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Maternal vaccination has been evaluated and found to be extremely effective at preventing illness in pregnant women and new-borns; however, uptake of such programmes has been low in some areas. To analyse factors contributing to uptake of vaccines globally, a systematic review on vaccine hesitancy was carried out by The Vaccine Confidence Project in 2012. In order to further analyse factors contributing to uptake of maternal immunisation, a further search within the broader systematic review was conducted using the terms 'Pregnan*' or 'Matern*'. Forty-two articles were identified. Pregnancy-related articles were further screened to identify those focused on concerns, trust and access issues regarding maternal vaccination reported by pregnant women and healthcare workers. Thirty-five relevant articles were included which were then searched using the snowballing technique to identify additional relevant references cited in these articles. A search alert was also conducted from February to April 2015 in PubMed to ensure that no new relevant articles were missed. A total of 155 relevant articles were included. Most of the literature which was identified on hesitancy surrounding vaccination during pregnancy reports on determinants of influenza vaccine uptake in North America. Research conducted in low-income countries focused primarily on tetanus vaccine acceptance. The main barriers cited were related to vaccine safety, belief that vaccine not needed or effective, not recommended by healthcare worker, low knowledge about vaacines, access issues, cost, conflicting advice. From the point of view of healthcare workers, barriers included inadequate training, inadequate reimbursement and increased workload. Twenty-seven out of 46 (59%) articles mentioning ethnicity reported lower rates of coverage among ethnic minorities. Barriers to vaccination in pregnancy are complex and vary depending on context and population. There are wide gaps in knowledge regarding the attitudes of healthcare workers and how ethnicity and gender dynamics influence a pregnant woman's decision to vaccinate., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Delayed diagnosis of jersey finger injuries often results in retraction of the flexor digitorum profundus tendon. Current practice recommends limiting tendon advancement to 1 cm in delayed repairs. The purpose of this study was to investigate the biomechanical consequences of tendon shortening on the force required to form a fist. The flexor digitorum profundus muscle was isolated in ten cadaveric forearms and the force required to form a fist was recorded. Simulated jersey finger injuries to the ring finger were then created and repaired. The forces required to pull the fingertips to the palm after serial tendon advancements were measured. There was a near linear increase in the force required for making a fist with shortening up to 2.5 cm. The force required to make a fist should be taken into account when considering the limit of 'safe' tendon shortening in delayed repair of jersey finger injuries., (© The Author(s) 2015.)

Background: Women in sub-Saharan Africa are disproportionately affected by high rates of HIV, yet relatively few products exist for female-initiated HIV prevention. New antiretroviral (ARV)-based prevention options could present opportunities for women to expand their HIV prevention choices; however, acceptability and adherence play a key role in the effectiveness of these products and implementation is still in early stages. To better understand which HIV prevention options might best serve women in sub-Saharan Africa, how and why, this review will explore qualitative evidence from clinical trials and implementation studies alike using a meta-ethnographic approach to synthesise data and interpret results., Methods/design: This systematic review will use a meta-ethnographic approach to analyse qualitative data extracted from multiple studies featuring actual use of female-initiated technologies for HIV prevention. The search strategy will be applied in seven databases and papers will be selected using strict inclusion and exclusion criteria. The review will closely follow the guidance set forth by preferred reporting items for systematic reviews and meta-analyses (PRISMA) and Centre for Reviews Dissemination (CRD) where the guidance applies to qualitative data. Two reviewers will review all papers during the paper selection phase, with consultation from a third reviewer to confirm consensus. All papers included in the review will be read and analysed by two reviewers. The final analysis will be conducted by three primary reviewers with additional input from all other authors., Discussion: With new HIV prevention technologies currently in early implementation phases and still more on the horizon, there is much to learn about how best these products may be delivered. A review such as this could help to inform the real-world implementation of the next wave of new HIV prevention technologies such as ARV-based oral pre-exposure prophylaxis (PrEP).

Unlabelled: The purpose of this systematic review is to identify, describe and assess the potential effectiveness of strategies to respond to issues of vaccine hesitancy that have been implemented and evaluated across diverse global contexts., Methods: A systematic review of peer reviewed (January 2007-October 2013) and grey literature (up to October 2013) was conducted using a broad search strategy, built to capture multiple dimensions of public trust, confidence and hesitancy concerning vaccines. This search strategy was applied and adapted across several databases and organizational websites. Descriptive analyses were undertaken for 166 (peer reviewed) and 15 (grey literature) evaluation studies. In addition, the quality of evidence relating to a series of PICO (population, intervention, comparison/control, outcomes) questions defined by the SAGE Working Group on Vaccine Hesitancy (WG) was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria; data were analyzed using Review Manager., Results: Across the literature, few strategies to address vaccine hesitancy were found to have been evaluated for impact on either vaccination uptake and/or changes in knowledge, awareness or attitude (only 14% of peer reviewed and 25% of grey literature). The majority of evaluation studies were based in the Americas and primarily focused on influenza, human papillomavirus (HPV) and childhood vaccines. In low- and middle-income regions, the focus was on diphtheria, tetanus and pertussis, and polio. Across all regions, most interventions were multi-component and the majority of strategies focused on raising knowledge and awareness. Thirteen relevant studies were used for the GRADE assessment that indicated evidence of moderate quality for the use of social mobilization, mass media, communication tool-based training for health-care workers, non-financial incentives and reminder/recall-based interventions. Overall, our results showed that multicomponent and dialogue-based interventions were most effective. However, given the complexity of vaccine hesitancy and the limited evidence available on how it can be addressed, identified strategies should be carefully tailored according to the target population, their reasons for hesitancy, and the specific context., (Copyright © 2015. Published by Elsevier Ltd.)

In March 2012, the SAGE Working Group on Vaccine Hesitancy was convened to define the term "vaccine hesitancy", as well as to map the determinants of vaccine hesitancy and develop tools to measure and address the nature and scale of hesitancy in settings where it is becoming more evident. The definition of vaccine hesitancy and a matrix of determinants guided the development of a survey tool to assess the nature and scale of hesitancy issues. Additionally, vaccine hesitancy questions were piloted in the annual WHO-UNICEF joint reporting form, completed by National Immunization Managers globally. The objective of characterizing the nature and scale of vaccine hesitancy issues is to better inform the development of appropriate strategies and policies to address the concerns expressed, and to sustain confidence in vaccination. The Working Group developed a matrix of the determinants of vaccine hesitancy informed by a systematic review of peer reviewed and grey literature, and by the expertise of the working group. The matrix mapped the key factors influencing the decision to accept, delay or reject some or all vaccines under three categories: contextual, individual and group, and vaccine-specific. These categories framed the menu of survey questions presented in this paper to help diagnose and address vaccine hesitancy., (Copyright © 2015. Published by Elsevier Ltd.)

Purpose: The primary care sector is experiencing considerable change. How change and uncertainty are accommodated by the professional identity of medicine has not been examined. The purpose of this paper is to address the youth healthcare as an exemplar as this field is often a source of uncertainty for general practitioners (GPs)., Design/methodology/approach: Using heterogeneity sampling, 22 GPs participated in focus groups to explore perceptions of youth healthcare, factors that help and hinder it, and training needs. Analysis of the research material was guided by a theoretical model on professional identity., Findings: GPs described tensions that challenged their professional identity - the challenges of working with young people and their complex issues, the extent to which youth healthcare sits within the purview of general practice, and the scope of training required. These tensions appeared to destabilise professional identity. Some participants had customised their identity by enriching understandings of and approach to general practice. Participants also reported work customisation as a way of managing the complex demands of the general practice role. Deepened insight appeared to bolster perceived capacity to support a complex patient cohort. Research limitations/implications - Participants are not representative of the primary care sector - furthermore, the methodology limits the generalisability of the findings., Practical Implications: To bolster youth health, mere clinician training is insufficient. Youth health requires explicit support from governments and training providers to be incorporated into the healthcare landscape., Originality/value: This study extends current research on professional identity by examining youth healthcare within the changing context of primary care.

Importance: The value of robotically assisted surgery for mitral valve disease is questioned because the high cost of care associated with robotic technology may outweigh its clinical benefits., Objective: To investigate conditions under which benefits of robotically assisted surgery mitigate high technology costs., Design, Setting, and Participants: Clinical cohort study at a large multispecialty academic medical center comparing costs of robotically assisted surgery with 3 contemporaneous conventional surgical approaches for degenerative mitral valve disease. From January 1, 2006, through December 31, 2010, a total of 1290 patients with a mean (SD) age of 57 (11) years underwent mitral valve repair for regurgitation from posterior leaflet prolapse. Robotically assisted surgery was performed in 473 patients, complete sternotomy in 227, partial sternotomy in 349, and anterolateral thoracotomy in 241. Comparisons were based on intent to treat, with 3 propensity-matched groups formed based on demographics, symptoms, cardiac and noncardiac comorbidities, valve pathophysiologic disorders, and echocardiographic measurements: robotic vs sternotomy (198 pairs) vs partial sternotomy (293 pairs) vs thoracotomy (224 pairs)., Interventions: Mitral valve repair., Main Outcomes and Measures: Cost of care (expressed as robotic capital investment, maintenance of equipment, and direct technical hospital costs) and benefit of care (based on differences in recovery time)., Results: Cost of care (median [15th and 85th percentiles]) for robotically assisted surgery exceeded that of alternative approaches by 26.8% (-5.3% and 67.9%), 32.1% (-6.1% and 69.6%), and 20.7% (-2.4% and 48.4%) for complete sternotomy, partial sternotomy, and anterolateral thoracotomy, respectively. Higher operative costs were partially offset by lower postoperative costs and earlier return to work: a median (15th and 85th percentiles) of 35 (19 and 63) days for robotically assisted surgery, 49 (21 and 109) days for complete sternotomy, 56 (30 and 119) days for partial sternotomy, and 42 (18 and 90) days for anterolateral thoracotomy. Resulting net differences (median [15th and 85th percentiles]) in the cost of robotic surgery vs the 3 alternatives were 15.6% (-14.7% and 55.1%), 15.7% (-19.4% and 51.2%), and 14.8% (-7.4% and 43.6%), respectively. Beyond a volume threshold of 55 to 100 robotically assisted operations per year, distribution of the cost of this technology broadly overlapped those of conventional approaches., Conclusions and Relevance: In exchange for higher procedural costs, robotically assisted surgery for mitral valve repair offers the clinical benefit of least-invasive surgery, lowest postoperative cost, and fastest return to work. The value of robotically assisted surgery that is similar to that of conventional approaches can be realized only in high-volume centers.

Vaccine "hesitancy" is an emerging term in the literature and discourse on vaccine decision-making and determinants of vaccine acceptance. It recognizes a continuum between the domains of vaccine acceptance and vaccine refusal and de-polarizes previous characterization of individuals and groups as either anti-vaccine or pro-vaccine. The primary aims of this systematic review are to: 1) identify research on vaccine hesitancy; 2) identify determinants of vaccine hesitancy in different settings including its context-specific causes, its expression and its impact; and 3) inform the development of a model for assessing determinants of vaccine hesitancy in different settings as proposed by the Strategic Advisory Group of Experts Working Group (SAGE WG) for dealing with vaccine hesitancy. A broad search strategy, built to capture multiple dimensions of public trust, confidence and hesitancy around vaccines, was applied across multiple databases. Peer-reviewed studies were selected for inclusion if they focused on childhood vaccines [≤ 7 years of age], used multivariate analyses, and were published between January 2007 and November 2012. Our results show a variety of factors as being associated with vaccine hesitancy but they do not allow for a complete classification and confirmation of their independent and relative strength of influence. Determinants of vaccine hesitancy are complex and context-specific - varying across time, place and vaccines., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

As clinical team leader on an acute inpatient mental health ward at Cygnet Health Care's Kewstoke Hospital, my role is to supervise and support my team and to work with the ward's 15 patients.

Primary care represents a fundamental component of the health system, particularly for young people. However, youth access to primary care is less than ideal. To optimize clinician capacity to promote youth health, an interactive training module was developed and tailored to the needs of general practitioners. As part of an exploratory study, 11 participants were interviewed to determine the perceived capacity of the module to promote youth-friendly primary care. Findings suggest the module can enhance clinician skills, knowledge, and confidence to promote youth health; however, it has a limited ability to inform how organizational capacity might be bolstered-this includes the development of interagency networks. In this epoch of primary care reform, these findings are important for two key reasons. First, they reveal the need to bolster clinicians' perceived ability to use youth healthcare skills; second, they highlight the complementary importance of organizational support to ensure and sustain youth-friendly practices. The article concludes with a discussion of key implications for policymakers, practitioners, and researchers.

Aim: Human dignity as an important consideration in health care has been primarily investigated from an adult perspective. This paper explores young people's perceptions of dignity and how it impacts on their health-care experience., Method: A qualitative pilot study was undertaken at the Children's Hospital, Westmead in from 2010 to 2011. Semistructured interviews were conducted with five inpatients, and data were analysed using a grounded theory approach., Results: The adolescents interviewed perceived dignity as a way of protecting their personhood. Privacy and maintaining integrity were the means by which dignity could be preserved in a health-care setting., Conclusions: The study found that young people had unique perceptions of privacy and personhood with regards to dignity. Of the concepts of dignity in the existing literature, the dignity of identity was most applicable to adolescents' conceptions. This understanding of young people's views of dignity could prevent dignity violations in health care and beneficially impact their development., (© 2013 The Authors. Journal of Paediatrics and Child Health © 2013 Paediatrics and Child Health Division (Royal Australasian College of Physicians).)

For mammals, acetylcholine (ACh) promotes endothelium-dependent vasodilation primarily through nitric oxide (NO) and prostaglandin-mediated pathways, with varying reliance on endothelial-derived hyperpolarizing factors. Currently, no studies have been conducted on small systemic arteries from wild birds. We hypothesized that ACh-mediated vasodilation of isolated small arteries from mourning doves (Zenaida macroura) would likewise depend on endothelial-derived factors. Small resistance mesenteric and cranial tibial (c. tibial) arteries (80-150 μm, inner diameter) were cannulated and pre-constricted to 50 % of resting inner diameter with phenylephrine then exposed to increasing concentrations of ACh (10(-9)-10(-5) M) or the NO donor, sodium nitroprusside (SNP; 10(-12)-10(-3) M). For mesenteric arteries, ACh-mediated vasodilation was significantly blunted with the potassium channel antagonist tetraethylammonium chloride (TEA, 10 mM); whereas responses were only moderately impaired with endothelial disruption or inhibition of prostaglandins (indomethacin, 10 μM). In contrast, endothelial disruption as well as exposure to TEA largely abolished vasodilatory responses to ACh in c. tibial arteries while no effect of prostaglandin inhibition was observed. For both vascular beds, responses to ACh were moderately dependent on the NO signaling pathway. Inhibition of NO synthase had no impact, despite complete reversal of phenylephrine-mediated tone with SNP, whereas inhibition of soluble guanylate cyclase (sGC) caused minor impairments. Endothelium-independent vasodilation also relied on potassium channels. In summary, ACh-mediated vasodilation of mesenteric and c. tibial arteries occurs through the activation of potassium channels to induce hyperpolarization with moderate reliance on sGC. Prostaglandins likewise play a small role in the vasodilatory response to ACh in mesenteric arteries.

Breast cancer progression is associated with loss of estrogen receptor (ER-α), often due to epigenetic silencing. IGFBP genes have consistently been identified among the most common to be aberrantly methylated in tumours. To understand the impact of losing IGFBP-3 tumour expression via DNA methylation, we treated four breast cancer cell lines (MCF-7, T47D, Hs578T and MDA-MB-231) with a DNA methyltransferase inhibitor, 5-Aza-2'-deoxycytidine (AZA) to determine IGFBP-3's role in the effects of AZA on total cell number and survival relative to changes in the ER. AZA induced cell growth inhibition, death and a reduction in the formation of colonies, despite increasing ER-α expression in ER-negative cells but reducing ER-α in ER-positive cells. Regardless of the differential effects on the ER-α, AZA consistently increased the abundance of IGFBP-3 and negating this increase in IGFBP-3 with siRNA reduced the AZA-induced growth inhibition and induction of cell death and virtually negated the AZA-induced inhibition of colony formation. With ER-α positive cells AZA increased the abundance of the tumour suppressor gene, p53 and induced demethylation of the IGFBP-3 promoter, whereas with ER negative cells, AZA epigenetically increased the transcription factor AP2-α, which when silenced prevented the increase in IGFBP-3. IGFBP-3 plays an important role in the anti-tumorigenic effects of AZA on breast cancer cells., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: The intensity, spread, and effects of public opinion about vaccines are growing as new modes of communication speed up information sharing, contributing to vaccine hesitancy, refusals, and disease outbreaks. We aimed to develop a new application of existing surveillance systems to detect and characterise early signs of vaccine issues. We also aimed to develop a typology of concerns and a way to assess the priority of each concern., Methods: Following preliminary research by The Vaccine Confidence Project, media reports (eg, online articles, blogs, government reports) were obtained using the HealthMap automated data collection system, adapted to monitor online reports about vaccines, vaccination programmes, and vaccine-preventable diseases. Any reports that did not meet the inclusion criteria--any reference to a human vaccine or vaccination campaign or programme that was accessible online--were removed from analysis. Reports were manually analysed for content and categorised by concerns, vaccine, disease, location, and source of report, and overall positive or negative sentiment towards vaccines. They were then given a priority level depending on the seriousness of the reported event and time of event occurrence. We used descriptive statistics to analyse the data collected during a period of 1 year, after refinements to the search terms and processes had been made., Findings: We analysed data from 10,380 reports (from 144 countries) obtained between May 1, 2011, and April 30, 2012. 7171 (69%) contained positive or neutral content and 3209 (31%) contained negative content. Of the negative reports, 1977 (24%) were associated with impacts on vaccine programmes and disease outbreaks; 1726 (21%) with beliefs, awareness, and perceptions; 1371 (16%) with vaccine safety; and 1336 (16%) with vaccine delivery programmes. We were able to disaggregate the data by country and vaccine type, and monitor evolution of events over time and location in specific regions where vaccine concerns were high., Interpretation: Real-time monitoring and analysis of vaccine concerns over time and location could help immunisation programmes to tailor more effective and timely strategies to address specific public concerns., Funding: Bill & Melinda Gates Foundation., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Our objective was to compare the stiffness of lateral mass screws versus two different spinous process wiring constructs in a cadaveric model of plated anterior cervical pseudoarthrosis. When treating an anterior plated pseudoarthrosis via a posterior approach, it is unclear whether the added expense, muscle exposure, and risk of lateral mass fixation are justified biomechanically versus a simpler, cheaper, and potentially less morbid wiring technique, because the presence of the anterior plate likely reduces motion over the unplated situation. Seven cadaveric cervical spines were loaded in compression, flexion, extension, lateral bending, and torsion. Each load sequence was applied to: 1) the intact spine; 2) after application of a plated ACDF construct (pACDF); and 3) after the insertion of lateral mass (LM) screws, ``modified'' triple wiring (TW), or Roger's wiring (RW), in alternating order for each specimen. For each sequence, load deformation curves and stiffness were obtained. Supplemental LM fixation significantly (p ≤ 0.05) increased stiffness versus pACDF in all six modes tested. TW significantly increased stiffness versus pACDF in compression, flexion, and torsion, but not in extension, or lateral bending. RW significantly increased stiffness versus pACDF only in axial torsion. When comparing LM to the wiring constructs, LM fixation was significantly stiffer than RW in flexion, extension, and lateral bending; LM fixation was stiffer than TW in lateral bending. LM fixation produced the stiffest overall constructs in stabilizing a plated pseudarthrosis ACDF model. It was significantly stiffer in more modes versus RW than TW.

Background: Atrial fibrillation (AF) after cardiac surgery is a common marker of poor outcomes. Quantitative electrocardiographic (ECG) measurements may be valuable predictors of postoperative AF., Methods: We evaluated clinical and ECG predictors of postoperative AF in 13,356 patients who underwent cardiac surgery in sinus rhythm., Results: A total of 4724 patients (35%) developed postoperative AF. P-wave amplitude in leads aVR and V(1) were the strongest ECG predictors. A less negative P-wave amplitude in lead aVR was associated with increased risk for postoperative AF (odds ratio, 1.46; 95% confidence interval, 1.32-1.61), as was a more positive or a more negative P-wave amplitude in lead V(1) (odds ratio, 1.25; 95% confidence interval, 1.16-1.36) after adjusting for clinical and procedural predictors of postoperative AF. Reclassification analysis showed a 7% discrimination improvement (P < .0001)., Conclusions: P-wave amplitude in lead aVR and lead V(1) are powerful predictors of postoperative AF and, in combination with other clinical predictors, can guide application of prophylactic interventions., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Yersinia pestis forms a biofilm in the foregut of its flea vector that promotes transmission by flea bite. As in many bacteria, biofilm formation in Y. pestis is controlled by intracellular levels of the bacterial second messenger c-di-GMP. Two Y. pestis diguanylate cyclase (DGC) enzymes, encoded by hmsT and y3730, and one phosphodiesterase (PDE), encoded by hmsP, have been shown to control biofilm production in vitro via their opposing c-di-GMP synthesis and degradation activities, respectively. In this study, we provide further evidence that hmsT, hmsP, and y3730 are the only three genes involved in c-di-GMP metabolism in Y. pestis and evaluated the two DGCs for their comparative roles in biofilm formation in vitro and in the flea vector. As with HmsT, the DGC activity of Y3730 depended on a catalytic GGDEF domain, but the relative contribution of the two enzymes to the biofilm phenotype was influenced strongly by the environmental niche. Deletion of y3730 had a very minor effect on in vitro biofilm formation, but resulted in greatly reduced biofilm formation in the flea. In contrast, the predominant effect of hmsT was on in vitro biofilm formation. DGC activity was also required for the Hms-independent autoaggregation phenotype of Y. pestis, but was not required for virulence in a mouse model of bubonic plague. Our results confirm that only one PDE (HmsP) and two DGCs (HmsT and Y3730) control c-di-GMP levels in Y. pestis, indicate that hmsT and y3730 are regulated post-transcriptionally to differentially control biofilm formation in vitro and in the flea vector, and identify a second c-di-GMP-regulated phenotype in Y. pestis.

A 52-year-old female patient who presented with a history of increasing shortness of breath and fatigue was diagnosed with a combination of cor triatriatum and myxomatous mitral valve disease. Transesophageal echocardiography revealed cor triatriatum and severe mitral regurgitation (MR) due to myxomatous degeneration. The patient underwent a successful removal of the left atrial membrane and repair of the mitral valve. This combination of cor triatriatum and myxomatous mitral valve disease is exceedingly rare; in the present patient the symptoms caused by MR led to the discovery of a left atrial membrane.

General practitioners (GPs) are the health care providers from which young people are most likely to seek help. However, the rate at which young people access GPs is less than ideal. Four focus groups were conducted with groups of GPs in New South Wales to inform the development of a GP training program on youth health. Analysis of the focus group interviews yielded three themes that describe the context in which GPs work with young people, how GPs see young people and their work with them, and GPs' expressed training preferences. GPs described working with young people as difficult, which in turn suggests that the self-efficacy of GPs may need to be addressed in training and resource development. GPs also described systemic barriers to working with young people that can be addressed through training, advocacy and policy development.

Plague is a flea-borne zoonosis caused by the bacterium Yersinia pestis. Y. pestis mutants lacking the yersiniabactin (Ybt) siderophore-based iron transport system are avirulent when inoculated intradermally but fully virulent when inoculated intravenously in mice. Presumably, Ybt is required to provide sufficient iron at the peripheral injection site, suggesting that Ybt would be an essential virulence factor for flea-borne plague. Here, using a flea-to-mouse transmission model, we show that a Y. pestis strain lacking the Ybt system causes fatal plague at low incidence when transmitted by fleas. Bacteriology and histology analyses revealed that a Ybt-negative strain caused only primary septicemic plague and atypical bubonic plague instead of the typical bubonic form of disease. The results provide new evidence that primary septicemic plague is a distinct clinical entity and suggest that unusual forms of plague may be caused by atypical Y. pestis strains.

Progression of breast cancer is associated with remodeling of the extracellular matrix, often involving a switch from estrogen dependence to a dependence on EGF receptor (EGFR)/HER-2 and is accompanied by increased expression of the main binding protein for insulin-like growth factors (IGFBP-3). We have examined the effects of IGFBP-3 on EGF responses of breast epithelial cells in the context of changes in the extracellular matrix. On plastic and laminin with MCF-10A normal breast epithelial cells, EGF and IGFBP-3 each increased cell growth and together produced a synergistic response, whereas with T47D breast cancer cells IGFBP-3 alone had no effect, but the ability of EGF to increase cell proliferation was markedly inhibited in the presence of IGFBP-3. In contrast on fibronectin with MCF-10A cells, IGFBP-3 alone inhibited cell growth and blocked EGF-induced proliferation. With the cancer cells, IGFBP-3 alone had no effect but enhanced the EGF-induced increase in cell growth. The insulin-like growth factor-independent effects of IGFBP-3 alone on cell proliferation were completely abrogated in the presence of an EGFR, tyrosine kinase inhibitor, Iressa. Although IGFBP-3 did not affect EGFR phosphorylation [Tyr(1068)], it was found to modulate receptor internalization and was associated with activation of Rho and subsequent changes in MAPK phosphorylation. The levels of fibronectin and IGFBP-3 within breast tumors may determine their dependence on EGFR and their response to therapies targeting this receptor.

Protection against virulent pathogens that cause acute, fatal disease is often hampered by development of microbial resistance to traditional chemotherapeutics. Further, most successful pathogens possess an array of immune evasion strategies to avoid detection and elimination by the host. Development of novel, immunomodulatory prophylaxes that target the host immune system, rather than the invading microbe, could serve as effective alternatives to traditional chemotherapies. Here we describe the development and mechanism of a novel pan-anti-bacterial prophylaxis. Using cationic liposome non-coding DNA complexes (CLDC) mixed with crude F. tularensis membrane protein fractions (MPF), we demonstrate control of virulent F. tularensis infection in vitro and in vivo. CLDC+MPF inhibited bacterial replication in primary human and murine macrophages in vitro. Control of infection in macrophages was mediated by both reactive nitrogen species (RNS) and reactive oxygen species (ROS) in mouse cells, and ROS in human cells. Importantly, mice treated with CLDC+MPF 3 days prior to challenge survived lethal intranasal infection with virulent F. tularensis. Similarly to in vitro observations, in vivo protection was dependent on the presence of RNS and ROS. Lastly, CLDC+MPF was also effective at controlling infections with Yersinia pestis, Burkholderia pseudomallei and Brucella abortus. Thus, CLDC+MPF represents a novel prophylaxis to protect against multiple, highly virulent pathogens.

Objective: Determine the effects of matrix metalloproteinases (MMPs)-2, -9, macrophage inflammatory protein-2 (MIP-2), tissue inhibitors of matrix metalloproteinase (TIMP)-1 and -2 by immunohistochemical expression in fungal affected and purulonecrotic corneas., Procedure: Paraffin-embedded equine corneal samples; normal (n = 9), fungal affected (FA; n = 26), and purulonecrotic without fungi (PN; n = 41) were evaluated immunohistochemically for MMP-2, -9, MIP-2, TIMP-1 and -2. The number of immunoreactive inflammatory cells was counted and statistics analyzed. Western blot was performed to detect MMP-2, MMP-9, TIMP-1 and TIMP-2 proteins., Results: Matrix metalloproteinases-2, -9, MIP-2, TIMP-1 and -2 immunoreactivity was identified in corneal epithelium of normal corneas, and in corneal epithelium, inflammatory cells, keratocytes, and vascular endothelial cells of both FA and PN samples. Inflammatory cell immunoreactivity was significantly higher in FA and PN samples than in the normal corneas. There was positive correlation between MMP-2 and MIP-2, MMP-9 and MIP-2, and MMP-9 and TIMP-1 in inflammatory cell immunoreactivity in FA samples. There was positive correlation between MMP-9 and MIP-2, MMP-9 and TIMP-2, MIP-2 and TIMP-1, and MIP-2 and TIMP-2 in inflammatory cell immunoreactivity in PN samples. Western blot confirmed the presence of all four proteins in equine corneal samples., Conclusion: Increased immunoreactivity of MMP-2 and -9 in FA and PN samples is indirectly related to MIP-2 through its role in neutrophil chemo-attraction. Tissue inhibitors of matrix metalloproteinase-1 and TIMP-2 are up-regulated in equine purulonecrotic and fungal keratitis secondary to MMP-2 and MMP-9 expression. The correlation between MMPs -2 and -9, MIP-2, TIMPs -1 and -2 suggests that these proteins play a specific role in the pathogenesis of equine fungal keratitis.

Yersinia pestis, the agent of plague, is transmitted to mammals by infected fleas. Y. pestis exhibits a distinct life stage in the flea, where it grows in the form of a cohesive biofilm that promotes transmission. After transmission, the temperature shift to 37 degrees C induces many known virulence factors of Y. pestis that confer resistance to innate immunity. These factors are not produced in the low-temperature environment of the flea, however, suggesting that Y. pestis is vulnerable to the initial encounter with innate immune cells at the flea bite site. In this study, we used whole-genome microarrays to compare the Y. pestis in vivo transcriptome in infective fleas to in vitro transcriptomes in temperature-matched biofilm and planktonic cultures, and to the previously characterized in vivo gene expression profile in the rat bubo. In addition to genes involved in metabolic adaptation to the flea gut and biofilm formation, several genes with known or predicted roles in resistance to innate immunity and pathogenicity in the mammal were upregulated in the flea. Y. pestis from infected fleas were more resistant to phagocytosis by macrophages than in vitro-grown bacteria, in part attributable to a cluster of insecticidal-like toxin genes that were highly expressed only in the flea. Our results suggest that transit through the flea vector induces a phenotype that enhances survival and dissemination of Y. pestis after transmission to the mammalian host.

We compared the biomechanical strength of the 2.5 mm PushLock suture anchor with a traditional Bio-SutureTak suture anchor in repair of ulnar collateral ligament injuries. Iatrogenic ulnar collateral ligament injuries in 18 cadaveric thumbs were repaired and used to test for load to failure and cyclic loading. The average force required to generate a 2 mm gap was 7.7 N for the 2.5 mm PushLock and 6.3 N for the Bio-SutureTak (p = 0.04). The ultimate load to failure was 28.0 N for the 2.5 mm PushLock and 18.8 N for the Bio-SutureTak (p = 0.16). There were no statistical differences between the two suture anchors under cyclic loading. The 2.5 mm PushLock suture anchor provides significantly stronger resistance to 2 mm gap formation at the repair site and is less likely to fail at the suture-ligament interface. However, there was no difference in the load to failure between the two suture anchors.

Plague is a zoonosis transmitted by fleas and caused by the gram-negative bacterium Yersinia pestis. During infection, the plasmidic caf1M1A1 operon that encodes the Y. pestis F1 protein capsule is highly expressed, and anti-F1 antibodies are protective. Surprisingly, the capsule is not required for virulence after injection of cultured bacteria, even though it is an antiphagocytic factor and capsule-deficient Y. pestis strains are rarely isolated. We found that a caf-negative Y. pestis mutant was not impaired in either flea colonization or virulence in mice after intradermal inoculation of cultured bacteria. In contrast, absence of the caf operon decreased bubonic plague incidence after a flea bite. Successful development of plague in mice infected by flea bite with the caf-negative mutant required a higher number of infective bites per challenge. In addition, the mutant displayed a highly autoaggregative phenotype in infected liver and spleen. The results suggest that acquisition of the caf locus via horizontal transfer by an ancestral Y. pestis strain increased transmissibility and the potential for epidemic spread. In addition, our data support a model in which atypical caf-negative strains could emerge during climatic conditions that favor a high flea burden. Human infection with such strains would not be diagnosed by the standard clinical tests that detect F1 antibody or antigen, suggesting that more comprehensive surveillance for atypical Y. pestis strains in plague foci may be necessary. The results also highlight the importance of studying Y. pestis pathogenesis in the natural context of arthropod-borne transmission.

Yersinia pestis is the causative agent of plague. Unlike the other pathogenic Yersinia species, Y. pestis has evolved an arthropod-borne route of transmission, alternately infecting flea and mammalian hosts. Distinct subsets of genes are hypothesized to be differentially expressed during infection of the arthropod vector and mammalian host. Genes crucial for mammalian infection are referred to as virulence factors whilst genes playing a role in the flea vector are termed transmission factors. This article serves as a review of known factors involved in flea-borne transmission and introduces an 'in vivo' microarray approach to elucidating the genetic basis of Y. pestis infection of- and transmission by the flea.

Purpose: High epidermal growth factor receptor (EGFR) gene copy number is associated with poor prognosis in lung cancer, but such findings have not been reported for HNSCC. A better understanding of the EGFR pathway may improve the use of EGFR inhibitors in HNSCC., Patients and Methods: EGFR status was analyzed in 86 tumor samples from 82 HNSCC patients by fluorescent in situ hybridization (FISH) to determine EGFR gene copy number, by polymerase chain reaction and direct sequencing for activating mutations, and by DNA microarray and immunohistochemistry for RNA and protein expression. The results were associated with patient characteristics and clinical end points., Results: Forty-three (58%) of 75 samples with FISH results demonstrated EGFR high polysomy and/or gene amplification (FISH positive). The FISH-positive group did not differ from the FISH-negative group with respect to age, sex, race, tumor grade, subsites and stage, or EGFR expression by analyses of RNA or protein. No activating EGFR mutations were found. However, the FISH-positive group was associated with worse progression-free and overall survival (P < .05 and P < .01, respectively; log-rank test). When microarray data were interrogated using the FISH results as a supervising parameter, ECop (which is known to coamplify with EGFR and regulate nuclear factor-kappa B transcriptional activity) had higher expression in FISH-positive tumors., Conclusion: High EGFR gene copy number by FISH is frequent in HNSCC and is a poor prognostic indicator. Additional investigation is indicated to determine the biologic significance and implications for EGFR inhibitor therapies in HNSCC.

Human smooth pursuit eye movements are principally driven by visual feedback and cannot normally be initiated at will. However, when tracking periodic motion, smooth eye movements reverse direction prior to target reversal, driven by anticipation, not visual feedback. Here, we investigate cognitive control over such eye reversals. Target stimuli were discrete double ramps-constant speed (30 degrees /s) rightwards followed by similar leftward movement, reversal time ranging from 420 ms to 840 ms. Three experimental conditions were examined. In the precued condition, double ramps of randomised reversal time were presented. Prior to ramp presentation audio precues were given with an interval indicating start and reversal time of the unseen, upcoming double ramp. Subjects were able to use these cues to voluntarily control timing of anticipatory eye reversal, so that when occasional false precues gave underestimates of target reversal time, eye reversal occurred before target reversal. Precued eye reversal times were comparable to those in a second, predictable condition, in which double ramps with identical reversal time were given repeatedly without precues. In contrast, reversal occurred much later in a third, reactive condition, also without precues, when unexpected early target reversals occurred sporadically within a series having identical, predictable reversal times. The findings provide evidence that timing of anticipatory smooth eye movement, both at the start of the double-ramp and at its reversal, can be independently controlled at will using non-motion-based timing cues.

Home mechanical ventilation was once a remote idea and thought to be used only in extreme cases. However, patient preference as well as limited financial resources to care for these patients in a long-term setting is forcing acute care facilities and families to make the choice of home care. This article describes how an interdisciplinary team used a quality process to develop and implement tools to assist with discharge planning in this complex patient population.

The Wnt/beta-catenin/Tcf and IkappaB/NF-kappaB cascades are independent pathways involved in cell cycle control, cellular differentiation, and inflammation. Constitutive Wnt/beta-catenin signaling occurs in certain cancers from mutation of components of the pathway and from activating growth factor receptors, including RON and MET. The resulting accumulation of cytoplasmic and nuclear beta-catenin interacts with the Tcf/LEF transcription factors to induce target genes. The IkappaB kinase complex (IKK) that phosphorylates IkappaB contains IKKalpha, IKKbeta, and IKKgamma. Here we show that the cyclin D1 gene functions as a point of convergence between the Wnt/beta-catenin and IkappaB pathways in mitogenic signaling. Mitogenic induction of G(1)-S phase progression and cyclin D1 expression was PI3K dependent, and cyclin D1(-/-) cells showed reduced PI3K-dependent S-phase entry. PI3K-dependent induction of cyclin D1 was blocked by inhibitors of PI3K/Akt/IkappaB/IKKalpha or beta-catenin signaling. A single Tcf site in the cyclin D1 promoter was required for induction by PI3K or IKKalpha. In IKKalpha(-/-) cells, mitogen-induced DNA synthesis, and expression of Tcf-responsive genes was reduced. Reintroduction of IKKalpha restored normal mitogen induction of cyclin D1 through a Tcf site. In IKKalpha(-/-) cells, beta-catenin phosphorylation was decreased and purified IKKalpha was sufficient for phosphorylation of beta-catenin through its N-terminus in vitro. Because IKKalpha but not IKKbeta induced cyclin D1 expression through Tcf activity, these studies indicate that the relative levels of IKKalpha and IKKbeta may alter their substrate and signaling specificities to regulate mitogen-induced DNA synthesis through distinct mechanisms.

The most important factor allowing the generation of pursuit eye movements prior to target onset is confidence in the likelihood of imminent target appearance. We show how these anticipatory pursuit responses are essentially ballistic motor primitives and how the signal that drives them in normally defined by stored information concerning target speed, duration and direction. But we also show how static cues may be used to grade the level of these motor primitives 'on-line'. We further demonstrate that, when concatenated, these graded motor primitives can be rapidly combined to form predictive smooth movement trajectories in response to complex multi-ramp sequences.

A second adenomatous polyposis coli (APC)-like gene, APC2/APCL, was recently described and localized to chromosome 19. We have fine mapped APC2 to a small region of chromosome 19p13.3 containing markers D19S883 and WI-19632, a region commonly lost in a variety of cancers, particularly ovarian cancer. Interphase fluorescence in situ hybridization analysis revealed an APC2 allelic imbalance in 19 of 20 ovarian cancers screened and indicates that APC2 could be a potential tumor suppressor gene in ovarian cancer. When overexpressed in SKOV3 ovarian cancer cells, which express low levels of APC2, exogenous APC2 localized to the Golgi apparatus, actin-containing structures, and occasionally to microtubules. Antibodies against the NH2 terminus of human APC2 show that endogenous APC2 is diffusely distributed in the cytoplasm and colocalizes with both the Golgi apparatus and actin filaments. APC2 remained associated with actin filaments after treatment with the actin-disrupting agent, cytochalasin D. These results suggest that APC2 is involved in actin-associated events and could influence cell motility or adhesion through interaction with actin filaments, as well as functioning independently or in cooperation with APC to down-regulate beta-catenin signaling.

Mitomycin C (MMC) is a clinically used anticancer drug that is reduced to cytotoxic metabolites by cellular reductases via a process known as bioreductive drug activation. The identification of key enzymes responsible for drug activation has been investigated extensively with the ultimate aim of tailoring drug administration to patients whose tumors possess the biochemical machinery required for drug activation. In the case of MMC, considerable interest has been centered upon the enzyme DT-diaphorase (DTD) although conflicting reports of good and poor correlations between enzyme activity and response in vitro and in vivo have been published. The principle aim of this study was to provide a definitive answer to the question of whether tumor response to MMC could be predicted on the basis of DTD activity in a large panel of human tumor xenografts. DTD levels were measured in 45 human tumor xenografts that had been characterized previously in terms of their sensitivity to MMC in vitro and in vivo (the in vivo response profile to MMC was taken from work published previously). A poor correlation between DTD activity and antitumor activity in vitro as well as in vivo was obtained. This study also assessed the predictive value of an alternative approach based upon the ability of tumor homogenates to metabolize MMC. This approach is based on the premise that the overall rate of MMC metabolism may provide a better indicator of response than single enzyme measurements. MMC metabolism was evaluated in tumor homogenates (clarified by centrifugation at 1000 x g for 1 min) by measuring the disappearance of the parent compound by HPLC. In responsive [T/C <10% (T/C defined as the relative size of treated and control tumors)] and resistant (T/C >50%) tumors, the mean half life of MMC was 75+/-48.3 and 280+/-129.6 min, respectively. The difference between the two groups was statistically significant (P < 0.005). In conclusion, these results unequivocally demonstrate that response to MMC in vivo cannot be predicted on the basis of DTD activity. Measurement of MMC metabolism by tumor homogenates on the other hand may provide a better indicator of tumor response, and further studies are required to determine whether this approach has real clinical potential in terms of individualizing patient chemotherapy.

A grounded theory approach was used to generate theory about clients' perceptions of polysomnography, and the relationships between these perceptions and compliance with therapy. Interviews were conducted with two groups of clients: those who complied with recommended therapy (Continuous Positive Airways Pressure) and those who did not. Compliance with suggested therapy appeared to be related to the degree of benefit derived by the client. In addition, there were problems with the process of diagnosis and follow-up that impacted on client satisfaction and may have influenced their compliance. These findings have highlighted issues which have been used to generate theories that will be tested in future research.

The analysis and visualization of large data sets collected by use of laser Doppler velocimetry has presented a challenge to researchers using this technique to investigate complex flow fields. This paper describes an automated procedure for analysis and animation of two- and three-dimensional laser Doppler velocimetry data. The procedure consists of a suite of FORTRAN programs for calculating phase window averages of velocity and the Reynolds stress tensor, calculating the principal normal stresses, maximum shear stresses, and preparation of data files for input into Plot-3D compatible data visualization software. An example application of these techniques to data collected from an in vitro investigation of the retrograde flow field associated with a bileaflet mechanical heart valve is also presented.

Seventeen nurses in eight rural general practices participated in a distance education project. Low-cost videoconferencing equipment was assessed for its suitability in two training sessions, concerning asthma and travel immunization. The intended learning outcomes were reached and although initially apprehensive, the nurses quickly became accustomed to the medium. Videoconferencing has now become an accepted part of in-service training. Technical reliability remains the most important problem.

Objective: Our purpose was to determine the prognostic significance of human papillomavirus deoxyribonucleic acid in cervical cancers., Study Design: The polymerase chain reaction was used to detect human papillomavirus deoxyribonucleic acid types 6, 11, 16, 18, 31, 33, 52, or 58 in tumors from 148 patients (equal numbers of whom were disease free or had relapses) surgically treated for stage IB or IIA cancers in a major Australian hospital. Cox regression modeling was used to assess the effect of human papillomavirus status on tumor recurrence, taking into account patient age, clinical stage, histologic node status, and type of tumor., Results: Seventy of 74 (95%) of the recurring tumors and 62 of 74 (84%) of the nonrecurring tumors were human papillomavirus deoxyribonucleic acid positive. The rates of positivity of types 16 and 18 were 64% versus 31% in the recurrers and 65% versus 14% in the nonrecurrers. Human papillomavirus type 18 positivity was associated with a greater risk of recurrence than was type 16 positivity (hazard ratio 1.8; p = 0.03). Clinical stage, nodal metastasis, and young age (< or = 35 years) also had adverse effects on relapse (hazard ratio for each approximately 2)., Conclusion: Human papillomavirus type 18 positivity is a risk factor for tumor recurrence in surgically treated cervical cancer.

The polymerase chain reaction (PCR) was used to detect human papillomavirus (HPV) DNA in Formalin-acetic acid alcohol (FAA)-fixed paraffin-embedded tissue from 40 patients whose primary cervical cancers showed a tentacular pattern of invasion at their advancing edges, and 40 patients (matched by age, International Federation of Obstetrics and Gynecology (FIGO) stage and histology type) whose tumors showed broad front invasion. The rate of HPV DNA positivity was the same in both the tentacular and the broad front tumors (83%), but the ratios of HPV 16 to HPV 18 in the two groups were markedly different (20:10 versus 27:4, respectively). HPV type 18 was detected more frequently in tentacular than broad front tumors (P = 0.03). The overall rates of recurrence and mortality were 15 and 9%, respectively (18 and 10% in the tentacular group compared with 13 and 8% in the broad front group). Univariate analysis showed statistically significant associations between HPV 18 and tumor recurrence (P = 0.04), but not between a tentacular pattern of invasion and tumor recurrence (P < 0.05). The findings to emerge from this survey indicate that the presence of particular HPV types may, in part, mediate the histological and clinical behavior of cervical cancers.

The role of cellular immunity in the establishment and progression of immunosuppressive lentivirus infection remains equivocal. To develop a model system with which these aspects of the host immune response can be studied experimentally, we examined the response of cats to a hybrid peptide containing predicted T-and B-cell epitopes from the gag and env genes of feline immunodeficiency virus (FIV). Cats were immunized with an unmodified 17-residue peptide incorporating residues 196 to 208 (from gag capsid protein p24) and 395 to 398 (from env glycoprotein gp120) of the FIV Glasgow-8 strain by using Quil A as an adjuvant. Virus-specific lymphocytotoxicity was measured by chromium-51 release assays. The target cells were autologous or allogeneic skin fibroblasts either infected with recombinant FIV gag vaccinia virus or pulsed with FIV peptides. Effector cells were either fresh peripheral blood mononuclear cells or T-cell lines stimulated with FIV peptides in vitro. Cytotoxic effector cells from immunized cats lysed autologous, but not allogeneic, target cells when they were either infected with recombinant FIV gag vaccinia virus or pulsed with synthetic peptides comprising residues 196 to 205 or 200 to 208 plus 395. Depletion of CD8+ T cells, from the effector cell population abrogated the lymphocytotoxicity. Immunized cats developed an antibody response to the 17-residue peptide immunogen and to recombinant p24. However, no antibodies which recognized smaller constituent peptides could be detected. This response correlated with peptide-induced T-cell proliferation in vitro. This study demonstrates that cytotoxic T lymphocytes specific for FIV can be induced following immunization with an unmodified short synthetic peptide and defines a system in which the protective or pathological role of such responses can be examined.