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Unfamiliar voice identification is error-prone. Whilst the investigation of system variables may indicate ways of boosting earwitness performance, this is an under-researched area. Two experiments were conducted to investigate how methods of presenting voices during a parade affect accuracy and self-rated confidence. In each experiment participants listened to a target voice, and were later asked to identify that voice from a nine-person target present or target absent parade. In Experiment 1, accuracy did not vary across parades comprising 15 or 30 s sample durations. Overall, when the target was present, participants correctly identified the target voice with 39% accuracy. However, when the target was absent, participants correctly rejected the parade 6% of the time. There was no relationship between accuracy and confidence. In Experiment 2, performance with a serial procedure, in which participants responded after hearing all nine voices, was compared with a sequential procedure, in which participants made a decision after listening to each voice. Overall accuracy was higher with the sequential procedure. These results highlight the importance of system variable research in voice identification. Different methods of presenting voices have the potential to support higher levels of accuracy than the procedure currently recommended in England and Wales.

Antibiotics are known to enter the environment, not only by human excretion but also through livestock/aquaculture, healthcare facilities, and pharmaceutical industry waste. Once in the environment, antibiotics have the ability to provide a selective pressure in microbial communities thus selecting for resistance. Bayou Lafourche of Southeastern Louisiana serves as the raw source of drinking water for 300,000 people in the region and has previously been shown to receive high amounts of fecal contamination. Four sites along the bayou and one site from its input source on the Mississippi River were monitored for water chemistry, total and fecal coliform estimates, and presence of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARG) for a period of 1 year. Four waste-associated bacterial isolates were tested for resistance to antibiotics (tetracycline, sulfamethoxazole/trimethoprim, cefoxitin, meropenem, imipenem, erythromycin, and vancomycin). Resistant bacteria were further examined with PCR/electrophoresis to confirm the presence of antibiotic resistance genes (Sul1, tet(A), tet(W), tet(X), IMP, KPC, and OXA-48). The bayou appears to meet the Louisiana Department of Environmental Quality (LDEQ) criteria for water chemistry, yet fecal coliforms were consistently higher than LDEQ thresholds, thus indicating fecal contamination. Enterobacteriaceae isolates showed 13.6%, 10.9%, and 19.8% resistant to tetracycline, sulfamethoxazole/trimethoprim, and cefoxitin, respectively, and 11 isolates were confirmed for presence of either tet(A) or Sul1 resistance genes. High fecal coliforms and presence of ARB/ARG may both indicate a presence of anthropogenic or agricultural source of fecal contamination.

Background: Despite the key role that people who inject drugs (PWID) play in the hepatitis C virus (HCV) epidemic, HCV treatment rates among this population have been historically low. Integrated models of HCV and substance use care have the potential to overcome some barriers to access; however, the evidence base is uncertain. This systematic review assesses the impacts of integrated HCV and substance use services on engagement in HCV care among PWID., Methods: We searched five databases up to December 2018 to identify original quantitative studies evaluating the impacts of co-location of HCV and substance use services on engagement in the HCV cascade of care among adult PWID. We conducted a narrative synthesis, categorizing models based on patient entry point (a: HCV facility, b: substance use disorder (SUD) facility, and c: other facilities), and levels of integrated services offered (a: HCV/substance use testing only, b: HCV/substance use treatment, and c: testing/treatment + other services)., Results: A total of 46 articles corresponding to 44 original studies were included. Almost all studies (n = 42) were conducted in high-income countries and only six studies in the Direct-Acting Antiviral (DAA) era. Twenty-six studies discussed the integration of services at SUD facilities, one at HCV facilities, and seventeen at other facilities. Analysis of included studies indicated that overall integrated care resulted in improved engagement in HCV care (e.g., testing, treatment uptake and cure). However, the quality of evidence was predominantly low to moderate., Conclusions: Available evidence suggests that integration of HCV and substance use services may improve engagement along the continuum of HCV care among PWID. Given limitations in data quality, and very few studies conducted in the DAA era and in low- and middle-income settings, further research is urgently needed to inform strategies to optimize HCV care access and outcomes among PWID globally., (Copyright © 2019 Elsevier B.V. All rights reserved.)

This study examines the occurrence of humpback whale (Megaptera novaeangliae) song in the northeast Pacific from three years of continuous recordings off central California (36.713°N, 122.186°W). Song is prevalent in this feeding and migratory habitat, spanning nine months of the year (September-May), peaking in winter (November-January), and reaching a maximum of 86% temporal coverage (during November 2017). From the rise of song in fall through the end of peak occurrence in winter, song length increases significantly from month to month. The seasonal peak in song coincides with the seasonal trough in day length and sighting-based evidence of whales leaving Monterey Bay, consistent with seasonal migration. During the seasonal song peak, diel variation shows maximum occurrence at night (69% of the time), decreasing during dawn and dusk (52%), and further decreasing with increasing solar elevation during the day, reaching a minimum near solar noon (30%). Song occurrence increased 44% and 55% between successive years. Sighting data within the acoustic detection range of the hydrophone indicate that variation in local population density was an unlikely cause of this large interannual variation. Hydrographic data and modeling of acoustic transmission indicate that changes in neither habitat occupancy nor acoustic transmission were probable causes. Conversely, the positive interannual trend in song paralleled major ecosystem variations, including similarly large positive trends in wind-driven upwelling, primary productivity, and krill abundance. Further, the lowest song occurrence during the first year coincided with anomalously warm ocean temperatures and an extremely toxic harmful algal bloom that affected whales and other marine mammals in the region. These major ecosystem variations may have influenced the health and behavior of humpback whales during the study period., Competing Interests: The authors have read the journal's policy and have the following competing interest: MF is the owner of Aguasonic Acoustics. There are no patents, products in development or marketed products to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Hospitals are common recruitment sites for injury and disability studies. However, the clinical and rehabilitation environment can create unique challenges for researchers to recruit participant populations. While there is growing injury and disability focused research involving Indigenous people to understand the types of services and supports required by this population to enhance their recovery experiences, there is limited knowledge of researchers' experiences implementing recruitment processes in the tertiary hospital environment. This paper reflects on the specific challenges of recruiting Indigenous patients following a traumatic brain injury from two tertiary hospitals in Northern Australia., Methods: Between July 2016 and April 2018, research staff recruited eligible patients from one hospital in Queensland and one hospital in the Northern Territory. Qualitative records summarising research staff contact with patients, family members and clinical hospital staff were documented. These qualitative records, in addition to field trip notes and researcher reflections were reviewed to summarise the main challenges in gaining access to patients who fit the eligibility criteria., Results: During the recruitment process, there were five main challenges encountered: (1) Patients discharging against medical advice from hospital; (2) Discharge prior to formal emergence from Post Traumatic Amnesia as per the Westmead Post Trauma Amnesia Scale; (3) Patients under adult guardianship orders; (4) Narrow participant eligibility criteria and (5) Coordinating around patient commitments and treatment. Details of how the recruitment processes were modified throughout the recruitment phase of the study to ensure greater access to patients that met the criteria are described., Conclusion: Based on our recruitment experiences, several recommendations are proposed for future TBI studies with Indigenous Australians. In addition to treatment, Indigenous TBI patients have wide range of needs that must be addressed while in hospital. Patient engagement and data collection processes should be flexible to respond to patient needs and the hospital environment. Employment of a centralized recruiter at each hospital site may help to minimise the challenges researchers need to navigate in the hospital environment. To improve recruitment processes in hospitals, it is essential for researchers examining other health or injury outcomes to describe their recruitment experiences.

Background: Prearrest diversion strategies are being adopted across the Western world, enabling the police to identify and divert people suspected of having mental disorder towards health and community services rather than the criminal justice system., Aims: To quantify longer-term criminal justice and mental health outcomes after prearrest diversion of people with suspected mental disorder and consider economic correlates., Methods: A systematic review of published literature on longer term outcomes after prearrest diversion., Results: Only two quasi-experimental studies, with four independent samples, could be included. Findings for criminal and mental health outcomes were inconclusive, but potential for adverse outcomes was identified. Ten studies with cost data suggested that prearrest diversion can lead to overall cost savings., Conclusions: There is still inadequate evidence on which to base prearrest diversion programmes. Although some benefits have been identified by the review, so have possible harms. Future research and funding strategies must build in high-quality, systematic evaluation of outcomes before implementing a theoretically attractive strategy more widely., (© 2019 The Authors Criminal Behaviour and Mental Health Published by John Wiley & Sons Ltd.)

The sea-surface microlayer (SML) at the air-sea interface is a distinct, under-studied habitat compared to the subsurface and copepods, important components of ocean food webs, have developed key adaptations to exploit this niche. By using automated SML sampling, high-throughput sequencing and unmanned aerial vehicles, we report on the distribution and abundance of pontellid copepods in relation to the unique biophysicochemical signature of the SML. We found copepods in the SML even during high exposure to sun-derived ultraviolet radiation and their abundance was significantly correlated to increased algal biomass. We additionally investigated the significance of the pontellids' blue pigmentation and found that the reflectance peak of the blue pigment matched the water-leaving spectral radiance of the ocean surface. This feature could reduce high visibility at the air-sea boundary and potentially provide camouflage of copepods from their predators.

Introduction: Many clinicians have suggested that a history of bladder and bowel dysfunction (BBD) in childhood predisposes to the development of interstitial cystitis/bladder pain syndrome (IC/BPS) or irritable bowel syndrome (IBS) in adulthood. We hypothesized that BBD symptoms in childhood would predict the IBS-associated phenotype in adult IC/BPS patients., Methods: Consecutive female patients (n=190) with a diagnosis of IC/BPS were administered a modified form of a clinical BBD questionnaire (BBDQ) to capture childhood BBD-like symptoms, as well as Interstitial Cystitis Symptoms Index (ICSI), Interstitial Cystitis Problem Index (ICPI), Pelvic Pain and Urgency/Frequency (PUF) questionnaires and UPOINT categorization. Patients were stratified to IBS-positive or IBS-negative according to clinical assessment of IBS-like symptoms., Results: The 127 patients (67%) identified with IBS-like symptoms recalled significantly higher BBDQ scores than the 63 patients (33%) who were IBS-negative (2.8 vs. 2.3; p=0.05). The IBS-positive patients also reported a higher number of UPOINT domains than their non-IBS counterparts (3.8 vs. 2.9; p=0.0001), while their PUF total scores were significantly higher (13.6 vs. 12.3; p=0.04). IBS-positive patients more often recalled that in childhood they did not have a daily bowel movement (BM) (p=0.04) and had "to push for a BM" (p=0.009). In childhood, they "urinated only once or twice per day" (p=0.03) and recalled "painful urination" more than those without IBS (p=0.03). There were no significant differences between the groups in answers to the other five questions of the BBDQ., Conclusions: Our symptom recollection survey was able to predict the IBS phenotype of IC/BPS based on a childhood BBDQ. Further prospective studies are needed to further evaluate these novel findings., Competing Interests: Competing interests: Dr. Nickel has been a consultant for Astellas, Auxillium, Eli Lilly, Farr Labs, Ferring, GSK, Pfizer, Taris Biomedical, Tribute, and Trillium Therapeutics; a speaker for Astellas and Eli Lilly; and has participated in clinical trials supported by GSK, Johnson & Johnson, Pfizer, and Taris Biomedical. The remaining authors report no competing personal or financial interests.

The oncogenic transcription factor FoxM1 plays a vital role in cell cycle progression, is activated in numerous human malignancies, and is linked to chromosome instability. We characterize here a cullin 4-based E3 ubiquitin ligase and its substrate receptor, VprBP/DCAF1 (CRL4 VprBP ), which we show regulate FoxM1 ubiquitylation and degradation. Paradoxically, we also found that the substrate receptor VprBP is a potent FoxM1 activator. VprBP depletion reduces expression of FoxM1 target genes and impairs mitotic entry, whereas ectopic VprBP expression strongly activates a FoxM1 transcriptional reporter. VprBP binding to CRL4 is reduced during mitosis, and our data suggest that VprBP activation of FoxM1 is ligase independent. This implies a nonproteolytic activation mechanism that is reminiscent of, yet distinct from, the ubiquitin-dependent transactivation of the oncoprotein Myc by other E3s. Significantly, VprBP protein levels were upregulated in high-grade serous ovarian patient tumors, where the FoxM1 signature is amplified. These data suggest that FoxM1 abundance and activity are controlled by VprBP and highlight the functional repurposing of E3 ligase substrate receptors independent of the ubiquitin system., (Copyright © 2017 American Society for Microbiology.)

Background: In Australia, 'Alcohol Management Plans' (AMPs) provide the policy infrastructure for State and Commonwealth Governments to address problematic alcohol use among Aboriginal and Torres Strait Islanders. We report community residents' experiences of AMPs in 10 of Queensland's 15 remote Indigenous communities., Methods: This cross-sectional study used a two-stage sampling strategy: N = 1211; 588 (48%) males, 623 (52%) females aged ≥18 years in 10 communities. Seven propositions about 'favourable' impacts and seven about 'unfavourable' impacts were developed from semi-structured interviews. For each proposition, one-sample tests of proportions examined participant agreement and multivariable binary logistic regressions assessed influences of gender, age (18-24, 25-44, 45-64, ≥65 years), residence (≥6 years), current drinking and Indigenous status. Confirmatory factor analyses estimated scale reliability (ρ), item loadings and covariances., Results: Slim majorities agreed that: AMPs reduced violence (53%, p = 0.024); community a better place to live (54%, 0.012); and children were safer (56%, p < 0.001). More agreed that: school attendance improved (66%, p < 0.001); and awareness of alcohol's harms increased (71%, p < 0.001). Participants were equivocal about improved personal safety (53%, p = 0.097) and reduced violence against women (49%, p = 0.362). The seven 'favourable' items reliably summarized participants' experiences of reduced violence and improved community amenity (ρ = 0.90). Stronger agreement was found for six 'unfavourable' items: alcohol availability not reduced (58%, p < 0.001); drinking not reduced (56%, p < 0.001)); cannabis use increased (69%, p < 0.001); more binge drinking (73%, p < 0.001); discrimination experienced (77%, p < 0.001); increased fines, convictions and criminal records for breaching restrictions (90%, p < 0.001). Participants were equivocal (51% agreed, p = 0.365) that police could enforce restrictions effectively. 'Unfavourable' items were not reliably reflected in one group (ρ = 0.48) but in: i) alcohol availability and consumption not reduced and ii) criminalization and discrimination. In logistic regressions, longer-term (≥ 6 years) residents more likely agreed that violence against women had reduced and that personal safety had improved but also that criminalization and binge drinking had increased. Younger people disagreed that their community was a better place to live and strongly agreed about discrimination. Current drinkers' views differed little from the sample overall., Conclusions: The present Government review provides an opportunity to reinforce 'favourable' outcomes while targeting: illicit alcohol, treatment and diversion services and reconciliation of criminalization and discrimination issues.

Purpose: Identifying Hunner lesions in patients with interstitial cystitis/bladder pain syndrome presents an opportunity for objective classification into Hunner lesion interstitial cystitis/bladder pain syndrome (classic interstitial cystitis) and nonHunner lesion bladder pain syndrome. While currently the former diagnosis requires cystoscopy, limited data suggest that these subtypes can be distinguished without endoscopy based on the degree of bladder focused centricity and the infrequent association with generalized pain conditions., Materials and Methods: Patients in a prospective, single center database of interstitial cystitis/bladder pain syndrome who had documented cystoscopic findings were categorized with Hunner lesion interstitial cystitis/bladder pain syndrome or nonHunner lesion bladder pain syndrome. Demographics, pain and symptom scores, voiding symptoms, irritable bowel syndrome and clinical UPOINT (urinary, psychosocial, organ specific, infection, neurological and tenderness) scoring were comparatively analyzed., Results: We reviewed the records of 469 patients, including 359 with documented local anesthetic cystoscopic findings, 44 (12.3%) with Hunner lesion interstitial cystitis/bladder pain syndrome and 315 (87.7%) with nonHunner bladder pain syndrome. Patients with Hunner lesions were older (p = 0.004) and had greater urinary frequency (p = 0.013), more nocturia (p = 0.0004) and higher ICSI (Interstitial Cystitis Symptom Index) scores (p = 0.017). Hunner lesion prevalence was significantly lower in those younger than 50 years vs those 50 years old or older (7.8% vs 14.9%, p = 0.0095). There was no difference in the number of UPOINT phenotype domains reported, overall UPOINT scores or the prevalence of irritable bowel syndrome between the groups., Conclusions: A subtype of interstitial cystitis with Hunner lesions has worse bladder centric symptoms but did not show a distinct bladder centric phenotype. Given the management implications of distinguishing classic interstitial cystitis from nonHunner lesion bladder pain syndrome, we recommend cystoscopy with local anesthesia in patients diagnosed with interstitial cystitis/bladder pain syndrome., (Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Favourable impacts are reported from complex alcohol control strategies, known as 'Alcohol Management Plans' (AMPs) implemented 14 years ago in 19 Aboriginal and Torres Strait Islander (Indigenous) communities in Queensland (Australia). However, it is not clear that all communities benefited and that positive impacts were sustained. Service providers, key stakeholders and community leaders provided insights about issues and impacts., Methods: Participants (N=382) were recruited from knowledgeable and experienced persons using agency lists and by recommendation across sectors which have a mandate for managing alcohol-related issues and consequences of AMP policies in communities. In semi-structured interviews, participants (51% Indigenous, 55% male and comprised of at least one-third local community residents) were asked whether they believed alcohol controls had been effective and to describe any favourable and unfavourable outcomes experienced or perceived. Inductive techniques were used for thematic analysis of the content of transcribed recorded interviews. Comments reflecting themes were assessed across service sectors, by gender, Indigenous status and remoteness., Results: Participants attributed reduced violence and improved community amenity to AMPs, particularly for 'very remote' communities. Participants' information suggests that these important achievements happened abruptly but may have become undermined over time by: the availability of illicit alcohol and an urgency to consume it; migration to larger centres to seek alcohol; criminalization; substitution of illicit drugs for alcohol; changed drinking behaviours and discrimination. Most issues were more frequently linked with 'very remote' communities., Conclusion: Alcohol restrictions in Queensland's Indigenous communities may have brought favourable changes, a significant achievement after a long period of poorly regulated alcohol availability from the 1980s up to 2002. Subsequently, over the past decade, an urgency to access and consume illicit alcohol appears to have emerged. It is not clear that relaxing restrictions would reverse the harmful impacts of AMPs without significant demand reduction, treatment and diversion efforts., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: Indigenous children in Australia are more likely than non-Indigenous children to be in contact with the child safety system. A large number of Queensland's Indigenous population live in remote and isolated communities in north Queensland where the state government's Alcohol Management Plans (AMPs) are in effect. In these communities it is an offence to have in one's possession more than the regulated amount and type of alcohol. A breach of these restrictions can result in convictions under the Liquor Act 1992 ., Findings: During an evaluation of AMPs, influential stakeholders and key service providers voiced their belief that a conviction for a breach of the AMP would impact a person's eligibility to hold a Positive Notice Blue Card (PNBC). On its own, however, a breach of the Liquor Act 1992 will not impact a person's eligibility for a PNBC. A PNBC is required for any person volunteering or working with children. Without a PNBC, a person is ineligible to work in child-related employment, volunteer at child-related activities or provide out-of-home care for children., Conclusion: This misconception needs to be addressed in these already-disadvantaged communities to ensure that Indigenous community members have every opportunity to hold a PNBC. Focused strategies with evaluation and research are needed in this important policy area.

To ensure success in a partnership agreement, healthcare organizations should create a funds flow framework. An effective funds flow framework will address not only the partner organizations' current challenges but also potential changes within the organizations. Funds flow frameworks are unique to the organizations and partnerships that use them.

Very high rates of injury and death during the 1990s were linked with increased alcohol availability and misuse in discrete Indigenous communities in rural and remote Queensland (Australia). To address widespread concerns about a public health crisis, from 2002, the Queensland Government implemented alcohol control strategies known as 'Alcohol Management Plans' (AMPs) in 19 of these communities. Although resources for prevention and treatment were promised, AMPs became increasingly focused on local prohibition, restricted access to alcohol and punitive measures for breaching restrictions. An examination of legislation, regulations, explanatory notes, and published documents indicates this focus evolved across four phases since 2002. The first phase, from 2002 to 2004, saw 'restricted areas' with alcohol 'carriage limits' introduced, restricting the amounts and types of liquor permitted within some communities. The second phase (2002-2007) featured evaluations and reviews by the Queensland Government bringing recommendations for more stringent controls. Additionally, beyond the 'restricted areas', licenced premises situated within the 'catchments' of the targeted communities, mainly located in the nearby regional towns, became subject to 'minimising harm' provisions. These more stringent controls were implemented widely in the third phase (2008-2011) when: the operations of seven community-managed liquor outlets were terminated; the trading arrangements of two others were modified; Police powers to search and seize were increased; and 'attempting' to take liquor into a 'restricted area' also became an offence. Some communities have seen a reduction in alcohol-related harms that have been attributed to these alcohol control strategies. This commentary maps the recent regulatory history of Queensland's alcohol controls targeting discrete Indigenous communities highlighting their increasing focus on punitive measures to reduce access to alcohol. With AMPs in Queensland currently under Government review, and with community resolve for change rising, the limits to Government controls and punitive measures may have been reached., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Introduction: Phenotypic differentiation of patients with interstitial cystitis/bladder pain syndrome (IC/BPS) may improve our understanding of the condition, as well as the development of patient-specific treatment strategies. We identified a distinct subgroup of IC/BPS patients with a multiple sensitivity phenotype., Methods: We defined patients with this IC/BPS associated multiple sensitivity syndrome as having at least 3 confirmed allergies/sensitivities to medications and/or environmental factors and a diagnosis of IC/BPS. These IC/BPS patients identified with a multiple sensitivity phenotype (cases) were compared to age-matched IC/BPS patients with few or no allergies (controls) at a 1:2 ratio. Comparisons were undertaken using standardized case assessment parameters (age, duration of symptoms, medical history, Interstitial Cystitis Symptoms Index [ICSI] and pelvic pain and urinary urgency/frequency [PUF] symptom scores, and urinary, psychosocial, organ specific, infection, neurologic/systemic, tenderness [UPOINT] categorization)., Results: The study consisted of 17 cases and 34 age-matched controls; the mean age was 55 and 56 years, respectively. There was statistically more medication and environmental allergies in the cases versus controls. Cases reported more concomitant illnesses (9.6 vs. 6.2, p < 0.001) and number of bodily systems affected (6.0 vs. 3.8, p ≤ 0.001). The prevalence of irritable bowel syndrome and fibromyalgia was higher in the case group (p = 0.028, p ≤ 0.001, respectively). Additionally, there were more reported psychiatric diseases (p = 0.019), allergic/immune diseases (p = 0.003), and pulmonary diseases (p < 0.001) in the case group. UPOINT classification differed with more patients in the case group being categorized in the psychosocial and neuropathic/systemic domains (p = 0.045, p = 0.007, respectively). Total UPOINT classification (out of 6) was also higher in cases than controls (4.6 vs. 3.2, p = 0.001, respectively)., Conclusions: We have characterized a distinct phenotypic group of patients with IC/BPS and multiple sensitivities. The limitations of our study include the retrospective case-control matching design, biases in phenotype definition, single centre patient recruitment, and the lack of follow-up. Nonetheless, the observation of this specific phenotype suggests that further research in this group may help develop targeted therapeutic strategies for patients with a concomitant multiple sensitivity syndrome and IC/BPS.

Objective: To assess a flexible therapeutic strategy for patients referred to a specialized interstitial cystitis/bladder pain syndrome (IC/BPS) clinic using an individualized phenotype-directed treatment plan based on clinically based urinary, psychosocial, organ-specific, infection, neurologic or nonbladder, and tenderness of pelvic floor (UPOINT) categorization, instead of the traditional algorithmic stepwise approach., Methods: Consecutive patients referred to a specialized tertiary IC/BPS clinic with at least 1 follow-up posttreatment visit were categorized according to their UPOINT status and treated according to previously published individualized phenotype-based treatment plan. Patients were assessed at baseline and up to 2 years with validated symptom scores (interstitial cystitis symptom score [ICSI]; and pain urgency frequency questionnaire) as well as pain and voiding assessments., Results: Follow-up visit data were available for 93 patients (mean age, 45.2 years; median age, 44 years; mean ICSI, 13.2±3.6). Patients reported a median of 4 UPOINT domains (mean, 3.7±0.94) with the following distribution: U=100%; P=31.2%; O=97.8%; I=45.2%; N=39.8%; and T=55.9%. The mean decrease in ICSI was 3.4 points. Significant clinical improvement (>30% decrease in ICSI) was observed in 46.2% compared with initial baseline visit. Pain urgency frequency, and pain and urgency scoring changes were comparable. No correlation between severity of symptoms and number of domains and ICSI decrease was observed., Conclusion: Almost 50% of patients referred to a tertiary IC/BPS clinic, regardless of the complexity or severity of condition, experienced clinically significant improvement using an individualized phenotype-directed therapeutic approach., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We hypothesized that changes in southeastern Bering Sea foraging conditions for black-legged kittiwakes (Rissa tridactyla) have caused shifts in habitat use with direct implications for population trends. To test this, we compared at-sea distribution, breeding performance, and nutritional stress of kittiwakes in three years (2008-2010) at two sites in the Pribilof Islands, where the population has either declined (St. Paul) or remained stable (St. George). Foraging conditions were assessed from changes in (1) bird diets, (2) the biomass and distribution of juvenile pollock (Theragra chalcogramma) in 2008 and 2009, and (3) eddy kinetic energy (EKE; considered to be a proxy for oceanic prey availability). In years when biomass of juvenile pollock was low and patchily distributed in shelf regions, kittiwake diets included little or no neritic prey and a much higher occurrence of oceanic prey (e.g. myctophids). Birds from both islands foraged on the nearby shelves, or made substantially longer-distance trips overnight to the basin. Here, feeding was more nocturnal and crepuscular than on the shelf, and often occurred near anticyclonic, or inside cyclonic eddies. As expected from colony location, birds from St. Paul used neritic waters more frequently, whereas birds from St. George typically foraged in oceanic waters. Despite these distinctive foraging patterns, there were no significant differences between colonies in chick feeding rates or fledging success. High EKE in 2010 coincided with a 63% increase in use of the basin by birds from St. Paul compared with 2008 when EKE was low. Nonetheless, adult nutritional stress, which was relatively high across years at both colonies, peaked in birds from St. Paul in 2010. Diminishing food resources in nearby shelf habitats may have contributed to kittiwake population declines at St Paul, possibly driven by increased adult mortality or breeding desertion due to high foraging effort and nutritional stress.

A 2-year-old girl presented to the emergency department at 3:00 h with severe pain in her right eye and a rust coloured, blood stained frothy discharge that had woken her. An examination of her eye revealed a shiny metallic looking foreign body, which was immediately removed by the on-call ophthalmologist. That morning the patient underwent ocular examination under anaesthesia and was found to have severe tissue necrosis resulting from an electrochemical burn. She was treated with daily rodding for 3 days and betamethasone ointment four times a day, which was gradually tapered. At 3 months her only eye pathology was a mild symblepharon between the bulbar and tarsal conjunctiva. This is the first case of delayed symptoms after placement of a button battery into the conjunctival fornix. This case highlights the serious nature of button battery injuries to the eye and the potential to miss the diagnosis owing to a delayed onset of symptoms.

Objective: To review inhalational exposures and respiratory disease risks in US military personnel deployed to Iraq and Afghanistan and to develop consensus recommendations for medical screening and diagnostic referral., Methods: A Working Group of physicians and exposure scientists from academia and from the Departments of Defense and Veterans Affairs was convened in February 2010., Results: Despite uncertainty about the number of people affected and risk factors for adverse pulmonary outcomes in this occupational setting, the Working Group recommended: (1) standardized approaches to pre- and postdeployment medical surveillance; (2) criteria for medical referral and diagnosis; and (3) case definitions for major deployment-related lung diseases., Conclusions: There is a need for targeted, practical medical surveillance for lung diseases and for a standardized diagnostic approach for all symptomatic deployed personnel.

Objective: To determine if metformin improves markers of inflammation, thrombosis, and intrahepatic fat contents in children with uncomplicated obesity., Methods: Obese children with normal glucose tolerance but elevated highly sensitive C-reactive protein (hsCRP) and/or fibrinogen concentrations (>2 standard deviations) were randomized to structured diet/exercise or diet/exercise and metformin for 6 months. Blood samples, dual energy X-ray absorptiometry data, and liver magnetic resonance images were obtained., Results: Forty-two of 66 recruited children (7-18 years) completed 6 months. Weight loss was modest but more pronounced in the metformin group (-4.9 +/- 1.0 kg) than in the diet/exercise group (-1.7 +/- 1.1 kg, p<0.03), whereas hsCRP and fibrinogen decreased more in the diet/exercise pubertal group. Baseline intrahepatic fat was high but decreased only in the diet/exercise (not metformin) pubertal group., Conclusions: Six months of metformin therapy improved weight loss and reduced abdominal adiposity, but did not enhance the beneficial effect of diet and exercise on markers related to inflammation, thrombosis, or hepatic fat in obese children with normal glucose tolerance.

Within the systematic review process, the searching phase is critical to the final synthesis product, its use and value. Yet, relatively little is known about the utility of different search strategies for reviews of complex, inter-disciplinary evidence. This article used a recently completed programme of work on cultural and sporting engagement to conduct an empirical evaluation of a comprehensive search strategy. Ten different types of search source were evaluated, according to three dimensions: (i) effectiveness in identifying relevant studies; (ii) efficiency in identifying studies; and (iii) adding value by locating studies that were not identified by any other sources. The study found that general bibliographic databases and specialist databases ranked the highest on all three dimensions. Overall, websites and journals were the next most valuable types of source. For reviewers, these findings highlight that general and specialist databases should remain a core component of the comprehensive search strategy, supplemented with other types of sources that can efficiently identify unique or grey literature. For policy makers and other research commissioners, this study highlights the value of methodological analysis for improving the understanding of, and practice in, policy relevant, inter-disciplinary systematic reviews. Copyright © 2011 John Wiley & Sons, Ltd., (Copyright © 2011 John Wiley & Sons, Ltd.)

Satellite cells are the resident stem cell population of the adult mammalian skeletal muscle and they play a crucial role in its homeostasis and in its regenerative capacity after injury. We show here that the Polycomb group (PcG) gene Bmi1 is expressed in both the Pax7 positive (+)/Myf5 negative (-) stem cell population as well as the Pax7+/Myf5+ committed myogenic progenitor population. Depletion of Pax7+/Myf5- satellite cells with reciprocal increase in Pax7+/Myf5+ as well as MyoD positive (+) cells is seen in Bmi1-/- mice leading to reduced postnatal muscle fiber size and impaired regeneration upon injury. Bmi1-/- satellite cells have a reduced proliferative capacity and fail to re-enter the cell cycle when stimulated by high serum conditions in vitro, in keeping with a cell intrinsic defect. Thus, both the in vivo and in vitro results suggest that Bmi1 plays a crucial role in the maintenance of the stem cell pool in postnatal skeletal muscle and is essential for efficient muscle regeneration after injury especially after repeated muscle injury.

Objectives: To determine the prevalence and clinical significance of documented bacteriuria and/or urinary tract infection in an interstitial cystitis/painful bladder syndrome (IC/PBS) population., Methods: Urine cultures were obtained at the initial assessment (documentation of sterile urine mandatory at diagnosis) and during routine follow-up, at each active treatment visit, and during and after the presentation and treatment of symptom flares in consecutively assessed female patients with IC/PBS. At each visit, the following questionnaires were completed: the O'Leary-Sant IC Symptom and Problem Index, the Pain Urgency Frequency questionnaire, and pain, frequency, and urgency Likert scales (0-10)., Results: A total of 100 patients with IC were followed up for 2 years. Of these 100 patients, 31 (31%) had ≥ 1 documented positive urine culture with a traditional uropathogen (mean 1.8, range 1-5). No difference was seen in the patients identified with bacteriuria and those without bacteriuria in age, symptom duration, O'Leary-Sant IC Symptom and Problem Indexes, Pain Urgency Frequency questionnaire, or pain, frequency, and urgency Likert scales. No correlation was found between the number of bacteriuria episodes and any symptom index evaluated. No significant difference was seen in any of the symptom indexes evaluated at baseline, during the bacteriuria episodes, or after successful bacterial eradication in the group identified with bacteriuria., Conclusions: The presence of bacteriuria can be documented in an IC/PBS population of women whose urine has frequently been cultured; however, the patients with bacteriuria did not differ from those without evidence of bacteriuria, the bacteriuria episodes did not appear to be associated with the symptom flares, and antibiotic treatment of documented bacteriuria was not associated with significant IC/PBS-related symptom amelioration., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Thiol (-SH) groups were introduced into unfractionated heparin by reaction of carboxyl groups in its uronic acid residues with 3,3'dithiobis(propanoic)hydrazide. Thiolated heparin derivatives were then linked to pyridyl disulfide-activated polyethylene oxide-polypropylene oxide-polyethylene oxide triblocks, which had previously been coated onto the surfaces of 1.15 microm polystyrene microspheres. The heparin immobilization reaction was monitored spectrophotometrically as colored pyridine-2-thione was released. In addition, the zeta potentials of uncoated, triblock-coated, and heparin-containing microsphere suspensions were recorded to demonstrate the successful attachment of heparin on the surface. However this "side-on" attachment of heparin to pendant, polyethylene oxide chains did not significantly increase the anticoagulant or anti-Factor Xa activity of microsphere suspensions., (Copyright 2010 Elsevier B.V. All rights reserved.)

Background: Metabolic syndrome (MS)-related comorbidities in obesity, such as hypertension, dyslipidemia, and glucose intolerance, are increasingly recognized in children, predisposing them to early cardiovascular disease., Objective: The objective of the study was to investigate whether markers of inflammation and prothrombosis are abnormal in obese children without established MS comorbidities across puberty, as compared with lean, age-matched controls., Subjects and Methods: Obese children (body mass index >95%) with normal fasting glucose, blood pressure, cholesterol and triglycerides were recruited; lean controls (body mass index 10-75%) had no first-degree relatives with MS. High-sensitivity C-reactive protein (hsCRP), IL-6, plasminogen activator inhibitor 1, and fibrinogen concentrations were measured. Body composition was assessed by waist circumference and dual-energy x-ray absorptiometry., Results: Of 623 children screened, 203 enrolled (106 males, 97 females), aged 7-18 yr, 115 obese, 88 lean (balanced for age and gender), 99 prepubertal, and 104 pubertal. Many screen failures were due to silent comorbidities. Obese subjects with insulin resistance but without MS comorbidities had about 10 times higher hsCRP concentrations than controls and higher fibrinogen, IL-6, and plasminogen activator inhibitor-1 (P < 0.01 all). Differences were significant, even in the prepubertal cohort. hsCRP and fibrinogen correlated with waist circumference (r = 0.73 and 0.40, respectively) and percent fat mass (r = 0.76 and 0.47) (P < 0.0001)., Conclusion: Childhood obesity per se is associated with a proinflammatory and prothrombotic state before other comorbidities of the MS are present and even before the onset of puberty. Whether biomarkers like hsCRP and fibrinogen are useful in assessing cardiovascular risk and whether these abnormalities are reversible with earlier therapeutic interventions in very young obese children requires further study.

Purpose: We have proposed a clinical phenotype system (UPOINT) to classify patients with urological pelvic pain to improve the understanding of etiology and guide therapy. We examined the relationship between UPOINT and symptoms in patients with interstitial cystitis/painful bladder syndrome., Materials and Methods: Patients with interstitial cystitis/painful bladder syndrome were classified in each domain of UPOINT, that is urinary, psychosocial, organ specific, infection, neurological/systemic and tenderness. Symptoms were assessed using the Interstitial Cystitis Symptom Index, Pain/Urgency/Frequency score and visual analogue scale for pain/urgency/frequency. Clinically relevant associations were calculated., Results: The mean age of 100 consecutive patients with interstitial cystitis/painful bladder syndrome was 48 years, median symptom duration was 7 years and median Interstitial Cystitis Symptom Index score was 12.8. The percent positive for each domain was urinary 100%, psychosocial 34%, organ specific 96%, infection 38%, neurological/systemic 45% and tenderness 48%. All patients were included in at least 2 domains, with 2 domains for 13%, 3 domains--35%, 4 domains--34%, 5 domains--13% and 6 domains--5%. The number of domains was associated with greater symptom duration (p = 0.014) but not age. The number of domains was also associated with poorer general interstitial cystitis and pain symptoms (Interstitial Cystitis Symptom Index p = 0.012, pain p = 0.036) but not with frequency or urgency. The psychosocial domain was associated with increased pain, urgency and frequency, while tenderness was associated with increased Interstitial Cystitis Symptom Index score, pain/urgency/frequency score and urgency. The neurological/systemic domain was associated with increased Interstitial Cystitis Symptom Index score while the infection domain was not associated with any increased symptoms., Conclusions: The UPOINT phenotyping system can classify patients with interstitial cystitis according to clinically relevant domains. Increased symptom duration leads to a greater number of domains, and domains that function outside of the bladder (psychosocial, neurological, tenderness) predict a significant impact on symptoms. We hypothesize that the UPOINT system can direct multimodal therapy and improve outcomes.

Aims: Hazardous alcohol use is a leading cause of death among adolescents and young adults world-wide, yet few effective prevention interventions exist. This study was the first to examine a computerized harm minimization intervention to reduce alcohol misuse and related harms in adolescents., Design: Cluster randomized controlled trial of a six-session curriculum-integrated harm minimization prevention program. The intervention was delivered by computer in the form of a teenage drama, which provided education through alcohol-related scenarios to which young people could relate., Setting: Schools in Australia., Participants: A total of 1466 year 8 students (13 years) from 16 high schools in Australia were allocated randomly to a computerized prevention program (n = 611, eight schools) or usual classes (n = 855, eight schools)., Measurements: Change in knowledge, alcohol use, alcohol-related harms and alcohol expectancies., Findings: A computerized prevention program was more effective than usual classes in increasing alcohol-related knowledge of facts that would inform safer drinking choices and decreasing the positive social expectations which students believed alcohol may afford. For females it was effective in decreasing average alcohol consumption, alcohol-related harms and the frequency of drinking to excess (more than four standard drinks; 10 g ethanol). For males the behavioural effects were not significant., Conclusions: A harm minimization approach is effective in educating young people about alcohol-related risks and is effective in reducing risky drinking and harms among girls. Reduction of problems among boys remains a challenge.

Objective: To report a multicentre, community based open-label study designed to assess the efficacy and safety of intravesical sodium chondroitin sulphate in the treatment of patients with the clinical diagnosis of interstitial cystitis (IC). Chondroitin sulphate is a naturally occurring glycosaminoglycan (GAG) in the bladder mucus layer and changes in this GAG have been implicated in the pathogenesis of IC, and small single-centre studies have suggested that intravesical chondroitin sulphate may have efficacy in IC., Patients and Methods: Patients with IC were treated with sodium chondroitin sulphate (Uracyst, Stellar Pharmaceuticals Inc., London ON, Canada) solution 2.0% via urinary catheter weekly for 6 weeks and then monthly for 16 weeks for a total of 10 treatments. The primary efficacy endpoint was the percentage of responders to treatment as indicated by a marked or moderate improvement on a seven-point patient Global Response Assessment (GRA) scale at week 10 (4 weeks after the initial six treatments) compared with baseline. A major secondary efficacy endpoint (durability) was the percentage of responders on the GRA scale after 10 treatments. Additional secondary efficacy objectives were differences from baseline in Patient Symptom/Problem Index scores over the course of the treatment compared with baseline., Results: In all, 47% of the 53 enrolled patients with long standing moderately severe IC (mean [SD, range] diagnosis of IC 3.0 [3.4, 0.1-16] years; duration of symptoms 9.2 [9.2, 1-39] years; baseline symptom score 14.2 [3.2]) were responders at week 10. At 24 weeks, 60% were responders. There was a statistically and clinically significant decrease in the mean (SD) symptom and bother scores from baseline at 10 weeks and 24 weeks, at 9.0 (4.3) and 8.1 (5.0), respectively (P < 0.001). There were no significant safety issues during the study., Conclusions: This multicentre community based real-life clinical practice study suggests that intravesical chondroitin sulphate may have an important role in the treatment of IC and validates the rationale for a randomized placebo-controlled trial.

We previously developed an immunohistochemical method for estimating cell cycle state and phase in tissue samples, including biopsies that are too small for flow cytometry. We have used our technique to examine whether primary abnormalities of the cell cycle exist in laryngeal neoplasia. Antibodies against the markers of cell cycle entry, minichromosome maintenance protein-2 (Mcm-2) and Ki67, and putative markers of cell cycle phase, cyclin D1 (G1-phase), cyclin A (S-phase), cyclin B1 (G2-phase) and phosphohistone H3 (Mitosis) were applied to paraffin-embedded sections of normal larynx (n = 8), laryngeal dysplasia (n = 10) and laryngeal squamous cell carcinoma (n = 10). Cells expressing each marker were determined as a percentage of total cells, termed the labelling index (LI), and as a percentage of Mcm-2-positive cells, termed the labelling fraction (LF). The frequency of coexpression of each putative phase marker was investigated by confocal microscopy. There was a correlation between Mcm-2 and Ki67 LIs (rho = 0.93) but Mcm-2 LIs were consistently higher. All cells expressing a phase marker coexpressed Mcm-2, whereas Ki67 was not expressed in a proportion of these cells. The putative phase markers showed little coexpression. Labelling index values increased on progression from normal larynx through laryngeal dysplasia to squamous cell carcinoma for Mcm-2 (P = 0.001), Ki67 (P = 0.0002), cyclin D1 (P = 0.015), cyclin A (P = 0.0001) and cyclin B1 (P = 0.0004). There was no evidence of an increase in the LF for any phase marker. Immunohistochemistry can be used to estimate cell cycle state and phase in laryngeal biopsies. Our data argues against primary cell cycle phase abnormalities in laryngeal neoplasia.

Heparin was modified with adipic dihydrazide and covalently linked to surface-activated silica wafers. X-ray photoelectron spectroscopy was used at each stage of derivatization and showed that successful immobilization had taken place. Surfaces were imaged with atomic force microscopy to determine the uniformity of the heparin layer as well as its thickness. In situ ellipsometry was used to estimate layer thickness as well, and to study protein concentration and adsorption time effects on the adsorption and elution kinetics exhibited by human plasma fibrinogen. The adsorbed amount of fibrinogen increased with time and concentration on each type of surface. Under all experimental conditions, fibrinogen adsorbed at a lower rate and to a lower extent on heparinized as compared to unheparinized silica. In addition, buffer elution experiments showed that fibrinogen was less tightly bound to heparinized silica. In order to examine behavior relative to fibrinogen mobility at these interfaces, the sequential adsorption of fibrinogen was recorded. The difference in adsorption rates between the first and second adsorption cycles, evaluated at identical mass density, indicated that post-adsorptive molecular rearrangements had taken place. In general, higher solution concentration and longer adsorption time in the first adsorption step led to more rearrangement, and these history dependent effects were more pronounced on the heparinized silica. These rearrangements are suggested to involve clustering of adsorbed fibrinogen, in this way increasing the amount of unoccupied area at the interface. These rearrangements were presumably facilitated on the heparinized silica by enhanced lateral mobility of fibrinogen at this negatively charged, highly hydrophilic interface.

An immunohistochemical method for assessing cell cycle phase distribution in neurosurgical biopsies would enable such data to be incorporated into diagnostic algorithms for the estimation of prognosis and response to adjuvant chemotherapy in glial neoplasms, without the requirement for flow cytometric analysis. Paraffin-embedded sections of intracerebral gliomas (n = 48), consisting of diffuse astrocytoma (n = 9), anaplastic astrocytoma (n = 8) and glioblastoma (n = 31), were analysed by immunohistochemistry using markers of cell cycle entry, Mcm-2 and Ki67, and putative markers of cell cycle phase, cyclins D1 (G1-phase), cyclin A (S-phase), cyclin B1 (G2-phase) and phosphohistone H3 (Mitosis). Double labelling confocal microscopy confirmed that the phase markers were infrequently coexpressed. Cell cycle estimations by immunohistochemistry were corroborated by flow cytometric analysis. There was a significant increase in Mcm-2 (P < 0.0001), Ki67 (P < 0.0001), cyclin A (P < 0.0001) and cyclin B1 (P = 0.002) expression with increasing grade from diffuse astrocytoma through anaplastic astrocytoma to glioblastoma, suggesting that any of these four markers has potential as a marker of tumour grade. In a subset of glioblastomas (n = 16) for which accurate clinical follow-up data were available, there was a suggestion that the cyclin A:Mcm-2 labelling fraction might predict a relatively favourable response to radical radiotherapy. These provisional findings, however, require confirmation by a larger study. We conclude that it is feasible to obtain detailed cell cycle data by immunohistochemical analysis of tissue biopsies. Such information may facilitate tumour grading and may enable information of prognostic value to be obtained in the routine diagnostic laboratory.

We have investigated whether immunohistochemical markers can identify differences in cell cycle phase distribution in ovarian serous neoplasms, including borderline tumours of different grades. Sections of normal ovary (n=18), serous cystadenoma (n=21), borderline serous tumours (n=21) and serous cystadenocarcinoma (n=15) were analysed by immunohistochemistry using markers of cell cycle entry (Mcm-2) and cell cycle phase, including cyclin D1 (mid-to-late G1), cyclin A (S phase), cyclin B1 (G2 phase) and phosphohistone H3 (mitosis). Double-labelling confocal microscopy confirmed marker phase specificity and phase estimations were corroborated by flow cytometry. On progression from normal ovary through serous cystadenoma and borderline tumours to cystadenocarcinomas, expression of Mcm-2 (P<0.0001), cyclin D1 (P=0.002), cyclin A (P<0.0001), cyclin B1 (P<0.0001) and phosphohistone H3 (P<0.0001) increased, paralleled by an increase in the S-phase fraction (cyclin A : Mcm-2 ratio; P=0.002). Borderline tumours of increasing grade also showed increased Mcm-2 and cyclin A expression, together with an increase in the S-phase fraction. Immunohistochemistry can be used to estimate cell cycle phase distribution in ovarian serous neoplasms, giving results similar to flow cytometric analysis and enabling direct assessment of tumour heterogeneity. Immunohistochemical estimates of the S-phase fraction may identify serous borderline tumours likely to exhibit malignant progression and/or select serous cystadenocarcinomas likely to respond to adjuvant therapy.

Purpose: Vacuum-assisted closure (VAC), originally developed as an adjunct to wound care, has gained popularity in managing complex, chronic wounds. This study was designed to compare VAC with traditional saline-wet-to-dry (WD) dressings on acute wound healing in a pig model., Methods: Nine animals were divided into groups of 3. Three rows of 2, 4-cm diameter circular defects were excised on each animal. Vacuum-assisted closure therapy was applied to 2 adjacent wound beds, WD dressings were applied to 2 adjacent wound beds, and ventilated transparent dressing covered the 2 remaining wounds as controls. Random members from each group had their wounds harvested on postoperative days (POD) number 4, 7, and 9, respectively. The specimens were histopathologically evaluated and graded with regard to immature granulation tissue, mature granulation tissue, necropurulent surface crust, proliferating cell nuclear antigen (PCNA), and collagen deposition., Results: The WD-treated wounds had less necropurulent material on the surface compared with the VAC and control groups (p < 0.05). Day 9 specimens demonstrated increased immature collagen in the VAC and WD groups compared with control. No other statistically significant variations existed between the treatment groups., Conclusions: Under the conditions of this study, the histopathologic observations do not support more rapid wound healing for the acutely injured VAC-treated wound compared with the WD-treated wound in young healthy pigs.

Objective: Minichromosome maintenance protein 2 (Mcm2) is an accurate indicator of cell cycle entry in tissue samples, but its expression in inflammatory bowel disease (IBD) has not previously been investigated. We have used immunohistochemistry to assess the expression of Mcm2, in comparison to the existing proliferation marker Ki-67, in active IBD and IBD without inflammatory activity., Materials and Methods: For this experimental study, sections from colonic biopsy and resection specimens of 48 patients with IBD (5 inactive/quiescent Crohn's disease (CD), 13 active CD, 19 inactive/quiescent ulcerative colitis (UC) and 11 active UC) and 15 normal controls were immunostained with antibodies to Mcm2 and Ki-67. The percentage of immunopositive epithelial nuclei was determined by calculating a labelling index (LI) for entire glands and for gland thirds (superficial, middle and basal)., Results: The Mcm2 LI was significantly increased in the superficial third of glands in active vs. inactive/quiescent UC (P < 0.0001) and active vs. inactive/quiescent CD (P = 0.001). The Mcm2 LI was significantly greater than the Ki-67 LI in active IBD, both in entire glands (P < 0.0001) and in the superficial third of glands (UC, P = 0.001; CD, P = 0.0002). Mcm2 LIs for entire glands were significantly higher in UC (all cases) compared to CD (all cases) (P = 0.032)., Conclusions: There is increased cell cycle entry, as indicated by expression of Mcm2 and to a lesser extent Ki-67, in the superficial third of colonic glands in active IBD compared to inactive/quiescent IBD. Detection of Mcm2 may contribute to improved histological assessment of small tissue biopsies and may enable the development of a direct stool-based test for detection of active IBD and potentially for assessment of disease activity.

Purpose: To test the hypothesis that prognostic information in breast cancer may be derived from an accurate assessment of epithelial cell cycle entry, as indicated by expression of minichromosome maintenance (MCM) proteins., Materials and Methods: We used immunohistochemistry to examine the distribution of Mcm-2 in breast tissue. Power calculations based on a pilot study of 67 whole tissue sections led to selection of an independent 347-core breast carcinoma tissue microarray validation set. We tested for associations between Mcm-2 (and Ki-67) labeling index (LI) and various clinicopathologic parameters., Results: Mcm-2 was expressed more frequently than the standard proliferation marker Ki-67 in whole tissue sections of normal breast (P =.0003) and breast carcinoma (P <.0001). In 221 assessable cores of invasive carcinoma, the Mcm-2 LI showed a positive association with tumor size (P =.002), mitotic index (P <.0001), histologic grade (P <.0001), and the Nottingham Prognostic Index (NPI) score (P <.0001). Using a cutoff value of 50%, Mcm-2 LI was associated with overall survival (P =.0007), disease-free interval (P =.0002), and with the development of regional recurrence (P =.011) and distant metastases (P =.0016). Cox regression analysis suggested that the Mcm-2 LI is a strong prognostic factor in breast cancer that is independent and superior to histologic grade, lymph node stage, and Ki-67 LI, but not the NPI score., Conclusion: Mcm-2 may be of utility as a prognostic marker to refine the prediction of outcome in breast cancer, for example when combined with parameters currently used in the NPI.

An immunohistochemical method for assessing cell-cycle phase distribution in colorectal resection specimens would enable phase data to be incorporated into diagnostic algorithms for the estimation of prognosis and response to adjuvant chemotherapy in colorectal cancer. In contrast to flow cytometry, an immunohistochemical method would also allow the phase distribution to be examined within morphologically heterogeneous regions of neoplasms. Paraffin sections of normal colon (n = 25), colonic adenoma (n = 15), and colonic adenocarcinoma (n = 30) were analysed by immunohistochemistry using antibodies against markers of cell-cycle entry, Mcm-2 and Ki67, and putative markers of the cell-cycle phase, cyclins D1 and E (putative markers of G1 phase), cyclin A (S phase), cytoplasmic cyclin B1 (G2 phase), and phosphohistone H3 (M phase). The phase specificity of each marker was assessed by examining the degree of co-expression of adjacent phase markers using double-antibody fluorescence confocal microscopy and by comparison with flow cytometric analysis performed on adjacent tissue sections. The S-phase specificity of detectable cyclin A was also assessed in combination with in situ DNA replication using fluorescence confocal microscopy. All cells expressing phase markers co-expressed Mcm-2. Adjacent phase markers were not significantly co-expressed, confirming the relative specificity of these markers in tissue sections of colon. Cell-cycle phase distribution, calculated by immunohistochemistry, compared well with phase analyses obtained by flow cytometry. No cells expressed cyclin A in the absence of active DNA replication. The S-phase labelling index, as defined by detectable cyclin A expression, showed a positive correlation with the Mcm-2 labelling index and increased in the progression from normal colon to adenocarcinoma. In conclusion, a combination of these cell-cycle phase markers can be used to calculate the distribution of cells throughout each phase of the cell cycle in colorectal tissue sections. Detectable cyclin A can be used as a surrogate marker of S phase and may be of value in predicting prognosis and response to adjuvant therapy., (Copyright 2003 John Wiley & Sons, Ltd.)

Histological classification of laryngeal epithelial lesions is highly subjective, and methods of cytological detection are not well developed. Improved determination of aberrant cell cycle entry may allow increased objectivity in histological assessment and enable the development of less invasive diagnostic cytology tests. Sections of normal larynx (n=10), laryngeal dysplasia (n=20) and laryngeal squamous cell carcinoma (SCC) (n=10) were classified according to the Ljubljana classification and stained for markers of cell cycle entry, minichromosome maintenance protein-2 (Mcm-2) and Ki67. Expression patterns were compared using double labelling confocal microscopy. There was a correlation between Mcm-2 and Ki67 labelling indices (rho=0.93; 95% CI [0.84, 0.97]) and both markers showed increased expression from normal epithelium to SCC (Mcm-2, P=0.001; Ki67, P=0.0002). Importantly, there was minimal expression of Mcm-2 or Ki67 in the most superficial layers of normal larynx and abnormal or atypical hyperplasia, in contrast to carcinoma in situ and SCC. Clusters of Mcm-2/5-positive cells were present in cytological preparations from SCC, but not from those showing atypical hyperplasia or inflammation in non-neoplastic tissue. Minichromosome maintenance protein-2 staining may increase the objectivity and reliability of histological grading of laryngeal epithelial lesions. Laryngeal brushings, combined with immuno-enhanced liquid-based cytology, could be useful, as a less invasive approach, to the detection of laryngeal malignant and premalignant lesions.

Objective: To describe 2 cases of coexisting rheumatoid arthritis (RA) and Wegener's granulomatosis (WG), and to summarize the clinical and serological data for all 6 patients reported in the English literature since 1966., Methods: Medline review over a 35-year period (1966-2002) revealed 4 reported cases of RA associated with WG. Patients were diagnosed based on symptoms, radiographic changes, bronchoalveolar lavage fluid analysis, hematuria, serology, and biopsy. We describe 2 additional cases of WG developing in Caucasian women with RA. These are the first reported patients to possess positive antineutrophil cytoplasmic antibodies (ANCA) and autoantibodies to proteinase 3 (PR3)., Results: All 6 cases of coexisting RA and WG were female. The diagnosis of RA preceded WG diagnosis in all cases; mean age at RA onset was 43.7 +/- 15.0 years, duration of RA prior to WG diagnosis 7.9 +/- 9.1 years. Clinical findings included erosive articular disease on radiographs (n = 4; 67%), positive rheumatoid factor (n = 6; 100%), upper respiratory involvement (n = 5; 83%), lower respiratory signs (n = 4; 67%), renal involvement (n = 2; 33%), and positive ANCA (n = 2/3; 67%). Five patients were treated with corticosteroids and cyclophosphamide, with clinical improvement., Conclusion: Although rare, WG may develop in patients with preexisting RA and may present with end-organ involvement.

Vulval intraepithelial neoplasia (VIN) is defined histopathologically by distinctive abnormalities of cellular maturation and differentiation. To investigate the functional properties of VIN, the expression of several proteins involved in the regulation of the cell cycle as well as in situ DNA replication competence was analysed by immunohistochemistry. Snap-frozen vulval biopsies were graded as normal squamous epithelium (n=6), undifferentiated HPV positive VIN 1 (n=3), VIN 2 (n=8) and VIN 3 (n=20). Immunohistochemistry was performed using the following markers: cyclin D1 (expressed in middle/late G1), cyclin B1 (expressed in G2/early M), phosphorylated histone H3 (expressed during mitosis) and minichromosome maintenance (Mcm) proteins 2 and 5 (expressed during the cell cycle, but not in differentiated or quiescent cells). In situ DNA replication competence was used to identify S-phase cells. The percentage of positively stained nuclei in three representative microscopic fields was calculated per biopsy. In normal vulva, the expression of all markers was restricted to the proliferative compartment of the basal layer of the epithelium. In contrast in high-grade VIN, the majority of epithelial cells expressed the Mcm proteins from basal to superficial layer. The detection of cyclins B1 and D1, phospho-histone H3 and in situ DNA replication was also found through the full thickness of these lesions but by a lower proportion of the cells. This is consistent with these markers providing a series of 'snapshots' of the cell cycle status of individual cells. The low-grade VIN showed reduced expression of the cell cycle markers in relation to the level of dysplasia. The combination of these analyses establishes that the majority of VIN cells remain in a functional replicative or prereplicative state of the cell cycle. Clinical application of these analyses may provide a basis for improved diagnosis of VIN.

We have investigated the potential utility of monoclonal antibodies against mini-chromosome maintenance-2 protein (Mcm2) in predicting meningioma recurrence. MCM proteins are members of the DNA-binding prereplicative complex and are essential for eukaryotic DNA replication. They are present throughout the cell cycle, but are down-regulated in quiescence and cell differentiation, making them specific markers of proliferating cells. We analysed 10 benign meningiomas that subsequently recurred within a 5-year period, together with 20 matched non-recurrent benign meningiomas. There was no significant correlation between histological subtype, mitotic count or Ki-67 labelling index and tumour recurrence. We observed that whilst the average Mcm2 labelling index (LI) of the tumour section as a whole (LI(Ave)) is not significantly different between recurrent and nonrecurrent meningiomas, the Mcm2 labelling index in the area of highest proliferative activity within the tumour section (LI(Max)) is significantly higher in recurrent meningiomas (p < 0.0001). Seven out of the 10 recurrent meningiomas displayed a Mcm2 LI((Max) greater than 30%, compared to 0 out of 20 for non-recurrent tumours. In conclusion, these results suggest that analysis of Mcm2 expression may facilitate identification of patients with a high risk of meningioma recurrence, for whom adjuvant radiotherapy may be of benefit.

Objective: To evaluate plasma taurine concentrations (PTC), whole blood taurine concentrations (WBTC), and echocardiographic findings in dogs fed 1 of 3 protein-restricted diets that varied in fat and L-carnitine content., Animals: 17 healthy Beagles., Design: Baseline PTC and WBTC were determined, and echocardiography was performed in all dogs consuming a maintenance diet. Dogs were then fed 1 of 3 protein-restricted diets for 48 months: a low-fat (LF) diet, a high-fat and L-carnitine supplemented (HF + C) diet, or a high-fat (HF) diet. All diets contained methionine and cystine concentrations at or above recommended Association of American Feed Control Officials (AAFCO) minimum requirements. Echocardiographic findings, PTC, and WBTC were evaluated every 6 months., Results: The PTC and WBTC were not significantly different among the 3 groups after 12 months. All groups had significant decreases in WBTC from baseline concentrations, and the HF group also had a significant decrease in PTC. One dog with PT and WBT deficiency developed dilated cardiomyopathy (DCM). Taurine supplementation resulted in significant improvement in cardiac function. Another dog with decreased WBTC developed changes compatible with early DCM., Conclusions and Clinical Relevance: Results revealed that dogs fed protein-restricted diets can develop decreased taurine concentrations; therefore, protein-restricted diets should be supplemented with taurine. Dietary methionine and cystine concentrations at or above AAFCO recommended minimum requirements did not prevent decreased taurine concentrations. The possibility exists that AAFCO recommended minimum requirements are not adequate for dogs consuming protein-restricted diets. Our results also revealed that, similar to cats, dogs can develop DCM secondary to taurine deficiency, and taurine supplementation can result in substantial improvement in cardiac function.

Turnover of carnitine in the body is primarily the result of renal excretion, and high-fat (HF) diets have been shown to increase urine carnitine excretion in healthy people. Recently, increased renal excretion of carnitine was observed in dogs diagnosed with cystinuria and carnitine deficiency. Carnitine deficiency has been linked to dilated cardiomyopathy and lipid storage myopathies in dogs and humans, and low-fat (LF) diets have been beneficial in some human patients with carnitine deficiency. In addition, HF, protein-restricted diets are often recommended for management of cystinuria in dogs. However, whether HF diets increase renal carnitine excretion in dogs or whether dogs with carnitine deficiency would benefit from LF diets remains unknown. Therefore, the purpose of this study was to determine the influence of dietary fat and carnitine on renal carnitine excretion in healthy dogs. Results from this study revealed that an HF diet increased urine carnitine excretion in dogs; however, carnitine excretion with the HF diet was not significantly different from that in dogs consuming an LF diet. Nonetheless, these results raise the possibility that increased renal carnitine excretion associated with HF diets could be one risk factor for development of carnitine deficiency in dogs with an underlying disorder in carnitine metabolism, and some dogs with carnitine deficiency may benefit from an LF diet. Another important observation in this study was that renal excretion of carnitine exceeded dietary intake in all diet groups, confirming previous reports that concluded that canine renal tubular cells reabsorb carnitine poorly when compared with those of humans.

Five client owned dogs with cystinuria were diagnosed with carnitine and taurine deficiency while participating in a clinical trial that used dietary management of their urolithiasis. Stored 24-hour urine samples collected from the cystinuric dogs before enrollment in the clinical diet trial were quantitatively evaluated for carnitine and taurine. These results were compared to those obtained from 18 healthy Beagles. Both groups of dogs were fed the same maintenance diet for a minimum of 2 weeks before 24-hour urine collection. The protocol used for 24-hour urine collections was the same for cystinuric dogs and healthy Beagles except that cystinuric dogs were catheterized at baseline, 8 hours, 12 hours, and at the end of the collection, whereas Beagles were catheterized at baseline, 8 hours, and at the end of the collection. Three of 5 dogs with cystinuria had increased renal excretion of carnitine. None of the cystinuric dogs had increased renal excretion of taurine, but cystinuric dogs excreted significantly less (P < .05) taurine in their urine than the healthy Beagles. Carnitinuria has not been recognized previously in either humans or dogs with cystinuria, and it may be 1 risk factor for developing carnitine deficiency. Cystinuric dogs in this study were not taurinuric; however, cystine is a precursor amino acid for taurine synthesis. Therefore, cystinuria may be 1 risk factor for developing taurine deficiency in dogs. We suggest that dogs with cystinuria be monitored for carnitine and taurine deficiency or supplemented with carnitine and taurine.

Purpose: Heparin binds to human platelets and can cause activation and aggregation, although the mechanisms are unknown. To determine how heparin alters platelet function, we identified platelet-binding sites for heparin and measured heparin's influence on the function of platelet integrin alpha(IIb)beta(3) (glycoprotein IIb/IIIa)., Methods: Photoaffinity cross-linking and affinity chromatography experiments were performed to identify platelet membrane proteins that bind heparin. Heparin's effect on fibrinogen binding to platelets was measured with a radioligand-binding assay. The translocation to the cytoskeleton of Rap2, a guanosine triphosphate-binding protein, was measured from platelets aggregating in response to heparin and other agonists., Results: Cross-linking and affinity chromatographic experiments positively identified the integrin alpha(IIb)beta(3) as a heparin-binding site. Heparin aggregation was calcium dependent. Low concentrations of unfractionated porcine mucosal heparin (2-5 U/mL) significantly increased fibrinogen I 125 binding to activated platelets, whereas higher doses did not. Heparin-mediated platelet aggregation was completely blocked by GRGDS peptide (5 mmol/L), a competitive inhibitor of fibrinogen binding, and was blocked by EDTA (2 mmol/L), which dissociates the functional integrin complex. Aggregation was associated with Rap2 translocation to the cytoskeleton, a sign of outside-in signaling., Conclusions: Heparin binds to the alpha(IIb)beta(3) integrin in vitro and ex vivo, and heparin increases fibrinogen binding to the integrin. Heparin-mediated aggregation requires an intact integrin and ligand and leads to Rap2 translocation to the cytoskeleton-an outside-in signal of ligand engagement. Heparin may directly modulate platelet integrin function, most likely through direct binding and modulation of integrin function.

Skeletal muscle samples from 38 draft horse-related animals 1-23 years of age were evaluated for evidence of aggregates of glycogen and complex polysaccharide characteristic of equine polysaccharide storage myopathy (EPSSM). Cardiac muscle from 12 of these horses was also examined. Antemortem serum levels of creatine kinase (CK) and aspartate aminotransferase (AST) from 9 horses with EPSSM and 5 horses without EPSSM were compared. Skeletal muscle from 17 horses contained inclusions of periodic acid-Schiff (PAS)-positive, amylase-resistant complex polysaccharide. Similar inclusions were also present in the cardiac muscle of 1 horse. A vacuolar myopathy with aggregates of PAS-positive, amylase-sensitive glycogen was seen in 8 other horses, and these findings are also considered diagnostic for EPSSM. Antemortem serum activities of CK and AST were often higher in EPSSM horses than in horses without EPSSM. Using the presence of amylase-resistant complex polysaccharide as the criterion for diagnosis of EPSSM, the incidence in this population was 45%. Inclusion of horses with aggregates of glycogen but no amylase-resistant complex polysaccharide as representative of the range of pathologic findings in horses with EPSSM resulted in a 66% incidence in this population.

Path analysis was used to examine the antecedents of posttraumatic stress (PTS) symptoms in Tamil asylum-seekers, refugees, and immigrants in Australia. The Harvard Trauma Questionnaire and a postmigration living difficulties questionnaire were completed by 62 asylum-seekers, 30 refugees, and 104 immigrants who responded to a mail-out. Demographic characteristics, residency status, and measures of trauma and postmigration stress were fitted to a structural model in PTS symptoms. Premigration trauma exposure accounted for 20% of the variance of PTS symptoms. Postmigration stress contributed 14% of the variance. Although limited by sampling constraints and retrospective measurement, the study supports the notion that both traumatic and posttraumatic events contribute to the expression of PTS symptoms.

A new hetero-bifunctional photo crosslinking reagent, 2-(4-azidoanilyl)-4-(4-azabicyclo-[2,2, 2]hexylammonio)-6-morpholino-1,3,5-triazine chloride, was designed to detect and isolate heparin-binding protein(s) that may act as heparin-receptor(s) on the platelet surface. In a preliminary study using ethanol as a model substrate, the reagent was shown to react with the alcoholic hydroxy group under mild conditions and its crosslinking photoreactivity was high. The reagent effectively formed similar covalent bonds with heparin, while preserving its anticoagulant anti-Xa activity. [3H]Heparin labeled with this reagent crosslinked to antithrombin III very specifically but not to ovalbumin, as analyzed by the Bio-imaging Analyzer System (BAS, Fuji Photo Film, Tokyo). Affinity crosslinking of [3H]heparin was then used to detect heparin-binding proteins on the surface of intact platelets. Several discrete protein bands were detected by the BAS-imaging of SDS-PAGE.