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Articles by Jennifer Smith in JoVE

 JoVE Immunology and Infection

In Vivo Imaging Systems (IVIS) Detection of a Neuro-Invasive Encephalitic Virus

1Experimental Pathology, University of Texas Medical Branch

JoVE 4429

Utilizing luciferase and in vivo imaging systems (IVIS) as a novel means to identify disease endpoints before clinical developments occur. IVIS has allowed us to visualize in real time the invasion of encephalitic viruses over multiple days, providing a more accurate disease model for future study. It has also allowed us to identify the potential protective features of antivirals and vaccines faster than currently utilized animal models. The capability to utilize individual animals over multiple time points ensures reduced animal requirements, costs, and overall morbidity to the animals utilized ensuring a more humane and more scientific means of disease study.

Other articles by Jennifer Smith on PubMed

Cytoscape: a Community-based Framework for Network Modeling

Cytoscape is a general network visualization, data integration, and analysis software package. Its development and use has been focused on the modeling requirements of systems biology, though it has been used in other fields. Cytoscape's flexibility has encouraged many users to adopt it and adapt it to their own research by using the plugin framework offered to specialize data analysis, data integration, or visualization. Plugins represent collections of community-contributed functionality and can be used to dynamically extend Cytoscape functionality. This community of users and developers has worked together since Cytoscape's initial release to improve the basic project through contributions to the core code and public offerings of plugin modules. This chapter discusses what Cytoscape does, why it was developed, and the extensions numerous groups have made available to the public. It also describes the development of a plugin used to investigate a particular research question in systems biology and walks through an example analysis using Cytoscape.

Herpes Simplex Virus Type-2 Seropositivity Among Ever Married Women in South and North Vietnam: a Population-based Study

To investigate herpes simplex virus type-2 (HSV-2) seropositivity and associated risk factors in Vietnamese women.

Feasibility of Contracting for Medication Therapy Management Services in a Physician's Office

The feasibility of contracting for medication therapy management (MTM) services in a physician's office was studied.

RNA Search with Decision Trees and Partial Covariance Models

The use of partial covariance models to search for RNA family members in genomic sequence databases is explored. The partial models are formed from contiguous subranges of the overall RNA family multiple alignment columns. A binary decision-tree framework is presented for choosing the order to apply the partial models and the score thresholds on which to make the decisions. The decision trees are chosen to minimize computation time subject to the constraint that all of the training sequences are passed to the full covariance model for final evaluation. Computational intelligence methods are suggested to select the decision tree since the tree can be quite complex and there is no obvious method to build the tree in these cases. Experimental results from seven RNA families shows execution times of 0.066-0.268 relative to using the full covariance model alone. Tests on the full sets of known sequences for each family show that at least 95 percent of these sequences are found for two families and 100 percent for five others. Since the full covariance model is run on all sequences accepted by the partial model decision tree, the false alarm rate is at least as low as that of the full model alone.

Nurse Anesthesia Program Requirements for Esophageal/precordial Stethoscope Earpieces: a Survey

Student nurse anesthetists are often required to purchase an auscultatory earpiece device for use in the clinical setting. Although the device is required, students have observed that many anesthesia providers in the clinical setting no longer use this piece of equipment. The purpose of this project was to determine the number of anesthesia programs that required mandatory purchase of the auscultatory earpiece by student nurse anesthetists. A brief survey was developed to collect data from the directors of all 105 accredited nurse anesthesia programs in the United States. The survey was completed by 63 (60%) of the program directors, and 62 completed surveys were used in the analysis. Results revealed that 95% of the responding nurse anesthesia programs (59 of 62) require esophageal/ precordial stethoscope earpieces for their students, but 46% (27) of those programs provide the earpieces. Most (76%) of the programs required the use of the earpieces in the clinical setting, but only 45% thought that they should be used for monitoring every anesthetic delivered.

Superior Efficacy of a Recombinant Flagellin:H5N1 HA Globular Head Vaccine is Determined by the Placement of the Globular Head Within Flagellin

Transmission of highly pathogenic avian influenza (HPAI) between birds and humans is an ongoing threat that holds potential for the emergence of a pandemic influenza strain. A major barrier to an effective vaccine against avian influenza has been the generally poor immunopotency of many of the HPAI strains coupled with the manufacturing constraints employing conventional methodologies. Fusion of flagellin, a toll-like receptor-5 ligand, to vaccine antigens has been shown to enhance the immune response to the fused antigen in preclinical studies. Here, we have evaluated the immunogenicity and efficacy of a panel of flagellin-based hemagglutinin (HA) globular head fusion vaccines in inbred mice. The HA globular head of these vaccines is derived from the A/Vietnam/1203/04 (VN04; H5N1) HA molecule. We find that replacement of domain D3 of flagellin with the VN04 HA globular head creates a highly effective vaccine that elicits protective HAI titers which protect mice against disease and death in a lethal challenge model.

Statistical and Trial Design Considerations in Central Nervous System Prophylaxis Studies

The prognosis is very poor for patients with cancer who develop central nervous system (CNS) involvement. Prophylactic therapy may be a viable strategy for patients at high risk of CNS metastases. This article explores the rationale, feasibility, and ethics of prophylactic therapy. We discuss various study design considerations for CNS prophylaxis trials, with particular focus on statistical issues, and provide guidance to clinicians trying to decide how to investigate prophylactic therapy The pool of patients eligible for inclusion in clinical trials is limited. To answer pressing clinical questions, innovative trial designs are needed, along with operational strategies that include risk factor enrichment, target-based end point selection and validation, flexible study accrual and monitoring, and techniques that permit early termination when initial treatment outcomes are poor. Two proposed trials for patients with glioblastoma multiforme and non-Hodgkin lymphoma are presented to highlight design considerations.

Liporhinophyma: an Unusual Presentation of Rhinophyma

Human Papillomavirus Testing for Cervical Cancer Screening: Results from a 6-year Prospective Study in Rural China

Long-term follow-up evaluations of cervical screening approaches are limited in low-resource areas. This prospective study assessed the risk of future cervical intraepithelial neoplasia grade 2 or worse (CIN2+) associated with baseline human papillomavirus (HPV) and cytologic status. In rural China, 1,997 women were screened with 6 screening tests, including colposcopic evaluations, and underwent biopsies in 1999. In December 2005, 1,612 women with cervical intraepithelial neoplasia grade 1 or less at baseline were rescreened by visual inspection, liquid-based cytology, and HPV-DNA testing. All women underwent colposcopy at follow-up, with biopsies taken from women with visually apparent lesions or cytologic abnormalities. Twenty women developed incident CIN2+. The crude relative risk of CIN2+ for baseline HPV-positive women was 52 (95% confidence interval: 12.1, 222.5). The crude relative risk of CIN2+ was 167 (95% confidence interval: 21.9, 1,265) for baseline and follow-up repeatedly HPV-positive women compared with repeatedly HPV-negative women. Among 1,374 baseline HPV-negative women, 2 and no incident CIN2+ cases were detected in baseline cytologically normal and abnormal subgroups, respectively. Among 238 baseline HPV-positive women, 6 of 18 incident cases of CIN2+ developed in the cytologically normal group. This study demonstrates that a single oncogenic HPV-DNA test is more effective than cytology in predicting future CIN2+ status.

Sweeping "new" Proposed Consumer Product Safety Legislation

Human Papillomavirus Type-distribution in Cervical Cancer in China: the Importance of HPV 16 and 18

Prophylactic vaccination against HPV 16 and 18 has the potential for effective prevention of high-grade precancer (cervical intraepithelial neoplasia [CIN)] 2/3) and ICC caused by these viruses (globally 50 and 70%, respectively) when employed in women prior to starting sexual activity. To provide data for decisions on HPV vaccination in China, we determined HPV type-distribution in ICC and CIN 2/3 from women of different regions within China. A multicenter study was conducted by randomized sampling of paraffin blocks of 664 ICC (630 squamous cell carcinoma [SCC]; 34 adenocarcinoma [ADC]), 569 CIN 2/3 cases from seven regions of China. Histological diagnosis was confirmed in 1,233 cases by consensus review. HPV DNA was detected using the SPF10 LiPA25 version 1 assay. HPV prevalence was 97.6% in SCC, 85.3% in adenocarcinoma, and 98.9% in CIN 2/3. HPV 16 (76.7%) and HPV 18 (7.8%) were the most common, together accounting for 84.5% of SCC, followed by HPV 31 (3.2%), HPV 52 (2.2%), and HPV 58 (2.2%). HPV positivity in SCC did not differ notably by region. However, SCC cases from women

How Much Will It Hurt? HPV Vaccine Side Effects and Influence on Completion of the Three-dose Regimen

We examined the prevalence of reported pain following human papillomavirus (HPV) vaccination and whether it differed from that for other adolescent vaccines or affected completion of the HPV vaccine regimen. In 2008, we conducted cross-sectional surveys with parents of adolescent girls aged 11-20 living in areas of North Carolina with elevated cervical cancer rates who had received at least one dose of HPV vaccine. Pain from HPV vaccination, while commonly reported by parents, was less frequent compared to other adolescent vaccines and did not appear to affect vaccine regimen completion. These findings may be important to increase HPV vaccination coverage.

Self-assembled Monolayers of Alkanethiols on InAs

We describe the deposition and properties of self-assembled monolayers (SAMs) of methyl-terminated alkanethiols on InAs(001) surface. For these model hydrophobic films, we used water contact angle measurements to survey the preparation of alkanethiol monolayers from base-activated ethanolic solutions as a function of the solution and deposition parameters, including chain length of alkanethiols, deposition time, and solution temperature and pH. We then used X-ray photoelectron spectroscopy (XPS), ellipsometry, and electrochemistry to characterize the composition and structure of octadecanethiol (ODT) monolayers deposited on InAs under optimized conditions. When applied to a thoroughly degreased InAs(001) wafer surface, the basic ODT solution removes the native oxide without excessively etching the underlying InAs(001) substrate. The resulting film contains approximately one monolayer of ODT molecules, attached to the InAs surface almost exclusively via thiolate bonds to In atoms, with organic chains extended away from the surface. These ODT monolayers are stable against degradation and oxidation in air, organic solvents, and aqueous buffers. The same base-activated ODT treatment can also be used to passivate exposed InAs/AlSb quantum well (QW) devices, preserving the unique electronic properties of InAs surfaces and allowing the operation of such passivated devices as continuous flow pH-sensors.

Cavitation in the Embryonic Tracheal System of Manduca Sexta

Insect tracheae form during embryonic development and initially contain liquid, which impedes transport of oxygen and carbon dioxide. Only later do tracheae fill with gas and come to support high rates of gas flux. This liquid-to-gas transition is poorly understood. Using eggs of the sphingid moth Manduca sexta, we show that longitudinal tracheae in embryos fill with gas in less than 5 s, without invasion of external air, by a process of cavitation. Cavitation requires that tracheal liquids be under tension, and we propose two complementary processes for generating it. One likely, classical mechanism is tracheolar fluid absorption, first proposed by Wigglesworth. Our data support this mechanism in Manduca: after cavitation, liquids are progressively drawn out of finer tracheal branches. The second, previously unknown, mechanism is evaporative water loss across the eggshell, which leads both to declining egg volume and to a larger negative pressure potential of water. The pressure potential helps to drive rapid expansion of small bubbles nucleated near spiracles. Once bubbles are large enough to have displaced liquid across the diameter of a trachea, negative capillary pressure reinforces subsequent expansion of the bubble. Together with predictions from modern cavitation theory, our observations substantiate Wigglesworth's contention that gas filling is promoted by increasing hydrophobicity associated with tanning of the spiracles and major tracheal branches.

Beta-2-transferrin to Detect Cerebrospinal Fluid Pleural Effusion: a Case Report

Pleural effusion secondary to ventriculoperitoneal shunt insertion is a rare and potentially life-threatening occurrence.

Cell-type Specific Transcriptional Activities Among Different Papillomavirus Long Control Regions and Their Regulation by E2

This study systematically examined the viral long control region (LCR) activities and their responses to E2 for human papillomavirus (HPV) types 11, 16, and 18 as well as bovine papillomavirus 1 (BPV1) in a number of different cell types, including human cervical cancer cell lines, human oral keratinocytes, BJ fibroblasts, as well as CV1 cells. The study revealed cell- and virus-type specific differences among the individual LCRs and their regulation by E2. In addition, the integration of the LCR into the host genome was identified as a critical determinant for LCR activity and its response to E2. Collectively, these data indicate a more complex level of transcriptional regulation of the LCR by cellular and viral factors than previously appreciated, including a comparatively low LCR activity and poor E2 responsiveness for HPV16 in most human cells. This study should provide a valuable framework for future transcriptional studies in the papillomavirus field.

Human Papillomavirus Vaccine Initiation in an Area with Elevated Rates of Cervical Cancer

We assessed human papillomavirus (HPV) vaccination of adolescent girls living in communities with elevated cervical cancer rates.

Availability of Human Papillomavirus Vaccine at Medical Practices in an Area with Elevated Rates of Cervical Cancer

To assess availability of human papillomavirus (HPV) vaccine at medical practices in an area with elevated cervical cancer rates.

Biaryl Purine Derivatives As Potent Antiproliferative Agents: Inhibitors of Cyclin Dependent Kinases. Part I

The introduction of an aryl ring onto the 4-position of the C-6 benzyl amino group of the Cdk inhibitor roscovitine (2), maintained the potent Cdk inhibition demonstrated by roscovitine (2) as well as greatly improving the antiproliferative activity. A series of C-6 biarylmethylamino derivatives was prepared addressing modifications on the C-6 biaryl rings, N-9 and C-2 positions to provide compounds that displayed potent cytotoxic activity against tumor cell lines. In particular, derivative 21h demonstrated a >750-fold improvement in the growth inhibition of HeLa cells compared to roscovitine (2).

Drugging the Heat Shock Factor 1 Pathway: Exploitation of the Critical Cancer Cell Dependence on the Guardian of the Proteome

Hyperspectral and Physiological Analyses of Coral-algal Interactions

Space limitation leads to competition between benthic, sessile organisms on coral reefs. As a primary example, reef-building corals are in direct contact with each other and many different species and functional groups of algae. Here we characterize interactions between three coral genera and three algal functional groups using a combination of hyperspectral imaging and oxygen microprofiling. We also performed in situ interaction transects to quantify the relative occurrence of these interaction on coral reefs. These studies were conducted in the Southern Line Islands, home to some of the most remote and near-pristine reefs in the world. Our goal was to determine if different types of coral-coral and coral-algal interactions were characterized by unique fine-scale physiological signatures. This is the first report using hyperspectral imaging for characterization of marine benthic organisms at the micron scale and proved to be a valuable tool for discriminating among different photosynthetic organisms. Consistent patterns emerged in physiology across different types of competitive interactions. In cases where corals were in direct contact with turf or macroalgae, there was a zone of hypoxia and altered pigmentation on the coral. In contrast, interaction zones between corals and crustose coralline algae (CCA) were not hypoxic and the coral tissue was consistent across the colony. Our results suggest that at least two main characteristic coral interaction phenotypes exist: 1) hypoxia and coral tissue disruption, seen with interactions between corals and fleshy turf and/or some species of macroalgae, and 2) no hypoxia or tissue disruption, seen with interactions between corals and some species of CCA. Hyperspectral imaging in combination with oxygen profiling provided useful information on competitive interactions between benthic reef organisms, and demonstrated that some turf and fleshy macroalgae can be a constant source of stress for corals, while CCA are not.

The Rat Genome Database Curators: Who, What, Where, Why

Analyzing Performance with Computer Access Technology Using Unconstrained Text Entry Protocol

Recent work in human-computer interaction has demonstrated the use of unconstrained text entry protocols, which provide a more natural environment for research participants. We demonstrate the application of this approach to the analysis of word completion. Eleven participants (five nondisabled and six with disabilities) were recruited and asked to transcribe sentences using an on-screen keyboard both with and without word completion while time-stamped keystroke data were collected. The subsequent analysis demonstrates how the entire input stream (including erroneous keystrokes and the keystrokes used to correct errors) can be included in evaluation of performance with a text entry device or keystroke reduction method. Three new measures of keystroke savings are introduced, and the application of these measures is demonstrated.

Prevalence and Risk Factors of Human Papillomavirus Infection by Penile Site in Uncircumcised Kenyan Men

Human papillomavirus (HPV) prevalence was estimated from 2,705 sexually active, uncircumcised, human immunodeficiency virus seronegative men aged 17-28 years in Kisumu, Kenya. HPV prevalence was 51.1% (95% confidence interval: 49.2-53.0%) in penile cells from the glans/coronal sulcus and/or shaft. HPV prevalence varied by anatomical site, with 46.5% positivity in the glans/coronal sulcus compared with 19.1% in the shaft (p < 0.0001). High-risk HPV was detected in 31.2% of glans and 12.3% of shaft samples (p < 0.0001). HPV16 was the most common type and 29.2% of men were infected with more than one HPV type. Risk factors for HPV infection included presence of C. trachomatis, N. gonorrhea, self-reported sexually transmitted infections, and less frequent bathing. Lifetime number of sexual partners and herpes simplex virus type-2 seropositivity were also marginally associated with HPV infection.

Immunoglobulin Aggregation Leading to Russell Body Formation is Prevented by the Antibody Light Chain

Russell bodies (RBs) are intracellular inclusions filled with protein aggregates. In diverse lymphoid disorders these occur as immunoglobulin (Ig) deposits, accumulating in abnormal plasma or Mott cells. In heavy-chain deposition disease truncated antibody heavy-chains (HCs) are found, which bear a resemblance to diverse polypeptides produced in Ig light-chain (LC)-deficient (L(-/-)) mice. In L(-/-) animals, the known functions of LC, providing part of the antigen-binding site of an antibody and securing progression of B-cell development, may not be required. Here, we show a novel function of LC in preventing antibody aggregation. L(-/-) mice produce truncated HC naturally, constant region (C)gamma and Calpha lack C(H)1, and Cmicro is without C(H)1 or C(H)1 and C(H)2. Most plasma cells found in these mice are CD138(+) Mott cells, filled with RBs, formed by aggregation of HCs of different isotypes. The importance of LC in preventing HC aggregation is evident in knock-in mice, expressing Cmicro without C(H)1 and C(H)2, which only develop an abundance of RBs when LC is absent. These results reveal that preventing antibody aggregation is a major function of LC, important for understanding the physiology of heavy-chain deposition disease, and in general recognizing the mechanisms, which initiate protein conformational diseases.

Machine-smoking Studies of Cigarette Filter Color to Estimate Tar Yield by Visual Assessment and Through the Use of a Colorimeter

This paper explores using the intensity of the stain on the end of the filter ("filter color") as a vehicle for estimating cigarette tar yield, both by instrument reading of the filter color and by visual comparison to a template. The correlation of machine-measured tar yield to filter color measured with a colorimeter was reasonably strong and was relatively unaffected by different puff volumes or different tobacco moistures. However, the correlation of filter color to machine-measured nicotine yield was affected by the moisture content of the cigarette. Filter color, as measured by a colorimeter, was generally comparable to filter extraction of either nicotine or solanesol in its correlation to machine-smoked tar yields. It was found that the color of the tar stain changes over time. Panelists could generally correctly order the filters from machine-smoked cigarettes by tar yield using the intensity of the tar stain. However, there was considerable variation in the panelist-to-panelist tar yield estimates. The wide person-to-person variation in tar yield estimates, and other factors discussed in the text could severely limit the usefulness and practicality of this approach for visually estimating the tar yield of machine-smoked cigarettes.

The Carolina HPV Immunization Attitudes and Beliefs Scale (CHIAS): Scale Development and Associations With Intentions to Vaccinate

: No standardized instruments, to our knowledge, exist to assess attitudes and beliefs about human papillomavirus (HPV) vaccination.

Association Between Cervical Dysplasia and Human Papillomavirus in HIV Seropositive Women from Johannesburg South Africa

To examine the association between CD4 counts, HPV infection and the risk of cervical neoplasia among HIV-seropositive women.

Human Papillomavirus Knowledge and Vaccine Acceptability Among a National Sample of Heterosexual Men

If approved for use in young males in the United States, prophylactic human papillomavirus (HPV) vaccine may reduce the incidence of HPV-related disease in vaccinated males and their sexual partners. We aimed to characterise heterosexual men's willingness to get HPV vaccine and identify correlates of vaccine acceptability.

A Spleen Tyrosine Kinase Inhibitor Reduces the Severity of Established Glomerulonephritis

Antibody-mediated glomerulonephritis, including that resulting from immune complexes, is an important cause of renal failure and is in need of more specific and effective treatment. Binding of antibody or immune complexes to Fc receptors activates intracellular signal transduction pathways, including spleen tyrosine kinase (Syk), leading to the production of inflammatory cytokines. We examined the effect of R788 (fostamatinib disodium), an oral prodrug of the selective Syk inhibitor R406, in nephrotoxic nephritis in Wistar-Kyoto rats. Treatment with R788 reduced proteinuria, tissue injury, glomerular macrophage and CD8+ cell numbers, and renal monocyte chemoattractant protein-1 (MCP-1) and IL-1beta, even when we started treatment after the onset of glomerulonephritis. When we administered R788 from days 4 to 10, glomerular crescents reduced by 100% (P < 0.01) compared with the vehicle group. When we administered R788 treatment from days 7 to 14, established glomerular crescents reversed (reduced by 21%, P < 0.001), and renal function was better than the vehicle group (P < 0.001). In vitro, R406 downregulated MCP-1 production from mesangial cells and macrophages stimulated with aggregated IgG. These results suggest that Syk is an important therapeutic target for the treatment of glomerulonephritis.

Histone Chaperone Chz1p Regulates H2B Ubiquitination and Subtelomeric Anti-silencing

Chz1p is a histone chaperone that interacts physically and functionally with the histone variant Htz1p, which has been implicated in establishing and maintaining boundaries between transcriptionally inactive heterochromatin and active euchromatin. To investigate the role of Chz1p in chromatin organization, we performed genome-wide expression arrays and chromatin immunoprecipitations of SIR complex components and modified histones in a CHZ1 deletion strain. Deletion of CHZ1 led to reduced ubiquitination of subtelomere-associated H2B, reduced subtelomeric H3K79 di-methylation, and increased binding of Sir3p, and Sir4p at telomere-distal euchromatin regions, correlating with decreased gene expression in subtelomeric regions. This anti-silencing defect appears to be mediated by enhanced association of de-ubiquitinase Ubp10p with subtelomeric DNA, as detected by chromatin immunoprecipitation analysis. In support of this, we show that deletion of UBP10 can antagonize the subtelomeric silencing phenotype of Deltachz1. Taken together, the results demonstrate a novel role for Chz1p in epigenetic regulation, through H2B de-ubiquitination by Ubp10p.

Eribulin Binds at Microtubule Ends to a Single Site on Tubulin to Suppress Dynamic Instability

Eribulin mesylate (E7389), a synthetic analogue of the marine natural product halichondrin B, is in phase III clinical trials for the treatment of cancer. Eribulin targets microtubules, suppressing dynamic instability at microtubule plus ends through an inhibition of microtubule growth with little or no effect on shortening [Jordan, M. A., et al. (2005) Mol. Cancer Ther. 4, 1086-1095]. Using [(3)H]eribulin, we found that eribulin binds soluble tubulin at a single site; however, this binding is complex with an overall K(d) of 46 microM, but also showing a real or apparent very high affinity (K(d) = 0.4 microM) for a subset of 25% of the tubulin. Eribulin also binds microtubules with a maximum stoichiometry of 14.7 +/- 1.3 molecules per microtubule (K(d) = 3.5 microM), strongly suggesting the presence of a relatively high-affinity binding site at microtubule ends. At 100 nM, the concentration that inhibits microtubule plus end growth by 50%, we found that one molecule of eribulin is bound per two microtubules, indicating that the binding of a single eribulin molecule at a microtubule end can potently inhibit its growth. Eribulin does not suppress dynamic instability at microtubule minus ends. Preincubation of microtubules with 2 or 4 microM vinblastine induced additional lower-affinity eribulin binding sites, most likely at splayed microtubule ends. Overall, our results indicate that eribulin binds with high affinity to microtubule plus ends and thereby suppresses dynamic instability.

Prevalence of Type-specific Human Papillomavirus in Endocervical, Upper and Lower Vaginal, Perineal and Vaginal Self-collected Specimens: Implications for Vaginal Self-collection

To determine why a vaginal self-collection tested for high-risk human papillomavirus (HR-HPV) by Hybrid Capture 2(R) (hc2) has lower sensitivity and specificity for cervical intraepithelial neoplasia Grade 2 or worse (> or = CIN 2), we collected 5 specimens (endocervix, upper and lower vagina, perineum, vaginal self-collection) from 2,625 women. Endocervical and self-collected specimens had HR-HPV tests by hc2. All 5 anogenital specimens were tested for 37 HPV genotypes [Linear Array(R), (LA)] from 397 women hc2 positive in endocervical or self-collected specimens and for a randomly selected 71 of 2,228 women hc2 negative on both specimens. Three hundred nintey-five women who screened positive by hc2 or had abnormal cytology underwent colposcopic evaluation. Of 47 women with > or = CIN 2, hc2 was positive in 97.9% (46/47) of endocervical and 80.9% (38/47), p = 0.008 of self-collected specimens. Seven of 9 women with > or = CIN 2 and negative self-collected hc2 tests were positive for HR-HPV by LA. Of 2,578 women without > or = CIN 2, hc2 was positive in 9.8% (253/2,578) of endocervical and 11.4% (294/2,578), p = 0.001 of self-collected specimens. Of the 41 more women without > or = CIN 2 that tested hc2 positive on the self-collected but negative on endocervical specimen, LA tested positive for HR-HPV in 24, negative for HPV in 11 and negative for HR-HPV but positive for low-risk HPV in 6. Lower sensitivity of self-collected specimens is secondary to lower levels of vaginal HR-HPV. The principal cause of the lower specificity of self-collected specimens is HR-HPV present solely in the vagina, which is not associated with > or = CIN 2.

The Effects of Top-down Versus Bottom-up Control on Benthic Coral Reef Community Structure

While climate change and associated increases in sea surface temperature and ocean acidification, are among the most important global stressors to coral reefs, overfishing and nutrient pollution are among the most significant local threats. Here we examined the independent and interactive effects of reduced grazing pressure and nutrient enrichment using settlement tiles on a coral-dominated reef via long-term manipulative experimentation. We found that unique assemblages developed in each treatment combination confirming that both nutrients and herbivores are important drivers of reef community structure. When herbivores were removed, fleshy algae dominated, while crustose coralline algae (CCA) and coral were more abundant when herbivores were present. The effects of fertilization varied depending on herbivore treatment; without herbivores fleshy algae increased in abundance and with herbivores, CCA increased. Coral recruits only persisted in treatments exposed to grazers. Herbivore removal resulted in rapid changes in community structure while there was a lag in response to fertilization. Lastly, re-exposure of communities to natural herbivore populations caused reversals in benthic community trajectories but the effects of fertilization remained for at least 2 months. These results suggest that increasing herbivore populations on degraded reefs may be an effective strategy for restoring ecosystem structure and function and in reversing coral-algal phase-shifts but that this strategy may be most effective in the absence of other confounding disturbances such as nutrient pollution.

Using Delta 15N Values in Algal Tissue to Map Locations and Potential Sources of Anthropogenic Nutrient Inputs on the Island of Maui, Hawai'i, USA

Macroalgal blooms of Hypnea musciformis and Ulvafasciata in coastal waters of Maui only occur in areas of substantial anthropogenic nutrient input, sources of which include wastewater effluent via injection wells, leaking cesspools and agricultural fertilizers. Algal delta(15)N signatures were used to map anthropogenic nitrogen through coastal surveys (island-wide and fine-scale) and algal deployments along nearshore and offshore gradients. Algal delta(15)N values of 9.8 per thousand and 2.0-3.5 per thousand in Waiehu and across the north-central coast, respectively, suggest that cesspool and agricultural nitrogen reached the respective adjacent coastlines. Effluent was detected in areas proximal to the Wastewater Reclamation Facilities (WWRF) operating Class V injection wells in Lahaina, Kihei and Kahului through elevated algal delta(15)N values (17.8-50.1 per thousand). From 1997 to 2008, the three WWRFs injected an estimated total volume of 193 million cubic meters (51 billion gallons) of effluent with a nitrogen mass of 1.74 million kilograms (3.84 million pounds).

Sixty-four-slice CT Angiography to Determine the Three Dimensional Relationships of Vascular and Soft Tissue Wounds in Lower Extremity War Time Injuries

This article analyzes the use and benefits of the 64-slice CT scanner in determining the 3D relationships of vascular and soft tissue wounds in lower extremity war time injuries. A brief overview of CT scanning is given as well as the techniques used to produce the images needed for diagnosis. The series follows two similar cases of war time injury patients at the Walter Reed Army Medical Center. The first case is a 30-year-old active duty male, who presented with multiple trauma from a motor vehicle accident because of an improvised explosive device (IED) blast, sustaining substantial lower extremity injuries. The second case is a 34-year-old active duty male, who presented with multiple trauma blast injuries. Both cases were of interest because the vasculature was found to be very close to the surface of the wound, which put the arteries at risk for rupture and for iatrogenic injury during repeated debridements.

Acceptability of HPV Vaccine Among a National Sample of Gay and Bisexual Men

Due to higher rates of human papillomavirus (HPV) infection and anal cancer among gay and bisexual men, we aimed to characterize their willingness to get HPV vaccine and identify correlates of vaccine acceptability.

Genome-wide SiRNA Screen Identifies SMCX, EP400, and Brd4 As E2-dependent Regulators of Human Papillomavirus Oncogene Expression

An essential step in the pathogenesis of human papillomavirus (HPV)-associated cancers is the dysregulated expression of the viral oncogenes. The papillomavirus E2 protein can silence the long control region (LCR) promoter that controls viral E6 and E7 oncogene expression. The mechanisms by which E2 represses oncogene expression and the cellular factors through which E2 mediates this silencing are largely unknown. We conducted an unbiased, genome-wide siRNA screen and series of secondary screens that identified 96 cellular genes that contribute to the repression of the HPV LCR. In addition to confirming a role for the E2-binding bromodomain protein Brd4 in E2-mediated silencing, we identified a number of genes that have not previously been implicated in E2 repression, including the demethylase JARID1C/SMCX as well as EP400, a component of the NuA4/TIP60 histone acetyltransferase complex. Each of these genes contributes independently and additively to E2-mediated silencing, indicating that E2 functions through several distinct cellular complexes to repress E6 and E7 expression.

Key Features and Context-dependence of Fishery-induced Trophic Cascades

Trophic cascades triggered by fishing have profound implications for marine ecosystems and the socioeconomic systems that depend on them. With the number of reported cases quickly growing, key features and commonalities have emerged. Fishery-induced trophic cascades often display differential response times and nonlinear trajectories among trophic levels and can be accompanied by shifts in alternative states. Furthermore, their magnitude appears to be context dependent, varying as a function of species diversity, regional oceanography, local physical disturbance, habitat complexity, and the nature of the fishery itself. To conserve and manage exploited marine ecosystems, there is a pressing need for an improved understanding of the conditions that promote or inhibit the cascading consequences of fishing. Future research should investigate how the trophic effects of fishing interact with other human disturbances, identify strongly interacting species and ecosystem features that confer resilience to exploitation, determine ranges of predator depletion that elicit trophic cascades, pinpoint antecedents that signal ecosystem state shifts, and quantify variation in trophic rates across oceanographic conditions. This information will advance predictive models designed to forecast the trophic effects of fishing and will allow managers to better anticipate and avoid fishery-induced trophic cascades.

Coordinate Down-regulation of Adenylyl Cyclase Isoforms and the Stimulatory G Protein (G(s)) in Intestinal Epithelial Cell Differentiation

The intestinal epithelium is dynamic, with proliferation of undifferentiated crypt cells balanced by terminal differentiation and cell death at the colon surface or small intestinal villus tips. Cyclic AMP, induced by agonists such as prostaglandin E(2) and vasoactive intestinal polypeptide, promotes proliferation and ion secretion and suppresses apoptosis in intestinal epithelial cells. Here, we show that cell differentiation in a model intestinal epithelium leads to attenuation of cAMP production in response to G protein-coupled receptor and receptor-independent agonists. Concomitantly, key components of the cAMP cascade, the alpha subunit of the stimulatory G protein, G(s), and adenylyl cyclase (AC) isoforms 3, 4, 6, and 7 are down-regulated. By contrast, AC1, AC2, AC8, and AC9, and the receptors for prostaglandin E(2) and vasoactive intestinal polypeptide, are not expressed or not affected by differentiation. We confirmed key findings in normal murine colon epithelium, in which the major AC isoforms and G(s)alpha are markedly down-regulated in differentiated surface cells. Suppression of AC isoforms and G(s)alpha is functionally important, because their constitutive expression completely reverses differentiation-induced cAMP attenuation. Thus, down-regulation of AC isoforms and G(s)alpha is an integral part of the intestinal epithelial differentiation program, perhaps serving to release cells from cAMP-promoted anti-apoptosis as a prerequisite for cell death upon terminal differentiation.

Crossbyanols A-D, Toxic Brominated Polyphenyl Ethers from the Hawai'ian Bloom-forming Cyanobacterium Leptolyngbya Crossbyana

Periodically, the marine cyanobacterium Leptolyngbya crossbyana forms extensive blooms on Hawai'ian coral reefs and results in significant damage to the subtending corals. Additionally, corals near mats of this cyanobacterium, but not directly overgrown, have been observed to undergo bleaching. Therefore, samples of this cyanobacterium were chemically investigated for bioactive secondary metabolites that might underlie this toxicity phenomenon. (1)H NMR spectroscopy-guided fractionation led to the isolation of four heptabrominated polyphenolic ethers, crossbyanols A-D (1-4). Structure elucidation of these compounds was made challenging by their very low proton to carbon (H/C) ratio, but was completed by combining standard NMR and MS data with 2 Hz-optimized HMBC data. Derivatization of crossbyanol A as the diacetate assisted in the assignment of its structure. Crossbyanol B (2) showed antibiotic activity with an MIC value of 2.0-3.9 microg/mL against methicillin-resistant Staphylococcus aureus (MRSA) and relatively potent brine shrimp toxicity (IC(50) 2.8 ppm).

NCoR1 Mediates Papillomavirus E8;E2C Transcriptional Repression

The papillomavirus E2 open reading frame encodes the full-length E2 protein as well as an alternatively spliced product called E8;E2C. E8;E2C has been best studied for the high-risk human papillomaviruses, where it has been shown to regulate viral genome levels and, like the full-length E2 protein, to repress transcription from the viral promoter that directs the expression of the viral E6 and E7 oncogenes. The repression function of E8;E2C is dependent on the 12-amino-acid N-terminal sequence from the E8 open reading frame (ORF). In order to understand the mechanism by which E8;E2C mediates transcriptional repression, we performed an unbiased proteomic analysis from which we identified six high-confidence candidate interacting proteins (HCIPs) for E8;E2C; the top two are NCoR1 and TBLR1. We established an interaction of E8;E2C with an NCoR1/HDAC3 complex and demonstrated that this interaction requires the wild-type E8 open reading frame. Small interfering RNA (siRNA) knockdown studies demonstrated the involvement of NCoR1/HDAC3 in the E8;E2C-dependent repression of the viral long control region (LCR) promoter. Additional genetic work confirmed that the papillomavirus E2 and E8;E2C proteins repress transcription through distinct mechanisms.

Comparison of the DNA Methylation Profiles of Human Peripheral Blood Cells and Transformed B-lymphocytes

Epidemiological studies of DNA methylation (DNAm) profiles may hold substantial promise for identifying mechanisms through which genetic and environmental factors jointly contribute to disease risk. Different cell types are likely to have different DNAm patterns. We investigate the DNAm differences between two types of biospecimens available in many genetic epidemiology studies. We compared DNAm patterns in two different DNA samples from each of 34 participants in the Genetic Epidemiology Network of Arteriopathy study (20 Caucasians and 14 African-Americans). One was extracted from peripheral blood cells (PBC) and the other from transformed B-lymphocytes (TBL). The genome-wide DNAm profiles were compared at over 27,000 genome-wide methylation sites. We found that 26 out of the 34 participants had correlation coefficients higher than 0.9 between methylation profiles of PBC and TBL. Although a high correlation was observed in the DNAm profile between PBC and TBL, we also observed variation across samples from different DNA resources and donors. Using principal component analysis of the DNAm profiles, the two sources of the DNA samples could be accurately predicted. We also identified 3,723 autosomal DNAm sites that had significantly different methylation statuses in PBC compared to TBL (Bonferroni corrected p value <0.05). Both PBC and TBL provide a rich resource for understanding the DNAm profiles in humans participating in epidemiologic studies. While the majority of DNAm findings in PBC and TBL may be consistent, caution must be used when interpreting results because of the possibility of cell type-specific methylation modification.

Gay and Bisexual Men's Willingness to Receive Anal Papanicolaou Testing

We assessed the willingness of gay and bisexual men, who have high rates of anal cancer that might be prevented through regular screening, to receive anal Papanicolaou tests.

Universal Model for Water Costs of Gas Exchange by Animals and Plants

For terrestrial animals and plants, a fundamental cost of living is water vapor lost to the atmosphere during exchange of metabolic gases. Here, by bringing together previously developed models for specific taxa, we integrate properties common to all terrestrial gas exchangers into a universal model of water loss. The model predicts that water loss scales to gas exchange with an exponent of 1 and that the amount of water lost per unit of gas exchanged depends on several factors: the surface temperature of the respiratory system near the outside of the organism, the gas consumed (oxygen or carbon dioxide), the steepness of the gradients for gas and vapor, and the transport mode (convective or diffusive). Model predictions were largely confirmed by data on 202 species in five taxa--insects, birds, bird eggs, mammals, and plants--spanning nine orders of magnitude in rate of gas exchange. Discrepancies between model predictions and data seemed to arise from biologically interesting violations of model assumptions, which emphasizes how poorly we understand gas exchange in some taxa. The universal model provides a unified conceptual framework for analyzing exchange-associated water losses across taxa with radically different metabolic and exchange systems.

Statewide HPV Vaccine Initiation Among Adolescent Females in North Carolina

Cervical cancer incidence in the United States may be greatly reduced through widespread human papillomavirus (HPV) vaccination. We estimated the statewide level of HPV vaccine initiation among adolescent girls in North Carolina and identified correlates of vaccine initiation.

Increased Risk of HIV Acquisition Among Kenyan Men with Human Papillomavirus Infection

Few data on the effect of human papillomavirus (HPV) infection on human immunodeficiency virus (HIV) acquisition are available.

Investigation of Support Vector Machines and Raman Spectroscopy for Lymph Node Diagnostics

This study concerns the combination of Raman spectroscopy and multivariate statistical analyses for the assessment of lymph nodes in the course of breast cancer diagnostics and staging. Axillary lymph node samples derived from breast cancer patients were measured by Raman microspectroscopy. The resulting Raman maps were pre-processed and cleaned of background noise and low intensity spectra using a novel method based on selecting spectra depending on the distribution of the mean of arbitrary units of all spectra within individual samples. The obtained dataset was used to build different types of Support Vector Machine (SVM) models, including linear, polynomial and radial basis function (RBF). All trained models were tested with an unseen independent dataset in order to allow an assessment of the predictive power of the algorithms. The best performance was achieved by the RBF SVM model, which classified 100% of the independent testing data correctly. In order to compare the SVM performance with traditional chemometric methods a linear discriminant analysis (LDA) model and a partial least square discriminant analysis (PLS-DA) model were generated. The results demonstrate the enhanced performance and clinical potential of the combination of SVMs and Raman spectroscopy and the benefits of the implemented filtering.

TC83 Replicon Vectored Vaccine Provides Protection Against Junin Virus in Guinea Pigs

Junin virus (JUNV) is the etiological agent of the potentially lethal, reemerging human disease, Argentine hemorrhagic fever (AHF). The mechanism of the disease development is not well understood and no antiviral therapy is available. Candid 1, a live-attenuated vaccine, has been developed by the US Army and is being used in the endemic area to prevent AHF. This vaccine is only approved for use in Argentina. In this study we have used the alphavirus-based approach to engineer a replicon system based on a human (United States Food and Drug Administration Investigational New Drug status) vaccine TC83 that express heterologous viral antigens, such as glycoproteins (GPC) of Junin virus (JUNV). Preclinical studies testing the immunogenicity and efficacy of TC83/GPC were performed in guinea pigs. A single dose of the live-attenuated alphavirus based vaccine expressing only GPC was immunogenic and provided partial protection, while a double dose of the same vaccine provided a complete protection against JUNV. This is the first scientific report to our knowledge that the immune response against GPC alone is sufficient to prevent lethal disease against JUNV in an animal model.

Determination of Drug Binding to Microtubules in Vitro

Many naturally occurring compounds and their synthetic analogs bind to soluble tubulin or to tubulin in microtubules. These compounds are often important drugs or drug candidates. They can potently alter both the dynamics and the polymer mass of microtubules. The binding affinity of a drug for soluble tubulin heterodimers is a common and relatively readily determined biochemical characteristic of a tubulin-targeted drug. However, it is only one important aspect of the drug-tubulin interaction. In solution and in cells, soluble tubulin is in equilibrium with polymerized microtubules. It is as important to determine drug binding to microtubules as it is to determine binding to soluble tubulin, since drug binding to microtubules frequently alters their function. The affinity of a compound for microtubules often differs vastly from its affinity for soluble tubulin. Here, we present detailed instructions for assessing binding stoichiometry and affinity to assembled unstabilized microtubules using radiolabeled drug. In addition, using examples from binding results with several important drugs including vinca alkaloids, colchicine, eribulin, and taxanes, we discuss aspects of the interactions with microtubules that may alter the experimental design of the drug-binding experiments.

Decreased Transcription-coupled Nucleotide Excision Repair Capacity is Associated with Increased P53- and MLH1-independent Apoptosis in Response to Cisplatin

One of the most commonly used classes of anti-cancer drugs presently in clinical practice is the platinum-based drugs, including cisplatin. The efficacy of cisplatin therapy is often limited by the emergence of resistant tumours following treatment. Cisplatin resistance is multi-factorial but can be associated with increased DNA repair capacity, mutations in p53 or loss of DNA mismatch repair capacity.

Does Food Supplementation Really Enhance Productivity of Breeding Birds?

Food availability influences multiple stages of the breeding cycle of birds, and supplementary feeding has helped in its understanding. Most supplementation studies have reported advancements of laying, whilst others, albeit less numerous, have also demonstrated fitness benefits such as larger clutches, shorter incubation periods, and greater hatching success. Relatively few studies, however, have investigated the effects of supplementary feeding for protracted periods across multiple stages of the breeding cycle. These effects are important to understand since long-term food supplementation of birds is recommended in urban habitats and is used as a tool to increase reproductive output in endangered species. Here, we compare the breeding phenology and productivity of blue tits Cyanistes caeruleus and great tits Parus major breeding in food-supplemented and non-supplemented blocks in a broadleaf woodland in central England over three seasons (2006-2008). Supplementation was provided continuously from several weeks pre-laying until hatching, and had multiple significant effects. Most notably, supplementation reduced brood size significantly in both species, by half a chick or more at hatching (after controlling for year and hatching date). Reduced brood sizes in supplemented pairs were driven by significantly smaller clutches in both species and, in blue tits, significantly lower hatching success. These are novel and concerning findings of food supplementation. As expected, supplementary feeding advanced laying and shortened incubation periods significantly in both species. We discuss the striking parallels between our findings and patterns in blue and great tit reproduction in urban habitats, and conclude that supplementary feeding may not always enhance the breeding productivity of birds.

Genetic Loci Modulate Macrophage Activity and Glomerular Damage in Experimental Glomerulonephritis

The Wistar Kyoto (WKY) rat is uniquely susceptible to experimentally induced crescentic glomerulonephritis. Two major quantitative trait loci (QTLs) on chromosomes 13 (Crgn1) and 16 (Crgn2) with logarithm of odds >8, as well as five other loci (Crgn3 through 7), largely explain this genetic susceptibility. To understand further the effects of Crgn1 and Crgn2, we generated a double-congenic strain by introgressing these loci from glomerulonephritis-resistant Lewis rats onto the WKY genetic background. Induction of nephrotoxic nephritis in the double-congenic rats (WKY.LCrgn1,2) produced markedly fewer glomerular crescents, reduced macrophage infiltration, and decreased expression of glomerular TNF-alpha and inducible nitric oxide synthase expression compared with control animals. Bone marrow and kidney transplantation studies between parental and WKY.LCrgn1,2 strains, together with in vitro experiments, demonstrated that Crgn1 and Crgn2 contribute exclusively to circulating cell-related glomerular injury by regulating macrophage infiltration and activation. The residual genetic susceptibility to crescentic glomerulonephritis in WKY.LCrgn1,2 rats associated with macrophage activity (especially with enhanced metalloelastase expression) rather than macrophage infiltration. Taken together, these results demonstrate that a genetic influence on macrophage activation, rather than number, determines glomerular damage in immune-mediated glomerulonephritis.

Impact of Hookworm Infection and Deworming on Anaemia in Non-pregnant Populations: a Systematic Review

To summarise age- and intensity-stratified associations between human hookworm infection and anaemia and to quantify the impact of treatment with the benzimidazoles, albendazole and mebendazole, on haemoglobin and anaemia in non-pregnant populations.

Regulation of the Expression and Activity of the Antiangiogenic Homeobox Gene GAX/MEOX2 by ZEB2 and MicroRNA-221

Tumors secrete proangiogenic factors to induce the ingrowth of blood vessels from the stroma. These peptides bind to cell surface receptors on vascular endothelial cells (ECs), triggering signaling cascades that activate and repress batteries of downstream genes responsible for the angiogenic phenotype. To determine if microRNAs (miRNAs) affect regulation of the EC phenotype by GAX, a homeobox gene and negative transcriptional regulator of the angiogenic phenotype, we tested the effect of miR-221 on GAX expression. miR-221 strongly upregulated GAX, suggesting that miR-221 downregulates a repressor of GAX. We next expressed miR-221 in ECs and identified ZEB2, a modulator of the epithelial-mesenchymal transition, as being strongly downregulated by miR-221. Using miR-221 expression constructs and an inhibitor, we determined that ZEB2 is upregulated by serum and downregulates GAX, while the expression of miR-221 upregulates GAX and downregulates ZEB2. A mutant miR-221 fails to downregulate ZEB2 or upregulate GAX. Finally, using chromatin immunoprecipitation, we identified two ZEB2 binding sites that modulate the ability of ZEB2 to downregulate GAX promoter activity. We conclude that miR-221 upregulates GAX primarily through its ability to downregulate the expression of ZEB2. These observations suggest a strategy for inhibiting angiogenesis by either recapitulating miR-221 expression or inhibiting ZEB2 activation.

Human Papillomavirus Vaccines: Current Status and Future Prospects

Worldwide, cervical cancer is the second most common cancer of women. Less-developed countries bear the greatest burden in terms of morbidity and mortality, largely due to the lack of organized screening programmes. Cervical cancer is the first cancer shown to be caused solely by virological agents: oncogenic genotypes of human papillomavirus (HPV). Two recently developed prophylactic cervical cancer vaccines, which are based on viral-like particle (VLP) technology of HPV, have the capacity to diminish a large proportion of cervical cancer cases worldwide. However, to be successful public health tools, they need to be widely implemented to the appropriate target population, preferably prior to first sexual intercourse. To increase vaccination coverage, national programmes in some countries have also included catch-up vaccination, for a limited time period, to young adult women aged up to 26 years. Despite the excellent efficacy for high-grade dysplasia due to vaccine-related HPV types (near to 100%) and immunogenicity induced against the HPV types 16 and 18 in females naive to those HPV types pre-vaccination, some form of cervical precancer screening will still be necessary. Immunity to HPV is primarily type specific, and thus protection induced by the current generation of vaccines, based on a limited number of HPV VLP types, cannot provide complete protection against all oncogenic HPV types. Both these vaccines translate to protection of cervical cancer in the order of 70-75%, which represents the percentage of invasive cancers attributable to HPV-16 and -18. Challenges to ensuring the successful control of this largely preventable disease include endorsement by governments and policy makers, affordable prices, education at all levels, overcoming barriers to vaccination and continued adherence to screening programmes.

The Lagoon at Caroline/Millennium Atoll, Republic of Kiribati: Natural History of a Nearly Pristine Ecosystem

A series of surveys were carried out to characterize the physical and biological parameters of the Millennium Atoll lagoon during a research expedition in April of 2009. Millennium is a remote coral atoll in the Central Pacific belonging to the Republic of Kiribati, and a member of the Southern Line Islands chain. The atoll is among the few remaining coral reef ecosystems that are relatively pristine. The lagoon is highly enclosed, and was characterized by reticulate patch and line reefs throughout the center of the lagoon as well as perimeter reefs around the rim of the atoll. The depth reached a maximum of 33.3 m in the central region of the lagoon, and averaged between 8.8 and 13.7 m in most of the pools. The deepest areas were found to harbor large platforms of Favia matthaii, which presumably provided a base upon which the dominant corals (Acropora spp.) grew to form the reticulate reef structure. The benthic algal communities consisted mainly of crustose coralline algae (CCA), microfilamentous turf algae and isolated patches of Halimeda spp. and Caulerpa spp. Fish species richness in the lagoon was half of that observed on the adjacent fore reef. The lagoon is likely an important nursery habitat for a number of important fisheries species including the blacktip reef shark and Napoleon wrasse, which are heavily exploited elsewhere around the world but were common in the lagoon at Millennium. The lagoon also supports an abundance of giant clams (Tridacna maxima). Millennium lagoon provides an excellent reference of a relatively undisturbed coral atoll. As with most coral reefs around the world, the lagoon communities of Millennium may be threatened by climate change and associated warming, acidification and sea level rise, as well as sporadic local resource exploitation which is difficult to monitor and enforce because of the atoll's remote location. While the remote nature of Millennium has allowed it to remain one of the few nearly pristine coral reef ecosystems in the world, it is imperative that this ecosystem receives protection so that it may survive for future generations.

JAAD Grand Rounds Quiz*: Dusky Intertriginous Plaques and Acral Erythema After Bone Marrow Transplant

LEARNING OBJECTIVES: At the conclusion of this learning activity, physician participants should be able to assess their own diagnostic and patient management skills and use the results of this exercise to help determine personal learning needs that can be addressed through subsequent CME involvement. Instructions for claiming CME credit appear in the front advertising section. See last page of Contents for page number. INSTRUCTIONS: In answering each question, refer to the specific directions provided. Because it is often necessary to provide information occurring later in a series that give away answers to earlier questions, please answer the questions in each series in sequence.

HPV Vaccine Acceptability Among Kenyan Women

As human papillomavirus (HPV) vaccines become available in less-developed countries, understanding women's attitudes towards HPV vaccines can help guide approaches to immunization programs. We assessed knowledge and interest in prophylactic HPV vaccines among Kenyan women seeking women's health services (N=147). They knew little about cervical cancer or HPV vaccine. Most women (95%, 95% confidence interval [CI]: 92%, 99%), however, were willing to have their daughters vaccinated with a vaccine that would prevent cervical cancer, with preference for an inexpensive vaccine requiring fewer doses.

Identifying Optimal Initial Infusion Rates for Unfractionated Heparin in Morbidly Obese Patients

Most literature available for unfractionated heparin (UFH) supports the use of actual body weight for dosing all patients, yet a small proportion of the patients in these studies were morbidly obese. The most appropriate dosing strategy for therapeutic UFH in this patient population is not clearly defined.

The Role of Organizational Culture and Leadership in Water Safety Plan Implementation for Improved Risk Management

Appropriate implementation of WSPs offers an important opportunity to engage in and promote preventative risk management within water utilities. To ensure success, the whole organization, especially executive management, need to be advocates. Illustrated by two case studies, we discuss the influence of organizational culture on buy-in and commitment to public health protection and WSPs. Despite an internal desire to undertake risk management, some aspects of organizational culture prevented these from reaching full potential. Enabling cultural features included: camaraderie; competition; proactive, involved leaders; community focus; customer service mentality; transparency; accountability; competent workforce; empowerment; appreciation of successes, and a continual improvement culture. Blocking features included: poor communication; inflexibility; complacency; lack of awareness, interest or reward and coercion. We urge water utilities to consider the influence of organizational culture on the success and sustainability of WSP adoption, and better understand how effective leadership can mould culture to support implementation.

Nubian Complex Strategies in the Egyptian High Desert

Systematic survey by the Abydos Survey for Paleolithic Sites project has recorded Nubian Complex artifact density, distribution, typology, and technology across the high desert landscape west of the Nile Valley in Middle Egypt. Our work contrasts with previous investigations of Nubian Complex settlement systems in Egypt, which focused on a small number of sites in the terraces of the Nile Valley, the desert oases, and the Red Sea Mountains. Earlier research interpreted the Nubian Complex, in particular, as a radiating settlement system that incorporated a specialized point production. Our high desert data, however, indicate that the Nubian Complex associated with early modern humans in this region of the high desert reflects a circulating, rather than a radiating, settlement system, and that point production has been over-emphasized. Data available from our work, as well as sites investigated by others, do not conclusively identify Nubian Complex behavioral strategies as modern. These data, however, do contribute to the understanding of landscape use by early modern human populations living along the Nile Valley Corridor route out of Africa.

Impact of Gauze-based NPWT on the Patient and Nursing Experience in the Treatment of Challenging Wounds

Negative pressure wound therapy is widely used in the treatment of hard-to-heal wounds; however, pain during dressing changes, which is often associated with pain on the commencement and cessation of pressure application and because of in-growth of new granulation tissue into interstices of foam dressings, is often experienced. Anecdotal reports have suggested that choice of gauze as the negative pressure wound therapy dressing may reduce the pain associated with dressing changes. A prospective, multi-center, non-comparative clinical investigation was carried out using gauze-based negative pressure wound therapy in chronic and acute wounds. Over 152 patients were evaluated. Median duration of therapy was 18 days with 91% of patients progressing towards healing at the end of therapy. Wound pain and odour were significantly reduced (P < 0.001) over the course of therapy. Wound pain during dressing changes was reported to be absent in 80% of dressing removals. No damage to the wound bed following dressing removal was observed in 96% of dressing changes. Dressing applications were considered easy in 79% of assessments and took a median of 20 min to complete. In patients susceptible to pain, gauze-based negative pressure therapy may be a viable option to maximise patient comfort.

How Parents Hear About Human Papillomavirus Vaccine: Implications for Uptake

To examine correlates of human papillomavirus (HPV) vaccine awareness and information sources in a state requiring schools to inform parents about HPV vaccine.

Management of a Massive Stage IV Sacral Decubitus Ulcer with Anterior Flap Hip Disarticulation and Myocutaneous Gastrocnemius Fillet Flap In-continuity

Severe sacral decubitus ulcers represent a common and often recalcitrant clinical problem in paralyzed or bedridden patients and require treatment strategies ranging from specialty beds and local wound care to aggressive debridement and local or free tissue flap coverage. This article presents the case of a young soldier who sustained severe injuries as a result of an improvised explosive device blast, including bilateral sciatic nerve injuries, sacrogluteal degloving, and severe left acetabular and femoral head fractures. The patient subsequently developed a recalcitrant stage IV sacral decubitus ulcer, left acetabular protrusio with minimal left lower extremity function, and ankylosis of the posterior right hip due to heterotopic ossification. A novel left anterior (quadriceps-based) hip disarticulation was performed with a double gastrocnemius myocutaneous fillet flap in-continuity. The procedure was successful in providing robust, partially sensate soft tissue coverage for the decubitus ulcer, permitting removal of the bridging posterior heterotopic ossification of the right hip, and removing the left hip for which reconstructive options were limited due to the absence of superior and inferior gluteal nerve function. The patient healed uneventfully and was subsequently able to resume unrestricted positioning for sitting and wheelchair mobilization and became a limited ambulator with a hip disarticulation prosthesis and contralateral ankle-foot orthosis.

The Association Between Cervical Abnormalities and Attitudes Toward Cervical Cancer Prevention

We investigated whether a history of cervical abnormalities predicts responses to cervical cancer prevention for women and their daughters.

Microleakage of Nano-particle-filled Resin-modified Glass Ionomer Using Atraumatic Restorative Technique in Primary Molars

This study compared the marginal leakage of nano-particle-filled resin-modified glass ionomer (RMGIC) restorations made using atraumatic restorative technique (ART) and conventional technique. Twenty primary molars with carious dentin on the buccal surfaces were restored with RMGIC using ART. The teeth were thermally cycled, sectioned and stained with methylene blue. Micro-leakage was compared to a second set of teeth restored conventionally. No significant difference (p > 0.05) in leakage was noted between the conventional and ART groups. The authors concluded that ART with RMGIC provides margins that show comparable leakage to conventionally restored primary teeth.

Mice Lacking Alpha/beta and Gamma Interferon Receptors Are Susceptible to Junin Virus Infection

Junin virus (JUNV) causes a highly lethal human disease, Argentine hemorrhagic fever. Previous work has demonstrated the requirement for human transferrin receptor 1 for virus entry, and the absence of the receptor was proposed to be a major cause for the resistance of laboratory mice to JUNV infection. In this study, we present for the first time in vivo evidence that the disruption of interferon signaling is sufficient to generate a disease-susceptible mouse model for JUNV infection. After peripheral inoculation with virulent JUNV, adult mice lacking alpha/beta and gamma interferon receptors developed disseminated infection and severe disease.

The Impact of Highly Active Antiretroviral Therapy on Prevalence and Incidence of Cervical Human Papillomavirus Infections in HIV-positive Adolescents

The implementation of highly active antiretroviral therapy (HAART) among HIV-positive patients results in immune reconstitution, slower progression of HIV disease, and a decrease in the occurrence of opportunistic infections. However, the impact of HAART on cervical human papillomavirus (HPV) infection, clearance, and persistence in high-risk adolescents remains controversial.

Providing Context and Interpretability to Genetic Association Analysis Results Using the KGraph

The KGraph is a data visualization system that has been developed to display the complex relationships between the univariate and bivariate associations among an outcome of interest, a set of covariates, and a set of genetic variations such as single-nucleotide polymorphisms (SNPs). It allows for easy simultaneous viewing and interpretation of genetic associations, correlations among covariates and SNPs, and information about the replication and cross-validation of these associations. The KGraph allows the user to more easily investigate multicollinearity and confounding through visualization of the multidimensional correlation structure underlying genetic associations. It emphasizes gene-environment interactions, gene-gene interactions, and correlations, all important components of the complex genetic architecture of most human traits. The KGraph was designed for use in gene-centric studies, but can be integrated into association analysis workflows as well. The software is available at

Dynamic Coinfection with Multiple Viral Subtypes in Acute Hepatitis C

Acute hepatitis C virus (HCV) infection is rarely studied, but virus sequence evolution and host-virus dynamics during this early stage may influence the outcome of infection. Hypervariable region 1 (HVR1) is genetically diverse and under selective pressure from the host immune response. We analyzed HVR1 evolution by frequent sampling of an acutely infected HCV cohort.

Randomized Comparison of Whole Brain Radiotherapy, 20 Gy in Four Daily Fractions Versus 40 Gy in 20 Twice-daily Fractions, for Brain Metastases. In Regard to Graham Et Al. (Int J Radiat Oncol Biol Phys 2010;77(3):648-54.)

Comparison of Bivalirudin and Argatroban for the Management of Heparin-induced Thrombocytopenia

To compare the effectiveness of bivalirudin and argatroban in achieving anticoagulation goals and to compare clinical outcomes assessing the safety and efficacy in patients with known or suspected heparin-induced thrombocytopenia (HIT).

2009-2010 National Health Law Moot Court Competition

Human Papillomavirus and Cervical Neoplasia Among Female Sex Workers in Madagascar

Human papillomavirus (HPV) prevalence and type distribution were estimated among 90 female sex workers (FSWs) aged 18 to 58 years in Antananarivo, Madagascar.

A Global Review of Age-specific and Overall Prevalence of Cervical Lesions

Overall and age-specific cervical cytological and histological abnormalities prevalence data across geographical regions, in conjunction with human papillomavirus vaccination status, will be important for the future evaluation of HPV prophylactic vaccine effectiveness.

Is Fatality-free Travel on North Carolina's Streets and Highways Feasible? It's Time to Think the Unthinkable

The persistent downward trajectory in the traffic fatality rate during the past 90 years suggests that fatality-free travel on North Carolina's streets and highways may one day be a reality. Multiple interventions, including raising the driving age to 17 years and banning cell phone use, will help North Carolina achieve this vision.

Bringing the Excitement and Motivation of Research to Students; Using Inquiry and Research-based Learning in a Year-long Biochemistry Laboratory: Part I-guided Inquiry-purification and Characterization of a Fusion Protein: Histidine Tag, Malate Dehydrogenase, and Green Fluorescent Protein

A successful laboratory experience provides the foundation for student success, creating active participation in the learning process. Here, we describe a new approach that emphasizes research, inquiry and problem solving in a year-long biochemistry experience. The first semester centers on the purification, characterization, and analysis of a novel fusion protein within a guided research experience. Throughout the semester, students gradually acquire skills as they are allowed to work independently. A fusion protein, malate dehydrogenase-green fluorescent protein with a histidine affinity tag (MGH), is used throughout the semester. The fusion protein allows for a high throughput analysis and is stable for duration of the semester. Students start with the purification and analysis of the plasmid DNA and end with an enzymatic analysis of MGH. As students take ownership of their experiments and choose two different chromatographic resins, they make many choices throughout the semester. Skills, motivation, confidence levels, and attitudes were assessed before and after the semester. Students achieved high levels of critical biochemical laboratory skills and critical thinking while increasing their confidence and motivation for working in a biochemical research setting.

Bringing the Excitement and Motivation of Research to Students; Using Inquiry and Research-based Learning in a Year-long Biochemistry Laboratory : Part II-research-based Laboratory-a Semester-long Research Approach Using Malate Dehydrogenase As a Research Model

Research-based learning in a teaching environment is an effective way to help bring the excitement and experience of independent bench research to a large number of students. The program described here is the second of a two-semester biochemistry laboratory series. Here, students are empowered to design, execute and analyze their own experiments for the entire semester. This style of laboratory replaces a variety of shorter labs in favor of an in depth research-based learning experience. The concept is to allow students to function in independent research groups. The research projects are focused on a series of wild-type and mutant clones of malate dehydrogenase. A common research theme for the laboratory helps instructors administer the course and is key to delivering a research opportunity to a large number of students. The outcome of this research-based learning laboratory results in students who are much more confident and skilled in critical areas in biochemistry and molecular biology. Students with research experience have significantly higher confidence and motivation than those students without a previous research experience. We have also found that all students performed better in advanced courses and in the workplace.

Enterovirus--a Double Act

This case report describes twins presenting approximately 24 h apart both with enterovirus meningoencephalitis. The presenting symptoms are described along with laboratory results. Both had extremely high white cell counts in cerebrospinal fluid, which were predominantly lymphocytes. Clinical course and outcomes are described. There was a potential delay in diagnosis of the second twin given the pathology of the twin sibling and the symptoms presented.

The Hazards of Honey: Infantile Botulism

Infantile botulism is a rare cause of neuromuscular weakness resulting from ingestion of Clostridium botulinum-an anaerobic Gram-positive bacillus found universally in soil. The only definite food source known to cause infantile botulism is honey; previously, links to formula milk have been postulated but not definitely sourced. We present an interesting case report of a 2-month-old infant with this rare condition, including the diagnostic difficulties that ensued. A brief overview of the condition follows. This is the first case in the UK in which C botulinum was successfully isolated from both the patient and the suspected source-a jar of honey. The importance of food labelling as a public health message is highlighted.

Effect of IL-11 on Glomerular Expression of TGF-beta and Extracellular Matrix in Nephrotoxic Nephritis in Wistar Kyoto Rats

The effect of interleukin-11 (IL-11) on transforming growth factor-ß (TGF-ß) is controversial and has not been examined in renal diseases. In this study, we (i) characterised the up-regulation of TGF-ß1, phospho-p38 MAPK (p-p38 MAPK) and extracellular matrix during pathogenesis of glomerulonephritis and (ii) examined the effect of rhIL-11 on these processes in vivo.

HPV Vaccine Acceptability in Heterosexual, Gay, and Bisexual Men

We know little about men's beliefs about human papillomavirus (HPV) vaccine and willingness to receive it. In January 2009, the authors recruited 296 heterosexual men and 312 gay and bisexual men from a national panel of U.S. households to complete an online survey about HPV and HPV vaccine. The authors analyzed data using logistic regression, controlling for age, education, number of lifetime sexual partners, and urban residence. More gay and bisexual men than heterosexual men were willing to receive HPV vaccine (73% vs. 37%; adjusted odds ratio = 4.99; 95% confidence interval = 3.36, 7.49). Gay and bisexual men reported greater awareness of HPV vaccine, perceived worry about HPV-related diseases, perceived effectiveness of HPV vaccine, and anticipated regret if they declined vaccination and later developed HPV-related disease compared with heterosexual men (all ps < .05). The lower acceptability and different beliefs among heterosexual men suggest that novel interventions for this group may be needed.

Longitudinal Predictors of Human Papillomavirus Vaccine Initiation Among Adolescent Girls in a High-risk Geographic Area

Human papillomavirus (HPV) vaccine uptake is low among adolescent girls in the United States. We sought to identify longitudinal predictors of HPV vaccine initiation in populations at elevated risk for cervical cancer.

Evaluation of Oncogenic Human Papillomavirus RNA and DNA Tests with Liquid-based Cytology in Primary Cervical Cancer Screening: the FASE Study

The APTIMA HPV Assay (AHPV) allows detection of 14 high-risk human papillomavirus (HPV) RNA types in cervical specimens. Until present, the assay has been compared to HPV DNA tests only in triage settings. Herein, we compare AHPV with a DNA assay (Hybrid Capture 2; HC2) and liquid-based cytology (LBC; using PreservCyt ThinPrep liquid Pap) in a screening setting (French APTIMA screening evaluation [FASE] study). Women (N = 5,006) aged 20-65 were screened by gynecologists in 17 private practices in Paris, France. One cervical specimen was collected and tested with LBC, AHPV and HC2 assays. Women were referred to colposcopy if they were ASC-US+ in LBC or HPV positive in either HPV assay. To control for verification bias, a random group (14%) with normal LBC and dually HPV negative tests underwent colposcopy. Data from 4,429 women were analyzed. Sensitivity, specificity and predictive values were calculated for the three tests. AHPV and HC2 were highly sensitive for CIN2+ (92.0% and 96.7%) and CIN3+ (95.7% and 95.3%) detection and much more sensitive than LBC (69.1% for CIN2+ and 73.3% for CIN3+). Specificity of AHPV was higher than that of HC2, but similar to that of LBC (p < 0.001). Combining LBC with either HPV test slightly increased sensitivity but compromised specificity. AHPV assay is both specific and sensitive for the detection of high-grade precancerous lesions and may be considered as an option for routine cervical cancer screening for women over 20 years of age.

Optimising Human Papillomavirus Self-testing for High Risk Women

Human papillomavirus self-tests that can be used at home and returned by mail may increase cervical cancer screening rates. Growing evidence suggests that self-test methods could increase screening for high-risk and hard-to-reach populations. The purpose of this study was to identify which self-test device women prefer and why.

Predicting Spontaneous Clearance of Acute Hepatitis C Virus in a Large Cohort of HIV-1-infected Men

An epidemic of acute hepatitis C virus (HCV) infection in HIV-positive men-who-have-sex-with-men (MSM) is emerging in Europe, Australia and the USA. The aim of this study was to characterise the natural history of primary HCV in this setting and to assess host and viral factors which predict spontaneous clearance.

Young Males' Perspectives on Pregnancy, Fatherhood and Condom Use: Where Does Responsibility for Birth Control Lie?

To improve our understanding of males' role in contraceptive practices, this paper explores the relationship between young males' perspectives on pregnancy and fatherhood and their attitudes, beliefs and practices in relation to condom use and birth control.

Factors Associated with Positive Outcomes in 131 Patients Treated with Gauze-based Negative Pressure Wound Therapy

Negative Pressure Wound Therapy (NPWT) is commonly used in many surgical specialties to improve wound management and healing outcomes. This study reports the ability of gauze-based NPWT to address several treatment goals commonly defined at the onset of therapy. A prospective, multi-center, non-comparative clinical investigation was carried out using gauze-based NPWT in chronic and acute wounds. 131 patients including traumatic, post-surgical and chronic wounds were assessed. Weekly percentage reductions in wound area, depth and volume were 8.3%, 15.8% and 20.5% respectively (p < 0.001). A reduction in exudate level was observed from baseline to treatment discontinuation (p < 0.001). An increase (p = 0.007) in red granulation tissue and a decrease (p < 0.001) in non-viable tissue was observed. Baseline wound characteristics associated with slower rates of progress included chronic wound aetiologies, longer wound duration prior to NPWT and presence of diabetes as a co-morbidity. Important indicators of wounds which had improved sufficiently and no longer required NPWT included reduction in volume and exudate levels. Gauze-based NPWT can be used to address many of the treatment goals commonly defined at the onset of therapy including reduction in wound volume, management of exudate and infection status, and improvement in wound bed quality.

Melanocortin MC₁ Receptor in Human Genetics and Model Systems

The melanocortin MC(1) receptor is a G-protein coupled receptor expressed in the melanocytes of the skin and hair and is known for its key role in the regulation of human pigmentation. Melanocortin MC(1) receptor activation after ultraviolet radiation exposure results in a switch from the red/yellow pheomelanin to the brown/black eumelanin pigment synthesis within cutaneous melanocytes; this pigment is then transferred to the surrounding keratinocytes of the skin. The increase in melanin maturation and uptake results in tanning of the skin, providing a physical protection of skin cells from ultraviolet radiation induced DNA damage. Melanocortin MC(1) receptor polymorphism is widespread within the Caucasian population and some variant alleles are associated with red hair colour, fair skin, poor tanning and increased risk of skin cancer. Here we will discuss the use of mouse coat colour models, human genetic association studies, and in vitro cell culture studies to determine the complex functions of the melanocortin MC(1) receptor and the molecular mechanisms underlying the association between melanocortin MC(1) receptor variant alleles and the red hair colour phenotype. Recent research indicates that melanocortin MC(1) receptor has many non-pigmentary functions, and that the increased risk of skin cancer conferred by melanocortin MC(1) receptor variant alleles is to some extent independent of pigmentation phenotypes. The use of new transgenic mouse models, the study of novel melanocortin MC(1) receptor response genes and the use of more advanced human skin models such as 3D skin reconstruction may provide key elements in understanding the pharmacogenetics of human melanocortin MC(1) receptor polymorphism.

Environment-responsive Transcription Factors Bind Subtelomeric Elements and Regulate Gene Silencing

Subtelomeric chromatin is subject to evolutionarily conserved complex epigenetic regulation and is implicated in numerous aspects of cellular function including formation of heterochromatin, regulation of stress response pathways and control of lifespan. Subtelomeric DNA is characterized by the presence of specific repeated segments that serve to propagate silencing or to protect chromosomal regions from spreading epigenetic control. In this study, analysis of genome-wide chromatin immunoprecipitation and expression data, suggests that several yeast transcription factors regulate subtelomeric silencing in response to various environmental stimuli through conditional association with proto-silencing regions called X elements. In this context, Oaf1p, Rox1p, Gzf1p and Phd1p control the propagation of silencing toward centromeres in response to stimuli affecting stress responses and metabolism, whereas others, including Adr1p, Yap5p and Msn4p, appear to influence boundaries of silencing, regulating telomere-proximal genes in Y' elements. The factors implicated here are known to control adjacent genes at intrachromosomal positions, suggesting their dual functionality. This study reveals a path for the coordination of subtelomeric silencing with cellular environment, and with activities of other cellular processes.

Invasive Squamous Cell Carcinoma and Sorafenib in a Black Patient

Avian Influenza Viruses and Avian Paramyxoviruses in Wintering and Breeding Waterfowl Populations in North Carolina, USA

Although wild ducks are recognized reservoirs for avian influenza viruses (AIVs) and avian paramyxoviruses (APMVs), information related to the prevalence of these viruses in breeding and migratory duck populations on North American wintering grounds is limited. Wintering (n=2,889) and resident breeding (n=524) ducks were sampled in North Carolina during winter 2004-2006 and summer 2005-2006, respectively. Overall prevalence of AIV was 0.8% and restricted to the winter sample; however, prevalence in species within the genus Anas was 1.3% and was highest in Black Ducks (7%; Anas rubripes) and Northern Shovelers (8%; Anas clypeata). Of the 24 AIVs, 16 subtypes were detected, representing nine hemagglutinin and seven neuraminidase subtypes. Avian paramyxoviruses detected in wintering birds included 18 APMV-1s, 15 APMV-4s, and one APMV-6. During summers 2005 and 2006, a high prevalence of APMV-1 infection was observed in resident breeding Wood Ducks (Aix sponsa) and Mallards (Anas platyrhynchos).

Microbial Diversity Associated with Four Functional Groups of Benthic Reef Algae and the Reef-building Coral Montastraea Annularis

The coral reef benthos is primarily colonized by corals and algae, which are often in direct competition with one another for space. Numerous studies have shown that coral-associated Bacteria are different from the surrounding seawater and are at least partially species specific (i.e. the same bacterial species on the same coral species). Here we extend these microbial studies to four of the major ecological functional groups of algae found on coral reefs: upright and encrusting calcifying algae, fleshy algae, and turf algae, and compare the results to the communities found on the reef-building coral Montastraea annularis. It was found using 16S rDNA tag pyrosequencing that the different algal genera harbour characteristic bacterial communities, and these communities were generally more diverse than those found on corals. While the majority of coral-associated Bacteria were related to known heterotrophs, primarily consuming carbon-rich coral mucus, algal-associated communities harboured a high percentage of autotrophs. The majority of algal-associated autotrophic Bacteria were Cyanobacteria and may be important for nitrogen cycling on the algae. There was also a rich diversity of photosynthetic eukaryotes associated with the algae, including protists, diatoms, and other groups of microalgae. Together, these observations support the hypothesis that coral reefs are a vast landscape of distinctive microbial communities and extend the holobiont concept to benthic algae.

RGD: a Comparative Genomics Platform

The Rat Genome Database (RGD) ( provides a comprehensive platform for comparative genomics and genetics research. RGD houses gene, QTL and polymorphic marker data for rat, mouse and human and provides easy access to data through sophisticated searches, disease portals, interactive pathway diagrams and rat and human genome browsers.

Aerosol Vaccination Induces Robust Protective Immunity to Homologous and Heterologous Influenza Infection in Mice

Live-attenuated influenza vaccine (LAIV) delivered by large droplet intranasal spray is efficacious against infection. However, many of the large droplets are trapped in the external nares and do not reach the target nasal airway tissues. Smaller droplets might provide better distribution yielding similar protection with lower doses. We evaluated 20 and 30 μm aerosol delivery of influenza virus in mice. A 15s aerosol exposure optimally protected against homologous and heterologous influenza infection and induced a robust immune response. These results demonstrate the feasibility of nasal vaccination using aerosolized particles, providing a strategy to improve vaccine efficacy and delivery.

The Rat Genome Database Curation Tool Suite: a Set of Optimized Software Tools Enabling Efficient Acquisition, Organization, and Presentation of Biological Data

The Rat Genome Database (RGD) is the premier repository of rat genomic and genetic data and currently houses over 40,000 rat gene records as well as human and mouse orthologs, 1771 rat and 1911 human quantitative trait loci (QTLs) and 2209 rat strains. Biological information curated for these data objects includes disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components. A suite of tools has been developed to aid curators in acquiring and validating data objects, assigning nomenclature, attaching biological information to objects and making connections among data types. The software used to assign nomenclature, to create and edit objects and to make annotations to the data objects has been specifically designed to make the curation process as fast and efficient as possible. The user interfaces have been adapted to the work routines of the curators, creating a suite of tools that is intuitive and powerful. Database URL:

Ambulatory Intravenous Ceftriaxone in Paediatric A&E: a Useful Alternative to Hospital Admission?

Treatment of children with intravenous ceftriaxone on an ambulatory basis is described. This allows a child to remain at home, but also be reviewed regularly when attending the Emergency Department for antibiotics.

Decreased Circulation in the Feline Choriocapillaris Underlying Retinal Photocoagulation Lesions

To investigate the effects of argon laser photocoagulation on the choroidal circulation in cats.

Spatial Modelling of Soil-transmitted Helminth Infections in Kenya: a Disease Control Planning Tool

Implementation of control of parasitic diseases requires accurate, contemporary maps that provide intervention recommendations at policy-relevant spatial scales. To guide control of soil transmitted helminths (STHs), maps are required of the combined prevalence of infection, indicating where this prevalence exceeds an intervention threshold of 20%. Here we present a new approach for mapping the observed prevalence of STHs, using the example of Kenya in 2009.

Human Papillomavirus Vaccine and Behavioural Disinhibition

We sought to identify characteristics of parents who believe in sexual disinhibition and that Pap smears can safely be stopped after females receive the human papillomavirus (HPV) vaccine.

Lack of Association of Herpes Simplex Virus Type 2 Seropositivity with the Progression of HIV Infection in the HERS Cohort

Many studies have chronicled the "epidemiologic synergy" between human immunodeficiency virus (HIV) and herpes simplex virus type 2 (HSV-2). HIV adversely affects the natural history of HSV-2 and results in more frequent and severe HSV-2 reactivation. Few longitudinal studies, however, have examined whether HSV-2 is associated with increased HIV plasma viral loads or decreased CD4 counts. The authors estimated the effect of HSV-2 seropositivity on HIV RNA viral load and on CD4 count over time among 777 HIV-seropositive US women not receiving suppressive HSV-2 therapy in the HIV Epidemiology Research Study (1993-2000). Linear mixed models were used to assess the effect of HSV-2 on log HIV viral load and CD4 count/mm(3) prior to widespread initiation of highly active antiretroviral therapy. Coinfection with HSV-2 was not associated with HIV RNA plasma viral loads during study follow-up. There was a statistically significant association between HSV-2 seropositivity and CD4 count over time, but this difference was small and counterintuitive at an increase of 8 cells/mm(3) (95% confidence interval: 2, 14) per year among HSV-2-seropositive women compared with HSV-2-seronegative women. These data do not support a clinically meaningful effect of baseline HSV-2 seropositivity on the trajectories of HIV plasma viral loads or CD4 counts.

Assessment of Gauze-based Negative Pressure Wound Therapy in the Split-thickness Skin Graft Clinical Pathway-an Observational Study

Objectives: Negative pressure wound therapy (NPWT) is a useful therapy in the preparation of wounds prior to application of a split-thickness skin graft (STSG) both "pregraft" and "postgraft" on top of the STSG. Customarily, a foam-based NPWT has been used, but gauze-based therapy is finding an increasing use. Gauze is easy to apply and forgiving of complicated wound geometries so it can be an ideal material in this indication. The aim of this study was to quantitatively assess the clinical efficacy of gauze-based NPWT as an adjunctive therapy to STSG procedures. Methods: A prospective, noncomparative, multicenter evaluation was carried out to assess the performance of gauze-based NPWT. Twenty-one patients had NPWT applied prior to definitive closure by STSG or flap techniques (pregraft group). A further 21 patients underwent an STSG procedure and had gauze-based NPWT placed immediately on top of the STSG (postgraft group). Negative pressure was applied at -80 mm Hg. Results: In the pregraft group, NPWT was used for a median of 12 days. Improvement in quality of wound bed with decreased nonviable tissue (from 20% to 0% median wound area) and increased granulation tissue (from 20% to 90% median wound area) was observed. In the postgraft group, median duration of therapy was 5 days at which point median percentage skin graft-take was 96%. Conclusions: Gauze-based NPWT appears to be an effective addition to the care and management of wounds intended for definitive closure by STSG.

Gender Specific Differences in the Immune Response to Infection

There are many instances where males and females differ in the susceptibility to infections. The reason for these differences in susceptibility is multifactorial. The primary cause is thought to be due to differences induced by sex hormones and their effects on gene expression as well as the immune system, but may also be due to innate physiological differences between males and females. This review summarizes gender specific differences seen in infections caused by bacteria, fungi, parasites and viruses. Ultimately, gender specific differences appear to be dependent on the microbe causing the infection, as not every infection with a specific microbial type results in increased susceptibility of one gender over the other. This suggests that there is an interaction between gender specific immune differences and the specific immune response to individual microbes.

Aerosol Inoculation with a Sub-lethal Influenza Virus Leads to Exacerbated Morbidity and Pulmonary Disease Pathogenesis

A mouse model has been extensively used to investigate disease intervention approaches and correlates of immunity following influenza virus infection. The majority of studies examining cross-reactive and protective immune responses have used intranasal (IN) virus inoculation; however, infectious aerosols are a common means of transmitting influenza in the human population. In this study, IN and aerosol routes of inoculation were compared and end-points of immunity and disease pathogenesis were evaluated in mice using mouse-adapted H3N2 A/Aichi/2/68 (x31). Aerosol inoculation with sub-lethal x31 levels caused more robust infection, which was characterized by enhanced morbidity, mortality, pulmonary cell infiltration, and inflammation, compared to IN-inoculated mice, as well as higher levels of IL-6 expression in the lung. Treatment with IL-6-blocking antibodies reduced pulmonary infiltrates and lung pathology in aerosol-inoculated mice. This study shows that aerosol inoculation results in a distinctive host response and disease outcome compared to IN inoculation, and suggests a possible role for IL-6 in lung pathogenesis.

Evaluation of Therapeutic Anticoagulation with Enoxaparin and Associated Anti-Xa Monitoring in Patients with Morbid Obesity: a Case Series

Our purpose was to describe anti-Xa levels, dosage requirements, and complications associated with enoxaparin treatment doses in patients with morbid obesity. Inpatients with a BMI >40 kg/m(2) at an academic medical center prescribed therapeutic enoxaparin from 2004 to 2010 who also had an associated anti-Xa level were included in this retrospective evaluation. Twenty-six patients were identified having median weight of 162 kg (range 106-243), median BMI of 49.5 kg/m(2) (range 40.1-98.1), and median enoxaparin duration of 4 days (range 1-32). Venous thromboembolism was the most common reason for anticoagulation (n = 19, 73%). The median starting dose was 0.8 mg/kg actual body weight (range 0.51-1; absolute dose 80-150 mg) every 12 h. Twelve patients (46%) achieved a goal anti-Xa level, 10 (38%) were above goal and 4 (15%) were uninterpretable. Among the 10 patients with anti-Xa levels above goal, the median initial dose was 0.85 mg/kg (range 0.75-1) versus 0.74 mg/kg (range 0.51-1) for patients at goal with similar median peak serum creatinine (PSCr) values between these two groups (P > 0.05). No bleeding events occurred in patients achieving goal anticoagulation versus 4/10 (40%) with high anti-Xa levels (P = 0.033) with similar median PSCr between these groups. No thrombotic events occurred while on therapy. The majority in this cohort with morbid obesity achieved anti-Xa levels at or above goal at doses less than the recommended 1 mg/kg every 12 h. Bleeding events were more frequent among patients with anti-Xa levels above goal, despite similar PSCr values.

The Rat Genome Database Pathway Portal

The set of interacting molecules collectively referred to as a pathway or network represents a fundamental structural unit, the building block of the larger, highly integrated networks of biological systems. The scientific community's interest in understanding the fine details of how pathways work, communicate with each other and synergize, and how alterations in one or several pathways may converge into a disease phenotype, places heightened demands on pathway data and information providers. To meet such demands, the Rat Genome Database [(RGD)] has adopted a multitiered approach to pathway data acquisition and presentation. Resources and tools are continuously added or expanded to offer more comprehensive pathway data sets as well as enhanced pathway data manipulation, exploration and visualization capabilities. At RGD, users can easily identify genes in pathways, see how pathways relate to each other and visualize pathways in a dynamic and integrated manner. They can access these and other components from several entry points and effortlessly navigate between them and they can download the data of interest. The Pathway Portal resources at RGD are presented, and future directions are discussed. Database URL:

Potential Impact of Antiretroviral Therapy and Screening on Cervical Cancer Mortality in HIV-positive Women in Sub-Saharan Africa: a Simulation

Despite having high cervical cancer incidence and mortality rates, screening for cervical precancerous lesions remains infrequent in sub-Saharan Africa. The need to screen HIV-positive women because of the higher prevalence and faster progression of cervical precancerous lesions may be heightened by the increased access to highly-active antiretroviral therapy (HAART). Policymakers need quantitative data on the effect of HAART and screening to better allocate limited resources. Our aim was to quantify the potential effect of these interventions on cervical cancer mortality.

Cross-clamping During Elective Abdominal Aortic Aneurysm Surgery: a Template for Two Simulation Case Scenarios

Trafficking-deficient HERG K⁺ Channels Linked to Long QT Syndrome Are Regulated by a Microtubule-dependent Quality Control Compartment in the ER

The human ether-a-go-go related gene (hERG) encodes the voltage-gated K(+) channel that underlies the rapidly activating delayed-rectifier current in cardiac myocytes. hERG is synthesized in the endoplasmic reticulum (ER) as an "immature" N-linked glycoprotein and is terminally glycosylated in the Golgi apparatus. Most hERG missense mutations linked to long QT syndrome type 2 (LQT2) reduce the terminal glycosylation and functional expression. We tested the hypothesis that a distinct pre-Golgi compartment negatively regulates the trafficking of some LQT2 mutations to the Golgi apparatus. We found that treating cells in nocodazole, a microtubule depolymerizing agent, altered the subcellular localization, functional expression, and glycosylation of the LQT2 mutation G601S-hERG differently from wild-type hERG (WT-hERG). G601S-hERG quickly redistributed to peripheral compartments that partially colocalized with KDEL (Lys-Asp-Glu-Leu) chaperones but not calnexin, Sec31, or the ER golgi intermediate compartment (ERGIC). Treating cells in E-4031, a drug that increases the functional expression of G601S-hERG, prevented the accumulation of G601S-hERG to the peripheral compartments and increased G601S-hERG colocalization with the ERGIC. Coexpressing the temperature-sensitive mutant G protein from vesicular stomatitis virus, a mutant N-linked glycoprotein that is retained in the ER, showed it was not restricted to the same peripheral compartments as G601S-hERG at nonpermissive temperatures. We conclude that the trafficking of G601S-hERG is negatively regulated by a microtubule-dependent compartment within the ER. Identifying mechanisms that prevent the sorting or promote the release of LQT2 channels from this compartment may represent a novel therapeutic strategy for LQT2.

Treatment with a Cyclin-dependent Kinase Inhibitor, Seliciclib, is Effective in Reducing Glomerular Macrophage Numbers and the Severity of Established Experimental Glomerulonephritis

The cyclin-dependent kinase inhibitor, seliciclib (R-roscovitine, CYC202), has anti-proliferative activity through its inhibition of cyclin-dependent kinase 2. We hypothesized that treatment with seliciclib would reduce glomerular macrophage numbers and glomerular crescent formation in experimental crescentic glomerulonephritis even when treatment is started after onset of disease.

Parent Attitudes About School Requirements for Human Papillomavirus Vaccine in High-risk Communities of Los Angeles, California

Human papillomavirus (HPV) immunization requirements for school entry could increase HPV vaccine uptake but are controversial. This study assessed parents' attitudes about HPV immunization requirements.

Pharmacists' Guide to Infant Formulas for Term Infants

To provide pharmacists with the basic knowledge to counsel caregivers in appropriate infant formula selection and use.

The Brd4 Extraterminal Domain Confers Transcription Activation Independent of PTEFb by Recruiting Multiple Proteins, Including NSD3

Bromodomain protein 4 (Brd4) plays critical roles in development, cancer progression, and virus-host pathogenesis. To gain mechanistic insight into the various biological functions of Brd4, we performed a proteomic analysis to identify and characterize Brd4-associated cellular proteins. We found that the extraterminal (ET) domain, whose function has to date not been determined, interacts with NSD3, JMJD6, CHD4, GLTSCR1, and ATAD5. These ET-domain interactions were also conserved for Brd2 and Brd3, the other human BET proteins tested. We demonstrated that GLTSCR1, NSD3, and JMJD6 impart a pTEFb-independent transcriptional activation function on Brd4. NSD3 as well as JMJD6 is recruited to regulated genes in a Brd4-dependent manner. Moreover, we found that depletion of Brd4 or NSD3 reduces H3K36 methylation, demonstrating that the Brd4/NSD3 complex regulates this specific histone modification. Our results indicate that the Brd4 ET domain through the recruitment of the specific effectors regulates transcriptional activity. In particular, we show that one of these effectors, NSD3, regulates transcription by modifying the chromatin microenvironment at Brd4 target genes. Our study thus identifies the ET domain as a second important transcriptional regulatory domain for Brd4 in addition to the carboxyl-terminal domain (CTD) that interacts with pTEFb.

Age-specific Prevalence of Human Papillomavirus Infection in Males: a Global Review

Global data on age-specific prevalence of human papillomavirus (HPV) infection in males, especially for oncogenic HPV types 16 and 18, are essential for future efforts to prevent HPV-related diseases, including expanded access to HPV prophylactic vaccines for boys and young men.

Comparative Pathology in Ferrets Infected with H1N1 Influenza A Viruses Isolated from Different Hosts

Virus replication and pulmonary disease pathogenesis in ferrets following intranasal infection with a pandemic influenza virus strain (A/California/4/09 [CA09]), a human seasonal influenza H1N1 virus isolate (A/New Caledonia/20/99 [Ncal99]), a classical swine influenza H1N1 virus isolate (A/Swine/Iowa/15/30 [Sw30]), or an avian H1N1 virus isolate (A/Mallard/MN/A108-2355/08 [Mal08]) were compared. Nasal wash virus titers were similar for Ncal99 and Sw30, with peak virus titers of 10(5.1) 50% tissue culture infectious doses (TCID(50))/ml and 10(5.5) TCID(50)/ml occurring at day 3 postinfection (p.i.), respectively. The mean peak titer for CA09 also occurred at day 3 p.i. but was higher (10(7) TCID(50)/ml). In contrast, the peak virus titers (10(3.6) to 10(4.3) TCID(50)/ml) for Mal08 were delayed, occurring between days 5 and 7 p.i. Disease pathogenesis was characterized by microscopic lesions in the nasal turbinates and lungs of all ferrets; however, Sw30 infection was associated with severe bronchointerstitial pneumonia. The results demonstrate that although CA09 is highly transmissible in the human population and replicates well in the ferret model, it causes modest disease compared to other H1N1 viruses, particularly Sw30 infection.

Prolonged Toxicity After Amitriptyline Overdose in a Patient Deficient in CYP2D6 Activity

Amitriptyline and its metabolite, nortriptyline, are metabolized, in part, by CYP2D6, a polymorphic enzyme. About 8% of Caucasians are deficient in CYP2D6 activity.

Scalpel Reduction of Giant Nasal Folliculosebaceous Hamartoma and Reconstruction Using Porcine Xenograft

Unique Scorpion Toxin with a Putative Ancestral Fold Provides Insight into Evolution of the Inhibitor Cystine Knot Motif

The three-disulfide inhibitor cystine knot (ICK) motif is a fold common to venom peptides from spiders, scorpions, and aquatic cone snails. Over a decade ago it was proposed that the ICK motif is an elaboration of an ancestral two-disulfide fold coined the disulfide-directed β-hairpin (DDH). Here we report the isolation, characterization, and structure of a novel toxin [U(1)-liotoxin-Lw1a (U(1)-LITX-Lw1a)] from the venom of the scorpion Liocheles waigiensis that is the first example of a native peptide that adopts the DDH fold. U(1)-LITX-Lw1a not only represents the discovery of a missing link in venom protein evolution, it is the first member of a fourth structural fold to be adopted by scorpion-venom peptides. Additionally, we show that U(1)-LITX-Lw1a has potent insecticidal activity across a broad range of insect pest species, thereby providing a unique structural scaffold for bioinsecticide development.

Bacterial Vaginosis As a Risk Factor for High-grade Cervical Lesions and Cancer in HIV-seropositive Women

To assess the effect of bacterial vaginosis (BV) on the risk of high-grade squamous intraepithelial lesions (HSIL) among HIV-seropositive women.

Subcutaneous Sarcoidosis in a Melanoma Scar

Cutaneous sarcoidosis often has been referred to. as the great imitator because skin lesions can present with various morphologies. Skin lesions may be the only site of involvement or may accompany systemic disease. Occasionally, sarcoidosis also may infiltrate scars from prior trauma, tattoos, or surgery. We report a case of subcutaneous sarcoidosis limited to a melanoma scar without any other cutaneous or systemic involvement. Familiarity with and proper diagnosis of cutaneous sarcoidosis can allow for appropriate systemic screening and timely management of the disease.

Mapping the Global Distribution of Trachoma: Why an Updated Atlas is Needed

Nutrient Co-limitation of Primary Producer Communities

Synergistic interactions between multiple limiting resources are common, highlighting the importance of co-limitation as a constraint on primary production. Our concept of resource limitation has shifted over the past two decades from an earlier paradigm of single-resource limitation towards concepts of co-limitation by multiple resources, which are predicted by various theories. Herein, we summarise multiple-resource limitation responses in plant communities using a dataset of 641 studies that applied factorial addition of nitrogen (N) and phosphorus (P) in freshwater, marine and terrestrial systems. We found that more than half of the studies displayed some type of synergistic response to N and P addition. We found support for strict definitions of co-limitation in 28% of the studies: i.e. community biomass responded to only combined N and P addition, or to both N and P when added separately. Our results highlight the importance of interactions between N and P in regulating primary producer community biomass and point to the need for future studies that address the multiple mechanisms that could lead to different types of co-limitation.

The Natural History of Early Hepatitis C Virus Evolution; Lessons from a Global Outbreak in Human Immunodeficiency Virus-1-infected Individuals

New insights into the early viral evolution and cellular immune response during acute hepatitis C virus (HCV) infection are being gained following a global outbreak in human immunodeficiency virus-1 (HIV)-positive men who have sex with men. Cross-sectional and longitudinal sequence analysis at both the population and individual level have facilitated tracking of the HCV epidemic across the world and enabled the development of tests of viral diversity in individual patients in order to predict spontaneous clearance of HCV and response to treatment. Immunological studies in HIV-positive cohorts have highlighted the role of the CD4+ T-cell response in the control of early HCV infection and will increase the opportunity for the identification of protective epitopes that could be used in future vaccine development.

The Occurrence of Antibodies to Heparin-platelet Factor 4 in Cardiac and Thoracic Surgical Patients Receiving Desirudin or Heparin for Postoperative Venous Thrombosis Prophylaxis

This randomized, exploratory study compared the incidence of heparin-dependent antibodies associated with subcutaneous (SC) desirudin or heparin given for deep-vein thrombosis prophylaxis following cardiac and thoracic surgery.

Prevention of Influenza Virus Shedding and Protection from Lethal H1N1 Challenge Using a Consensus 2009 H1N1 HA and NA Adenovirus Vector Vaccine

Vaccines against emerging pathogens such as the 2009 H1N1 pandemic virus can benefit from current technologies such as rapid genomic sequencing to construct the most biologically relevant vaccine. A novel platform (Ad5 [E1-, E2b-]) has been utilized to induce immune responses to various antigenic targets. We employed this vector platform to express hemagglutinin (HA) and neuraminidase (NA) genes from 2009 H1N1 pandemic viruses. Inserts were consensuses sequences designed from viral isolate sequences and the vaccine was rapidly constructed and produced. Vaccination induced H1N1 immune responses in mice, which afforded protection from lethal virus challenge. In ferrets, vaccination protected from disease development and significantly reduced viral titers in nasal washes. H1N1 cell mediated immunity as well as antibody induction correlated with the prevention of disease symptoms and reduction of virus replication. The Ad5 [E1-, E2b-] should be evaluated for the rapid development of effective vaccines against infectious diseases.

Statistical Analysis of Dynamic Transcriptional Regulatory Network Structure

Here, we present a detailed method for generating a dynamic transcriptional regulatory network from large-scale chromatin immunoprecipitation data, and functional analysis of participating factors through the identification and characterization of significantly overrepresented multi-input motifs in the network. This is done by visualizing interactive data using a network analysis tool, such as Cytoscape, clustering DNA targets of the transcription factors based on their network topologies, and statistically analyzing each cluster based on its size and properties of its members. These analyses yield testable predictions about the conditional and cooperative functions of the factors. This is a versatile approach that allows the visualization of network architecture on a genome-wide level and is applicable to understanding combinatorial control mechanisms of DNA-binding regulators that conditionally cooperate in a wide variety of biological models.

Desirudin: a Review of the Pharmacology and Clinical Application for the Prevention of Deep Vein Thrombosis

Direct thrombin inhibitors (DTIs) are an emerging class of anticoagulants in routine clinical practice, although they have been under investigation for quite some time. Desirudin (Iprivask®, Canyon Pharmaceuticals™) is a recombinant hirudin derivative that directly inhibits free and fibrin-bound thrombin. Desirudin was the first DTI approved for deep vein thrombosis (DVT) prophylaxis in Europe (Revasc®) and is the newest injectable DTI commercially available in the USA. Desirudin is one of the few nonheparin subcutaneous drugs that has demonstrable efficacy for DVT prophylaxis. Subcutaneous desirudin has been shown to be more effective than both subcutaneous unfractionated heparin and enoxaparin, with comparable bleeding rates in the prevention of DVT in patients undergoing elective hip replacement. Desirudin also offers the advantage of a fixed dosing regimen while being less immunogenic than unfractionated heparin. However, owing to its pharmacokinetic properties, patients with renal dysfunction require dosing modifications. The favorable profile shown with desirudin thus far will allow its clinical use to grow and will promote further investigation into broadening its clinical applications.

Gradient Porous Materials by Emulsion Centrifugation

Oil-in-water emulsions are centrifuged to generate a gradient distribution of emulsion droplets. This structure is locked by freezing or polymerization and the subsequent removal of the solvents produces gradient porous materials.

Effect of a Postviolation Driver Improvement Class on Traffic Convictions and Crashes

To investigate the effect of a driver improvement class on postclass moving traffic violations and crashes among drivers charged with speeding.

Rapid, Non-invasive Imaging of Alphaviral Brain Infection: Reducing Animal Numbers and Morbidity to Identify Efficacy of Potential Vaccines and Antivirals

Rapid and accurate identification of disease progression are key factors in testing novel vaccines and antivirals against encephalitic alphaviruses. Typical efficacy studies utilize a large number of animals and severe morbidity or mortality as an endpoint. New technologies provide a means to reduce and refine the animal use as proposed in Hume's 3Rs (replacement, reduction, refinement) described by Russel and Burch. In vivo imaging systems (IVIS) and bioluminescent enzyme technologies accomplish the reduction of animal requirements while shortening the experimental time and improving the accuracy in localizing active virus replication. In the case of murine models of viral encephalitis in which central nervous system (CNS) viral invasion occurs rapidly but the disease development is relatively slow, we visualized the initial brain infection and enhance the data collection process required for efficacy studies on antivirals or vaccines that are aimed at preventing brain infection. Accordingly, we infected mice through intranasal inoculation with the genetically modified pathogen, Venezuelan equine encephalitis, which expresses a luciferase gene. In this study, we were able to identify the invasion of the CNS at least 3 days before any clinical signs of disease, allowing for reduction of animal morbidity providing a humane means of disease and vaccine research while obtaining scientific data accurately and more rapidly. Based on our data from the imaging model, we confirmed the usefulness of this technology in preclinical research by demonstrating the efficacy of Ampligen, a TLR-3 agonist, in preventing CNS invasion.

Acceptability of School Requirements for Human Papillomavirus Vaccine

We characterized parental attitudes regarding school HPV vaccination requirements for adolescent girls. Study participants were 866 parents of 10–18 y-old girls in areas of North Carolina with elevated cervical cancer incidence. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression. Approximately half (47%) of parents agreed that laws requiring HPV immunization for school attendance "are a good idea" when opt-out provisions were not mentioned. Far more agreed that "these laws are okay only if parents can opt out if they want to" (84%). Predictors of supporting requirements included believing HPV vaccine is highly effective against cervical cancer (OR = 2.5, 95% CI:1.7–.0) or is more beneficial if provided at an earlier age (OR = 16.1, 95% CI:8.4–1.0). Parents were less likely to agree with vaccine requirements being a good idea if they expressed concerns related to HPV vaccine safety (OR = 0.3, 95% CI:0.1–.5), its recent introduction (OR = 0.3, 95% CI:0.2–.6). Parental acceptance of school requirements appears to depend on perceived HPV vaccine safety and efficacy, understanding of the optimal age for vaccine administration, and inclusion of opt-out provisions.

Evaluation of Pneumococcal Vaccination Rates After Vaccine Protocol Changes and Nurse Education in a Tertiary Care Teaching Hospital

Pneumococcal vaccination in eligible patients is recommended by the Infectious Disease Society of America and the Centers for Disease Control (CDC) Advisory Committee on Immunization Practices. Because hospitalization provides an opportunity to vaccinate patients at high risk for developing serious pneumonia complications, eligibility screening and administration of the pneumococcal vaccine prior to discharge in qualified patients are evaluated by the Joint Commission and the Centers for Medicare Medicaid Services (CMS) as part of pneumococcal vaccination core quality measures. Among patients with an inpatient diagnosis of pneumonia in 2008, 56% in our 580-bed tertiary care teaching hospital, compared with 84% nationwide, received pneumococcal vaccination. To improve pneumococcal vaccination rates for all patients in the study facility and not just those with pneumonia, a multifaceted intervention including a revised nurse screening tool, rescheduling of the vaccine order, storage of the vaccine in automated dispensing cabinets on the nursing unit, and creation of a vaccine tracking system was developed and implemented between August 2009 and October 2009.

Distribution of HPV Genotypes in Cervical Intraepithelial Lesions and Cervical Cancer in Tanzanian Women

Infection with human papillomavirus (HPV) is associated with uterine cervical intraepithelial neoplasia (CIN) and invasive cancers (ICC). Approximately 80% of ICC cases are diagnosed in under-developed countries. Vaccine development relies on knowledge of HPV genotypes characteristic of LSIL, HSIL and cancer; however, these genotypes remain poorly characterized in many African countries. To contribute to the characterization of HPV genotypes in Northeastern Tanzania, we recruited 215 women from the Reproductive Health Clinic at Kilimanjaro Christian Medical Centre. Cervical scrapes and biopsies were obtained for cytology and HPV DNA detection.

Effects of Coral Reef Benthic Primary Producers on Dissolved Organic Carbon and Microbial Activity

Benthic primary producers in marine ecosystems may significantly alter biogeochemical cycling and microbial processes in their surrounding environment. To examine these interactions, we studied dissolved organic matter release by dominant benthic taxa and subsequent microbial remineralization in the lagoonal reefs of Moorea, French Polynesia. Rates of photosynthesis, respiration, and dissolved organic carbon (DOC) release were assessed for several common benthic reef organisms from the backreef habitat. We assessed microbial community response to dissolved exudates of each benthic producer by measuring bacterioplankton growth, respiration, and DOC drawdown in two-day dark dilution culture incubations. Experiments were conducted for six benthic producers: three species of macroalgae (each representing a different algal phylum: Turbinaria ornata--Ochrophyta; Amansia rhodantha--Rhodophyta; Halimeda opuntia--Chlorophyta), a mixed assemblage of turf algae, a species of crustose coralline algae (Hydrolithon reinboldii) and a dominant hermatypic coral (Porites lobata). Our results show that all five types of algae, but not the coral, exuded significant amounts of labile DOC into their surrounding environment. In general, primary producers with the highest rates of photosynthesis released the most DOC and yielded the greatest bacterioplankton growth; turf algae produced nearly twice as much DOC per unit surface area than the other benthic producers (14.0±2.8 µmol h⁻¹ dm⁻²), stimulating rapid bacterioplankton growth (0.044±0.002 log10 cells h⁻¹) and concomitant oxygen drawdown (0.16±0.05 µmol L⁻¹ h⁻¹ dm⁻²). Our results demonstrate that benthic reef algae can release a significant fraction of their photosynthetically-fixed carbon as DOC, these release rates vary by species, and this DOC is available to and consumed by reef associated microbes. These data provide compelling evidence that benthic primary producers differentially influence reef microbial dynamics and biogeochemical parameters (i.e., DOC and oxygen availability, bacterial abundance and metabolism) in coral reef communities.

Are All Level I Trauma Centers Created Equal? A Comparison of American College of Surgeons and State-verified Centers

Scant literature investigates potential outcome differences between Level I trauma centers. We compared overall survival and survival after acute respiratory distress syndrome (ARDS) in patients admitted to American College of Surgeons (ACS)-verified versus state-verified Level I trauma centers. Using the National Trauma Data Bank Version 7.0, incident codes associated with admission to an ACS-verified facility were extracted and compared with the group admitted to state-verified centers. Overall, there were 382,801 (73.7%) patients admitted to ACS and 136,601 (26.3%) admitted to state centers. There was no adjusted survival advantage after admission to either type (4.9% for ACS vs 4.8% for state centers; 1.014 [95% CI, 0.987 to 1.042], P = 0.311). However, in the 3,088 cases of ARDS, mortality for admission to the ACS centers was 20.3 per cent (451 of 2,220) versus 27.1 per cent (235 of 868) for state centers. Adjusting for injury severity and facility size, admission to an ACS center was associated with a significantly greater survival after ARDS (0.75 [0.654 to 0.860]; P < 0.001). Level I verification does not necessarily imply similar outcomes in all subgroups. Federal oversight may become necessary to ensure uniformity of care, maximizing outcomes across all United States trauma systems. Further study is needed.

High-frequency Dynamics of Ocean PH: a Multi-ecosystem Comparison

The effect of Ocean Acidification (OA) on marine biota is quasi-predictable at best. While perturbation studies, in the form of incubations under elevated pCO(2), reveal sensitivities and responses of individual species, one missing link in the OA story results from a chronic lack of pH data specific to a given species' natural habitat. Here, we present a compilation of continuous, high-resolution time series of upper ocean pH, collected using autonomous sensors, over a variety of ecosystems ranging from polar to tropical, open-ocean to coastal, kelp forest to coral reef. These observations reveal a continuum of month-long pH variability with standard deviations from 0.004 to 0.277 and ranges spanning 0.024 to 1.430 pH units. The nature of the observed variability was also highly site-dependent, with characteristic diel, semi-diurnal, and stochastic patterns of varying amplitudes. These biome-specific pH signatures disclose current levels of exposure to both high and low dissolved CO(2), often demonstrating that resident organisms are already experiencing pH regimes that are not predicted until 2100. Our data provide a first step toward crystallizing the biophysical link between environmental history of pH exposure and physiological resilience of marine organisms to fluctuations in seawater CO(2). Knowledge of this spatial and temporal variation in seawater chemistry allows us to improve the design of OA experiments: we can test organisms with a priori expectations of their tolerance guardrails, based on their natural range of exposure. Such hypothesis-testing will provide a deeper understanding of the effects of OA. Both intuitively simple to understand and powerfully informative, these and similar comparative time series can help guide management efforts to identify areas of marine habitat that can serve as refugia to acidification as well as areas that are particularly vulnerable to future ocean change.

Sex, Condoms and Sexually Transmissible Infections: a Qualitative Study of Sexual Health in Young Australian Men

Young males have a key role in shaping contraceptive use in a sexual relationship, yet often remain the invisible partner in safe sex promotion. This article describes a conceptual model of STI risk and condom use based on the perceptions and experiences of condom use in a group of young Australian males. An explorative descriptive design was used to conceptualize participants' condom use histories into an organized description of behavior. Forty-two semi-structured interviews were conducted with a purposive sample of males aged 15 to 25 years over an 18 month period. A sequential analytical process of data immersion, coding, and category generation was used to identify personal meanings, motivations, and contextual factors associated with condom use and non-use. Three primary discourses associated with young males' perceptions of STI risk and responding approach to condom use constructed personal commitment to sexual safety as dynamic, context-dependent, and outcome-driven (pregnancy versus STIs as the primary motivator of condom use). A regretful discourse associated with experiences of, or suspected unwanted outcomes, also emerged through changes in risk appraisals and safe sex intentions and behavior. Interventions to increase condom use should go beyond the traditional focus on risky behavior and disease prevention frameworks by addressing the contextual influences on personal risk appraisals and deliver innovative messages to reduce negative social meanings associated with condom use.

Male Circumcision is Associated with a Lower Prevalence of Human Papillomavirus-associated Penile Lesions Among Kenyan Men

Human papillomavirus (HPV)-associated penile lesions in men may increase the risk of HPV transmission to their female partners. Risk factor data on HPV-associated penile lesions are needed from regions with a high burden of cervical cancer. Visual inspection of the penis was conducted using a colposcope at the 24-month visit among participants in a randomized controlled trial of male circumcision in Kenya, from May 2006 to October 2007. All photos were read independently by two observers for quality control. Penile exfoliated cells sampled from the glans/coronal sulcus and the shaft were tested for HPV DNA using GP5+/6+ PCR and for HPV16, 18 and 31 viral loads using a real time PCR assay. Of 275 men, 151 were circumcised and 124 uncircumcised. The median age was 22 years. Circumcised men had a lower prevalence of flat penile lesions (0.7%) versus uncircumcised (26.0%); adjusted odds ratio (OR) = 0.02; 95% confidence interval (CI) = 0.003-0.1. Compared to men who were HPV negative, men who were HPV DNA positive (OR = 6.5; 95% CI = 2.4-17.5) or who had high HPV16/18/31 viral load (OR = 5.2; 95% CI = 1.1-24.4) had higher odds of flat penile lesions. Among men with flat penile lesions, HPV56 (29.0%) and 16 (25.8%) were the most common types within single or multiple infections. Flat penile lesions are much more frequent in uncircumcised men and associated with higher prevalence of HPV and higher viral loads. This study suggests that circumcision reduces the prevalence of HPV-associated flat lesions and may ultimately reduce male-to-female HPV transmission.

Metabotropic Glutamate Receptor-1: a Potential Therapeutic Target for the Treatment of Breast Cancer

Metabotropic glutamate receptors are G-protein-coupled receptors normally expressed in the central nervous system where they mediate neuronal excitability, synaptic plasticity, and feedback inhibition of neurotransmitter release. However, recent data suggest that these receptors are also expressed and functional in some cancers, most notably melanoma. We detected the expression of metabotropic glutamate receptor-1 (gene: GRM1; protein: mGluR1) in triple negative breast cancer cells and evaluated its role in regulating the pro-proliferative phenotype of these cells. mGluR1 inhibitors (Riluzole or BAY36-7620) inhibited the proliferation of triple negative breast cancer cells in a time- and dose-dependent manner and this inhibition correlated with increased apoptosis as demonstrated by increase in PARP cleavage products and Annexin V staining. mGluR1 knockdown using Lentiviral constructs expressing shRNA targeting GRM1 also inhibited proliferation compared to non-silencing controls. In addition, treatment of mice bearing MDA-MB-231 xenografts with Riluzole or BAY36-7620, by intraperitoneal injection, resulted in a significant reduction in tumor volume of up to 80%. Moreover, Riluzole was effective against triple negative breast cancer xenografts in mice at doses equivalent to those currently being used in humans for the treatment of amyotrophic lateral sclerosis. Our observations implicate mGluR1 and glutamate signaling as a promising new molecular target for the treatment of breast cancer. Even more promising, Riluzole, because it is an oral drug that can be administered with low toxicity, represents a promising approach in the treatment of triple negative breast cancer.

Society, Demography and Genetic Structure in the Spotted Hyena

Spotted hyenas (Crocuta crocuta) are large mammalian carnivores, but their societies, called 'clans', resemble those of such cercopithecine primates as baboons and macaques with respect to their size, hierarchical structure, and frequency of social interaction among both kin and unrelated group-mates. However, in contrast to cercopithecine primates, spotted hyenas regularly hunt antelope and compete with group-mates for access to kills, which are extremely rich food sources, but also rare and ephemeral. This unique occurrence of baboon-like sociality among top-level predators has favoured the evolution of many unusual traits in this species. We briefly review the relevant socio-ecology of spotted hyenas, document great demographic variation but little variation in social structure across the species' range, and describe the long-term fitness consequences of rank-related variation in resource access among clan-mates. We then summarize patterns of genetic relatedness within and between clans, including some from a population that had recently gone through a population bottleneck, and consider the roles of sexually dimorphic dispersal and female mate choice in the generation of these patterns. Finally, we apply social network theory under varying regimes of resource availability to analyse the effects of kinship on the stability of social relationships among members of one large hyena clan in Kenya. Although social bonds among both kin and non-kin are weakest when resource competition is most intense, hyenas sustain strong social relationships with kin year-round, despite constraints imposed by resource limitation. Our analyses suggest that selection might act on both individuals and matrilineal kin groups within clans containing multiple matrilines.

Black Reefs: Iron-induced Phase Shifts on Coral Reefs

The Line Islands are calcium carbonate coral reef platforms located in iron-poor regions of the central Pacific. Natural terrestrial run-off of iron is non-existent and aerial deposition is extremely low. However, a number of ship groundings have occurred on these atolls. The reefs surrounding the shipwreck debris are characterized by high benthic cover of turf algae, macroalgae, cyanobacterial mats and corallimorphs, as well as particulate-laden, cloudy water. These sites also have very low coral and crustose coralline algal cover and are call black reefs because of the dark-colored benthic community and reduced clarity of the overlying water column. Here we use a combination of benthic surveys, chemistry, metagenomics and microcosms to investigate if and how shipwrecks initiate and maintain black reefs. Comparative surveys show that the live coral cover was reduced from 40 to 60% to <10% on black reefs on Millennium, Tabuaeran and Kingman. These three sites are relatively large (>0.75 km(2)). The phase shift occurs rapidly; the Kingman black reef formed within 3 years of the ship grounding. Iron concentrations in algae tissue from the Millennium black reef site were six times higher than in algae collected from reference sites. Metagenomic sequencing of the Millennium Atoll black reef-associated microbial community was enriched in iron-associated virulence genes and known pathogens. Microcosm experiments showed that corals were killed by black reef rubble through microbial activity. Together these results demonstrate that shipwrecks and their associated iron pose significant threats to coral reefs in iron-limited regions.

Risk Perception, Risk Management and Safety Assessment: What Can Governments Do to Increase Public Confidence in Their Vaccine System?

For decades vaccine program managers and governments have devoted many resources to addressing public vaccine concerns, vaccine risk perception, risk management and safety assessment. Despite ever growing evidence that vaccines are safe and effective, public concerns continue. Education and evidence based scientific messages have not ended concerns. How can governments and programs more effectively address the public's vaccine concerns and increase confidence in the vaccine safety system? Vaccination hesitation has been attributed to concerns about vaccine safety, perceptions of high vaccine risks and low disease risk and consequences. Even when the public believes vaccines are important for protection many still have concerns about vaccine safety. This overview explores how heuristics affect public perception of vaccines and vaccine safety, how the public finds and uses vaccine information, and then proposes strategies for changes in the approach to vaccine safety communications. Facts and evidence confirming the safety of vaccines are not enough. Vaccine beliefs and behaviours must be shaped. This will require a shift in the what, when, how and why of vaccine risk and benefit communication content and practice. A change to a behavioural change strategy such as the WHO COMBI program that has been applied to disease eradication efforts is suggested.

High Prevalence of Cervical Squamous Intraepithelial Lesions in Women on Antiretroviral Therapy in Cameroon: Is Targeted Screening Feasible?

Cervical cancer is the most common cancer in women in low-income countries. Although cervical cancer incidence and mortality is higher in HIV-positive women, resource limitations restrict the implementation of systematic screening programs in these women. We explored the potential for targeted screening by assessing the prevalence, severity and predictors of cervical squamous intra-epithelial lesions (SILs) in HIV-positive women in Cameroon.

Multiple Human Papillomavirus Infections and Type Competition in Men

There is little information on multiple human papillomavirus (HPV) infections and the potential for type competition in men, yet competition may impact the type-specific efficacy of HPV vaccination.

Nebulized Live-attenuated Influenza Vaccine Provides Protection in Ferrets at a Reduced Dose

Live-attenuated influenza vaccine (LAIV) is delivered to vaccine recipients using a nasal spray syringe. LAIV delivered by this method is immunogenic at current doses; however, improvements in nasal delivery might allow for significant dose reduction. We investigated LAIV vaccination in ferrets using a high efficiency nebulizer designed for nasal delivery. LAIV nasal aerosol elicited high levels of serum neutralizing antibodies and protected ferrets from homologous virus challenge at conventional (10(7)TCID(50)) and significantly reduced (10(3)TCID(50)) doses. Aerosol LAIV also provided a significant level of subtype-specific cross-protection. These results demonstrate the dose-sparing potential of nebulizer-based nasal aerosol LAIV delivery.

Microbial to Reef Scale Interactions Between the Reef-building Coral Montastraea Annularis and Benthic Algae

Competition between reef-building corals and benthic algae is of key importance for reef dynamics. These interactions occur on many spatial scales, ranging from chemical to regional. Using microprobes, 16S rDNA pyrosequencing and underwater surveys, we examined the interactions between the reef-building coral Montastraea annularis and four types of benthic algae. The macroalgae Dictyota bartayresiana and Halimeda opuntia, as well as a mixed consortium of turf algae, caused hypoxia on the adjacent coral tissue. Turf algae were also associated with major shifts in the bacterial communities at the interaction zones, including more pathogens and virulence genes. In contrast to turf algae, interactions with crustose coralline algae (CCA) and M. annularis did not appear to be antagonistic at any scale. These zones were not hypoxic, the microbes were not pathogen-like and the abundance of coral-CCA interactions was positively correlated with per cent coral cover. We propose a model in which fleshy algae (i.e. some species of turf and fleshy macroalgae) alter benthic competition dynamics by stimulating bacterial respiration and promoting invasion of virulent bacteria on corals. This gives fleshy algae a competitive advantage over corals when human activities, such as overfishing and eutrophication, remove controls on algal abundance. Together, these results demonstrate the intricate connections and mechanisms that structure coral reefs.

Population-based Human Papillomavirus 16, 18, 6 and 11 DNA Positivity and Seropositivity in Chinese Women

To optimize HPV vaccination implementation at the population-level in China, data are needed on age-specific HPV 16, 18, 6 and 11 prevalence. This cross-sectional, population-based study evaluated the age- and type-specific HPV 16, 18, 6 and 11 prevalence of DNA and serum antibodies among women in China. From July 2006 to April 2007, 17-54 year old women from three rural provinces (Xinjiang, Shanxi and Henan) and two cities (Beijing and Shanghai) provided cervical exfoliated cells for HPV DNA and liquid-based cervical cytology (SurePath). High- and low-risk HPV types were detected with HC-II (Qiagen), with genotyping of HPV-positive samples using Linear Array (Roche). HPV 16, 18, 6 and 11 serum antibodies were detected using a Luminex-based, competitive immunoassay (Merck). A total of 4,206 women with DNA and serum antibody results were included. HPV 16 DNA prevalence peaked in women aged 30-34 (4.2%) and 45-49 yr (3.8%), while HPV 18 DNA prevalence peaked at ages 40-44 yr (1.3%). Most women were dually DNA and serum antibody negative: HPV 16 (92.2%), 18 (97.2%), HPV 16 and 18 (90.2%), 6 (92.0%), 11 (96.6%), 6 and 11(89.9%) and HPV 16, 18, 6 and 11 (82.5%). Future national HPV vaccination programs in China should target younger women due to increased exposure to HPV types 16, 18, 6 and 11 with increasing age. Cumulative exposure of HPV may be underreported in this population, as cross-sectional data do not accurately reflect exposure to HPV infections over time.

Perceptions of Teen Motherhood in Australian Adolescent Females: Life-line or Lifederailment

The findings presented in this paper describe the beliefs and attitudes of three different groups of adolescent females about teen motherhood. These were elicited from a larger analysis that explored and theorized contraceptive pathways in a sample of young Australian women.

Neuropathology of H5N1 Virus Infection in Ferrets

Highly pathogenic H5N1 virus remains a potential threat to humans. Over 289 fatalities have been reported in WHO confirmed human cases since 2003, and lack of effective vaccines and early treatments contribute to increasing numbers of cases and fatalities. H5N1 encephalitis is a recognized cause of death in Vietnamese cases, and brain pathology is described in other human cases and naturally infected animals. However, neither pathogenesis of H5N1 viral infection in human brain nor post-infection effects in survivors have been fully investigated. We report the brain pathology in a ferret model for active infection and 18-day survival stages. This model closely resembles the infection pattern and progression in human cases of influenza A, and our report is the first description of brain pathology for longer term (18-day) survival in ferrets. We analyzed viral replication, type and severity of meningoencephalitis, infected cell types, and cellular responses to infection. We found viral replication to very high titers in ferret brain, closely correlating with severity of meningoencephalitis. Viral antigens were detected predominantly in neurons, correlating with inflammatory lesions, and less frequently in astrocytes and ependymal cells during active infection. Mononuclear cell infiltrates were observed in early stages predominantly in cerebral cortex, brainstem, and leptomeninges, and less commonly in cerebellum and other areas. Astrogliosis was mild at day 4 post-infection, but robust by day 18. Early and continuous treatment with an antiviral agent (peramivir) inhibited virus production to non-detectable levels, reduced severity of brain injury, and promoted higher survival rates.

Accuracy and Precision of the Prodigy AutoCode Blood Glucose Monitor

To assess the accuracy and precision of the Prodigy AutoCode blood glucose monitor.

Risk Assessment and Clinical Impact of Liquid-based Cytology, Oncogenic Human Papillomavirus (HPV) DNA and MRNA Testing in Primary Cervical Cancer Screening (the FASE Study)

New commercial HPV RNA assays require further validation studies in population-based cervical cancer screening settings. To assess the performance of (FDA-approved) APTIMA® HPV Assay (AHPV), Hybrid Capture 2 (HC2), in-house PCR genotyping, and ThinPrep LBC in population-based screening, stratified by three histological gold standards.

Functional Interferon System is Required for Clearance of Lassa Virus

Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever (LF) in humans, a deadly disease endemic to West Africa that results in 5,000 to 10,000 deaths annually. Here we present results demonstrating that functional type I and type II interferon (IFN) signaling is required for efficient control of LASV dissemination and clearance.

Age-specific Human Papillomavirus Antibody and Deoxyribonucleic Acid Prevalence: a Global Review

Global data on human papillomavirus (HPV) serological and deoxyribonucleic acid (DNA) prevalence are essential to optimize HPV prophylactic vaccination strategies.

Meta-analyses Identify 13 Loci Associated with Age at Menopause and Highlight DNA Repair and Immune Pathways

To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 × 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-κB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.

Pooled Analysis of a Self-sampling HPV DNA Test As a Cervical Cancer Primary Screening Method

Worldwide, one-seventh of cervical cancers occur in China, which lacks a national screening program. By evaluating the diagnostic accuracy of self-collected cervicovaginal specimens tested for human papillomavirus (HPV) DNA (Self-HPV testing) in China, we sought to determine whether Self-HPV testing may serve as a primary cervical cancer screening method in low-resource settings.

Burden of Invasive Cervical Cancer in North Carolina

OBJECTIVE: Cervical cancer causes over 4000 deaths yearly in the United States, although highly preventable through vaccination, screening, and early treatment. We aimed to determine demographic correlates for cervical cancer in North Carolina to identify target populations for interventions and to create a framework for state-level analyses. METHOD: Data on all reported invasive cervical cancer cases from 1998 to 2007 were obtained from the North Carolina Central Cancer Registry. Age-adjusted incidence and mortality rates were estimated using population data from the National Center for Health Statistics. RESULTS: Cervical cancer incidence and mortality rates varied greatly by county and were inversely associated with county prosperity. Hispanic women had the highest incidence rate, black women the highest mortality rate, although white women accounted for most cases. Incidence rates remained fairly steady above age 35 and mortality rates steadily increased with age. A later stage at diagnosis was more common for older women and for women without private insurance. CONCLUSION: Registry-based assessment illustrates the economic, racial, and age disparities associated with cervical cancer. This localized focus on demographic correlates is an important step toward eliminating this preventable disease and offers a template for cervical cancer prevention programs in other states.

Melanocortin-1 Receptor-mediated Signalling Pathways Activated by NDP-MSH and HBD3 Ligands

Binding of melanocortin peptide agonists to the melanocortin-1 receptor of melanocytes results in eumelanin production, whereas binding of the agouti signalling protein inverse agonist results in pheomelanin synthesis. Recently, a novel melanocortin-1 receptor ligand was reported. A β-defensin gene mutation was found to be responsible for black coat colour in domestic dogs. Notably, the human equivalent, β-defensin 3, was found to bind with high affinity to the melanocortin-1 receptor; however, the action of β-defensin as an agonist or antagonist was unknown. Here, we use in vitro assays to show that β-defensin 3 is able to act as a weak partial agonist for cAMP signalling in human embryonic kidney (HEK) cells expressing human melanocortin-1 receptor. β-defensin 3 is also able to activate MAPK signalling in HEK cells stably expressing either wild type or variant melanocortin-1 receptors. We suggest that β-defensin 3 may be a novel melanocortin-1 receptor agonist involved in regulating melanocyte responses in humans.

Cervical Cancer Awareness and Screening in Botswana

Cervical cancer remains a leading cause of death in many developing countries because limited screening by Papanicolaou (Pap) smear. We sought to better understand women's beliefs about cervical cancer and screening in Botswana, a middle-income African country with high rates of cervical cancer.

Alberta: Evaluation of Nursing Retention and Recruitment Programs

Retention and recruitment strategies are essential to address nursing workforce supply and ensure the viability of healthcare delivery in Canada. Knowledge transfer between experienced nurses and those new to the profession is also a focus for concern. The Multi-Employer/United Nurses of Alberta Joint Committee attempted to address these issues by introducing a number of retention and recruitment (R&R) initiatives for nurses in Alberta: in total, seven different programs that were introduced to some 24,000 nurses and employers across the province of Alberta in 2001 (the Transitional Graduate Nurse Recruitment Program) and 2007 (the remaining six R&R programs). Approximately 1,600 nurses participated in the seven programs between 2001 and 2009. Of the seven strategies, one supported entry into the workplace, two were pre-retirement strategies and four involved flexible work options. This project entailed a retrospective evaluation of the seven programs and differed from the other Research to Action (RTA) projects because it was solely concerned with evaluation of pre-existing initiatives. All seven programs were launched without a formal evaluation component, and the tracking of local uptake varied throughout the province. The union and various employers faced challenges in implementing these strategies in a timely fashion, as most were designed at the bargaining table during negotiations. As a result, systems, policy and procedural changes had to be developed to support their implementation after they became available.Participants in the programs indicated improvements over time in several areas, including higher levels of satisfaction with work–life balance, hours worked and their current practice and profession. The evaluation found that participation led to perceived improvements in nurses' confidence, greater control over their work environment, decreased stress levels, increased energy and morale and perceived improved ability to provide high-quality care. However, no formal implementation plan had been developed or made available to assist employers with implementation of the programs. The findings highlight the need for more discipline in communicating, implementing and evaluating initiatives such as those evaluated retrospectively in this project. In particular, key performance indicators, baseline data, monitoring mechanisms and an evaluation plan need to be developed prior to implementation.

Factors That Impact Turnaround Time of Surgical Pathology Specimens in an Academic Institution

Turnaround time of laboratory results is important for customer satisfaction. The College of American Pathologists' checklist requires an analytic turnaround time of 2 days or less for most routine cases and lets every hospital define what a routine specimen is. The objective of this study was to analyze which factors impact turnaround time of nonbiopsy surgical pathology specimens. We calculated the turnaround time from receipt to verification of results (adjusted for weekends and holidays) for all nonbiopsy surgical specimens during a 2-week period. Factors studied included tissue type, number of slides per case, decalcification, immunohistochemistry, consultations with other pathologists, and diagnosis. Univariate and multivariate analyses were performed. A total of 713 specimens were analyzed, 551 (77%) were verified within 2 days and 162 (23%) in 3 days or more. Lung, gastrointestinal, breast, and genitourinary specimens showed the highest percentage of cases being signed out in over 3 days. Diagnosis of malignancy (including staging of the neoplasia), consultation with other pathologists, having had a frozen section, and use of immunohistochemical stains were significantly associated with increased turnaround time in univariate analysis. Decalcification was not associated with increased turnaround time. In multivariate analysis, consultation with other pathologists, use of immunohistochemistry, diagnosis of malignancy, and the number of slides studied continued to be significantly associated with prolonged turnaround time. Our findings suggest that diagnosis of malignancy is central to significantly prolonging the turnaround time for surgical pathology specimens, thus institutions that serve cancer centers will have longer turnaround time than those that do not.

Ontology Searching and Browsing at the Rat Genome Database

The Rat Genome Database (RGD) is the premier repository of rat genomic and genetic data and currently houses over 40 000 rat gene records, as well as human and mouse orthologs, 1857 rat and 1912 human quantitative trait loci (QTLs) and 2347 rat strains. Biological information curated for these data objects includes disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components. RGD uses more than a dozen different ontologies to standardize annotation information for genes, QTLs and strains. That means a lot of time can be spent searching and browsing ontologies for the appropriate terms needed both for curating and mining the data. RGD has upgraded its ontology term search to make it more versatile and more robust. A term search result is connected to a term browser so the user can fine-tune the search by viewing parent and children terms. Most publicly available term browsers display a hierarchical organization of terms in an expandable tree format. RGD has replaced its old tree browser format with a 'driller' type of browser that allows quicker drilling up and down through the term branches, which has been confirmed by testing. The RGD ontology report pages have also been upgraded. Expanded functionality allows more choice in how annotations are displayed and what subsets of annotations are displayed. The new ontology search, browser and report features have been designed to enhance both manual data curation and manual data extraction. DATABASE URL:

Genetic Susceptibility to Experimental Autoimmune Glomerulonephritis in the Wistar Kyoto Rat

In experimental autoimmune glomerulonephritis (EAG), a model of Goodpasture's disease, Wistar Kyoto (WKY) rats immunized with collagenase-solubilized glomerular basement membrane (GBM) or the recombinant NC1 domain of the α3 chain of type IV collagen [α3(IV)NC1] develop anti-GBM antibodies and focal necrotizing glomerulonephritis with crescent formation. However, Lewis (LEW) rats, which share the same major histocompatibility complex (MHC) haplotype, are resistant to EAG development. A genome-wide linkage analysis of backcrossed animals with EAG revealed a major quantitative trait locus (QTL) on rat chromosome 13 (LOD = 3.9) linked to the percentage of glomerular crescents. To investigate the role of this QTL in EAG induction, reciprocal congenic rats were generated (LEW.WCrgn1 congenic and WKY.LCrgn1 congenic), immunized with recombinant rat α3(IV)NC1, and assessed for EAG development. WKY.LCrgn1 rats showed a marked reduction in albuminuria, severity of crescentic nephritis, and number of glomerular macrophages compared with WKY controls. No reduction in antibody levels was observed. However, LEW.WCrgn1 rats were resistant to EAG development, as were LEW controls. Macrophage activation in vitro was assessed in parental and congenic rat bone marrow-derived macrophages (BMDMs). WKY.LCrgn1 BMDMs showed a significant reduction in Fc receptor-mediated oxidative burst, phagocytosis of opsonised polystyrene beads, and LPS-induced levels of MCP-1 secretion and iNOS mRNA expression compared with WKY rats. These results confirm the importance of Crgn1 on chromosome 13 in EAG susceptibility, mediated partly through differences in Fc receptor-mediated macrophage activation.

HPV Genotypes in High Grade Cervical Lesions and Invasive Cervical Carcinoma As Detected by Two Commercial DNA Assays, North Carolina, 2001-2006

HPV typing using formalin fixed paraffin embedded (FFPE) cervical tissue is used to evaluate HPV vaccine impact, but DNA yield and quality in FFPE specimens can negatively affect test results. This study aimed to evaluate 2 commercial assays for HPV detection and typing using FFPE cervical specimens.

Prevalence of Human Papillomavirus and Cervical Intraepithelial Neoplasia in China: A Pooled Analysis of 17 Population-based Studies

High-risk (HR) human papillomavirus (HPV) prevalence has been shown to correlate well with cervical cancer incidence rates. Our study aimed to estimate the prevalence of HR-HPV and cervical intraepithelial neoplasia (CIN) in China and indirectly informs on the cervical cancer burden in the country. A total of 30,207 women from 17 population-based studies throughout China were included. All women received HPV DNA testing (HC2, Qiagen, Gaithersburg, MD), visual inspection with acetic acid and liquid-based cytology. Women positive for any test received colposcopy-directed or four-quadrant biopsies. A total of 29,579 women had HR-HPV testing results, of whom 28,761 had biopsy confirmed (9,019, 31.4%) or assumed (19,742, 68.6%) final diagnosis. Overall crude HR-HPV prevalence was 17.7%. HR-HPV prevalence was similar in rural and urban areas but showed dips in different age groups: at age 25-29 (11.3%) in rural and at age 35-39 (11.3%) in urban women. In rural and urban women, age-standardized CIN2 prevalence was 1.5% [95% confidence interval (CI): 1.4-1.6%] and 0.7% (95% CI: 0.7-0.8%) and CIN3+ prevalence was 1.2% (95% CI: 1.2-1.3%) and 0.6% (95% CI: 0.5-0.7%), respectively. Prevalence of CIN3+ as a percentage of either all women or HR-HPV-positive women steadily increased with age, peaking in 45- to 49-year-old women. High prevalence of HR-HPV and CIN3+ was detected in both rural and urban China. The steady rise of CIN3+ up to the age group of 45-49 is attributable to lack of lesion removal through screening. Our findings document the inadequacy of current screening in China while indirectly raising the possibility that the cervical cancer burden in China is underreported.

HPV Prevalence and Cervical Intraepithelial Neoplasia Among HIV-infected Women in Yunnan Province, China: a Pilot Study

To determine the prevalence of HPV and cervical neoplasia among HIV-infected women in southwestern China.

Prevalence of Trachoma in Unity State, South Sudan: Results from a Large-scale Population-based Survey and Potential Implications for Further Surveys

Large parts of South Sudan are thought to be trachoma-endemic but baseline data are limited. This study aimed to estimate prevalence for planning trachoma interventions in Unity State, to identify risk factors and to investigate the effect of different sampling approaches on study conclusions.

Training Substance Abuse Clinicians in Motivational Interviewing Using Live Supervision Via Teleconferencing

Training through traditional workshops is relatively ineffective for changing counseling practices. Teleconferencing supervision (TCS) was developed to provide remote, live supervision for training motivational interviewing (MI).

Natural Killer Cell Mediated Pathogenesis Determines Outcome of Central Nervous System Infection with Venezuelan Equine Encephalitis Virus in C3H/HeN Mice

TC83 is a human vaccine with investigational new drug status and is used as a prototype Venezuelan equine encephalitis virus for pathogenesis and antiviral research. Differing from other experimental models, the virus causes high titer infection in the brain and 90-100% mortality in the C3H/HeN murine model. To better characterize the susceptibility to disease development in C3H/HeN mice, we have analyzed the gene transcriptomes and cytokine production in the brains of infected mice. Our analysis indicated the potential importance of natural killer cells in the encephalitic disease development. This paper describes for the first time a pathogenic role for natural killer cells in VEEV encephalitis.

Smoking and Genetic Risk Variation Across Populations of European, Asian, and African American Ancestry--a Meta-analysis of Chromosome 15q25

Recent meta-analyses of European ancestry subjects show strong evidence for association between smoking quantity and multiple genetic variants on chromosome 15q25. This meta-analysis extends the examination of association between distinct genes in the CHRNA5-CHRNA3-CHRNB4 region and smoking quantity to Asian and African American populations to confirm and refine specific reported associations. Association results for a dichotomized cigarettes smoked per day phenotype in 27 datasets (European ancestry (N = 14,786), Asian (N = 6,889), and African American (N = 10,912) for a total of 32,587 smokers) were meta-analyzed by population and results were compared across all three populations. We demonstrate association between smoking quantity and markers in the chromosome 15q25 region across all three populations, and narrow the region of association. Of the variants tested, only rs16969968 is associated with smoking (P < 0.01) in each of these three populations (odds ratio [OR] = 1.33, 95% CI = 1.25-1.42, P = 1.1 × 10(-17) in meta-analysis across all population samples). Additional variants displayed a consistent signal in both European ancestry and Asian datasets, but not in African Americans. The observed consistent association of rs16969968 with heavy smoking across multiple populations, combined with its known biological significance, suggests rs16969968 is most likely a functional variant that alters risk for heavy smoking. We interpret additional association results that differ across populations as providing evidence for additional functional variants, but we are unable to further localize the source of this association. Using the cross-population study paradigm provides valuable insights to narrow regions of interest and inform future biological experiments.

"Old Dogs" and New Skills: How Clinician Characteristics Relate to Motivational Interviewing Skills Before, During, and After Training

The relationships between the occupational, educational, and verbal-cognitive characteristics of health care professionals and their motivational interviewing (MI) skills before, during, and after training were investigated.

Honaucins A-C, Potent Inhibitors of Inflammation and Bacterial Quorum Sensing: Synthetic Derivatives and Structure-activity Relationships

Honaucins A-C were isolated from the cyanobacterium Leptolyngbya crossbyana which was found overgrowing corals on the Hawaiian coast. Honaucin A consists of (S)-3-hydroxy-γ-butyrolactone and 4-chlorocrotonic acid, which are connected via an ester linkage. Honaucin A and its two natural analogs exhibit potent inhibition of both bioluminescence, a quorum-sensing-dependent phenotype, in Vibrio harveyi BB120 and lipopolysaccharide-stimulated nitric oxide production in the murine macrophage cell line RAW264.7. The decrease in nitric oxide production was accompanied by a decrease in the transcripts of several proinflammatory cytokines, most dramatically interleukin-1β. Synthesis of honaucin A, as well as a number of analogs, and subsequent evaluation in anti-inflammation and quorum-sensing inhibition bioassays revealed the essential structural features for activity in this chemical class and provided analogs with greater potency in both assays.

Vein Mapping Prior to Endovenous Catheter Ablation of the Great Saphenous Vein Predicts Risk of Endovenous Heat-induced Thrombosis

We investigate the value of vein mapping for predicting the risk of endovenous heat-induced thrombosis (EHIT) after endovenous laser treatment (EVLT) and radiofrequency ablation (RFA) of the great saphenous vein (GSV).

A Five-year Review of Pseudomonas Aeruginosa Bacteremia in Children Hospitalized at a Single Center in Southern China

Pediatric Pseudomonas aeruginosa bacteremia is uncommon. It is mostly seen with impaired immune defenses and is most often nosocomially acquired, but it does occasionally occur in the previously healthy. Empiric antibiotics not effective against P. aeruginosa can result in poor outcomes. To determine the risk factors for P. aeruginosa bacteremia, all pediatric cases of P. aeruginosa bacteremia hospitalized at a single center over a 5-year period were reviewed.

Vaccine-relevant Human Papillomavirus (HPV) Infections and Future Acquisition of High-risk HPV Types in Men

Little is known about type-specific associations between prevalent human papillomavirus (HPV) infections and risk of acquiring other HPV types in men. Data on natural clustering of HPV types are needed as a prevaccine distribution to which postvaccine data can be compared.

Highly Active Antiretroviral Therapy and Cervical Dysplasia in HIV-positive Women in South Africa

The risk of squamous intra-epithelial lesions (SIL) is higher in HIV-positive women. As these women begin to live longer due to highly active antiretroviral therapy (HAART), their risk of cervical cancer may increase. Few data exist regarding the effect of HAART on the incidence and progression of SIL in HIV-positive African women. The aim of this study was to evaluate the effect of HAART on the incidence and progression of SIL in HIV-positive women in South Africa.

Prevalence of Type-specific Human Papillomavirus Infection Among Women in France: Implications for Screening, Vaccination, and a Future Generation of Multivalent HPV Vaccines

To assess human papillomavirus (HPV) prevalence and genotype distribution by age and cervical cytology/histology status among women undergoing routine gynecological examinations, and to discuss the possible impact on preventive strategies. Liquid-based cytology (LBC) samples were tested for HPV DNA, mRNA, and HPV genotypes. Women with atypical squamous cells of undetermined significance or greater (ASC-US+) and/or at least one positive HPV test were referred to colposcopy. Those with normal colposcopy results had biopsies taken at the 6 and 12 O'clock positions of the normal transformation zone. Of the 5002 women, 515 (10.3%) were <25 and 4487 (89.7%) were ≥25years old. Overall HPV prevalence varied between 10.1% and 16.1% depending on the assay. Risk factors for HPV infection included greater number of recent sexual partners, history of abnormal cervical pathology, age <25years, and smoking. HPV prevalence increased with the cytological and histological severity of cervical lesions. Prevalence of HPV 16/18 was 5.2% and 2.7% in women <25 and ≥25years old, respectively. HPV 16 was the type most strongly associated with a diagnosis of cervical intraepithelial neoplasia grade 3 or higher (CIN3+) (odds ratio=11.64 vs. HPV 16 absent, P<0.001). A high proportion of high-grade cervical lesions (60.6% of genotyping assay-positive CIN2+) were associated with HPV types 31, 33, 45, 52, or 58. These data indicate that almost all young women could benefit from HPV prophylactic vaccination, but confirm the need for continued cervical screening and highlight the potential benefit of future vaccines targeting a wider range of HPV types.

Seroprevalence of Human Papillomavirus Types 6, 11, 16 and 18 in Chinese Women


Fecal Glucocorticoid Metabolites in Wild Yellow-bellied Marmots: Experimental Validation, Individual Differences and Ecological Correlates

Natural selection is expected to shape phenotypic traits that permit organisms to respond appropriately to the environments in which they live. One important mechanism by which animals cope with changes in their environment is through physiological responses to stressors mediated by glucocorticoid hormones. Here we perform biological and physiological validations of a minimally-invasive technique for assessing fecal corticosterone metabolites (FCMs) in captive and wild groups of yellow-bellied marmots (Marmota flaviventris). Then we draw from ten years of data on these obligate hibernators at the Rocky Mountain Biological Laboratory in Colorado, USA to assess the extent to which seasonal and daily changes explain naturalistic variation in baseline levels of FCMs. Interestingly, beyond important population-level variation with respect to year, season, time of day, sex, age and reproductive state, we found repeatable inter-individual differences in FCMs, suggesting this hormonal trait might be a meaningful target of selection. FCM levels were 68% lower in captive than wild marmots, suggesting that the natural environment in which these animals occur is generally more challenging or less predictable than life in captivity. Most live-trapping events failed to represent stressors for wild marmots such that repeated measurements of traits were possible with minimal "stress" to subjects. We also document the natural ranges of annual and seasonal variation necessary for understanding the extent to which anthropogenic assaults represent stressors for wild mammals. Taken together, this study provides a foundation for understanding the evolution of hormonal traits and has important welfare and conservation implications for field biologists.

Costs Associated with Management of Cervical Human Papillomavirus-related Conditions

Oncogenic types of human papillomavirus (HPV) have been linked to 99.7% of cervical cancer cases worldwide.

Knowledge and Acceptability of Pap Smears, Self-sampling and HPV Vaccination Among Adult Women in Kenya

Our study aimed to assess adult women's knowledge of human papillomavirus (HPV) and cervical cancer, and characterize their attitudes towards potential screening and prevention strategies.

Age-related Changes in Core Body Temperature and Activity in Triple-transgenic Alzheimer's Disease (3xTgAD) Mice

Alzheimer's disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4-9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4-10 months), 3xTgAD mice exhibited greater food intake compared to Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent, since the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model to study the underlying mechanisms involved in non-cognitive behavioural changes in AD.

Human Papillomavirus Infection and Increased Risk of HIV Acquisition. A Systematic Review and Meta-analysis

OBJECTIVES:: Human papillomavirus (HPV), one of the commonest sexually transmitted infections, may be a cofactor in HIV acquisition. We systematically reviewed the evidence for an association of HPV infection with HIV acquisition in women, heterosexual men and men who have sex with men (MSM). DESIGN:: Systematic review and meta-analysis. METHODS:: Studies meeting inclusion criteria in Pubmed, Embase and conference abstracts up to 29 July 2011 were identified. Random effects meta-analyses were performed to calculate summary hazard ratios (HR). Publication bias and statistical heterogeneity were evaluated and population attributable fractions (PAFs) calculated. RESULTS:: Eight articles were included, with previously unpublished data from five authors. Seven studies found an association between prevalent HPV and HIV acquisition. Risk of HIV acquisition in women doubled with prevalent HPV infection with any genotype [HR = 2.06 (95% CI = 1.44-2.94), I = 0%], although adjustment for confounders was often inadequate. The effect was similar for high-risk [HR = 1.99 (95% CI = 1.54-2.56), I = 8.4%] and low-risk [HR = 2.01 (95% CI = 1.27-3.20), I = 0%] HPV genotypes with weak evidence of publication bias (P = 0.06). Two studies in men were identified: both showed an association between HPV infection and HIV acquisition. Unpublished data from one of two studies in women indicated an association between genotypes targeted by HPV vaccines and HIV acquisition. PAFs for HIV attributable to infection with any HPV genotype ranged between 21 and 37%. CONCLUSION:: If further studies validate the association between HPV infection and HIV acquisition, HPV vaccines may reduce HIV incidence in high HPV prevalence populations, in addition to preventing cervical cancer. HIV surveillance studies during implementation of HPV vaccine programmes are warranted.

The Clinical Profile of Merkel Cell Carcinoma in Mainland China

Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy, but little is known about the presence or characteristics of MCC in mainland China. A retrospective chart review was conducted to describe the clinical profile of MCC in China.

Predicting Survival in Malignant Mesothelioma

Sexual Behaviour and Less Frequent Bathing Are Associated with Higher Human Papillomavirus Incidence in a Cohort Study of Uncircumcised Kenyan Men

OBJECTIVES: Data on the acquisition of human papillomavirus (HPV) infection in men are limited, especially from developing regions including Africa. The objective of this study was to characterise and determine the risk factors of HPV acquisition among a cohort of uncircumcised men participating in a randomised controlled trial (RCT) of male circumcision in Kisumu, Kenya. METHODS: Penile exfoliated cell specimens were collected at baseline, 6- and 12-month follow-up visits from the glans/coronal sulcus and shaft of men enrolled in the control arm of the RCT between 2002 and 2005. All participants were HIV seronegative, aged 17-24 years at baseline and remained uncircumcised over follow-up. Specimens were tested with GP5+/6+ PCR to detect 44 HPV types. Parametric frailty models were used to assess risk factors of HPV incidence. RESULTS: The median age of 966 participants was 20 years. The median follow-up time was 12.1 months. The incidence rate (IR) of any HPV infection was 49.3/1000 person-months with HPV16 having the highest IR (10.9/1000 person-months). The strongest risk factors for overall HPV incidence were bathing less frequently than daily (adjusted HR=2.6; 95% CI 1.0 to 6.5) and having ≥2 female sexual partners in the past year (adjusted HR=1.6; 95% CI 1.2 to 2.1). CONCLUSIONS: HPV IRs were notably high in this cohort of high-risk, uncircumcised men from Kisumu, Kenya, with the number of sexual partners and bathing frequency being the strongest risk factors.

Survival and Dispersal of Turf Algae and Macroalgae Consumed by Herbivorous Coral Reef Fishes

The mechanisms by which algae disperse across space on coral reefs are poorly known. We investigated the ability of four common Caribbean herbivorous fish species to disperse viable algal fragments through consumption of macroalgae and subsequent defecation. Fragments of all major algal taxa (Phaeophyta, Rhodophyta, and Chlorophyta) were found in 98.7 % of the fecal droppings of all fish species; however, the ability to survive gut passage and reattach to a substrate differed between algal taxa. While survival and reattachment approached zero for Phaeophyta and Chlorophyta, 76.4 % of the fragments belonging to the group Rhodophyta (mostly species in the order Gelidiaceae) survived gut passage, and were able to grow and reattach to the substrate by forming new rhizoids. Our results thus show that Gelidid algal species are dispersed by swimming herbivores. While the relative contribution of this mechanism to overall algal dispersal and recruitment in a wider ecological context remains unknown, our findings illustrate a previously undescribed mechanism of algal dispersal on coral reefs which is analogous to the dispersal of terrestrial plants, plant fragments, and seeds via herbivore ingestion and defecation.

Diel Variability in Seawater PH Relates to Calcification and Benthic Community Structure on Coral Reefs

Community structure and assembly are determined in part by environmental heterogeneity. While reef-building corals respond negatively to warming (i.e. bleaching events) and ocean acidification (OA), the extent of present-day natural variability in pH on shallow reefs and ecological consequences for benthic assemblages is unknown. We documented high resolution temporal patterns in temperature and pH from three reefs in the central Pacific and examined how these data relate to community development and net accretion rates of early successional benthic organisms. These reefs experienced substantial diel fluctuations in temperature (0.78°C) and pH (>0.2) similar to the magnitude of 'warming' and 'acidification' expected over the next century. Where daily pH within the benthic boundary layer failed to exceed pelagic climatological seasonal lows, net accretion was slower and fleshy, non-calcifying benthic organisms dominated space. Thus, key aspects of coral reef ecosystem structure and function are presently related to natural diurnal variability in pH.

Patterns of Persistent Genital Human Papillomavirus Infection Among Women Worldwide: A Literature Review and Meta-analysis

Persistent high-risk human papillomavirus (HR-HPV) infection is the strongest risk factor for high-grade cervical precancer. We performed a systematic review and meta-analysis of HPV persistence patterns worldwide. Medline and ISI Web of Science were searched through January 1, 2010 for articles estimating HPV persistence or duration of detection. Descriptive and meta-regression techniques were used to summarize variability and the influence of study definitions and characteristics on duration and persistence of cervical HPV infections in women. Among 86 studies providing data on over 100,000 women, 73% defined persistence as HPV positivity at a minimum of two time points. Persistence varied notably across studies and was largely mediated by study region and HPV type, with HPV-16, 31, 33 and 52 being most persistent. Weighted median duration of any-HPV detection was 9.8 months. HR-HPV (9.3 months) persisted longer than low-risk HPV (8.4 months), and HPV-16 (12.4 months) persisted longer than HPV-18 (9.8 months). Among populations of HPV-positive women with normal cytology, the median duration of any-HPV detection was 11.5 and HR-HPV detection was 10.9 months. In conclusion, we estimated that approximately half of HPV infections persist past 6 to 12 months. Repeat HPV testing at 12-month intervals could identify women at increased risk of high-grade cervical precancer due to persistent HPV infections.

Pathogen Recognition in the Human Female Reproductive Tract: Expression of Intracellular Cytosolic Sensors NOD1, NOD2, RIG-1, and MDA5 and Response to HIV-1 and Neisseria Gonorrhea

PROBLEM: Expression patterns and regulation of cytosolic pattern recognition receptors (PRR) NOD-1, NOD-2, RIG-1, and MDA5 have not been elucidated in the human female reproductive tract (FRT). METHOD OF STUDY: Primary epithelial cells (EC) isolated from Fallopian tube (FT), endometrium (EM), cervix (Cx), and ectocervix (Ecx) were treated with estradiol, poly(I:C), Neisseria gonorrhea (GC), and HIV-1. PRR mRNA expressions were analyzed by Real-time RT-PCR. Conditioned media were analyzed for IL-8 by ELISA. RESULTS: EC from all FRT compartments constitutively expressed NOD1, NOD2, RIG-1, and MDA5 with highest levels expressed by FT. Stimulation with poly(I:C) resulted in upregulation of NOD2, RIG-1, and MDA5 in all FRT compartments and correlated with increased secretion of IL-8, whereas estradiol treatment had no effects. Exposure to GC and HIV-1 IIIB but not BaL resulted in selective upregulation of NOD2 and MDA5. CONCLUSION: PRR are expressed throughout the FRT and differentially regulated by poly(I:C), GC and HIV-1.

Modelling the Global Competing Risks of a Potential Interaction Between Injectable Hormonal Contraception and HIV Risk

BACKGROUND:: Some, but not all, observational studieshave suggested an increase in risk of HIV acquisition for women using injectable hormonal contraception (IHC). METHODS:: We used country-level data to explore the effects of reducing IHC use on the number of HIV infections, the number of live births and the resulting net consequenceson AIDS deaths and maternal mortality for each country. RESULTS:: High IHC use coincides with high HIV incidence primarily in southern and eastern Africa. If IHC does increase the risk of HIV acquisition, this could generate 27 000-130 000 infections per year globally, 87-88% of which occur in this region. Reducing IHC use could result in fewer HIV infections but also a substantial increase in live births and maternal mortality in countries with high IHC use, high birth rates and high maternal mortality: mainly southern and eastern Africa, South-East Asia, and Central and South America. For most countries, the net impactof reducing IHC use on maternal and AIDS-related deaths is dependent on the magnitude of the assumed IHC-HIV interaction. CONCLUSIONS:: If IHC use increases HIV acquisition risk, reducing IHC could reduce new HIV infections; however, this must be balanced against other important consequences, including unintended pregnancy, which impacts maternal and infant mortality. Unless the true effect size approaches a relative risk of 2.19, it is unlikely that reductions in IHC could result in public health benefit, with the possible exception of those countries in southern Africa with the largest HIV epidemics.

Multi-wavelength Transmission Spectroscopy Revisited for Micron and Submicron Particle Characterization

Multi-wavelength transmission (MWT) ultraviolet-visible-near-infrared (UV-Vis-NIR) spectroscopy, a technique underappreciated for particle characterization, is systematically explored using a set of NIST traceable standards over the nominal size range of 20 to 20,000 nm. Experimental results demonstrate that the particle size distributions obtained from MWT spectral data are in excellent agreement with the values reported by the manufacturer. In addition, it is shown that quantitative information on the particle concentration can be obtained--which is not currently accessible from commercially available light scattering instrumentation. The results validate that MWT UV-Vis-NIR spectroscopy has a considerable dynamic range for particle size measurements and offers significant advantages over other particle characterization techniques. Among these are the simplicity of the instrumentation and the measurements and the wealth of quantitative information contained in the MWT spectra. Most importantly, with standardized measurement protocols and standardized spectrometer configurations, MWT measurements can be used to provide the user and the manufacturer of particles with traceable data (i.e., the spectra and the quantitative analysis) for quality assurance.

Early Childhood Infections and the Risk of Islet Autoimmunity: The Diabetes Autoimmunity Study in the Young (DAISY)

OBJECTIVE Type 1 diabetes is a common chronic childhood disease, and the incidence is increasing globally. Childhood infections are considered a potential environmental trigger of type 1 diabetes. Alternatively, improved hygiene and reduced childhood infections could explain the increase in type 1 diabetes in developed countries. The association of reported illnesses during infancy and later development of islet autoimmunity (IA) were examined in the Diabetes Autoimmunity Study in the Young. RESEARCH DESIGN AND METHODS Complete illness interviews through 9 months of age were collected for 1,729 children-1,174 without a family history of type 1 diabetes and 555 with a first-degree relative with type 1 diabetes. Persistent IA was defined as positive antibodies to insulin, glutamic acid decarboxylase, or tyrosine phosphatase on at least two consecutive study visits. RESULTS There were 109 children with persistent IA among the 1,729 children with illness records. A greater number of gastrointestinal illnesses were associated with an increased risk of IA, but only among children who were exposed to gluten-containing grains (wheat or barley) either <4 months of age (hazard ratio 1.37 [95% CI 1.22-1.55]; P < 0.0001) or ≥7 months of age (1.12 [1.05-1.19]; P = 0.0005) compared with 4-6 months of age (P for interaction = 0.02). There were no associations of upper respiratory symptoms, respiratory illnesses, or fevers with IA. CONCLUSIONS Specific pathogens such as enteroviruses or rotavirus may increase the risk of IA in the presence of existing inflammation induced by diet.

The Estimation of Tissue Loss During Tangential Hydrosurgical Debridement

ABSTRACT: The preservation of healthy tissue during surgical debridement is desirable as this may improve clinical outcomes. This study has estimated for the first time the amount of tissue lost during debridement using the VERSAJET system of tangential hydrosurgery. A multicenter, prospective case series was carried out on 47 patients with mixed wound types: 21 (45%) burns, 13 (28%) chronic wounds, and 13 (28%) acute wounds. Overall, 44 (94%) of 47 patients achieved appropriate debridement after a single debridement procedure as verified by an independent photographic assessment. The percentage of necrotic tissue reduced from a median of 50% to 0% (P < 0.001). Median wound area and depth increased by only 0.3 cm (6.8%) and 0.5 mm (25%), respectively. Notably, 43 (91%) of 47 wounds did not progress into a deeper compartment, indicating a high degree of tissue preservation.

The Effectiveness of Acupuncture Research Across Components of the Trauma Spectrum Response (tsr): a Systematic Review of Reviews

ABSTRACT: BACKGROUND: Co-morbid symptoms (for example, chronic pain, depression, anxiety, and fatigue) are particularly common in military fighters returning from the current conflicts, who have experienced physical and/or psychological trauma. These overlapping conditions cut across the boundaries of mind, brain and body, resulting in a common symptomatic and functional spectrum of physical, cognitive, psychological and behavioral effects referred to as the 'Trauma Spectrum Response' (TSR).While acupuncture has been shown to treat some of these components effectively, the current literature is often difficult to interpret, inconsistent or of variable quality. Thus, to gauge comprehensively the effectiveness of acupuncture across TSR components, a systematic review of reviews was conducted using the Samueli Institute's Rapid Evidence Assessment of the Literature (REAL(C)) methodology. METHODS: PubMed/MEDLINE, the Cochrane Database of Systematic Reviews, EMBASE, CINAHL, and PsycInfo were searched from inception to September 2011 for systematic reviews/meta-analyses. Quality assessment was rigorously performed using the Scottish Intercollegiate Guidelines Network (SIGN 50) checklist and The Grading of Recommendation Assessment, Development and Evaluation (GRADE) methodology. Adherence to the Standards for Reporting Interventions in Clinical Trials in Acupuncture (STRICTA) criteria was also assessed. RESULTS: Of the 1,480 citations identified by our searches, 52 systematic reviews/meta-analyses, all high quality except for one, met inclusion criteria for each TSR component except post-traumatic stress disorder (PTSD) and sexual function. The majority of reviews addressed most STRICTA components, but did not describe safety. CONCLUSIONS: Based on the results of our review, acupuncture appears to be effective for treating headaches and, although more research is needed, seems to be a promising treatment option for anxiety, sleep disturbances, depression and chronic pain. It does not, however, demonstrate any substantial treatment benefit for substance abuse. Because there were no reviews on PTSD or sexual function that met our pre-defined inclusion criteria, we cannot comment on acupuncture's effectiveness in treating these conditions. More quality data are also needed to determine whether acupuncture is appropriate for treating fatigue or cognitive difficulties. Further, while acupuncture has been shown to be generally safe, safety was not described in the majority of studies, making it difficult to provide any strong recommendations, Future research should address safety reporting in detail in order to increase our confidence in acupuncture's efficacy across the identified TSR components.

Age Trends in the Prevalence of Cervical Squamous Intraepithelial Lesions Among HIV-positive Women in Cameroon: a Cross-sectional Study


Health Promotion for Adolescent Childhood Leukemia Survivors: Building on Prevention Science and Ehealth

Teenage survivors of childhood acute lymphoblastic leukemia (ALL) have increased morbidity likely due to their prior multicomponent treatment. Habits established in adolescence can impact individuals' subsequent adult behaviors. Accordingly, healthy lifestyles, avoiding harmful actions, and appropriate disease surveillance are of heightened importance among teenage survivors. We review the findings from prevention science and their relevance to heath promotion. The capabilities and current uses of eHealth components including e-learning, serious video games, exergaming, behavior tracking, individual messaging, and social networking are briefly presented. The health promotion needs of adolescent survivors are aligned with those eHealth aspects to propose a new paradigm to enhance the wellbeing of adolescent ALL survivors. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.

Planning and Development of the Better Bites Program: A Pricing Manipulation Strategy to Improve Healthy Eating in a Hospital Cafeteria

The Better Bites program, a hospital cafeteria nutrition intervention strategy, was developed by combining evidence-based practices with hospital-specific formative research, including key informant interviews, the Nutrition Environment Measures Study in Restaurants, hospital employee surveys, and nutrition services staff surveys. The primary program components are pricing manipulation and marketing to promote delicious, affordable, and healthy foods to hospital employees and other cafeteria patrons. The pricing manipulation component includes decreasing the price of the healthy items and increasing the price of the unhealthy items using a 35% price differential. Point-of-purchase marketing highlights taste, cost, and health benefits of the healthy items. The program aims to increase purchases of healthy foods and decrease purchases of unhealthy foods, while maintaining revenue neutrality. This article addresses the formative research, planning, and development that informed the Better Bites program.

Model Organism Databases in Behavioral Neuroscience

Model Organism Databases (MODs) are an important informatics tool for researchers. They provide comprehensive organism specific genetic, genomic, and phenotype datasets. MODs ensure accurate data identification and integrity and provide official nomenclature for genes, Quantitative Trait Loci, and strains. Most importantly, the MODs provide professionally curated data drawn from the literature for function, phenotype and disease associations, and pathway involvement. These data, along with nomenclature and data identity, are incorporated into larger scale genomic databases and research publications. MODs also offer a number of software tools that allow researchers to access, display, and analyze data from reports to genome browsers.

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