CTLA-4: a negative regulator of autoimmune disease.

CTLA-4, a CD28 homologue expressed on activated T cells, binds with high affinity to the CD28 ligands, B7-1 (CD80) and B7-2 (CD86). This study was designed to examine the role of CTLA-4 in regulating autoimmune disease. Murine relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) is a demyelinating disease mediated by PLP139-151-specific CD4+ T cells in SJL/J mice. Anti-CTLA-4 mAbs (or their F(ab) fragments) enhanced in vitro proliferation and pro-inflammatory cytokine production by PLP139-151-primed lymph node cells. Addition of either reagent to in vitro activation cultures potentiated the ability of T cells to adoptively transfer disease to naive recipients. In vivo administration of anti-CTLA-4 mAb to recipients of PLP139-151-specific T cells resulted in accelerated and exacerbated disease. Finally, anti-CTLA-4 treatment of mice during disease remission resulted in the exacerbation of relapses. Collectively, these results suggest that CTLA-4 mediates the downregulation of ongoing immune responses and plays a major role in regulating autoimmunity

Callers’ attitudes and experiences of UK breastfeeding helpline support

Background: Breastfeeding peer support, is considered to be a key intervention for increasing breastfeeding duration rates. Whilst a number of national organisations provide telephone based breastfeeding peer support, to date there have been no published evaluations into callers’ experiences and attitudes of this support. In this study we report on the descriptive and qualitative insights provided by 908 callers as part of an evaluation of UK-based breastfeeding helpline(s). Methods: A structured telephone interview, incorporating Likert scale responses and open-ended questions was undertaken with 908 callers over May to August, 2011 to explore callers’ experiences of the help and support received via the breastfeeding helpline(s). Results: Overall satisfaction with the helpline was high, with the vast majority of callers’ recalling positive experiences of the help and support received. Thematic analysis was undertaken on all qualitative and descriptive data recorded during the evaluation, contextualised within the main areas addressed within the interview schedule in terms of ‘contact with the helplines’; ‘experiences of the helpline service’, ‘perceived effectiveness of support provision’ and ‘impact on caller wellbeing’. Conclusion: Callers valued the opportunity for accessible, targeted, non-judgmental and convenient support. Whilst the telephone support did not necessarily influence women’s breastfeeding decisions, the support they received left them feeling reassured, confident and more determined to continue breastfeeding. We recommend extending the helpline service to ensure support can be accessed when needed, and ongoing training and support for volunteers. Further advertising and promotion of the service within wider demographic groups is warranted

Alcohol Production as an Adaptive Livelihood Strategy for Women Farmers in Tanzania and Its Potential for Unintended Consequences on Women's Reproductive Health.

Although women occupy a central position in agriculture in many developing countries, they face numerous constraints to achieving their full potential including unequal access to assets and limited decision-making authority. We explore the intersection of agricultural livelihoods, food and economic security, and women's sexual and reproductive health in Iringa Region, Tanzania. Our goal was to understand whether the benefits of supporting women in the agricultural sector might also extend to more distal outcomes, including sexual and reproductive health. Using the Sustainable Livelihoods Framework to guide data collection, we conducted 13 focus group discussions (FGD) with female (n = 11) and male farmers (n = 2) and 20 in-depth interviews with agricultural extension officers (n = 10) and village agro-dealers (n = 10). Despite providing the majority of agricultural labor, women have limited control over land and earned income and have little bargaining power. In response to these constraints, women adopt adaptive livelihood strategies, such as alcohol production, that allow them to retain control over income and support their households. However, women's central role in alcohol production, in concert with the ubiquitous nature of alcohol consumption, places them at risk by enhancing their vulnerability to unsafe or transactional sex. This represents a dangerous confluence of risk for female farmers, in which alcohol plays an important role in income generation and also facilitates high-risk sexual behavior. Alcohol production and consumption has the potential to both directly and indirectly place women at risk for undesirable sexual and reproductive health outcomes. Group formation, better access to finance, and engaging with agricultural extension officers were identified as potential interventions for supporting women farmers and challenging harmful gender norms. In addition, joint, multi-sectoral approaches from health and agriculture and alternative income-generating strategies for women might better address the complexities of achieving safe and sustainable livelihoods for women in this context

Pre-pregnancy predictors of hypertension in pregnancy among Aboriginal and Torres Strait Islander women in north Queensland, Australia; a prospective cohort study

BACKGROUND Compared to other Australian women, Indigenous women are frequently at greater risk for hypertensive disorders of pregnancy. We examined pre-pregnancy factors that may predict hypertension in pregnancy in a cohort of Aboriginal and Torres Strait Islander women in north Queensland. METHODS Data on a cohort of 1009 Indigenous women of childbearing age (15–44 years) who participated in a 1998–2000 health screening program in north Queensland were combined with 1998–2008 Queensland hospitalisations data using probabilistic data linkage. Data on the women in the cohort who were hospitalised for birth (n = 220) were further combined with Queensland perinatal data which identified those diagnosed with hypertension in pregnancy. RESULTS Of 220 women who gave birth, 22 had hypertension in the pregnancy after their health check. The mean age of women with and without hypertension was similar (23.7 years and 23.9 years respectively) however Aboriginal women were more affected compared to Torres Strait Islanders. Pre-pregnancy adiposity and elevated blood pressure at the health screening program were predictors of a pregnancy affected by hypertension. After adjusting for age and ethnicity, each 1 cm increase in waist circumference showed a 4% increased risk for hypertension in pregnancy (PR 1.04; 95% CI; 1.02-1.06); each 1 point increase in BMI showed a 9% adjusted increase in risk (1.09; 1.04-1.14). For each 1 mmHg increase in baseline systolic blood pressure there was an age and ethnicity adjusted 6% increase in risk and each 1 mmHg increase in diastolic blood pressure showed a 7% increase in risk (1.06; 1.03-1.09 and 1.07; 1.03-1.11 respectively). Among those free of diabetes at baseline, the presence of the metabolic syndrome (International Diabetes Federation criteria) predicted over a three-fold increase in age-ethnicity-adjusted risk (3.5; 1.50-8.17). CONCLUSIONS Pre-pregnancy adiposity and features of the metabolic syndrome among these young Aboriginal and Torres Strait Islander women track strongly to increased risk of hypertension in pregnancy with associated risks to the health of babies.Sandra K Campbell, John Lynch, Adrian Esterman and Robyn McDermot

Foot health education for people with rheumatoid arthritis : the practitioner's perspective

Background: Patient education is considered to be a key role for podiatrists in the management of patients with rheumatoid arthritis (RA). Patient education has undoubtedly led to improved clinical outcomes, however no attempts have been made to optimise its content or delivery to maximise benefits within the context of the foot affected by rheumatoid arthritis. The aim of this study was to identify the nature and content of podiatrists' foot health education for people with RA. Any potential barriers to its provision were also explored. Methods: A focus group was conducted. The audio dialogue was recorded digitally, transcribed verbatim and analysed using a structured, thematic approach. The full transcription was verified by the focus group as an accurate account of what was said. The thematic analysis framework was verified by members of the research team to ensure validity of the data. Results: Twelve members (all female) of the north west Podiatry Clinical Effectiveness Group for Rheumatology participated. Six overarching themes emerged: (i) the essence of patient education; (ii) the content; (iii) patient-centred approach to content and timing; (iv) barriers to provision; (v) the therapeutic relationship; and (vi) tools of the trade. Conclusion: The study identified aspects of patient education that this group of podiatrists consider most important in relation to its: content, timing, delivery and barriers to its provision. General disease and foot health information in relation to RA together with a potential prognosis for foot health, the role of the podiatrist in management of foot health, and appropriate self-management strategies were considered to be key aspects of content, delivered according to the needs of the individual. Barriers to foot health education provision, including financial constraints and difficulties in establishing effective therapeutic relationships, were viewed as factors that strongly influenced foot health education provision. These data will contribute to the development of a patient-centred, negotiated approach to the provision of foot health education for people with RA

XRCC2 R188H (rs3218536), XRCC3 T241M (rs861539) and R243H (rs77381814) single nucleotide polymorphisms in cervical cancer risk

Human Papillomavirus (HPV) is the main cause of cervical cancer and its precursor lesions. Transformation may be induced by several mechanisms, including oncogene activation and genome instability. Individual differences in DNA damage recognition and repair have been hypothesized to influence cervical cancer risk. The aim of this study was to evaluate whether the double strand break gene polymorphisms XRCC2 R188H G>A (rs3218536), XRCC3 T241M C>T (rs861539) and R243H G>A (rs77381814) are associated to cervical cancer in Argentine women. A case control study consisting of 322 samples (205 cases and 117 controls) was carried out. HPV DNA detection was performed by PCR and genotyping of positive samples by EIA (enzyme immunoassay). XRCC2 and 3 polymorphisms were determined by pyrosequencing. The HPV-adjusted odds ratio (OR) of XRCC2 188 GG/AG genotypes was OR = 2.4 (CI = 1.1-4.9, p = 0.02) for cervical cancer. In contrast, there was no increased risk for cervical cancer with XRCC3 241 TT/CC genotypes (OR = 0.48; CI = 0.2-1; p = 0.1) or XRCC3 241 CT/CC (OR = 0.87; CI = 0.52-1.4; p = 0.6). Regarding XRCC3 R243H, the G allele was almost fixed in the population studied. In conclusion, although the sample size was modest, the present data indicate a statistical association between cervical cancer and XRCC2 R188H polymorphism. Future studies are needed to confirm these findings.Fil: Perez, Luis Orlando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET- La Plata. Instituto de Genética Veterinaria "Ing. Fernando Noel Dulout". Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Instituto de Genética Veterinaria; ArgentinaFil: Crivaro, Andrea Natalia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET- La Plata. Instituto de Genética Veterinaria "Ing. Fernando Noel Dulout". Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Instituto de Genética Veterinaria; ArgentinaFil: Barbisan, Gisela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET- La Plata. Instituto de Genética Veterinaria "Ing. Fernando Noel Dulout". Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Instituto de Genética Veterinaria; ArgentinaFil: Poleri, Lucía Belén. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET- La Plata. Instituto de Genética Veterinaria "Ing. Fernando Noel Dulout". Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Instituto de Genética Veterinaria; ArgentinaFil: Golijow, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET- La Plata. Instituto de Genética Veterinaria "Ing. Fernando Noel Dulout". Universidad Nacional de La Plata. Facultad de Ciencias Veterinarias. Instituto de Genética Veterinaria; Argentin

American Society for Enhanced Recovery (ASER) and Perioperative Quality Initiative (POQI) Joint Consensus Statement on Optimal Analgesia within an Enhanced Recovery Pathway for Colorectal Surgery: Part 2-From PACU to the Transition Home.

BACKGROUND: Within an enhanced recovery pathway (ERP), the approach to treating pain should be multifaceted and the goal should be to deliver "optimal analgesia", which we define in this paper as a technique that optimizes patient comfort and facilitates functional recovery with the fewest medication side effects. METHODS: With input from a multidisciplinary, international group of experts and through a structured review of the literature and use of a modified Delphi method, we achieved consensus surrounding the topic of optimal analgesia in the perioperative period for colorectal surgery patients. DISCUSSION: As a part of the first Perioperative Quality Improvement (POQI) workgroup meeting, we sought to develop a consensus document describing a comprehensive, yet rational and practical, approach for developing an evidence-based plan for achieving optimal analgesia, specifically for a colorectal surgery within an ERP. The goal was twofold: (a) that application of this process would lead to improved patient outcomes and (b) that investigation of the questions raised would identify knowledge gaps to aid the direction for research into analgesia within ERPs in the years to come. This document details the evidence for a wide range of analgesic components, with particular focus on care in the post-anesthesia care unit, general care ward, and transition to home after discharge. The preoperative and operative consensus statement for analgesia was covered in Part 1 of this paper. The overall conclusion is that the combination of analgesic techniques employed in the perioperative period is not important as long as it is effective in delivering the goal of "optimal analgesia" as set forth in this document

Considering the Case for Biodiversity Cycles: Reexamining the Evidence for Periodicity in the Fossil Record

Medvedev and Melott (2007) have suggested that periodicity in fossil biodiversity may be induced by cosmic rays which vary as the Solar System oscillates normal to the galactic disk. We re-examine the evidence for a 62 million year (Myr) periodicity in biodiversity throughout the Phanerozoic history of animal life reported by Rohde & Mueller (2005), as well as related questions of periodicity in origination and extinction. We find that the signal is robust against variations in methods of analysis, and is based on fluctuations in the Paleozoic and a substantial part of the Mesozoic. Examination of origination and extinction is somewhat ambiguous, with results depending upon procedure. Origination and extinction intensity as defined by RM may be affected by an artifact at 27 Myr in the duration of stratigraphic intervals. Nevertheless, when a procedure free of this artifact is implemented, the 27 Myr periodicity appears in origination, suggesting that the artifact may ultimately be based on a signal in the data. A 62 Myr feature appears in extinction, when this same procedure is used. We conclude that evidence for a periodicity at 62 Myr is robust, and evidence for periodicity at approximately 27 Myr is also present, albeit more ambiguous.Comment: Minor modifications to reflect final published versio

Predicting resistance as indicator for need to switch from first-line antiretroviral therapy among patients with elevated viral loads: Development of a risk score algorithm

Background: In resource-limited settings, where resistance testing is unavailable, confirmatory testing for patients with high viral loads (VL) delays antiretroviral therapy (ART) switches for persons with resistance. We developed a risk score algorithm to predict need for ART change by identifying resistance among persons with persistently elevated VL. Methods: We analyzed data from a Phase IV open-label trial. Using logistic regression, we identified demographic and clinical characteristics predictive of need for ART change among participants with VLs ≥1000 copies/ml, and assigned model-derived scores to predictors. We designed three models, including only variables accessible in resource-limited settings. Results: Among 290 participants with at least one VL ≥1000 copies/ml, 51 % (148/290) resuppressed and did not have resistance testing; among those who did not resuppress and had resistance testing, 47 % (67/142) did not have resistance and 53 % (75/142) had resistance (ART change needed for 25.9 % (75/290)). Need for ART change was directly associated with higher baseline VL and higher VL at time of elevated measure, and inversely associated with treatment duration. Other predictors included body mass index and adherence. Area under receiver operating characteristic curves ranged from 0.794 to 0.817. At a risk score ≥9, sensitivity was 14.7-28.0 % and specificity was 96.7-98.6 %. Conclusions: Our model performed reasonably well and may be a tool to quickly transition persons in need of ART change to more effective regimens when resistance testing is unavailable. Use of this algorithm may result in public health benefits and health system savings through reduced transmissions of resistant virus and costs on laboratory investigations

Mapping species distributions: A comparison of skilled naturalist and lay citizen science recording

To assess the ability of traditional biological recording schemes and lay citizen science approaches to gather data on species distributions and changes therein, we examined bumblebee records from the UK’s national repository (National Biodiversity Network) and from BeeWatch. The two recording approaches revealed similar relative abundances of bumblebee species but different geographical distributions. For the widespread common carder (Bombus pascuorum), traditional recording scheme data were patchy, both spatially and temporally, reflecting active record centre rather than species distribution. Lay citizen science records displayed more extensive geographic coverage, reflecting human population density, thus offering better opportunities to account for recording effort. For the rapidly spreading tree bumblebee (Bombus hypnorum), both recording approaches revealed similar distributions due to a dedicated mapping project which overcame the patchy nature of naturalist records. We recommend, where possible, complementing skilled naturalist recording with lay citizen science programmes to obtain a nation-wide capability, and stress the need for timely uploading of data to the national repository