A Class of Potent Inhibitors of the HIV-1 Nucleocapsid Protein Based on Aminopyrrolic Scaffolds.
The HIV-1 nucleocapsid protein 7 (NC) is a potential target for effective antiretroviral therapy due to its central role in virus replication, mainly linked to nucleic acid (NA) chaperone activity, and low susceptibility to drug resistance. By screening a compounds library, we identified the aminopyrrolic compound CN14_17, a known carbohydrate binding agent, that inhibits the NC chaperone activity in the low micromolar range. Different from most of available NC inhibitors, CN14_17 fully prevents the NC-induced annealing of complementary NA sequences. Using fluorescence assays and isothermal titration calorimetry, we found that CN14_17 competes with NC for the binding to NAs, preferentially targeting single-stranded sequences. Molecular dynamics simulations confirmed that binding to cTAR occurs preferably within the guanosine-rich single stranded sequence. Finally, CN14_17 exhibited antiretroviral activity in the low micromolar range, although with a moderate therapeutic index. Overall, CN14_17 might be the progenitor of a new promising class of NC inhibitors.


Assessing the measurement invariance of the Center for Epidemiologic Studies Depression Scale across immigrant and non-immigrant women in the postpartum period.
To assess the measurement invariance of the Center for Epidemiologic Studies Depression Scale (CES-D) 2 months after delivery in 656 English-speaking immigrant and non-immigrant women who had at least one other child under 16 and who gave birth in one of two urban Canadian centers. We also compared levels of depression in these two groups using this scale. Multiple group confirmatory factor analysis showed that configural, metric and partial scalar invariances were present and allowed for meaningful substantive comparisons to be made between immigrants and non-immigrants using linear and logistic regressions on an invariant 15-item version of the scale. We observed a novel 4-factor structure for the CES-D in postpartum women and established a 15-item version of this scale that was invariant across immigrant and non-immigrant groups. This suggests that women conceptualize postpartum depression (PPD) in similar ways using the 15-item version of this scale and that meaningful substantive comparisons can be made using it. Indeed, immigrants manifested higher levels of depressive symptoms than non-immigrants (unstandardized b = 1.34, p = 0.02) and an increased risk of being a potential case of PPD (OR = 2.16, 95%CI 1.10-4.19), even after adjustment for other risk factors. Immigrant and non-immigrant women appear to conceptualize PPD in similar ways using this 15-item version of the CES-D. Immigrants may develop more depressive symptoms and be at increased risk of developing an episode of PPD.


Regulation of cellular thiols in human lymphocytes by alpha-lipoic acid: a flow cytometric analysis.
Modulation of cellular thiols is an effective therapeutic strategy, particularly in the treatment of AIDS. Lipoic acid, a metabolic antioxidant, functions as a redox modulator and has proven clinically beneficial effects. It is also used as a dietary supplement. We utilized the specific capabilities of N-ethylmaleimide to block total cellular thiols, phenylarsine oxide to block vicinal dithiols, and buthionine sulfoximine to deplete cellular GSH to flow cytometrically investigate how these thiol pools are influenced by exogenous lipoate treatment. Low concentrations of lipoate and its analogue lipoamide increased Jurkat cell GSH in a dose-dependent manner between 10 (25 microM for lipoamide) to 100 microM. This was also observed in mitogenically stimulated peripheral blood lymphocytes (PBL). Studies with Jurkat cells and its Wurzburg subclone showed that lipoate dependent increase in cellular GSH was similar in CD4+ and - cells. Chronic (16 week) exposure of cells to lipoate resulted in further increase of total cellular thiols, vicinal dithiols, and GSH. High concentration (2 and 5 mM) of lipoate exhibited cell shrinkage, thiol depletion, and DNA fragmentation effects. Based on similar effects of octanoic acid, the cytotoxic effects of lipoate at high concentration could be attributed to its fatty acid structure. In certain diseases such as AIDS and cancer, elevated plasma glutamate lowers cellular GSH by inhibiting cystine uptake. Low concentrations of lipoate and lipoamide were able to bypass the adverse effect of elevated extracellular glutamate. A heterogeneity in the thiol status of PBL was observed. Lipoate, lipoamide, or N-acetylcysteine corrected the deficient thiol status of cell subpopulations. Hence, the favorable effects of low concentrations of lipoate treatment appears clinically relevant.


Compound-specific chlorine isotope fractionation in biodegradation of atrazine.
Atrazine is a frequently detected groundwater contaminant. It can be microbially degraded by oxidative dealkylation or by hydrolytic dechlorination. Compound-specific isotope analysis is a powerful tool to assess its transformation. In previous work, carbon and nitrogen isotope effects were found to reflect these different transformation pathways. However, chlorine isotope fractionation could be a particularly sensitive indicator of natural transformation since chlorine isotope effects are fully represented in the molecular average while carbon and nitrogen isotope effects are diluted by non-reacting atoms. Therefore, this study explored chlorine isotope effects during atrazine hydrolysis with Arthrobacter aurescens TC1 and oxidative dealkylation with Rhodococcus sp. NI86/21. Dual element isotope slopes of chlorine vs. carbon isotope fractionation (Λ = 1.7 ± 0.9 vs. Λ = 0.6 ± 0.1) and chlorine vs. nitrogen isotope fractionation (Λ = -1.2 ± 0.7 vs. Λ = 0.4 ± 0.2) provided reliable indicators of different pathways. Observed chlorine isotope effects in oxidative dealkylation (εCl = -4.3 ± 1.8‰) were surprisingly large, whereas in hydrolysis (εCl = -1.4 ± 0.6‰) they were small, indicating that C-Cl bond cleavage was not the rate-determining step. This demonstrates the importance of constraining expected isotope effects of new elements before using the approach in the field. Overall, the triple element isotope information brought forward here enables a more reliable identification of atrazine sources and degradation pathways.


E-cigarette manufacturers' compliance with clinical trial reporting expectations: a case series of registered trials by Juul Labs.
Electronic cigarettes (e-cigarettes) are a frequently debated topic in public health. It is essential that clinical trials examining e-cigarettes are fully and accurately reported, especially given long-standing concerns about tobacco industry research. We assess the reporting of clinical trials sponsored by Juul Labs, the largest e-cigarette company in the USA, against accepted reporting standards. We searched ClinicalTrials.gov for all trials sponsored by Juul Labs and determined those with registry data consistent with coverage by the Food and Drug Administration (FDA) Amendments Act 2007 (FDAAA). For trials with a primary completion date more than 1 year earlier, we searched ClinicalTrials.gov, the academic literature and a Juul-funded research database (JLI Science) for results. For located results, we compared reported outcomes with registered outcomes in line with Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines. We located five registered trials sponsored by Juul Labs that appeared covered by the FDAAA 2007 in the public data. All five trials did not have results available on ClinicalTrials.gov. We found one publication and four poster presentations reporting results for four of the five covered trials outside of ClinicalTrials.gov. Of 61 specified outcomes, 28 were CONSORT compliant. Specific outcome reporting issues are detailed. Our findings raise substantial concerns regarding these trials. Clinicians, public health professionals, and the public cannot make informed choices about the benefits or hazards of e-cigarettes if the results of clinical trials are not completely and transparently reported. Clarification and potential enforcement of reporting laws may be required.


Estriol: safety and efficacy.
While conventional hormone replacement therapy provides certain benefits, it is not without significant risks. Estriol has been found to provide some of the protection without the risks associated with stronger estrogens. Depending upon the situation, estriol may exert either agonistic or antagonistic effects on estrogen. Estriol appears to be effective at controlling symptoms of menopause, including hot flashes, insomnia, vaginal dryness, and frequent urinary tract infections. Results of research on its bone-density-maintaining effects have been contradictory, with the most promising results coming from Japanese studies. Estriol's effect on cardiac risk factors has also been somewhat equivocal; however, unlike conventional estrogen prescriptions, it does not seem to contribute to hypertension. Although estriol appears to be much safer than estrone or estradiol, its continuous use in high doses may have a stimulatory effect on both breast and endometrial tissue.


Management of Acute Lung Injuries and Acute Respiratory Distress Syndrome in the Tactical and Prolonged Field Care Setting.
The authors examine two acute lung injuries (ALI) that can occur in the tactical setting - positive pressure pulmonary edema and inhalation injury - as well as acute respiratory distress syndrome (ARDS), all of which can quickly progress in a prolonged field care (PFC) environment. These conditions present complex problems to emergency department (ED) and intensive care unit (ICU) teams worldwide, requiring intimate knowledge of their distinct disease pathophysiology and advanced critical care equipment. These challenges are compounded in the world of the Special Operations Forces (SOF) medic who often operates as the sole provider in environments with both limited resources and prolonged evacuation times. It is the hope of the authors that by breaking down these complex critical care topics and providing concrete guidance and treatment recommendations that we can ultimately improve the care SOF medics provide overseas in an austere operational environment.


Recombinant aequorin and recombinant semi-synthetic aequorins. Cellular Ca2+ ion indicators.
Properties of a recombinant aequorin were investigated in comparison with those of natural aequorin. In chromatographic behaviour the recombinant aequorin did not match any of ten isoaequorins tested, although it was very similar to aequorin J. Its sensitivity to Ca2+ was found to be higher than that of any isoaequorin except aequorin D. The recombinant aequorin exhibited no toxicity when tested in various kinds of cells, even where samples of natural aequorin had been found to be toxic. Properties of four recombinant semi-synthetic aequorins (fch-, hcp-, e- and n-types), prepared from the recombinant apo-aequorin and synthetic analogues of coelenterazine, were approximately parallel with those of corresponding semi-synthetic aequorins prepared from natural apo-aequorin. Both recombinant e-aequorin and natural e-aequorin J luminesced with high values of the luminescence intensity ratio I400/I465, although the ratios were not pCa-dependent. The recombinant aequorin and recombinant semi-synthetic aequorins are highly suited for monitoring cellular Ca2+.


Evidence-based antenatal interventions to reduce the incidence of small vulnerable newborns and their associated poor outcomes.
A package of care for all pregnant women within eight scheduled antenatal care contacts is recommended by WHO. Some interventions for reducing and managing the outcomes for small vulnerable newborns (SVNs) exist within the WHO package and need to be more fully implemented, but additional effective measures are needed. We summarise evidence-based antenatal and intrapartum interventions (up to and including clamping the umbilical cord) to prevent vulnerable births or improve outcomes, informed by systematic reviews. We estimate, using the Lives Saved Tool, that eight proven preventive interventions (multiple micronutrient supplementation, balanced protein and energy supplementation, low-dose aspirin, progesterone provided vaginally, education for smoking cessation, malaria prevention, treatment of asymptomatic bacteriuria, and treatment of syphilis), if fully implemented in 81 low-income and middle-income countries, could prevent 5·202 million SVN births (sensitivity bounds 2·398-7·903) and 0·566 million stillbirths (0·208-0·754) per year. These interventions, along with two that can reduce the complications of preterm (<37 weeks' gestation) births (antenatal corticosteroids and delayed cord clamping), could avert 0·476 million neonatal deaths (0·181-0·676) per year. If further research substantiates the preventive effect of three additional interventions (supplementation with omega-3 fatty acids, calcium, and zinc) on SVN births, about 8·369 million SVN births (2·398-13·857) and 0·652 million neonatal deaths (0·181-0·917) could be avoided per year. Scaling up the eight proven interventions and two intrapartum interventions would cost about US$1·1 billion in 2030 and the potential interventions would cost an additional $3·0 billion. Implementation of antenatal care recommendations is urgent and should include all interventions that have proven effects on SVN babies, within the context of access to family planning services and addressing social determinants of health. Attaining high effective coverage with these interventions will be necessary to achieve global targets for the reduction of low birthweight births and neonatal mortality, and long-term benefits on growth and human capital.


Drosophila RNAi screen reveals CD36 family member required for mycobacterial infection.
Certain pathogens, such as Mycobacterium tuberculosis, survive within the hostile intracellular environment of a macrophage. To identify host factors required for mycobacterial entry and survival within macrophages, we performed a genomewide RNA interference screen in Drosophila macrophage-like cells, using Mycobacterium fortuitum. We identified factors required for general phagocytosis, as well as those needed specifically for mycobacterial infection. One specific factor, Peste (Pes), is a CD36 family member required for uptake of mycobacteria, but not Escherichia coli or Staphylococcus aureus. Moreover, mammalian class B scavenger receptors (SRs) conferred uptake of bacteria into nonphagocytic cells, with SR-BI and SR-BII uniquely mediating uptake of M. fortuitum, which suggests a conserved role for class B SRs in pattern recognition and innate immunity.


Reciprocal specialization in multihost malaria parasite communities of birds: a temperate-tropical comparison.
How specialization of consumers with respect to resources varies with respect to latitude is poorly understood. Coexistence of many species in the tropics might be possible only if specialization also increases. Alternatively, lower average abundance of more diverse biotic resources in the tropics might force consumers to become more generalized foragers. We examine levels of reciprocal specialization in an antagonistic system-avian malaria-to determine whether the number of host species used and/or parasite lineages harbored differ between a temperate and a tropical assemblage. We evaluate the results of network analysis, which can incorporate both bird and parasite perspectives on specialization in one quantitative index, in comparison to null models. Specialization was significantly greater in both sample sites than predicted from null models. We found evidence for lower per-host species parasite diversity in temperate compared to tropical birds. However, specialization did not differ between the tropical and temperate sites from the parasite perspective. We supplemented the network analysis with estimates of specialization that incorporate phylogenetic relationships of associates and found no differences between sites. Thus, our analyses indicate that specialization within an antagonistic host-parasite (resource-consumer) system varies little between tropical and temperate localities.


Prostaglandin F2α formation is associated with mortality in a Swedish community-based cohort of older males.
An increasing number of clinical studies highlight the importance of the inflammatory mediator prostaglandin F2 α (PGF(2α)). Prostaglandin F2 α activity has been suggested to play pivotal roles in the development of cardiovascular diseases and cancer. However, whether systemic PGF(2α) concentrations may signal mortality is unknown. The aim was to evaluate in vivo PGF(2α) formation, by measuring urinary 15-keto-dihydro-PGF(2α), and mortality risk in a community setting. Urinary 15-keto-dihydro-PGF(2α) was measured in a Swedish population of 670 men (aged 77-78 years) and the participants were followed up for a median of 9.7 years (383 died, among them 156 of cardiovascular causes and 102 of cancer). In Cox regression models, urinary 15-keto-dihydro-PGF(2α) was significantly associated with cardiovascular mortality [multivariate hazard ratio (HR) for 1 SD increase of urinary 15-keto-dihydro-PGF(2α): 1.18; 95% CI:1.04-1.34; P = 0.01) independent of established cardiovascular risk factors including C-reactive protein. Urinary 15-keto-dihydro-PGF(2α) was also independently associated with total mortality (multivariate HR for 1 SD increase of urinary 15-keto-dihydro-PGF(2α): 1.11; 95% CI: 1.01-1.21; P = 0.03). The combination of 15-keto-dihydro-PGF(2α) concentrations above the median and high serum high-sensitive C-reactive protein (>3 mg/L) was independently associated with a two-fold increased risk of cancer and total mortality (P = 0.02 and P < 0.001, respectively). This is the first study to show that the inflammatory mediator PGF(2α) was independently associated with mortality and specifically cardiovascular mortality 10 years later. The results are in line with the emerging evidence of the importance of the inflammatory mediator PGF(2α) in fatal cardiovascular disease.


Coupled minimum-cost flow cell tracking for high-throughput quantitative analysis.
A growing number of screening applications require the automated monitoring of cell populations in a high-throughput, high-content environment. These applications depend on accurate cell tracking of individual cells that display various behaviors including mitosis, merging, rapid movement, and entering and leaving the field of view. Many approaches to cell tracking have been developed in the past, but most are quite complex, require extensive post-processing, and are parameter intensive. To overcome such issues, we present a general, consistent, and extensible tracking approach that explicitly models cell behaviors in a graph-theoretic framework. We introduce a way of extending the standard minimum-cost flow algorithm to account for mitosis and merging events through a coupling operation on particular edges. We then show how the resulting graph can be efficiently solved using algorithms such as linear programming to choose the edges of the graph that observe the constraints while leading to the lowest overall cost. This tracking algorithm relies on accurate denoising and segmentation steps for which we use a wavelet-based approach that is able to accurately segment cells even in images with very low contrast-to-noise. In addition, the framework is able to measure and correct for microscope defocusing and stage shift. We applied the algorithms on nearly 6000 images of 400,000 cells representing 32,000 tracks taken from five separate datasets, each composed of multiple wells. Our algorithm was able to segment and track cells and detect different cell behaviors with an accuracy of over 99%. This overall framework enables accurate quantitative analysis of cell events and provides a valuable tool for high-throughput biological studies.


Depolarization effects in the human eye.
We have studied the effects of depolarization in the living human eye by using a spatially resolved Mueller-matrix polarimeter [Opt. Lett. 24 (1999) 64]. Results show that the degree of polarization for the central part of double-pass images is about 0.85 and 0.70 for 2 mm and 5 mm of pupil, respectively. This parameter decreases towards the tails of the image. In the plane of the pupil, the degree of polarization also depends on the analyzed area, and it has been related to the different components of the light coming back from the retina. Values of polarizance suggest that the eye presents a slight polarizing power mainly due to the existence of both circular birefringence and dichroic properties. Polarizance is also larger at the central part of double-pass images (about 0.25 on average) and decreases along the radius. In addition, it has been shown that the major retinal layer where the light is reflected does not depend on the state of polarization of the incident light.


A Mixed-Methods Feasibility Study of Integrated Pediatric Complex Care: Experiences of Parents With Care and the Value of Parent Engagement in Research.
Introduction: Children with medical complexity (CMC) are among the most vulnerable children in society. These children and their families face challenges of fragmented care and are at risk for poorer health outcomes. Families with CMC play a vital role in providing care and navigating the complexities of healthcare systems. It is essential to understand the best ways to engage these families in research to improve the care and optimize the health of CMC. Objectives: This study explored parent engagement within the context of a feasibility study evaluating an Integrated Tertiary Complex Care (ITCC) clinic created to support CMC closer to home. This paper aimed: (1) to understand the family experiences of care and (2) to explore parent engagement in the study. Method: This mixed-methods feasibility study included three components. First, feedback from focus groups was used to identify the common themes that informed interviews with parents. Second, one-on-one interviews were conducted with parents to explore their experience with care, such as the ITCC clinic, using an interpretative description approach. Third, the questionnaires were completed by parents at baseline and 6-months post-baseline. These questionnaires included demographic and cost information and three validated scales designed to measure the caregiver strain, family-centered care, and parental health. The recruitment rate, percentage completion of the questionnaires, and open-ended comments were used to assess parent engagement in the study. Results: The focus groups involved 24 parents, of which 19 (14 women, five men) provided comments. The findings identified the importance of Complex Care Team (CC Team) accessibility, local access, and family-centered approach to care. The challenges noted were access to homecare nursing, fatigue, and lack of respite affecting caregiver well-being. In this study, 17 parents participated in one-on-one interviews. The identified themes relevant to care experience were proximity, continuity, and coordination of care. The parents who received care through the ITCC clinic appreciated receiving care closer to home. The baseline questionnaires were completed by 44 of 77 (57%) eligible parents. Only 24 (31%) completed the 6-month questionnaire. The challenges with study recruitment and follow-up were identified. Conclusion: Family engagement was a challenging yet necessary endeavor to understand how to tailor the healthcare to meet the complex needs of families caring for CMC.


Socioeconomic status scales-modified Kuppuswamy and Udai Pareekh's scale updated for 2019.
Socioeconomic status (SES) is one of the prime factors influencing the health status of a nation. It is the measure of the social standing of the individual or a family and has a wide impact on an individual/family's health, educational attainment, diet, lifestyle, etc., The per capita income of citizens is a major factor that decides the SES of the population. The affordability and utilization of the health facilities depend on the socioeconomic profile of the population. The periodic changes in the consumer price of goods globally as well as nationally due to inflation warrants that it is mandatory to constantly update the income-based socioeconomic scales so as the assessment is made correctly in practice. We are making an attempt to provide an updated Kuppuswamy and Udai Pareekh's socioeconomic scales for 2019.


The Development of In Vivo Measures to Assess the Impact of Sex-Drive Reducing Medications in an Offender with an Intellectual Disability.
The ability to adequately evaluate medications in the treatment of paraphilias has been limited by reliance upon self-report as a measure of effectiveness over periods of time that may be too short to detect reoffending. One solution to this shortcoming is the development of valid, long-term, stable assessment measures. The purpose of this case study was to analyze the effects of Prozac and Provera on an array of behaviors germane to the successful treatment of paraphilias, including: (a) sexual arousal in the laboratory and natural environment, (b) sexual thoughts (deviant and nondeviant) accompanied by arousal in the natural environment, and (c) overt actions in the community associated with increased risk of reoffending over a 31-month period for an exhibitionist with an intellectual disability. Despite the ineffectiveness of the medications, the measures demonstrated long-term, differentiated significant clinical responding; further underscored the importance of assessing deviant sexual arousal and adherence to relapse-prevention procedures in the natural environment; and provided a new methodology to assess sexual preoccupations and sexual arousal. Use of these in vivo measures raises questions regarding their potential to improve the predictability of risk assessments, and serve as an aide in the analysis of whether a treatment procedure is effective for an individual.


Gender, Productivity, and Philanthropic Fundraising in Academic Oncology.
Philanthropic donations are important funding sources in academic oncology but may be vulnerable to implicit or explicit biases toward women. However, the influence of gender on donations has not been assessed quantitatively. We queried a large academic cancer center's development database for donations over 10 years to the sundry funds of medical and radiation oncologists. Types of donations and total amounts for medical oncologists and radiation oncologists hired prior to April 1, 2018 (allowing ≥2 years on faculty prior to query), were obtained. We also obtained publicly available data on physician/academic rank, gender, specialty, disease site, and Hirsch-index (h-index), a metric of productivity. We identified 127 physicians: 64% men and 36% women. Median h-index was higher for men (31; range, 1-100) than women (17; range, 3-77; P=.003). Men were also more likely to have spent more time at the institution (median, 15 years; range, 2-43 years) than women (median, 12.5 years; range, 3-22 years; P=.025). Those receiving donations were significantly more likely to be men (70% vs 30%; P=.034). Men received significantly higher median amounts ($259,474; range, $0-$29,507,784) versus women ($37,485; range, $0-$7,483,726; P=.019). On multivariable analysis, only h-index and senior academic rank were associated with donation receipt, and only h-index with donation amount. We found significant gender disparities in receipt of philanthropic donations on unadjusted analyses. However, on multivariable analyses, only productivity and rank were significantly associated with donations, suggesting gender disparities in productivity and promotions may contribute to these differences.


Primary sclerosing cholangitis: a clinical update.
Primary sclerosing cholangitis (PSC) is a progressive cholestatic disorder that ultimately can lead to cirrhosis, liver failure, malignancy and death. It is strongly associated with inflammatory bowel disease (IBD), and though a rare disease, its incidence is increasing. There are no proven medical therapies for PSC. Ovid Medline was utilised to search for articles with keywords 'sclerosing cholangitis' and 'cholangiocarcinoma' and containing titles 'primary sclerosing cholangitis', and references of these papers were cross-referenced for further relevant manuscripts. PSC is a rare disease, and there is a strong association with risk loci within the major histocompatibility complex and other genes common to other autoimmune diseases. PSC is a premalignant condition, associated with higher rates of hepatobiliary and colorectal cancer in patients with ulcerative colitis (UC). The pathogenesis is unclear, and competing theories exist surrounding toxic bile acids, enhanced homing of particular T cells from the gut to the liver and increased passage of toxins to the liver through a permeable bowel wall. It is unclear whether the higher rate of colonic cancer in PSC/UC occurs in PSC/Crohn's disease. Ursodeoxycholic acid therapy reduces liver enzymes but has not been shown to improve survival. It may reduce the prevalence of bowel cancer. Recent genetic studies have revealed new risk loci, pointing to the importance of the immune system and its interaction with the biome. On the basis of the genetic studies discussed earlier, novel agents are being developed and trialled in the treatment of PSC.


Isolation and Characterization of NDM-Positive Escherichia coli from Municipal Wastewater in Jeddah, Saudi Arabia.
The emergence of resistance to last-resort antibiotics is a public health concern of global scale. Besides direct person-to-person propagation, environmental pathways might contribute to the dissemination of antibiotic-resistant bacteria and antibiotic resistance genes (ARGs). Here, we describe the incidence of blaNDM-1, a gene conferring resistance to carbapenems, in the wastewater of the city of Jeddah, Saudi Arabia, over a 1-year period. blaNDM-1 was detected at concentrations ranging from 10(4) to 10(5) copies/m(3) of untreated wastewater during the entire monitoring period. These results indicate the ubiquity and high incidence of blaNDM-1 in the local wastewater. To track the bacteria carrying blaNDM-1, we isolated Escherichia coli PI7, a strain of sequence type 101 (ST101), from wastewater around the Hajj event in October 2013. Genome sequencing of this strain revealed an extensive repertoire of ARGs as well as virulence and invasive traits. These traits were further confirmed by antibiotic resistance profiling and in vitro cell internalization in HeLa cell cultures. Given that this strain remains viable even after a certain duration in the sewerage, and that Jeddah lacks a robust sanitary infrastructure to fully capture all generated sewage, the presence of this bacterium in the untreated wastewater represents a potential hazard to the local public health. To the best of our knowledge, this is the first report of a blaNDM-1-positive E. coli strain isolated from a nonnosocomial environment in Saudi Arabia and may set a priority concern for the need to establish improved surveillance for carbapenem-resistant E. coli in the country and nearby regions.


Treatment of agoraphobia with group exposure in vivo and imipramine.
Seventy-six white agoraphobic women, 21 to 45 years old, were treated with combined group exposure in vivo and imipramine or placebo in a randomized double-blind study. A majority of the patients in both the placebo and imipramine groups showed moderate to marked improvement. However, imipramine therapy was significantly superior to placebo therapy on three of the four reported measures of improvement: primary phobia, spontaneous panic, and global improvement. There was a negative correlation between depression and outcome; ie, the more depressed patients fared worse on several outcome measures than those who were less depressed. A comparison of these patients with agoraphobic women previously treated with imipramine and imaginal desensitization showed a superiority of exposure in vivo midway in treatment, but no significant difference between the two groups at the completion of therapy.


Lycopene, a powerful antioxidant, significantly reduces the development of the adhesion phenotype.
Postoperative adhesions are a common medical complication of gynecologic and other pelvic surgeries resulting in persistent pelvic pain, obstruction of the intestines, and even infertility. The molecular mechanisms of postoperative adhesion development remain to be elucidated. We have recently described a role for reactive oxygen species, specifically superoxide, in the development of postoperative adhesions. In this study, we sought to determine whether lycopene, a potent antioxidant, reduces markers characteristic of the adhesion phenotype. Primary fibroblast cultures from normal peritoneum and adhesion tissues were utilized to determine mRNA levels of adhesion phenotype markers type I collagen, transforming growth factor-beta 1 (TGF-β1), and vascular endothelial growth factor (VEGF) in response to lycopene (24 hours, 10 μM) treatment. There was a 2 (p < 0.003), 4.7 (p < 0.004), and 1.6 fold (p < 0.004) increase in mRNA levels of type I collagen, TGF-β1, and VEGF, respectively, in adhesion as compared to normal peritoneal fibroblasts. Lycopene treatment led to a 6.8 and a 12.4 fold decrease in type I collagen mRNA levels, in normal peritoneal and adhesion fibroblasts, respectively (p < 0.005). Lycopene treatment led to a 4.2 (p < 0.03) and a 4.6 (p < 0.05) fold decrease in VEGF mRNA levels, in normal peritoneal and adhesion fibroblasts, respectively. Lycopene treatment led to a 7.0 fold decrease in TGF-β1 mRNA levels, in adhesion fibroblasts (p < 0.03). A 1.9 fold decrease in TGF-β1 mRNA was observed in normal peritoneal fibroblasts in response to treatment, although it was not significant. Lycopene substantially reduced levels of adhesion phenotype markers in normal peritoneal and adhesion fibroblasts and whether it will reduce postoperative adhesions needs to be further investigated.


X-ray ptychography with extended depth of field.
Ptychographic X-ray computed tomography is a coherent diffractive imaging method that offers nanometer-scale resolution with quantitative contrast. It offers the possibility to study relatively thick samples by using high energy X-ray photons and exploiting the phase contrast. However, the limited depth of field forces a compromise between resolution and sample thickness. Multi-slice techniques have been used to account for propagation effects within the sample, enabling imaging beyond the depth-of-field limit. Here we introduce and experimentally demonstrate our multi-slice algorithms that allow for the reconstruction of multiple object slices and the incident illumination, as well as the retrieval of unknown object thickness. Additionally, through numerical studies, we show that smaller scanning steps surprisingly increase the depth of field, which can be further extended by the use of multi-slice methods under conditions stated by theoretical expressions. The results presented here will be instrumental for the routine implementation of the technique for X-ray nanotomography.


Angiotensin II as a potential method of targeting cytotoxic-loaded microspheres in patients with colorectal liver metastases.
Regional chemotherapy is commonly used to treat patients with colorectal liver metastases. However, improvement in survival has still not been demonstrated. Cytotoxic loaded albumin microspheres for arterial administration have been described as a means of improving the the therapeutic index, but their distribution depends upon the prevailing pattern of arterial blood-flow at the time of injection. In this study, the ability of the vasoactive drug angiotensin II to target arterially injected microspheres to colorectal liver metastases is assessed in nine patients using scintigraphic planar and tomographic imaging. The median tumour: normal ratio in nine patients with colorectal liver metastases was 3.4:1 before the administration of angiotensin II. The corresponding ratio after administration of angiotensin II was 7.3:1. The median improvement factor was 1.8 (P less than 0.05). The data suggest that worthwhile tumour targeting can be achieved with angiotensin II in patients with colorectal liver metastases.


RASER-FISH: non-denaturing fluorescence in situ hybridization for preservation of three-dimensional interphase chromatin structure.
DNA fluorescence in situ hybridization (FISH) has been a central technique in advancing our understanding of how chromatin is organized within the nucleus. With the increasing resolution offered by super-resolution microscopy, the optimal maintenance of chromatin structure within the nucleus is essential for accuracy in measurements and interpretation of data. However, standard 3D-FISH requires potentially destructive heat denaturation in the presence of chaotropic agents such as formamide to allow access to the DNA strands for labeled FISH probes. To avoid the need to heat-denature, we developed Resolution After Single-strand Exonuclease Resection (RASER)-FISH, which uses exonuclease digestion to generate single-stranded target DNA for efficient probe binding over a 2 d process. Furthermore, RASER-FISH is easily combined with immunostaining of nuclear proteins or the detection of RNAs. Here, we provide detailed procedures for RASER-FISH in mammalian cultured cells to detect single loci, chromatin tracks and topologically associating domains with conventional and super-resolution 3D structured illumination microscopy. Moreover, we provide a validation and characterization of our method, demonstrating excellent preservation of chromatin structure and nuclear integrity, together with improved hybridization efficiency, compared with classic 3D-FISH protocols.


An integer programming approach to the phase problem for centrosymmetric structures.
The problem addressed in this paper is the determination of three-dimensional structures of centrosymmetric crystals from X-ray diffraction measurements. The 'minimal principle' that a certain quantity is minimized only by the crystal structure is employed to solve the phase problem. The mathematical formulation of the minimal principle is a nonconvex nonlinear optimization problem. To date, local optimization techniques and advanced computer architectures have been used to solve this problem, which may have a very large number of local optima. In this paper, the minimal principle model is reformulated for the case of centrosymmetric structures into an integer programming problem in terms of the missing phases. This formulation is solvable by well established combinatorial optimization techniques that are guaranteed to provide the global optimum in a finite number of steps without explicit enumeration of all possible combinations of phases. Computational experience with the proposed method on a number of structures of moderate complexity is provided and demonstrates that the approach yields a fast and reliable method that resolves the crystallographic phase problem for the case of centrosymmetric structures.


Rapid induction of alternative lengthening of telomeres by depletion of the histone chaperone ASF1.
The mechanism of activation of the alternative lengthening of telomeres (ALT) pathway of mammalian chromosome-end maintenance has been unclear. We have now discovered that co-depletion of the histone chaperones ASF1a and ASF1b in human cells induced all hallmarks of ALT in both primary and cancer cells. These included the formation of ALT-associated PML (promyelocytic leukemia) bodies (APBs), the presence of extrachromosomal telomeric DNA species, an elevated frequency of telomeric sister chromatid exchanges (t-SCE) events and intertelomeric exchange of an integrated tag. The induction of ALT characteristics in this setting led to the simultaneous suppression of telomerase. We determined that ALT induction is positively regulated by the proteins RAD17 and BLM and negatively regulated by EXO1 and DNA2. The induction of ALT phenotypes as a consequence of ASF1 depletion strongly supports the hypothesis that ALT is a consequence of histone management dysfunction.


Quality of care and interhospital collaboration: a study of patient transfers in Italy.
We examine the dynamics of patient-sharing relations within an Italian regional community of 35 hospitals serving approximately 1,300,000 people. We test whether interorganizational relations provide individual patients access to higher quality providers of care. We reconstruct the complete temporal sequence of the 3461 consecutive interhospital patient-sharing events observed between each pair of hospitals in the community during 2005-2008. We distinguish between transfers occurring between and within different medical specialties. We estimate newly derived models for relational event sequences that allow us to control for the most common forms of network-like dependencies that are known to characterize collaborative relations between hospitals. We use 45-day risk-adjusted readmission rate as a proxy for hospital quality. After controls (eg, geographical distance, size, and the existence of prior collaborative relations), we find that patients flow from less to more capable hospitals. We show that this result holds for patient being shared both between as well as within medical specialties. Nonetheless there are strong and persistent other organizational and relational effects driving transfers. Decentralized patient-sharing decisions taken by the 35 hospitals give rise to a system of collaborative interorganizational arrangements that allow the patient to access hospitals delivering a higher quality of care. This result is relevant for health care policy because it suggests that collaborative relations between hospitals may produce desirable outcomes both for individual patients, and for regional health care systems.


The influence of end abutment and cantilever fixed partial dentures on periodontal health.
The influence of end abutment and cantilever fixed partial dentures on periodontal health was examined in 12 patients with periodontally reduced residual dentition. The prosthetic appliances had been integrated for 4 to 6 years before the first follow-up examination and had no technical defects at baseline. Two follow-up examinations were performed at a 12-month interval to record clinical and microbiologic parameters of 62 abutment teeth, 45 of which were fitted with end abutment fixed partial dentures and 17 with cantilever fixed partial dentures. Both types of fixed partial dentures were represented in all patients. The patients were on a 6 to 8-week recall schedule throughout the study period and had good oral hygiene. At both examinations, subgingival plaque samples were taken at all proximal surfaces and evaluated by dark-field microscopy. The clinical parameters used were Gingival Index, Plaque Index, pocket probing depth, and attachment level. The results showed that both types of fixed partial dentures were compatible with periodontal health subject to optimal oral hygiene. The clinical parameters recorded remained stable at a very low level throughout the study period and were almost identical in both groups. A slight gain in clinical attachment level, with a mean value of 0.19 mm for abutment teeth fitted with cantilever fixed partial dentures and of 0.32 for end abutment fixed partial dentures, was registered during the study period. The composition of the subgingival plaque showed a microflora reflecting virtually health periodontal conditions. The proportion of motile rods and spirochetes was slightly elevated in both groups. In conclusion, it can be stated that both fixed partial denture types display identical characteristics in the periodontally damaged dentition and do not lead to deterioration of the periodontal situation if oral hygiene is closely monitored.


Some factors controlling the attachment of the rumen holotrich protozoa Isotricha intestinalis and I. prostoma to plant particles in vitro.
The rumen holotrich protozoa Isotricha intestinalis and I. prostoma showed chemotaxis to sucrose, glucose and fructose. They attached themselves, by means of an organelle on the anterior cell surface, to particulate sources of these carbohydrates provided soluble protein was present in the medium. The concentration of protein eliciting attachment varied with the species and the state of nutrition of the cell, but was between 20 and 150 microgram ml-1. Attachment occurred only if the concentration of carbohydrate, at its source, exceeded the chemotaxis threshold concentration (50 micrometer for sucrose) and if it was less than 1 mM. At concentrations exceeding 1 mM, indiscriminate attachment to gas-liquid and solid-liquid interfaces occurred, provided the protein concentration was high enough to elicit attachment. In the rumen, soluble carbohydrates diffusing from food particles may attract the protozoa which attach themselves to the particles in the presence of soluble plant protein at less than 20 microgram ml-1; these conditions exist in the host animal soon after feeding when fed infrequently. The attachment mechanism may confer an ecological advantage on the Isotricha spp. over other rumen organisms dependent on soluble carbohydrates as energy and carbon sources.


Intrinsic axonal degeneration pathways are critical for glaucomatous damage.
Glaucoma is a neurodegenerative disease affecting 70million people worldwide. For some time, analysis of human glaucoma and animal models suggested that RGC axonal injury in the optic nerve head (where RGC axons exit the eye) is an important early event in glaucomatous neurodegeneration. During the last decade advances in molecular biology and genome manipulation have allowed this hypothesis to be tested more critically, at least in animal models. Data indicate that RGC axon degeneration precedes soma death. Preventing soma death using mouse models that are mutant for BAX, a proapoptotic gene, is not sufficient to prevent the degeneration of RGC axons. This indicates that different degeneration processes occur in different compartments of the RGC during glaucoma. Furthermore, the Wallerian degeneration slow allele (Wld(s)) slows or prevents RGC axon degeneration in rodent models of glaucoma. These experiments and many others, now strongly support the hypothesis that axon degeneration is a critical pathological event in glaucomatous neurodegeneration. However, the events that lead from a glaucomatous insult (e.g. elevated intraocular pressure) to axon damage in glaucoma are not well defined. For developing new therapies, it will be necessary to clearly define and order the molecular events that lead from glaucomatous insults to axon degeneration.


Overexpression of dominant-negative Ikaros 6 protein is restricted to a subset of B common adult acute lymphoblastic leukemias that express high levels of the CD34 antigen.
Ikaros is a critical regulator of hematopoiesis. Its effects result in part from the balance between the isoforms that are produced by differential splicing of the pre-mRNA. Short isoforms that lack the DNA-binding domain act as dominant negatives by binding long isoforms through the C-terminal zinc-finger domain, which allows for the homo- or heterodimerization of the proteins. There are a number of evidences that different subsets of murine hematopoietic progenitors - as defined by phenotype - have different patterns of Ikaros expression. Forced expression of short isoforms (Ik5, Ik6 or Ik7) in murine or human hematopoietic progenitors alters the differentiation capacities of these cells. Human leukemias provide additional information: because of the blockade in differentiation, leukemias represent an equivalent of a particular stage of human hematopoietic hierarchy. We and others have shown that human acute leukemias are heterogeneous for the pattern of Ikaros isoform expression. The present study focused on adult de novo B ALLs and the Ikaros 6 isoform. ProB (BI, n=3), common B (BII, n=15) and preB (BIII, n=3) ALL were identified by their phenotype. RT-PCR and Western blot analyses of blast cell protein lysates suggest that approximately 50% of BII leukemias overexpress Ikaros 6 RNA and protein. Comparison of BII cells with high or normal levels of Ik6 shows a higher level of expression for the membrane stem cell antigen CD34 in the former, as detected with flow cytometry and confirmed with DNA arrays.


Hydrolysis of the E2P phosphoenzyme of the Ca(2+)-ATPase: a theoretical study.
Dephosphorylation of the E2P phosphoenzyme intermediate of the sarcoplasmic reticulum Ca(2+)-ATPase was studied using density functional theory. The hydrolysis reaction proceeds via a nucleophilic attack on the phosphorylated residue Asp351 by a water molecule, which is positioned by the nearby residue Glu183 acting as a base. The activation barrier was calculated to be 14.3 kcal/mol, which agrees well with values of 15-17 kcal/mol derived from experimentally observed rates. The optimized structure of the transition state reveals considerable bond breakage between phosphorus and the Asp351 oxygen (distance 2.19 Å) and little bond formation to the attacking water oxygen (distance 2.26 Å). Upon formation of the singly protonated phosphate product, Glu183 becomes protonated. The bridging aspartyl phosphate oxygen approaches Lys684 progressively when proceeding from the reactant state (distance 1.94 Å) via the transition state (1.78 Å) to the product state (1.58 Å). This stabilizes the negative charge that develops on the leaving group. The reaction was calculated to be slightly endergonic (+0.9 kcal/mol) and therefore reversible, in line with experimental findings. It is catalyzed by a preorganized active site with little movement of the nonreacting groups except for a rotation of Thr625 toward the phosphate group.


Intrathecal fentanyl for prevention of shivering in spinal anesthesia in cesarean section.
Shivering is one of the common problems in spinal anesthesia. The objective of the present study was to evaluate the effect of intrathecal fentanyl (25 µg) on incidence and severity of intraoperative and postoperative shivering. A double-blind randomized controlled study was conducted in eighty healthy women (ASA Physical status I) scheduled for elective cesarean section under spinal anesthesia. Subjects were randomly divided into two equal groups. The patients received 12.5 mg (2.5ml) of 0.5% hyperbaric bupivacaine combined with 25 µg (0.5 ml) fentanyl in Group F as a study group and 12.5 mg (2.5ml) of 0.5% hyperbaric bupivacaine combined with 0.5 ml normal saline in Group S as a control group. Incidence of shivering during 30 and 60 minutes of surgery and recovery and complications were evaluated. The total incidence of shivering in Group F was significantly lower than Group S (10% in group F; 75% in group S, p< 0.0001). Almost all patients started shivering in the first hour after spinal anesthesia and the rate of shivering especially in second 30 minutes was higher than first 30 minutes in both groups. None in Group F but 22 patients (55%) in Group S had shivering during recovery and all of them reported shivering at the first 30 minute at recovery. The severity of shivering in Group F was significantly lower than Group S (p <0.0001). Intrathecal bupivacaine combined with fentanyl is associated with a lower incidence and severity of shivering.


Pseudobacteraemia in a patient with neutropenic fever caused by a novel paenibacillus species: Paenibacillus hongkongensis sp. nov.
To characterise a strain of Gram negative aerobic straight or slightly curved rods (HKU3) isolated from the blood culture of a 9 year old Chinese boy with neutropenic fever and pseudobacteraemia. The isolate was phenotypically investigated by standard biochemical methods using conventional biochemical tests, scanning electron microscopy, and transmission electron microscopy. Genotypically, the 16S rRNA gene of the bacterium was amplified by the polymerase chain reaction (PCR) and sequenced. The sequence of the PCR product was compared with known 16S rRNA gene sequences in the Genbank by multiple sequence alignment. The G + C content was determined by thermal denaturation. A phylogenetic tree was constructed by the PileUp method. The cells of the bacterial strain were aerobic, sporulating, Gram negative straight or slight curved rods. The bacterium grew on horse blood agar as non-haemolytic, grey colonies of 1 mm in diameter after 24 hours of incubation at 37 degrees C in ambient air. No enhancement of growth was seen in 5% CO(2). It grew at 50 degrees C as pinpoint colonies after 72 hours of incubation, but did not grow at 65 degrees C or on MacConkey agar. It was non-motile. It produced catalase (weakly positive) and cytochrome oxidase. It reduced nitrate, produced beta galactosidase, hydrolysed esculin, and utilised sodium acetate. A scanning electron micrograph of the bacterium showed straight or slightly curved rods. A transmission electron micrograph of the cell wall of the bacterium revealed multiple electron dense layers, including the outer membrane, middle murein layer, and inner cytoplasmic membrane, compatible with its Gram smear appearance. 16S rRNA gene sequencing showed that there were 7.7%, 8.0%, 8.2%, and 8.6% differences between the 16S rRNA gene sequence of the bacterium and those of Paenibacillus macerans, Paenibacillus borealis, Bacillus ehimensis, and Paenibacillus amylolyticus, respectively. The mean (SD) G + C content of the bacterium was 47.6 (2.1) mol%. Phylogenetically, it belongs to the genus paenibacillus (previously called group 3 bacillus). A bacterium that exhibited phenotypic and genotypic characteristics that are very different from closely related members of paenibacillus was the cause of pseudobacteraemia in a patient with neutropenic fever. A new species, Paenibacillus hongkongensis sp. nov. is proposed, for which HKU3 is the type strain.


Crucial contextual attributes of nursing leadership towards a care ethics.
It is of importance to understand and communicate caring ethics as a ground for qualitative caring environments. Research is needed on nursing attributes that are visible in nursing leadership since it may give bases for reflections related to the patterns of specific contexts. The aim of this study was to illuminate the meaning of crucial attributes in nursing leadership toward an ethical care of patients in psychiatric in-patient settings. The design of the study was descriptive and qualitative with a phenomenological hermeneutical approach. Participants and research context: The study comprised focus group interviews with nurses working in indoor psychiatric care who participated after giving informed consent. Ethical considerations: Since the topic and informants are not labeled as sensitive and subject to ethical approval, it is not covered by the ethics committee's aim and purpose according to Swedish law. However, careful procedures have been followed according to ethics expressed in the Declaration of Helsinki. When identifying the thematic structures, analysis resulted in three major themes: To supply, including the following aspects: to supply evidence, to supply common space, and to supply good structures; To support, including the following aspects: to be a role model, to show appreciation and care, and to harbor; To shield, including the following aspects: to advocate, to emit non-tolerance of unethical behavior, and to reprove. Leadership is challenging for nurses and plays an important role in ethical qualitative care. These findings should not be understood as a description about nurse manager's role, which probably has different attributes and more focus on an organizational level. Making the understanding about crucial attributes explicit, the nurse may receive confirmation and recognition of crucial attributes for ethical care in order to move toward an ethical care.


The psychological costs of unsustainable housing commitments.
The extended recession and stagnant housing market in the 1990s following the boom of the late 1980s resulted in more than half a million housing repossessions. This study explores the impact of unsustainable housing commitments on psychological well-being. We test the hypotheses that housing payment problems and housing arrears have adverse impacts on heads of households' psychological well-being over and above those caused by financial hardship more generally. Data came from the British Household Panel Survey 1991-2003 and the samples for analysis consist of: (1) 5651 male head of households producing 26618 person-year observations, and (2) 2534 female head of households producing 9091 person-year observations. Summary statistics and multivariate, fixed effects regression models are used. Mental health was measured by the 12-item General Health Questionnaire. For male heads of households housing payment problems and entering arrears have significant detrimental effects on mental well-being and for female heads of households longer-term housing payment problems and arrears have significant detrimental effects on mental well-being. The sizes of these effects are in addition to and larger in magnitude than those associated with financial hardship more generally. The net effects appear to be relatively stable over the time of the panel data. This study provides evidence that housing payment problems have independent psychological costs over and above those associated with general financial hardship. The magnitude of the effect is similar to that shown for marital breakdown and job loss.


[Osteoporosis prevention initiated with peripheral quantitative computerized tomography. Thin-layer and multi-layer technique].
In a representative, randomized control group of 70 healthy confirmed postmenopausal women (natural menopause for one to four years) with an average age of 52 years, it was possible to carry out a prospective study over a period of two years, during which the bone mass was investigated regularly by means of peripheral quantitative computed tomography (pQCT, Densiscan type, thin- and multi-layer technology). The distal, purely trabecular and purely compact bone mass of the radius and tibia are measured separately. The epiphyseal trabecular bone masses of the radius and tibia (262 +/- 8 mg/cm3 and 252 +/- 8 mg/cm3, respectively) are initially homogeneous, but over time they show different rates of yearly loss of bone mass: 3.0 +/- 0.4%, compared with 1.5 +/- 0.3% (means +/- SEM). Based on the bimodal frequency distribution of the annual loss rates in the core trabecular volume of the distal radius, fast losers lose more than 3.5% per year, with no significant difference between the first and the second year of observation. Women in the quintile with the highest trabecular bone mass (328 to 458 mg/cm3 at baseline) are slow losers. These women show an absolute loss of 3 mg/cm3 per year, while the women in the lowest quintile (102 to 210 mg/cm3 at baseline), with a proportion of 64% fast losers, lose an average of 10 mg/cm3, irrespective of age, number of fertile years, age at menopause and body-mass index. The bone masses in the metaphyseal compact bone remain constant.2+ a screening program before architectural changes in trabecular bone reach a critical point (i.e. in the reversible stage of osteoporosis), these women can be reliably identified within six months and monitored effectively and economically. With the general risk factors of postmenopausal osteoporosis an individual's risk of rapid bone loss cannot be predicted or determined; therefore, the precise measurement of purely trabecular bone is indispensable.


Apoptosis stimulating protein of p53 (ASPP2) expression differs in diffuse large B-cell and follicular center lymphoma: correlation with clinical outcome.
ASPP2 interacts with the tumor suppressor protein p53, promotes damage-induced apoptosis, and can specifically stimulate p53 apoptotic function. Thus, ASPP2 may function as a tumor suppressor and/or play a role in the cellular response to cytotoxic injury. To explore the role of ASPP2 in human cancer, we determined ASPP2 expression in two lymphoma subtypes with differing clinical outcomes: diffuse large B-cell lymphoma (DLBCL) and follicular center lymphoma (FCL). A real-time reverse transcription-polymerase chain reaction (RT-PCR) assay was developed to detect ASPP2 mRNA. Sixty-one DLBCL and twenty-three FCL cases were analyzed and normalized ASPP2 levels were expressed relative to an mRNA standard. We found that ASPP2 mean expression strongly correlated with lymphoma subtype: DLBCL = 11.74 and FCL = 4.99 (p = 0.029, unpaired 2-tailed t-test). Importantly, ASPP2 expression was variable in DLBCL but not FCL (DLBCL-range, 0.04-94.6; FCL-range, 1.2-15.0). In these DLBCL cases, serum lactate dehydrogenase (LDH) was an independent predictor of survival with median survival in the high LDH group of 24 months and median survival not achieved in the normal-low LDH group (p = 0.014, Log-Rank Test). Mean ASPP2 levels trended toward an inverse correlation with LDH levels: High LDH, ASPP2 = 6.2; Normal-low LDH, ASPP2 = 18.2 (p = 0.074, unpaired 2-tailed t-test). In the DLBCL cases with ASPP2 levels > 7.8, only 10% (1/10) had a high LDH, in contrast to cases with ASPP2 levels < 7.8 in which 59% (26/44) had a high LDH (p = 0.011, Fisher Exact Test). Thus, low ASPP2 mRNA levels may correlate with poor clinical outcome in lymphoma which is consistent with the hypothesis that ASPP2 may play a role in tumor formation and/or sensitivity to cytotoxic agents. Larger studies as well as analysis of different tumor types are warranted.


In vitro effects of prolonged exposure to quercetin and epigallocatechin gallate of the peripheral blood mononuclear cell membrane.
The study aimed to assess biophysical changes that take place in the peripheral blood mononuclear cell (PBMC) membranes when exposed in vitro to 10 μM quercetin or epigallocatechin gallate (EGCG) for 24 and 48 h. PBMCs isolated from hypercholesterolemia patients were compared to those from normocholesterolemia subjects. The membrane fluidity and transmembrane potential were evaluated and the results were correlated with biochemical parameters relevant to oxidative stress, assessed in the patients' plasma. The baseline value of PBMC membrane anisotropy for the hypercholesterolemia patients was lower than that of the control group. These results correlated with the plasma levels of advanced glycation end products, which were significantly higher in the hypercholesterolemia group, and the total plasma antioxidant status, which was significantly higher in normocholesterolemia subjects. In the case of normocholesterolemia cells in vitro, polyphenols induced a decrease in membrane anisotropy (7.25-11.88% at 24 h, 1.82-2.26% at 48 h) and a hyperpolarizing effect (8.30-8.90% at 24 h and 4.58-13.00% at 48 h). The same effect was induced in hypercholesterolemia cells, but only after 48 h exposure to the polyphenols: the decrease in membrane anisotropy was 5.70% for quercetin and 2.33% for EGCG. After 48 h of in vitro incubation with the polyphenols, PBMCs isolated from hypercholesterolemia patients exhibited the effects that had been registered in cells from normocholesterolemia subjects after 24 h exposure. These results outlined the beneficial action of the studied polyphenols, quercetin and EGCG, as dietary supplements in normocholesterolemia and hypercholesterolemia patients.


Type II spiral ganglion afferent neurons drive medial olivocochlear reflex suppression of the cochlear amplifier.
The dynamic adjustment of hearing sensitivity and frequency selectivity is mediated by the medial olivocochlear efferent reflex, which suppresses the gain of the 'cochlear amplifier' in each ear. Such efferent feedback is important for promoting discrimination of sounds in background noise, sound localization and protecting the cochleae from acoustic overstimulation. However, the sensory driver for the olivocochlear reflex is unknown. Here, we resolve this longstanding question using a mouse model null for the gene encoding the type III intermediate filament peripherin (Prph). Prph((-/-)) mice lacked type II spiral ganglion neuron innervation of the outer hair cells, whereas innervation of the inner hair cells by type I spiral ganglion neurons was normal. Compared with Prph((+/+)) controls, both contralateral and ipsilateral olivocochlear efferent-mediated suppression of the cochlear amplifier were absent in Prph((-/-)) mice, demonstrating that outer hair cells and their type II afferents constitute the sensory drive for the olivocochlear efferent reflex.


Characterization of a novel alanine-rich protein located in surface microdomains in Trypanosoma brucei.
Heterologous expression in COS cells followed by orientation-specific polymerase chain reaction to select and amplify cDNAs encoding surface proteins in Trypanosoma brucei resulted in the isolation of a cDNA ( approximately 1.4 kilobase) which encodes an acidic, alanine-rich polypeptide that is expressed only in bloodstream forms of the parasite and has been termed bloodstream stage alanine-rich protein (BARP). Analysis of the amino acid sequence predicted the presence of a typical NH(2)-terminal leader sequence as well as a COOH-terminal hydrophobic extension with the potential to be replaced by a glycosylphosphatidylinositol anchor. A search of existing protein sequences revealed partial homology between BARP and the major surface antigen of procyclic forms of Trypanosoma congolense. BARP migrated as a complex, heterogeneous series of bands on Western blots with an apparent molecular mass ( approximately 50-70 kDa) significantly higher than predicted from the amino acid sequence ( approximately 26 kDa). Confocal microscopy demonstrated that BARP was present in small discrete spots that were distributed over the entire cellular surface. Detergent extraction experiments revealed that BARP was recovered in the detergent-insoluble, glycolipid-enriched fraction. These data suggested that BARP may be sequestered in lipid rafts.


MEASURING ECONOMIC GROWTH FROM OUTER SPACE.
GDP growth is often measured poorly for countries and rarely measured at all for cities or subnational regions. We propose a readily available proxy: satellite data on lights at night. We develop a statistical framework that uses lights growth to augment existing income growth measures, under the assumption that measurement error in using observed light as an indicator of income is uncorrelated with measurement error in national income accounts. For countries with good national income accounts data, information on growth of lights is of marginal value in estimating the true growth rate of income, while for countries with the worst national income accounts, the optimal estimate of true income growth is a composite with roughly equal weights. Among poor-data countries, our new estimate of average annual growth differs by as much as 3 percentage points from official data. Lights data also allow for measurement of income growth in sub- and supranational regions. As an application, we examine growth in Sub Saharan African regions over the last 17 years. We find that real incomes in non-coastal areas have grown faster by 1/3 of an annual percentage point than coastal areas; non-malarial areas have grown faster than malarial ones by 1/3 to 2/3 annual percent points; and primate city regions have grown no faster than hinterland areas. Such applications point toward a research program in which "empirical growth" need no longer be synonymous with "national income accounts."


Beta-carotene degradation products - formation, toxicity and prevention of toxicity.
Carotenoids are widely used as important micronutrients in food. Furthermore, carotenoid supplementation has been used in the treatment of diseases associated with oxidative stress such as various types of cancer, inflammatory diseases or cystic fibrosis. However, in some clinical studies harmful effects have been observed, e.g. a higher incidence of lung cancer in individuals exposed to extraordinary oxidative stress. The causal mechanisms of harmful effects are still unclear. Carotenoid breakdown products (CBPs) including highly reactive aldehydes and epoxides are formed during oxidative attacks in the course of antioxidative action. We investigated the formation of CBPs by stimulated neutrophils (and at further conditions), tested the hypothesis that CBPs may exert mitochondriotoxicity and tried to prevent toxicity in the presence of members of the antioxidative network. Stimulated neutrophils are able to degrade beta-carotene and to generate a number of CBPs. Concerning mitochondriotoxicity, we found that CBPs strongly inhibit state 3 respiration of rat liver mitochondria at concentrations between 0.5 and 20 microM. This was true for retinal, beta-ionone, and for mixtures of cleavage/breakdown products. The inhibition of mitochondrial respiration was accompanied by a reduction in protein sulfhydryl content, decreasing GSH levels and redox state, and elevated accumulation of malondialdehyde. Changes in mitochondrial membrane potential favor functional deterioration in the adenine nucleotide translocator as a sensitive target. The presence of additional antioxidants such as alpha-tocopherol, ascorbic acid, N-acetyl-cysteine or others could mitigate mitochondriotoxicity. The findings reflect a basic mechanism of increasing the risk of cancer induced by carotenoid degradation products.


Varied Definitions of Nasolabial Angle: Searching for Consensus Among Rhinoplasty Surgeons and an Algorithm for Selecting the Ideal Method.
The nasolabial angle (NLA) is an important aesthetic metric for nasal assessment and correction. Although the literature offers many definitions, none has garnered universal acceptance. To gauge the consensus level among practitioners, surveys were administered to a convenience sample of rhinoplasty surgeons soliciting practice characteristics, self-assessment of rhinoplasty experience and expertise, and preferred NLA definition. Choices of NLA definition included the angle between: (A) columella and line intersecting subnasale and labrale superius; (B) columella and line tangent to philtrum; (C) nostril long axis and Frankfort perpendicular; and (D) nostril long axis and vertical facial plane. Of the 82 total respondents, mean age was 50 years (range, 30-80years), and mean professional experience was 17 years (range, 0-67 years). Nineteen described themselves as novice rhinoplasty surgeons, 27 as intermediates, and 36 as experts. Mean number of lifetime rhinoplasties performed was 966 (range, 0-10,000). Twenty respondents (24%) agreed with definition A, 27 (33%) with B, 16 (20%) with C, and 13 (16%) with D. Six chose "other," offering their own explanations of NLA. Self-identified novices were more likely to prefer definition D than were experts (P = 0.009). No majority consensus was reached regarding the definition of NLA. Each method has its benefits and drawbacks, and establishing a single one may be unnecessary and even counterproductive in some cases. Having options available means that surgeons can tailor to each encounter, as long as they adopt a systematic methodology. We submit an algorithm to facilitate this effort.


Wild leafy vegetable use and knowledge across multiple sites in Morocco: a case study for transmission of local knowledge?
There are few publications on the use and diversity of wild leafy vegetables (WLVs) in Morocco. In order to address this gap, we conducted ethnobotanical field work in Taounate, Azilal and El House regions. Ethnobotanical collections, free listing, qualitative interviews and a 7 day food frequency questionnaire. More than 30 species in 23 genera of WLV were identified. Of these 4 had not previously recorded as WLVs used in Morocco in the literature. WLVs were used by 84% of households surveyed in Taounate (N = 61, in March 2005), and were used up to 4 times a week. Qualitative data revealed both positive and negative perceptions of WLVs and detailed knowledge about preparation among women. The greatest diversity of WLV knowledge and use was in the Rif Mountains (Taounate). There was significant variation in nomenclature and salience of WLVs, not only between regions, but also between villages in the same region. Within the same region (or even village) different local names were used for a given species or genus, and different species were identified by the same local name (including species from different botanical families). Data showed greater overlap in knowledge among villages using the same market. We believe the results suggest that markets are important sites for WLV knowledge transmission.


Estimating treatment effects for individual patients based on the results of randomised clinical trials.
To predict treatment effects for individual patients based on data from randomised trials, taking rosuvastatin treatment in the primary prevention of cardiovascular disease as an example, and to evaluate the net benefit of making treatment decisions for individual patients based on a predicted absolute treatment effect. As an example, data were used from the Justification for the Use of Statins in Prevention (JUPITER) trial, a randomised controlled trial evaluating the effect of rosuvastatin 20 mg daily versus placebo on the occurrence of cardiovascular events (myocardial infarction, stroke, arterial revascularisation, admission to hospital for unstable angina, or death from cardiovascular causes). Population 17,802 healthy men and women who had low density lipoprotein cholesterol levels of less than 3.4 mmol/L and high sensitivity C reactive protein levels of 2.0 mg/L or more. Data from the Justification for the Use of Statins in Prevention trial were used to predict rosuvastatin treatment effect for individual patients based on existing risk scores (Framingham and Reynolds) and on a newly developed prediction model. We compared the net benefit of prediction based rosuvastatin treatment (selective treatment of patients whose predicted treatment effect exceeds a decision threshold) with the net benefit of treating either everyone or no one. The median predicted 10 year absolute risk reduction for cardiovascular events was 4.4% (interquartile range 2.6-7.0%) based on the Framingham risk score, 4.2% (2.5-7.1%) based on the Reynolds score, and 3.9% (2.5-6.1%) based on the newly developed model (optimal fit model). Prediction based treatment was associated with more net benefit than treating everyone or no one, provided that the decision threshold was between 2% and 7%, and thus that the number willing to treat (NWT) to prevent one cardiovascular event over 10 years was between 15 and 50. Data from randomised trials can be used to predict treatment effect in terms of absolute risk reduction for individual patients, based on a newly developed model or, if available, existing risk scores. The value of such prediction of treatment effect for medical decision making is conditional on the NWT to prevent one outcome event. Trial registration number Clinicaltrials.gov NCT00239681.


Analysis of Differentially Expressed Genes and Molecular Pathways in Familial Hypercholesterolemia Involved in Atherosclerosis: A Systematic and Bioinformatics Approach.
Background and Aims: Familial hypercholesterolemia (FH) is one of the major risk factor for the progression of atherosclerosis and coronary artery disease. This study focused on identifying the dysregulated molecular pathways and core genes that are differentially regulated in FH and to identify the possible genetic factors and potential underlying mechanisms that increase the risk to atherosclerosis in patients with FH. Methods: The Affymetrix microarray dataset (GSE13985) from the GEO database and the GEO2R statistical tool were used to identify the differentially expressed genes (DEGs) from the white blood cells (WBCs) of five heterozygous FH patients and five healthy controls. The interaction between the DEGs was identified by applying the STRING tool and visualized using Cytoscape software. MCODE was used to determine the gene cluster in the interactive networks. The identified DEGs were subjected to the DAVID v6.8 webserver and ClueGo/CluePedia for functional annotation, such as gene ontology (GO) and enriched molecular pathway analysis of DEGs. Results: We investigated the top 250 significant DEGs (p-value < 0.05; fold two change ≥ 1 or ≤ -1). The GO analysis of DEGs with significant differences revealed that they are involved in critical biological processes and molecular pathways, such as myeloid cell differentiation, peptidyl-lysine modification, signaling pathway of MyD88-dependent Toll-like receptor, and cell-cell adhesion. The analysis of enriched KEGG pathways revealed the association of the DEGs in ubiquitin-mediated proteolysis and cardiac muscle contraction. The genes involved in the molecular pathways were shown to be differentially regulated by either activating or inhibiting the genes that are essential for the canonical signaling pathways. Our study identified seven core genes (UQCR11, UBE2N, ADD1, TLN1, IRAK3, LY96, and MAP3K1) that are strongly linked to FH and lead to a higher risk of atherosclerosis. Conclusion: We identified seven core genes that represent potential molecular biomarkers for the diagnosis of atherosclerosis and might serve as a platform for developing therapeutics against both FH and atherosclerosis. However, functional studies are further needed to validate their role in the pathogenesis of FH and atherosclerosis.


Determination of the quasi-TE mode (in-plane) graphene linear absorption coefficient via integration with silicon-on-insulator racetrack cavity resonators.
We examine the near-IR light-matter interaction for graphene integrated cavity ring resonators based on silicon-on-insulator (SOI) race-track waveguides. Fitting of the cavity resonances from quasi-TE mode transmission spectra reveal the real part of the effective refractive index for graphene, n(eff) = 2.23 ± 0.02 and linear absorption coefficient, α(gTE) = 0.11 ± 0.01dBμm(-1). The evanescent nature of the guided mode coupling to graphene at resonance depends strongly on the height of the graphene above the cavity, which places limits on the cavity length for optical sensing applications.


Estimating parameters and hidden variables in non-linear state-space models based on ODEs for biological networks inference.
Statistical inference of biological networks such as gene regulatory networks, signaling pathways and metabolic networks can contribute to build a picture of complex interactions that take place in the cell. However, biological systems considered as dynamical, non-linear and generally partially observed processes may be difficult to estimate even if the structure of interactions is given. Using the same approach as Sitz et al. proposed in another context, we derive non-linear state-space models from ODEs describing biological networks. In this framework, we apply Unscented Kalman Filtering (UKF) to the estimation of both parameters and hidden variables of non-linear state-space models. We instantiate the method on a transcriptional regulatory model based on Hill kinetics and a signaling pathway model based on mass action kinetics. We successfully use synthetic data and experimental data to test our approach. This approach covers a large set of biological networks models and gives rise to simple and fast estimation algorithms. Moreover, the Bayesian tool used here directly provides uncertainty estimates on parameters and hidden states. Let us also emphasize that it can be coupled with structure inference methods used in Graphical Probabilistic Models. Matlab code available on demand.


MSK activation and physiological roles.
Mitogen and stress activated protein kinase (MSK) 1 and 2 are nuclear serine/threonine protein kinases that are activated in vivo downstream of either the ERK1/2 or p38 mitogen activated protein kinase (MAPK) cascades. MSKs contain two kinase domains, an N-terminal kinase domain related to the AGC kinase family, and a C-terminal kinase domain related to the CaMK family. The upstream MAPK phosphorylates the C-terminal domain, which then phosphorylates and activates the N-terminal domain. Once activated, the N-terminal domain phosphorylates substrates. MSKs do not have a precisely defined substrate consensus sequence, however the do have a preference for a basic cluster prior to the phosphorylated residue. In cells MSKs phosphorylate several substrates including CREB, NFkB, HMGN1 and histone H3. The major role of MSKs appear to be in the regulation of immediate early (IE) genes, and consistent with this the transcription of several CRE dependent IE genes is compromised in MSK knockouts. The physiological roles of MSKs still remain to be completely determined, however recent work has suggested a role for MSKs in neuronal synaptic plasticity and in regulating cytokine production in the innate immune system.


Methylobacterium oxalidis sp. nov., isolated from leaves of Oxalis corniculata.
A pink-pigmented, facultatively methylotrophic bacterium, strain 35a(T), was isolated from the leaves of Oxalis corniculata. Cells of strain 35a(T) were Gram-reaction-negative, motile, non-spore-forming rods. The highest 16S rRNA gene pairwise sequence similarities for strain 35a(T) were found with the strains of Methylobacterium iners 5317S-33(T) (96.7%), 'Methylobacterium soli' YIM 48816 (96.6%) and Methylobacterium jeotgali S2R03-9(T) (96.3%). 16S rRNA gene sequence similarities with the type strains of all other recognized species of the genus Methylobacterium were below 96%. Major cellular fatty acids were C(18:1)ω7c, C(18:0) and C(16:0). The results of DNA-DNA hybridization experiments, analysis of cpn60 gene sequences, fatty acid profiles, whole-cell MALDI-TOF/MS spectral pattern analysis, and physiological and biochemical tests allowed genotypic and phenotypic differentiation of strain 35a(T) from its nearest phylogenetic neighbours. Strain 35a(T) is therefore considered to represent a novel species within the genus Methylobacterium, for which the name Methylobacterium oxalidis sp. nov. is proposed. The type strain is 35a(T) (=DSM 24028(T)=NBRC 107715(T)).


Comparative behaviour of the dynamically penalized likelihood algorithm in inverse radiation therapy planning.
This paper presents a description of tests carried out to compare the behaviour of five algorithms in inverse radiation therapy planning: (1) The Dynamically Penalized Likelihood (DPL), an algorithm based on statistical estimation theory; (2) an accelerated version of the same algorithm: (3) a new fast adaptive simulated annealing (ASA) algorithm; (4) a conjugate gradient method; and (5) a Newton gradient method. A three-dimensional mathematical phantom and two clinical cases have been studied in detail. The phantom consisted of a U-shaped tumour with a partially enclosed 'spinal cord'. The clinical examples were a cavernous sinus meningioma and a prostate case. The algorithms have been tested in carefully selected and controlled conditions so as to ensure fairness in the assessment of results. It has been found that all five methods can yield relatively similar optimizations, except when a very demanding optimization is carried out. For the easier cases. the differences are principally in robustness, ease of use and optimization speed. In the more demanding case, there are significant differences in the resulting dose distributions. The accelerated DPL emerges as possibly the algorithm of choice for clinical practice. An appendix describes the differences in behaviour between the new ASA method and the one based on a patent by the Nomos Corporation.


Battery ingestions: product accessibility and clinical course.
Results of 125 battery ingestions in 114 separate episodes over an 11-month period are analyzed. The 125 batteries included 119 button batteries and six cylindrical cells. The location of batteries just prior to ingestion (loose or discarded [48.7%], in product [34.4%], in manufacturer's battery packaging [3.4%]) determined the need for consumer education of this potential hazard. The observation that hearing aid batteries were the most common type swallowed (33.9%), and that 14 batteries were ingested by hearing-impaired children after they removed the batteries from their own aids, further directs appropriate prevention efforts. All the larger cylindrical batteries and 89.9% of the button cells passed through the gastrointestinal tract spontaneously. Endoscopic retrieval was unsuccessful in 66.7% of cases attempted. Ipecac syrup, administered to 11 patients, uniformly failed to expel the battery. Transit time was within 48 hours for 68.8% of button cells, and 85.4% of the batteries were passed by 72 hours, with a range of 12 hours to 14 days. Once beyond the esophagus, arrested battery progression failed to correlate with adverse outcome. Symptoms developed in 11 patients but were only severe in the single case of esophageal lodgment. The vast majority of battery ingestions are benign and can be managed without endoscopic or surgical intervention.


Influenza-induced monocyte-derived alveolar macrophages confer prolonged antibacterial protection.
Despite the prevalence and clinical importance of influenza, its long-term effect on lung immunity is unclear. Here we describe that following viral clearance and clinical recovery, at 1 month after infection with influenza, mice are better protected from Streptococcus pneumoniae infection due to a population of monocyte-derived alveolar macrophages (AMs) that produce increased interleukin-6. Influenza-induced monocyte-derived AMs have a surface phenotype similar to resident AMs but display a unique functional, transcriptional and epigenetic profile that is distinct from resident AMs. In contrast, influenza-experienced resident AMs remain largely similar to naive AMs. Thus, influenza changes the composition of the AM population to provide prolonged antibacterial protection. Monocyte-derived AMs persist over time but lose their protective profile. Our results help to understand how transient respiratory infections, a common occurrence in human life, can constantly alter lung immunity by contributing monocyte-derived, recruited cells to the AM population.


Antinociceptive potentiation and attenuation of tolerance by intrathecal β-arrestin 2 small interfering RNA in rats.
Tolerance to the analgesic effect of opioids complicates the management of persistent pain states. We tested whether the intrathecal infusion of small interfering RNA (siRNA) against β-arrestin 2 would reduce tolerance to chronic morphine use and the severity of precipitated morphine withdrawal. Intrathecal β-arrestin 2 (2 μg siRNA per 10 μl per rat) was injected once daily for 3 days. Rats then received a continuous intrathecal infusion of morphine (2 nmol h⁻¹) or saline for 7 days. Daily tail-flick (TF) and intrathecal morphine challenge tests were performed to assess the effect of intrathecal β-arrestin 2 siRNA on antinociception and tolerance to morphine. Naloxone withdrawal (2 mg kg⁻¹) was performed to assess morphine dependence. In the daily TF test, the antinociception of intrathecal morphine was increased and maintained in rats receiving β-arrestin 2 siRNA compared with the control group (morphine alone). In the probe response test, rats receiving morphine infusion with β-arrestin 2 siRNA treatment showed a significant left shift in their dose-response curve, as measured by per cent maximal possible effect (MPE), such that the AD₅₀ was significantly decreased by a factor of 5.6 when compared with that of morphine-infused rats. In the naloxone-induced withdrawal tests, rats receiving β-arrestin 2 siRNA injection with morphine infusion showed a significant reduction in four of the six signs of withdrawal. We show here that intrathecal β-arrestin 2 siRNA in rats enhances analgesia and attenuates naloxone-induced withdrawal symptoms. This may warrant further investigation in the context of long-term use of intrathecal opioids for controlling chronic pain.


Reasons and predictive factors for discontinuation of PDE-5 inhibitors despite successful intercourse in erectile dysfunction patients.
This study was aimed to identify characteristics of ED patients who discontinued PDE5i despite successful intercourse. Data were collected using a questionnaire from 34 urologic clinics regardless of the effect (success or failure) of PDE5i treatment by visiting the clinics (717), e-mail (64) or post (101) for 882 ED patients who had previously taken any kind of PDE5i on demand four or more times. Discontinuation of PDE5i was defined if the patient had never taken PDE5i for the previous 1 year despite successful intercourse. Of the 882 patients, 485 were included in the final analysis. Difference in the socio-demographic, ED- and partner-related data between the continuation and discontinuation group and factors influencing discontinuation of the PDE5i were analyzed. Among 485 respondents (mean age, 53.6), 116 (23.9%) had discontinued PDE5i use despite successful intercourse. Most common reasons for the discontinuation were 'reluctant medication-dependent intercourse' (31.0%), 'spontaneous recovery of erectile function without further treatment' (30.2%), and 'high cost' (26.7%). In multiple logistic regression analysis, independent factors influencing discontinuation of the drug were cause of ED (psychogenic), short duration of ED, low education (⩽ middle school), and religion (Catholic). In partner-related compliance, only partner's religion (Catholic) was a significant factor.


Chlamydia trachomatis in the pharynx and rectum of heterosexual patients at risk for genital infection.
Although urogenital infections with Chlamydia trachomatis are well recognized, less is known about infection at other body sites in adults. Pharyngeal specimens obtained from 706 heterosexual men and 686 women, and rectal specimens obtained from 1223 women who were at risk for chlamydia infection were cultured for C. trachomatis. Urogenital specimens were obtained from all patients. Chlamydia trachomatis was isolated from the pharynx in 3.7% of men and 3.2% of women. Recovery of chlamydiae was not associated with the presence of pharyngeal symptoms, but in women, but not men, it was associated with a history of oral-genital sex. The organism was also recovered from the rectum of 5.2% of the women. Rectal isolation did not correlate with a history of rectal symptoms or rectal sex but did correlate with concurrent genital infection. Infection at these sites may be important in the transmission or persistence of C. trachomatis infections.


Meta-analysis of association between the ASPN D-repeat and osteoarthritis.
Osteoarthritis (OA) is the most common form of human arthritis. Genetic factors have been implicated in OA. It was reported that an aspartic acid (D)-repeat polymorphism in the gene encoding asporin (ASPN) was associated with OA of knee and hip joints in Japanese; in the three independent studies performed, the D14 allele of the ASPN polymorphism was over-represented and the D13 allele was under-represented. Subsequently, four replication studies, three in Europeans and one in Chinese populations, have been reported; however, they showed inconsistent results. To evaluate between-study heterogeneity and to estimate the common genetic effect of the D-repeat polymorphism on OA, we performed a meta-analysis of the five reports that include seven association studies, using the DerSimonian-Laird procedure. We detected association between knee OA and the susceptible D14 allele [P = 0.003, summary odds ratio (OR) = 1.46] with significant heterogeneity (P = 0.047) among the studies. We also detected positive association between knee OA and the protective D13 allele (P = 0.026, summary OR = 0.84) with significant heterogeneity (P = 0.040) among the studies. Because of significant heterogeneity, we stratified the studies by ethnicity. We detected positive association between knee OA and the D14 allele (P = 0.0000013, summary OR = 1.95) with non-significant heterogeneity (P = 0.535) in Asian populations. In hip OA, significant heterogeneity was identified and there was no positive association for any allele in any comparison. The present results suggest that the association of the ASPN D14 allele and knee OA has global relevance, but that its effect has ethnic differences.


Outcomes and costs of community health worker interventions: a systematic review.
We conducted a systematic review on outcomes and costs of community health worker (CHW) interventions. CHWs are increasingly expected to improve health outcomes cost-effectively for the underserved. We searched Medline, Cochrane Collaboration resources, and the Cumulative Index to Nursing and Allied Health Literature for studies conducted in the United States and published in English from 1980 through November 2008. We dually reviewed abstracts, full-text articles, data abstractions, quality ratings, and strength of evidence grades and resolved disagreements by consensus. We included 53 studies on outcomes of CHW interventions and 6 on cost or cost-effectiveness. For outcomes, limited evidence (5 studies) suggests that CHW interventions can improve participant knowledge compared with alternative approaches or no intervention. We found mixed evidence for participant behavior change (22 studies) and health outcomes (27 studies). Some studies suggested that CHW interventions can result in greater improvements in participant behavior and health outcomes compared with various alternatives, but other studies suggested that CHW interventions provide no statistically different benefits than alternatives. We found low or moderate strength of evidence suggesting that CHWs can increase appropriate health care utilization for some interventions (30 studies). Six studies with economic information yielded insufficient data to evaluate the cost-effectiveness of CHW interventions relative to other interventions. CHWs can improve outcomes for underserved populations for some health conditions. The effectiveness of CHWs in many health care areas requires further research that addresses the methodologic limitations of prior studies and that contributes to translating research into practice.


Circulating markers of vascular injury and angiogenesis in antineutrophil cytoplasmic antibody-associated vasculitis.
To identify biomarkers that distinguish between active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and remission in a manner superior or complementary to established markers of systemic inflammation. Markers of vascular injury and angiogenesis were measured before and after treatment in a large clinical trial in AAV: 163 subjects enrolled in the Rituximab in ANCA-Associated Vasculitis trial were screened for the present study. Serum levels of E-selectin, intercellular adhesion molecule 3 matrix metalloproteinase protein 1 (MMP-1), MMP-3, MMP-9, P-selectin, thrombomodulin, and vascular endothelial growth factor were measured at study screening (time of active disease) and at month 6. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels had been measured at the time of the clinical visit. The primary outcome measure was the difference in marker level between screening and month 6 among patients whose disease was in remission (Birmingham Vasculitis Activity Score for Wegener's granulomatosis [BVAS/WG] score of 0) at month 6. All patients had severe active vasculitis at screening (mean ± SD BVAS/WG score 8.6 ± 3.2). Among the 123 patients whose disease was clinically in remission at month 6, levels of all markers except E-selectin showed significant declines. MMP-3 levels were also higher among the 23 patients with active disease at month 6 than among the 123 patients whose disease was in remission. MMP-3 levels correlated weakly with ESR and CRP levels. Many markers of vascular injury and angiogenesis are elevated in severe active AAV and decline with treatment, but MMP-3 appears to distinguish active AAV from remission better than the other markers studied. Further study of MMP-3 is warranted to determine its clinical utility in combination with conventional markers of inflammation and ANCA titers.


Effects of Sapindus mukorossi Seed Oil on Proliferation, Osteogenetic/Odontogenetic Differentiation and Matrix Vesicle Secretion of Human Dental Pulp Mesenchymal Stem Cells.
Stem cells have attracted great interest in the development of tissue engineering. However, the self-regeneration and multi-differentiation capabilities of stem cells are easily impaired during cell transplantation. Recent studies have demonstrated that Sapindus mukorossi (S. mukorossi) seed oil has various positive biological effects. However, it is not yet clear whether S. mukorossi seed oil can increase the growth and differentiation of dental pulp mesenchymal stem cells (DPSCs). The aim of this study is to investigate the effects of S. mukorossi seed oil on the proliferation and differentiation of DPSCs. DPSCs with and without S. mukorossi seed oil, respectively, were evaluated and compared. The viabilities of the cells were assessed by MTT tests. The osteogenetic and odontogenetic capacities of the DPSCs were tested using Alizarin red S staining and alkaline phosphatase (ALP) activity assays. In addition, real-time PCR was performed to examine the gene expression of ALP, BMP-2 and DMP-1. Finally, extracellular matrix vesicle secretion was detected via scanning electron microscopy. No significant difference was observed in the viabilities of the DPSCs with and without S. mukorossi seed oil, respectively. However, under osteogenic and odontogenic induction, S. mukorossi seed oil increased the secretion of mineralized nodules and the ALP activity of the DPSCs (p < 0.05). The ALP gene expression of the differentiation-induced DPSCs was also enhanced. Finally, a greater secretion of extracellular matrix vesicles was detected in the DPSCs following odontogenic induction complemented with S. mukorossi seed oil. Overall, the present results show that S. mukorossi seed oil promotes the osteogenic/odontogenic differentiation and matrix vesicle secretion of DPSCs.


The Bragg gap vanishing phenomena in one-dimensional photonic crystals.
We theoretically deduce the Bragg gap vanishing conditions in one-dimensional photonic crystals and experimentally demonstrate the m=0 band-gap vanishing phenomena at microwave frequencies. In the case of mismatched impedance, the Bragg gap will vanish as long as the discrete modes appear in photonic crystals containing dispersive materials, while for the matched impedance cases, Bragg gaps will always disappear. The experimental results and the simulations agree extremely well with the theoretical expectation.