chain reaction (PCR) and sequencing. A detailed medical history was available in all cases. Inflammatory disease activity was monitored monthly with measurements of serum amyloid A protein (SAA) and C-reactive protein (CRP) in symptomatic individuals. RESULTS: NLRP3 V198M was identified in 19 subjects. It was found in association with CAPS in five cases, in one patient with Schnitzler syndrome, in three patients who also had a nucleotide alteration in another fever gene, and in three other patients with evidence of an autoinflammatory phenotype. Seven asymptomatic individuals were detected during screening of family members. CONCLUSIONS: The NLRP3 V198M variant shows variable expressivity and reduced penetrance. It may be associated with classical inherited or apparently sporadic CAPS and with atypical autoinflammatory disease of varying severity, intriguingly including Schnitzler syndrome. The factors that influence the pathogenic consequences of this variant remain unknown. However, the remarkable response to interleukin 1 (IL-1) blockade in all but one individual in our series confirms that their clinical features are indeed mediated by IL-1.

Surveillance of survivors: follow-up after risk-reducing salpingo-oophorectomy in BRCA 1/2 mutation carriers.

OBJECTIVES: To characterize the post-operative care of BRCA1 and BRCA2 mutation carriers who undergo risk-reducing salpingo-oophorectomy (RRSO). METHODS: BRCA1 and BRCA2 mutation carriers from our Cancer Risk Program who elected RRSO were sent questionnaires regarding their post-surgical surveillance and treatment for menopause symptoms, primary peritoneal cancer and bone loss. RESULTS: In 51 mutation carriers who were surveyed a median of 6 years after RRSO, 24 (47%) received dual-energy X-ray absorptiometry (DXA) testing, yearly CA-125 serum testing and yearly pelvic examination. Three women received none of these examinations in follow-up. Respondents reported an average of 3.5 menopausal symptoms (range 0-9). The mean number of menopausal symptoms reported by respondents using HRT was 2.8, compared to 3.9 symptoms reported by women not using HRT (p=0.06). Six of 10 (60%) subjects who reported no history of DXA bone scan, and 10 of 15 (67%) subjects who reported no post-surgical CA-125 serum monitoring noted that their physicians "did not recommend" testing. Two out of six symptomatic women who were younger than 50 (33%) who had no other contraindication to the use of HRT reported their non-use was because their care providers "advised against" HRT use. CONCLUSION: We believe that the lack of post-RRSO health care guidelines has resulted in inconsistent care for this cohort of patients. We proposed that national guidelines be developed to standardize care with the goal of optimizing long term survival in this unique cohort of young cancer previvors.

Predictors of 5 year survival following hip fracture.

BACKGROUND: This study aims to assess the mortality associated with hip fracture at 5 years in a geriatric population, and evaluate the influence of age, cognitive state, mobility and residential status on long term survival after hip fracture. METHODS: A prospective audit was carried out of all patients with a hip fracture admitted to a university hospital over a 4 year period. Data from 2640 patients were analysed and multivariate analysis used to indicate the important variables predicting mortality. Patients fulfilling the criteria of age<80 years, Abbreviated Mental Test Score (AMT)≥7/10, independently mobile and admitted from own home were put into group A (low risk group). Patients not meeting the criteria were placed into group B (high risk group). RESULTS: 2640 patients fitted the inclusion criteria, 482 in group A and 2158 in group B. 850 patients (43.1%) died in their first year following hip fracture. 302 patients (63%) of group A were still alive at 5 years in comparison with only 367 (17%) of group B. Overall, 669 (25%) patients survived for 5 years. Increased survival was shown for the following variables: age<80 years RR 5.27 (p<0.01), AMT≥7/10 RR 6.03 (p<0.01), independent mobility RR 2.63 (p<0.01) and admitted from own home RR 4.52 (p<0.01). CONCLUSIONS: These findings will allow for early recognition of those patients with an increased chance of long-term survival following hip fracture. Such patients may be suitable for surgical treatment, such as total hip replacement, which has a good long-term outcome.

Efeito do exercício físico e do polimorfismo T-786C na pressão arterial e no fluxo sanguíneo de idosas / Effect of physical activity and t-786C polymorphism in blood pressure and blood flow in the elderly / Efecto del ejercicio físico y del polimorfismo T-786C en la presión arterial y en el flujo sanguíneo de añosas

FUNDAMENTO: O polimorfismo T-786C do gene da sintetase do óxido nítrico endotelial (eNOS) e a produção de ânion superóxido podem diminuir a produção e biodisponibilidade do óxido nítrico, comprometendo o grau de vasodilatação, podendo este efeito ser revertido pelo exercício físico. OBJETIVO: Investigar a influência do treinamento aeróbico e do polimorfismo T-786C nas concentrações dos metabólitos do óxido nítrico (NOx), no fluxo sanguíneo (FS) e na pressão arterial (PA). MÉTODOS: Trinta e duas idosas pré-hipertensas (59 ± 6 anos) foram separadas em dois grupos de acordo com o polimorfismo T-786C (TT e TC+CC). Foram analisadas as concentrações de NOx (plasma) e fluxo sanguíneo por pletismografia de oclusão venosa em repouso, 1, 2 e 3 minutos pós-oclusão (FS-0, FS-1, FS-2, FS-3, respectivamente). As avaliações foram realizadas antes e após 6 meses de um programa de exercício aeróbico. RESULTADOS: Nas avaliações pré-treinamento, os níveis de NOx foram menores no grupo TC+CC em relação ao grupo TT. O grupo TT apresentou correlações entre NOx e FS-0 (r = 0,6) e pressão arterial diastólica (PAD) e FS-0 (r = -0,7), porém nenhuma correlação foi encontrada no grupo TC+CC. Nas avaliações pós-treinamento, ocorreram correlações entre NOx e FS-0 (r = 0,6) e nas mudanças do NOx e PAD (r = -0,6) no grupo TT. Também foram obtidas correlações entre PAD e FS-1 (r = -0,8), PAD e FS-2 (r = -0,6), PAD e FS-3 (r = -0,6), nas mudanças entre NOx e FS-1 (r = 0,8) e mudanças do NOx e PAD (r = -0,7) no grupo TC+CC. CONCLUSÃO: Conclui-se que 6 meses de exercício aeróbico podem contribuir para aumentar as relações existentes entre NO, PA e FS em idosas portadores do alelo C.

BACKGROUND: The T-786C polymorphism of the gene for endothelial nitric oxide synthase (eNOS) and superoxide anion production may reduce production and bioavailability of nitric oxide, affecting the degree of vasodilation. This effect can be reversed by exercise. OBJECTIVE: To investigate the influence of aerobic training and T-786C polymorphism in the concentrations of nitric oxide metabolites (NOx) in blood flow (BF) and blood pressure (BP). METHODS: Thirty-two elderly pre-hypertensive women (59 ± 6 years old) were divided into two groups according to the T-786C polymorphism (TT and TC + CC). We analyzed the concentrations of NOx (plasma) and blood flow by venous occlusion plethysmography at rest, 1, 2 and 3 minutes post-occlusion (BF-0, BF-1 BF-2 BF-3, respectively). Evaluations were performed before and after 6 months of a program of aerobic exercise. RESULTS: In the pre-training evaluations, NOx levels were lower in TC + CC group than in TT group. The TT group showed correlations between NOx and BF-0 (r = 0.6) and diastolic blood pressure (DBP) and BF-0 (r = -0.7), but no correlation was found in TC + CC group. In the post-training evaluations, there were correlations between NOx and BF-0 (r = 0.6) and the changes in NOx and DBP (r = -0.6) in TT group. There were also correlations between DBP and BF-1 (r = -0.8), DBP, and BF-2 (r = -0.6), DBP, and BF-3 (r = -0.6), in the changes between NOx and BF-1 (r = 0.8) and changes in NOx and DBP (r = -0.7) in TC + CC group. CONCLUSION: It was concluded that 6 months of aerobic exercise can increase the relationship between NO, BP and BF in elderly of allele C carriers.

FUNDAMENTO: El polimorfismo T-786C del gen de la sintetasa del óxido nítrico endotelial (eNOS) y la producción de anión superóxido pueden disminuir la producción y biodisponibilidad del óxido nítrico, comprometiendo el grado de vasodilatación, pudiendo este efecto ser revertido por el ejercicio físico. OBJETIVO: Investigar la influencia del entrenamiento aeróbico y del polimorfismo T-786C en las concentraciones de los metabolitos del óxido nítrico (NOx), en el flujo sanguíneo (FS) y en la presión arterial (PA). MÉTODOS: Treinta y dos añosas prehipertensas (59 ± 6 años) fueron separadas en dos grupos de acuerdo con el polimorfismo T-786C (TT y TC+CC). Fueron analizadas las concentraciones de NOx (plasma) y flujo sanguíneo por pletismografía de oclusión venosa en reposo, 1, 2 y 3 minutos post oclusión (FS-0, FS-1, FS-2, FS-3, respectivamente). Las evaluaciones fueron realizadas antes y después de 6 meses de un programa de ejercicio aeróbico. RESULTADOS: En las evaluaciones pre entrenamiento, los niveles de NOx fueron menores en el grupo TC+CC en relación al grupo TT. El grupo TT presentó correlaciones entre NOx y FS-0 (r = 0,6) y presión arterial diastólica (PAD) y FS-0 (r = -0,7), sin embargo ninguna correlación fue encontrada en el grupo TC+CC. En las evaluaciones post entrenamiento, ocurrieron correlaciones entre NOx y FS-0 (r = 0,6) y en los cambios del NOx y PAD (r = -0,6) en el grupo TT. También fueron obtenidas correlaciones entre PAD y FS-1 (r = -0,8), PAD y FS-2 (r = -0,6), PAD y FS-3 (r = -0,6), en los cambios entre NOx y FS-1 (r = 0,8) y cambios del NOx y PAD (r = -0,7) en el grupo TC+CC. CONCLUSIÓN: Se concluye que 6 meses de ejercicio aeróbico pueden contribuir a aumentar las relaciones existentes entre NO, PA y FS en añosas portadoras del alelo C.

[Effect of physical activity and t-786C polymorphism in blood pressure and blood flow in the elderly]. / Efeito do exercício físico e do polimorfismo T-786C na pressão arterial e no fluxo sanguíneo de idosas.

BACKGROUND: the T-786C polymorphism of the gene for endothelial nitric oxide synthase (eNOS) and superoxide anion production may reduce production and bioavailability of nitric oxide, affecting the degree of vasodilation. This effect can be reversed by exercise. OBJECTIVE: to investigate the influence of aerobic training and T-786C polymorphism in the concentrations of nitric oxide metabolites (NOx) in blood flow (BF) and blood pressure (BP). METHODS: thirty-two elderly pre-hypertensive women (59 ± 6 years old) were divided into two groups according to the T-786C polymorphism (TT and TC + CC). We analyzed the concentrations of NOx (plasma) and blood flow by venous occlusion plethysmography at rest, 1, 2 and 3 minutes post-occlusion (BF-0, BF-1 BF-2 BF-3, respectively). Evaluations were performed before and after 6 months of a program of aerobic exercise. RESULTS: In the pre-training evaluations, NOx levels were lower in TC + CC group than in TT group. The TT group showed correlations between NOx and BF-0 (r = 0.6) and diastolic blood pressure (DBP) and BF-0 (r = -0.7), but no correlation was found in TC + CC group. In the post-training evaluations, there were correlations between NOx and BF-0 (r = 0.6) and the changes in NOx and DBP (r = -0.6) in TT group. There were also correlations between DBP and BF-1 (r = -0.8), DBP, and BF-2 (r = -0.6), DBP, and BF-3 (r = -0.6), in the changes between NOx and BF-1 (r = 0.8) and changes in NOx and DBP (r = -0.7) in TC + CC group. CONCLUSION: it was concluded that 6 months of aerobic exercise can increase the relationship between NO, BP and BF in elderly of allele C carriers.

Effects of aerobic exercise on the blood pressure, oxidative stress and eNOS gene polymorphism in pre-hypertensive older people.

The polymorphisms of endothelial nitric oxide synthase (eNOS) are associated with reduced eNOS activity. Aerobic exercise training (AEX) may influence resting nitric oxide (NO) production, oxidative stress and blood pressure. The purpose of this study was to investigate the effect of AEX on the relationship among blood pressure, eNOS gene polymorphism and oxidative stress in pre-hypertensive older people. 118 pre-hypertensive subjects (59 ± 6 years) had blood samples collected after a 12 h overnight fast for assessing plasma NO metabolites (NOx) assays, thiobarbituric acid reactive substances (T-BARS) and superoxide dismutase activity (ecSOD). eNOS polymorphism (T-786C and G-894T) was done by standard PCR methods. All people were divided according to the genotype results (G1: TT/GG, G2: TT/GT + TT, G3: TC + CC/GG, G4: TC + CC/GT + TT). All parameters were measured before and after 6 months of AEX (70% of VO(2 max)). At baseline, no difference was found in systolic and diastolic blood pressure, ecSOD and T-BARS activity. Plasma NOx levels were significantly different between G1 (19 ± 1 µM) and G4 (14.2 ± 0.6 µM) and between G2 (20.1 ± 1.7 µM) and G4 (14.2 ± 0.6 µM). Therefore, reduced NOx concentration in G4 group occurred only when the polymorphisms were associated, suggesting that these results are more related to genetic factors than NO-scavenging effect. After AEX, the G4 increased NOx values (17.2 ± 1.2 µM) and decreased blood pressure. G1, G3 and G4 decreased T-BARS levels. These results suggest the AEX can modulate the NOx concentration, eNOS activity and the relationship among eNOS gene polymorphism, oxidative stress and blood pressure especially in C (T-786C) and T (G-894T) allele carriers.

Plasma nitrate/nitrite levels are unchanged after long-term aerobic exercise training in older adults.

Reduced nitric oxide (NO) production and bioactivity is a major contributor to endothelial dysfunction. Animal data suggest that improvements in endothelial function in response to aerobic exercise training may depend on the duration of the training program. However, no studies have examined changes in NO (as assessed by the major NO metabolites, nitrate and nitrite, NO(x)) after long-term training in humans. In addition, aging may impair the ability of the vasculature to increase NO with exercise. Thus, we determined whether 24 weeks of aerobic exercise training increases plasma NO(x) levels in sedentary older adults. We also examined changes in forearm blood flow (FBF) at rest and during reactive hyperemia as a measure of vasomotor function. Plasma NO(x) levels were measured in 82 men and women using a modified Griess assay. FBF was assessed in a subset of individuals (n = 15) using venous occlusion plethysmography. After 24 weeks of exercise training, there were significant improvements in maximum oxygen consumption, HDL cholesterol, triglycerides, and body fat. Changes in plasma NO(x) levels ranged from -14.83 to +16.69 micromol/L; however, the mean change overall was not significant (-0.33 + or - 6.30 micromol/L, p = 0.64). Changes in plasma NO(x) levels were not associated with age, gender, race, HDL cholesterol, triglycerides, body weight, body fat, or maximal oxygen consumption. There were also no significant changes in basal FBF, peak FBF, hyperemic response, total hyperemic flow, or minimum forearm vascular resistance with exercise training. In conclusion, improvements in plasma NO(x) levels and FBF are not evident after long-term training in older adults.

Independent and combined influence of AGTR1 variants and aerobic exercise on oxidative stress in hypertensives.

Abstract Angiotensin II (AngII), via the AngII type 1 receptor (AT(1)R), contributes to oxidative stress. Aerobic exercise training (AEXT) reduces the risk of cardiovascular (CV) disease, presumably by reducing the grade of oxidative stress. We investigated the independent and combined influence of the AGTR1 A1166C and -825 T/A polymorphisms on oxidative stress and plasma AngII responses to AEXT in pre- and stage 1 hypertensives. Urinary 8-iso-PGF(2alpha) significantly increased with AEXT (p=0.002); however, there were no significant changes in superoxide dismutase activity or AngII levels. There was a significant difference in the change in AngII levels with AEXT between A1166C genotype groups (p=0.04) resulting in a significant interactive effect of the A1166C polymorphism and AEXT on the change in AngII (p<0.05). Only the TT genotype group of the -825 T/A polymorphism had a significant reduction in plasma AngII (p=0.02). Risk allele analysis revealed a significant reduction in plasma AngII (p=0.04) and a significant increase in urinary 8-iso-PGF(2alpha) (p=0.01) with AEXT in individuals with two risk alleles only. Our findings suggest that variation in the AGTR1 gene is associated with differential changes in plasma AngII but not oxidative stress.

Sharps injury reporting amongst surgeons.

INTRODUCTION: The aim of this study was to evaluate the level of sharps injury reporting amongst surgeons. SUBJECTS AND METHODS: A total of 164 surgeons completed a questionnaire on the reporting of sharps injuries, on the reasons for not reporting and their practise of universal precautions. RESULTS: Out of 164 surgeons, only 25.8% had reported all their injuries, 22.5% had reported some and 51.7% had reported none. The top three reasons for not reporting their injuries included perception of low risk of transmission, not being concerned and no time. Of the respondents, 15.9% practised all three universal precautions of double-gloving, face shields and hands-free technique. CONCLUSIONS: We showed that despite local trust adherence to Department of Health policy, sharps injury reporting rates are inadequate. Further investment into healthcare worker education as well as a facilitation of the process of reporting may be necessary to improve reporting rates.

Exercise training, NADPH oxidase p22phox gene polymorphisms, and hypertension.

INTRODUCTION: Oxidative stress that is mediated through NADPH oxidase activity plays a role in the pathology of hypertension, and aerobic exercise training reduces NADPH oxidase activity. The involvement of genetic variation in the p22phox (CYBA) subunit genes in individual oxidative stress responses to aerobic exercise training has yet to be examined in Pre and Stage 1 hypertensives. METHODS: Ninety-four sedentary Pre and Stage 1 hypertensive adults underwent 6 months of aerobic exercise training at a level of 70% VO2max to determine whether the CYBA polymorphisms, C242T and A640G, were associated with changes in urinary 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha), urinary nitric oxide metabolites (NOx), and plasma total antioxidant capacity (TAC). RESULTS: Demographic and subject characteristics were similar among genotype groups for both polymorphisms. At baseline, a significant (P = 0.03) difference among the C2424T genotype groups in 8-iso-PGF2alpha levels was detected, with the TT homozygotes having the lowest levels and the CC homozygotes having the highest levels. However, no differences were found at baseline between the A640G genotype groups. After 6 months of aerobic exercise training, there was a significant increase in VO2max (P < 0.0001) in the entire study population. In addition, there were significant increases in both urinary 8-iso-PGF2alpha (P = 0.002) and plasma TAC (P=0.03) levels and a significant decrease in endogenous urinary NOx (P < 0.0001). Overall, aerobic exercise training elicited no significant differences among genotype groups in either CYBA variant for any of the oxidative stress variables. CONCLUSIONS: We found that compared with CYBA polymorphisms C242T and A640G, it was aerobic exercise training that had the greatest influence on the selected biomarkers; furthermore, our results suggest that the C242T CYBA variant influences baseline levels of urinary 8-iso-PGF2alpha but not the aerobic exercise-induced responses.

The relationship of oxidative stress and cholesterol with dipping status before and after aerobic exercise training.

OBJECTIVE: The purpose of this study was to examine the effects of aerobic exercise training (AEXT) on dipping status in pre-hypertensive and stage-1 hypertensive individuals. A secondary purpose was to evaluate whether AEXT alters oxidative stress and endothelial biomarkers correlated to dipping status. METHODS: Twenty-three subjects underwent 24-h ambulatory blood pressure monitoring at baseline and after 6 months of AEXT. AEXT consisted of training at 70% VO(2max) 3 days/week for 6 months. Total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein (LDL)-cholesterol, oxidized LDL (ox-LDL), triglycerides, urinary and plasma nitric oxide end-products, superoxide dismutase and 8-iso-PGF(2alpha) were measured before and after AEXT. Statistically, ANOVA and linear regression were used. RESULTS: Before and after AEXT, there were no significant differences between dippers and non-dippers in any of the biomarkers except for total cholesterol following AEXT. In a sub-analysis following AEXT, 14 subjects retained their original dipping status, five subjects changed from dippers to non-dippers and four subjects changed from non-dippers to dippers. Significant differences existed between these groups in changes in total and LDL-cholesterol, ox-LDL, 8-iso-PGF(2alpha) and % Dip. CONCLUSIONS: Changes in cholesterol levels but not oxidative stress or endothelial biomarkers were related to changes in BP variables following AEXT in dippers and non-dippers.

Recruitment, genetic counseling, and BRCA testing for underserved women at a public hospital.

Genetic counseling and testing for heritable susceptibility to breast cancer caused by mutations in BRCA genes are largely unavailable to underserved women in the United States. Starting in 2002 the UCSF Cancer Risk Program offered this service free of charge to poor and medically indigent women at San Francisco General Hospital (SFGH). One recruitment strategy was a single-page questionnaire in four languages administered to women waiting for mammograms at SFGH. This report analyzes our first 3 years of experience with the recruitment questionnaire and compares the patient demographics and BRCA test results at SFGH with a more typical population undergoing genetic counseling and testing at UCSF's Mt. Zion Hospital (MZH). To our knowledge this is the first comprehensive clinical service for hereditary breast cancer in a U.S. public hospital. The ethnic mix of all 350 patients counseled was Caucasian 49% (approximately 20% of Caucasians reported Ashkenazi Jewish ancestry), Latina, 26%; African American, 13%; and Asian/other, 12%. Compared to the MZH population, SFGH patients were more ethnically diverse, less educated and more likely to be unemployed. Of 72 patients tested for BRCA mutations, 51 (71%) were negative, 5 were BRCA1 positive, and 12 were BRCA2 positive. Four (1 Caucasian, 1 Latina, 2 African American) had a total of 13 BRCA variants of unknown significance (VUS). The ratio of BRCA1/BRCA2 positive SFGH patients (5/12) was reversed compared to MZH (119/91). We evaluated 4573 recruitment questionnaires and 280 (6%) were judged to represent a high risk of heritable cancer. After additional screening and referral negotiation, 74 were scheduled for counseling. We judged the recruitment questionnaire to be a feasible, efficient, and reasonably cost-effective way to identify women at high risk of hereditary cancer in a traditionally underserved population. Underserved populations present special challenges for genetic counselors because of large, geographically dispersed families, cultural taboos about cancer diagnoses, and social marginalization. Despite these complexities, the clinical service at SFGH has been well accepted by patients and staff. Our successful venture can serve as a model for other public hospitals contemplating this clinical service.

A Titin mutation defines roles for circulation in endothelial morphogenesis.

Morphogenesis of the developing vascular network requires coordinated regulation of an extensive array of endothelial cell behaviors. Precisely regulated signaling molecules such as vascular endothelial growth factor (VEGF) direct some of these endothelial behaviors. Newly forming blood vessels also become subjected to novel biomechanical forces upon initiation of cardiac contractions. We report here the identification of a recessive mouse mutation termed shrunken-head (shru) that disrupts function of the Titin gene. Titin was found to be required for the initiation of proper heart contractions as well as for maintaining the correct overall shape and orientation of individual cardiomyocytes. Cardiac dysfunction in shrunken-head mutant embryos provided an opportunity to study the effects of lack of blood circulation on the morphogenesis of endothelial cells. Without blood flow, differentiating endothelial cells display defects in their shapes and patterns of cell-cell contact. These endothelial cells, without exposure to blood circulation, have an abnormal distribution within vasculogenic vessels. Further effects of absent blood flow include abnormal spatial regulation of angiogenesis and elevated VEGF signaling. The shrunken-head mutation has provided an in vivo model to precisely define the roles of circulation on cellular and network aspects of vascular morphogenesis.

Atrophin 2 recruits histone deacetylase and is required for the function of multiple signaling centers during mouse embryogenesis.

Atrophins are evolutionarily conserved proteins that are thought to act as transcriptional co-repressors. Mammalian genomes contain two atrophin genes. Dominant polyglutamine-expanded alleles of atrophin 1 have been identified as the cause of dentatorubralpallidoluysian atrophy, an adult-onset human neurodegenerative disease with similarity to Huntington's. In a screen for recessive mutations that disrupt patterning of the early mouse embryo, we identified a line named openmind carrying a mutation in atrophin 2. openmind homozygous embryos exhibit a variety of patterning defects that first appear at E8.0. Defects include a specific failure in ventralization of the anterior neural plate, loss of heart looping and irregular partitioning of somites. In mutant embryos, Shh expression fails to initiate along the anterior midline at E8.0, and Fgf8 is delocalized from the anterior neural ridge at E8.5, revealing a crucial role for atrophin 2 in the formation and function of these two signaling centers. Atrophin 2 is also required for normal organization of the apical ectodermal ridge, a signaling center that directs limb pattern. Elevated expression of atrophin 2 in neurons suggests it may interact with atrophin 1 in neuronal development or function. We further show that atrophin 2 associates with histone deacetylase 1 in mouse embryos, providing a biochemical link between Atr2 and a chromatin-modifying enzyme. Based on our results, and on those of others, we propose that atrophin proteins act as transcriptional co-repressors during embryonic development.

Predator-induced behavioral and morphological plasticity in the tropical marine Gastropod Strombus gigas.

Florida queen conch stocks once supported a significant fishery, but overfishing prompted the state of Florida to institute a harvest moratorium in 1985. Despite the closure of the fishery, the queen conch population has been slow to recover. One method used in the efforts to restore the Florida conch population has been to release hatchery-reared juvenile conch into the wild; however, suboptimal predator avoidance responses and lighter shell weights relative to their wild counterparts have been implicated in the high mortality rates of released hatchery juveniles. We conducted a series of experiments in which hatchery-reared juvenile conch were exposed to a predator, the spiny lobster (Panulirus argus), to determine whether they could develop behavioral and morphological characteristics that would improve survival. Experiments were conducted in tanks with a calcareous sand substrate to simulate a natural environment. Conditioned conch were exposed to caged lobsters while conch in the control tanks were exposed to empty cages. Conditioned conch moved significantly less and buried themselves more frequently than the naive control conch. Morphometric data indicated that the conditioned conch grew at a significantly slower rate than the naive conch, but the shell weights of the two groups were not significantly different. This implies that the conditioned conch had thicker or denser shells than the control group. As a result, the conditioned conch had significantly higher survival than naive conch in a subsequent predation experiment in which a lobster was allowed to roam free in each tank for 24 hours. In the future, the conditioning protocols documented in this study will be used to increase the survival of hatchery-reared conch in the wild.

Illumination and reading performance in age-related macular degeneration.

BACKGROUND: Previous studies have compared low vision reading performance at optimal task illuminance and consulting room illuminance (500 to 600 lux). However, it is uncertain the extent to which low vision reading performance can be improved when task illumination is increased from levels more representative of those found in the typical living room (50 lux) to levels likely to maximise performance. METHODS: Reading performance of 20 subjects with age-related macular degeneration (AMD) was assessed for a range of print sizes using sentence reading charts at six levels of task illuminance (50 to 5,000 lux). Subjects read without low vision devices. RESULTS: Sentence reading acuity and critical print size improved by a factor of two over the 50 to 5,000 lux range, while maximum reading rate improved by a factor of 1.4. For the majority of subjects (70 per cent), the optimal task illuminance (determined objectively) was higher (median 3,500 lux) than the subjectively preferred task illuminance (median 2,450 lux). Reading performance was significantly better at the optimal illuminance than at illuminances equivalent to those found in the domestic environment (50 lux) or consulting room (600 lux). CONCLUSIONS: The majority of AMD patients will require task illumination of at least 2,000 lux to maximise reading performance. Optimal illumination should be determined individually for each patient using both objective measures of performance, such as reading acuity, and subjective assessments of visual comfort.