Exertional rhabdomyolysis after spinning: case series and review of the literature.
Spinning is a popular indoor stationary cycling program that uses group classes as a motivational tool. Exertional rhabdomyolysis (ER) is frequently reported in athletes and military recruits; however, infrequently it has been reported after spinning class. ER is diagnosed by clinical history, physical exam, and laboratory values. Hydration, electrolyte management, and pain control are key components to treatment of this condition. Severe cases can be complicated by acute renal failure, compartment syndrome, arrhythmia, and disseminated intravascular coagulation. We describe three cases of admission due to rhabdomyolysis after spinning. The diagnosis, admission criteria, and medical treatment of ER are presented in the context of a literature review. A retrospective review of three cases with review of the current literature. The medical and laboratory records of three patient cases were reviewed. A search of the PubMed database was used to perform a comprehensive review of exertional rhabdomyolysis. Our institution's IRB reviewed this study. We report three cases of exertional rhabdomyolysis after spinning and describe the diagnostic workup and medical management of these patients. The diagnosis of ER is made by clinical history, physical exam, and laboratory values. The disease spectrum ranges from mild to severe with the potential of serious complications in some patients. We demonstrate three cases of ER in deconditioned individuals who presented to the emergency department for evaluation. Careful medical management and patient monitoring resulted in improved patient symptomatology and eventual return to physical activity.


Plasma metagenomic sequencing to detect and quantify bacterial DNA in ICU patients suspected of sepsis: A proof-of-principle study.
Timely recognition of sepsis and identification of pathogens can improve outcomes in critical care patients but microbial cultures have low accuracy and long turnaround times. In this proof-of-principle study, we describe metagenomic sequencing and analysis of nonhuman DNA in plasma. We hypothesized that quantitative analysis of bacterial DNA (bDNA) levels in plasma can enable detection and monitoring of pathogens. We enrolled 30 patients suspected of sepsis in the surgical trauma intensive care unit and collected plasma samples at the time of diagnostic workup for sepsis (baseline), and 7 days and 14 days later. We performed metagenomic sequencing of plasma DNA and used computational classification of sequencing reads to detect and quantify total and pathogen-specific bDNA fraction. To improve assay sensitivity, we developed an enrichment method for bDNA based on size selection for shorter fragment lengths. Differences in bDNA fractions between samples were evaluated using t test and linear mixed-effects model, following log transformation. We analyzed 72 plasma samples from 30 patients. Twenty-seven samples (37.5%) were collected at the time of infection. Median total bDNA fraction was 1.6 times higher in these samples compared with samples with no infection (0.011% and 0.0068%, respectively, p < 0.001). In 17 patients who had active infection at enrollment and at least one follow-up sample collected, total bDNA fractions were higher at baseline compared with the next sample (p < 0.001). Following enrichment, bDNA fractions increased in paired samples by a mean of 16.9-fold. Of 17 samples collected at the time when bacterial pathogens were identified, we detected pathogen-specific DNA in 13 plasma samples (76.5%). Bacterial DNA levels in plasma are elevated in critically ill patients with active infection. Pathogen-specific DNA is detectable in plasma, particularly after enrichment using selection for shorter fragments. Serial changes in bDNA levels may be informative of treatment response. Epidemiologic/Prognostic, Level V.


Recent weather extremes and impacts on agricultural production and vector-borne disease outbreak patterns.
We document significant worldwide weather anomalies that affected agriculture and vector-borne disease outbreaks during the 2010-2012 period. We utilized 2000-2012 vegetation index and land surface temperature data from NASA's satellite-based Moderate Resolution Imaging Spectroradiometer (MODIS) to map the magnitude and extent of these anomalies for diverse regions including the continental United States, Russia, East Africa, Southern Africa, and Australia. We demonstrate that shifts in temperature and/or precipitation have significant impacts on vegetation patterns with attendant consequences for agriculture and public health. Weather extremes resulted in excessive rainfall and flooding as well as severe drought, which caused ∼10 to 80% variation in major agricultural commodity production (including wheat, corn, cotton, sorghum) and created exceptional conditions for extensive mosquito-borne disease outbreaks of dengue, Rift Valley fever, Murray Valley encephalitis, and West Nile virus disease. Analysis of MODIS data provided a standardized method for quantifying the extreme weather anomalies observed during this period. Assessments of land surface conditions from satellite-based systems such as MODIS can be a valuable tool in national, regional, and global weather impact determinations.


Self-assembled monolayers of alpha,omega-diphosphonic acids on Ti enable complete or spatially controlled surface derivatization.
Alpha,omega-diphosphonic acids self-assemble on the native oxide surfaces of Ti or Ti-6Al-4V. Heating gives strongly bonded phosphonate monolayers. Infrared and X-ray spectroscopic and water contact angle data show that the films are bonded to the surface by one phosphonate unit; the other remains a phosphonic acid. Surface loadings were measured by quartz crystal microbalance procedures. Mechanical shear strengths for the films were also measured; these do not correlate simply with surface loadings. Films formed from 1,12-diphosphonododecane were treated with zirconium tetra(tert-butoxide) to give surface Zr complex species; derivatives of these surface complexes are stable to hydrolysis under physiological conditions and are mechanically strong. The complexation reaction can be accomplished over the entire surface; alternatively, dropwise application of the alkoxide to the surface enables spatial control of deposition. The cell attractive peptide derivative RGDC can be bound to these surface Zr alkoxide complexes through (maleimido)-alkylcarboxylate intermediates. Surfaces modified with RGDC were shown to be effective for osteoblast binding and proliferation.


The Samata intervention to increase secondary school completion and reduce child marriage among adolescent girls: results from a cluster-randomised control trial in India.
Secondary education and delayed marriage provide long-term socio-economic and health benefits to adolescent girls. We tested whether a structural and norms-based intervention, which worked with adolescent girls, their families, communities, and secondary schools to address poverty, schooling quality and gender norms, could reduce secondary school drop-out and child marriage among scheduled-caste/scheduled-tribe (SC/ST) adolescent girls in rural settings of southern India. 80 of 121 villages in Vijayapura and Bagalkote districts, Karnataka State, were randomly selected (control = 40; intervention = 40). All 12-13 year-old SC/ST girls in final year of primary school (standard 7th) were enrolled and followed for 3 years (2014-2017) until the end of secondary school (standard 10th). Primary trial outcomes were proportion of girls who completed secondary school and were married, by trial end-line (15-16 years). Analyses were intention-to-treat and used individual-level girl data. 92.6% (2275/2457) girls at baseline and 72.8% (1788/2457) at end-line were interviewed. At end-line, one-fourth had not completed secondary school (control = 24.9%; intervention = 25.4%), and one in ten reported being married (control = 9.6%; intervention = 10.1%). These were lower than expected based on district-level data available before the trial, with no difference between these, or other schooling or sexual and reproductive outcomes, by trial arm. There was a small but significant increase in secondary school entry (adjusted odds ratio AOR = 3.58, 95% confidence interval CI = 1.36-9.44) and completion (AOR=1.54, 95%CI = 1.02-2.34) in Vijayapura district. The sensitivity and attrition analyses did not impact the overall result indicating that attrition of girls at end-line was random without much bearing on overall result. Samata intervention had no overall impact, however, it added value in one of the two implementation districts- increasing secondary school entry and completion. Lower than expected school drop-out and child marriage rates at end-line reflect strong secular changes, likely due to large-scale government initiatives to keep girls in school and delay marriage. Although government programmes may be sufficient to reach most girls in these settings, a substantial proportion of SC/ST girls remain at-risk of early marriage and school drop-out, and require targeted programming. Addressing multiple forms of clustered disadvantage among hardest to reach will be key to ensuring India "leaves no-one behind" and achieves its gender, health and education Sustainable Development Goal aspirations. ClinicalTrials.gov registration number NCT01996241.


Invited article: CO2 laser production of fused silica fibers for use in interferometric gravitational wave detector mirror suspensions.
In 2000 the first mirror suspensions to use a quasi-monolithic final stage were installed at the GEO600 detector site outside Hannover, pioneering the use of fused silica suspension fibers in long baseline interferometric detectors to reduce suspension thermal noise. Since that time, development of the production methods of fused silica fibers has continued. We present here a review of a novel CO(2) laser-based fiber pulling machine developed for the production of fused silica suspensions for the next generation of interferometric gravitational wave detectors and for use in experiments requiring low thermal noise suspensions. We discuss tolerances, strengths, and thermal noise performance requirements for the next generation of gravitational wave detectors. Measurements made on fibers produced using this machine show a 0.8% variation in vertical stiffness and 0.05% tolerance on length, with average strengths exceeding 4 GPa, and mechanical dissipation which meets the requirements for Advanced LIGO thermal noise performance.


Comparative efficacies of permethrin-, deltamethrin- and alpha-cypermethrin-treated nets, against Anopheles arabiensis and Culex quinquefasciatus in northern Tanzania.
Mosquito nets treated with permethrin, deltamethrin or alpha-cypermethrin at 25 mg/m(2) were evaluated in experimental huts in an area of rice irrigation near Moshi, in northern Tanzania. The nets were deliberately holed to resemble worn nets. The nets treated with permethrin offered the highest personal protection against Anopheles arabiensis (61.6% reduction in fed mosquitoes) and Culex quinquefasciatus (25.0%). Deltamethrin and alpha-cypermethrin provided lower personal protection against An. arabiensis (46.4% and 45.6%, respectively) and no such protection against Cx. quinquefasciatus. Permethrin performed poorly in terms of mosquito mortality, however, killing only 15.2% of the An. arabiensis and 9.2% of the Cx. quinquefasciatus exposed to the nets treated with this pyrethroid (after correcting for control mortality). The alpha-cypermethrin and deltamethrin performed marginally better, with respective mortalities of 32.8% and 33.0% for An. arabiensis and 19.4% and 18.9% for Cx quinquefasciatus. The poor killing effect of permethrin was confirmed in a second trial where a commercial, long-lasting insecticidal net based on this pyrethroid (Olyset) produced low mortalities in both An. arabiensis (11.8%) and Cx. quinquefasciatus (3.6%). Anopheles arabiensis survivors collected from the verandahs of the experimental huts and tested on 0.75%-permethrin and 0.05%-deltamethrin papers, in World Health Organization susceptibility kits, showed mortalities of 96% and 100%, respectively. The continued use of permethrin-treated nets is recommended for personal protection against An. arabiensis. In control programmes that aim to interrupt transmission of pathogens by mosquitoes and/or manage pyrethroid resistance in such vectors, a combination of a pyrethroid and another insecticide with greater killing effect should be considered.


Pharmacological interventions for acute hepatitis B infection: an attempted network meta-analysis.
Infection with hepatitis B virus (HBV) can be symptomatic or asymptomatic. Apart from chronic HBV infection, the complications related to acute HBV infection are severe acute viral hepatitis and fulminant hepatitis characterised by liver failure. The optimal pharmacological treatment of acute HBV infection remains controversial. To assess the benefits and harms of pharmacological interventions in the treatment of acute HBV infection through a network meta-analysis and to generate rankings of the available treatments according to their safety and efficacy. As it was not possible to assess whether the potential effect modifiers were similar across different comparisons, we did not perform the network meta-analysis, and instead, assessed the benefits and harms of different interventions using standard Cochrane methodological procedures. We searched CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, WHO International Clinical Trials Registry Platform, and randomised clinical trials (RCTs) registers to August 2016 to identify RCTs on pharmacological interventions for acute HBV infection. RCTs, irrespective of language, blinding, or publication status in participants with acute HBV infection. We excluded trials if participants had previously undergone liver transplantation and had other coexisting viral diseases such as hepatitis C virus and HIV. We considered any of the various pharmacological interventions compared with each other or with placebo, or no intervention. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager 5. We assessed risk of bias, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. Seven trials (597 participants) met our review inclusion criteria. All trials provided information for one or more outcomes; however, five participants were excluded from analysis by study authors. All the trials were at high risk of bias. Overall, all the evidence was low or very low quality evidence because of risk of bias (downgraded one level for risk of bias), small sample size (downgraded one level for imprecision), and wide CIs (downgraded one more level for imprecision in some comparisons). Of the seven trials, six were two-armed trials, while one trial was a three-armed trial. The comparisons included hepatitis B immunoglobulin (HBIG) versus placebo (one trial; 55 participants); interferon versus placebo (two trials; 200 participants); lamivudine versus placebo or no intervention (four trials; 316 participants); lamivudine versus entecavir (one trial; 90 participants); and entecavir versus no intervention (one trial; 131 participants). One trial included only people with acute HBV with hepatic encephalopathy (i.e. people with fulminant liver failure); one trial included only people with severe acute HBV, but it did not state whether any of the people also had fulminant HBV infection; three trials excluded fulminant HBV infection; and two trials did not report the severity of acute HBV infection. The mean or median follow-up period in the trials ranged from three to 12 months in the trials that provided this information.There was no evidence of any differences in short-term mortality (less than one year) in any of the comparisons: HBIG versus placebo (OR 1.13, 95% CI 0.36 to 3.54; participants = 55; 1 trial), lamivudine versus placebo or no intervention (OR 1.29, 95% CI 0.33 to 4.99; participants = 250; 2 trials); lamivudine versus entecavir (OR 1.23, 95% CI 0.13 to 11.65; participants = 90; 1 trial), or entecavir versus no intervention (OR 1.05, 95% CI 0.12 to 9.47; participants = 131; 1 trial). The proportion of people who progressed to chronic HBV infection was higher in the lamivudine group than the placebo or no intervention group (OR 1.99, 95% CI 1.05 to 3.77; participants = 285; 3 trials) and in the lamivudine group versus entecavir group (OR 3.64, 95% CI 1.31 to 10.13; participants = 90; 1 trial). There was no evidence of a difference in the proportion of people who progressed to chronic HBV infection between the entecavir and the no intervention groups (OR 0.58, 95% CI 0.23 to 1.49; participants = 131; 1 trial). None of the trials reported progression to fulminant HBV infection. Three trials with 371 participants reported serious adverse events. There were no serious adverse events in any of the groups (no intervention: 0/183 (0%), interferon: 0/67 (0%), lamivudine: 0/100 (0%), and entecavir: 0/21 (0%)). The proportion of people with adverse events was higher in the interferon group than the placebo group (OR 348.16, 95% CI 45.39 to 2670.26; participants = 200; 2 trials). There was no evidence of a difference in the proportion of people with adverse events between the lamivudine group and the placebo or no intervention group (OR 1.42, 95% CI 0.34 to 5.94; participants = 35; 1 trial) or number of adverse events between the lamivudine group and the placebo or no intervention group (rate ratio 1.72, 95% CI 1.01 to 2.91; participants = 35; 1 trial). One trial with 100 participants reported quality of life at one week. The scale used to report the health-related quality of life was not stated and lacked information on whether higher score meant better or worse, making it difficult to interpret the results. None of the trials reported quality of life beyond one week or other clinical outcomes such as mortality beyond one year, liver transplantation, cirrhosis, decompensated cirrhosis, or hepatocellular carcinoma.Two trials received funding from pharmaceutical companies; three trials were funded by parties without any vested interest in the results or did not receive any special funding; the source of funding was not available in the remaining two trials. Low or very low quality evidence suggests that progression to chronic HBV infection was higher in people receiving lamivudine compared with placebo, no intervention, or entecavir. Low quality evidence suggests that interferon may increase the adverse events after treatment for acute HBV infection. Based on a very low quality evidence, there is currently no evidence of benefit of any intervention in acute HBV infection. There is significant uncertainty in the results and further RCTs are required.


Complexity of cancer stem cells.
Heterogeneity of tumor tissue has been accounted for in recent years by a hierarchy-based model in which cancer stem cells (CSCs) have the ability both to self-renew and to give rise to differentiated tumor cells and are responsible for the overall organization of a tumor. Research into CSCs has progressed rapidly and concomitantly with recent advances in the biology of normal tissue stem cells, resulting in the identification of CSCs in a wide range of human tumors. Studies of mouse models of human cancer have provided further insight into the characteristics of CSCs as well as a basis for the development of novel therapies targeted to these cells. However, recent studies have revealed complexities, such as plasticity of stem cell properties and clonal diversity of CSCs, in certain tumor types that have led to revision of the original CSC model. In this review, we summarize the history of the discovery and characterization of CSCs, as well as address recent advances that have revealed the complexity of these cells and their therapeutic implications.


NEOTROPICAL XENARTHRANS: a data set of occurrence of xenarthran species in the Neotropics.
Xenarthrans-anteaters, sloths, and armadillos-have essential functions for ecosystem maintenance, such as insect control and nutrient cycling, playing key roles as ecosystem engineers. Because of habitat loss and fragmentation, hunting pressure, and conflicts with domestic dogs, these species have been threatened locally, regionally, or even across their full distribution ranges. The Neotropics harbor 21 species of armadillos, 10 anteaters, and 6 sloths. Our data set includes the families Chlamyphoridae (13), Dasypodidae (7), Myrmecophagidae (3), Bradypodidae (4), and Megalonychidae (2). We have no occurrence data on Dasypus pilosus (Dasypodidae). Regarding Cyclopedidae, until recently, only one species was recognized, but new genetic studies have revealed that the group is represented by seven species. In this data paper, we compiled a total of 42,528 records of 31 species, represented by occurrence and quantitative data, totaling 24,847 unique georeferenced records. The geographic range is from the southern United States, Mexico, and Caribbean countries at the northern portion of the Neotropics, to the austral distribution in Argentina, Paraguay, Chile, and Uruguay. Regarding anteaters, Myrmecophaga tridactyla has the most records (n = 5,941), and Cyclopes sp. have the fewest (n = 240). The armadillo species with the most data is Dasypus novemcinctus (n = 11,588), and the fewest data are recorded for Calyptophractus retusus (n = 33). With regard to sloth species, Bradypus variegatus has the most records (n = 962), and Bradypus pygmaeus has the fewest (n = 12). Our main objective with Neotropical Xenarthrans is to make occurrence and quantitative data available to facilitate more ecological research, particularly if we integrate the xenarthran data with other data sets of Neotropical Series that will become available very soon (i.e., Neotropical Carnivores, Neotropical Invasive Mammals, and Neotropical Hunters and Dogs). Therefore, studies on trophic cascades, hunting pressure, habitat loss, fragmentation effects, species invasion, and climate change effects will be possible with the Neotropical Xenarthrans data set. Please cite this data paper when using its data in publications. We also request that researchers and teachers inform us of how they are using these data.


Subretinal transplantation of forebrain progenitor cells in nonhuman primates: survival and intact retinal function.
Cell-based therapy rescues retinal structure and function in rodent models of retinal disease, but translation to clinical practice will require more information about the consequences of transplantation in an eye closely resembling the human eye. The authors explored donor cell behavior using human cortical neural progenitor cells (hNPC(ctx)) introduced into the subretinal space of normal rhesus macaques. hNPC(ctx) transduced with green fluorescent protein (hNPC(ctx)-GFP) were delivered bilaterally into the subretinal space of six normal adult rhesus macaques under conditions paralleling those of the human operating room. Outcome measures included clinical parameters of surgical success, multifocal electroretinogram (mfERG), and histopathologic analyses performed between 3 and 39 days after engraftment. To test the effects of GFP transduction on cell bioactivity, hNPC(ctx)-GFP from the same batch were also injected into Royal College of Surgeons (RCS) rats and compared with nonlabeled hNPC(ctx). Studies using RCS rats indicated that GFP transduction did not alter the ability of the cells to rescue vision. After cells were introduced into the monkey subretinal space by a pars plana transvitreal approach, the resultant detachment was rapidly resolved, and retinal function showed little or no disturbance in mfERG recordings. Retinal structure was unaffected and no signs of inflammation or rejection were seen. Donor cells survived as a single layer in the subretinal space, and no cells migrated into the inner retina. Human neural progenitor cells can be introduced into a primate eye without complication using an approach that would be suitable for extrapolation to human patients.


CRB2 Loss in Rod Photoreceptors Is Associated with Progressive Loss of Retinal Contrast Sensitivity.
Variations in the Crumbs homolog-1 (CRB1) gene are associated with a wide variety of autosomal recessive retinal dystrophies, including early onset retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA). CRB1 belongs to the Crumbs family, which in mammals includes CRB2 and CRB3. Here, we studied the specific roles of CRB2 in rod photoreceptor cells and whether ablation of CRB2 in rods exacerbates the Crb1-disease. Therefore, we assessed the morphological, retinal, and visual functional consequences of specific ablation of CRB2 from rods with or without concomitant loss of CRB1. Our data demonstrated that loss of CRB2 in mature rods resulted in RP. The retina showed gliosis and disruption of the subapical region and adherens junctions at the outer limiting membrane. Rods were lost at the peripheral and central superior retina, while gross retinal lamination was preserved. Rod function as measured by electroretinography was impaired in adult mice. Additional loss of CRB1 exacerbated the retinal phenotype leading to an early reduction of the dark-adapted rod photoreceptor a-wave and reduced contrast sensitivity from 3-months-of-age, as measured by optokinetic tracking reflex (OKT) behavior testing. The data suggest that CRB2 present in rods is required to prevent photoreceptor degeneration and vision loss.


Extended depth-of-field microscopic imaging with a variable focus microscope objective.
Increasing the depth-of-field (DOF) while maintaining high resolution imaging has been a classical challenge for conventional microscopes. Extended DOF (EDOF) is especially essential for imaging thick specimens. We present a microscope capable of capturing EDOF images in a single shot. A volumetric optical sampling method is applied by rapidly scanning the focus of a vari-focal microscope objective throughout the extended depths of a thick specimen within the duration of a single detector exposure. An EDOF image is reconstructed by deconvolving the captured image with the response function of the system. Design of a vari-focal objective and algorithms for restoring EDOF images are presented. Proof-of-concept experimental results demonstrate significantly extended DOF compared to the conventional microscope counterparts.


Smoking cessation in pregnancy: a review of postpartum relapse prevention strategies.
Review and examine existing research, current strategies, and directions for future research on smoking cessation relapse and relapse prevention in pregnancy and postpartum. A MEDLINE/PubMed search in 2002 and 2003 for articles containing the key words "smoking," "pregnancy," "cessation," and "cessation relapse prevention" and references of retrieved papers yielded a review of more than 500 articles. Only 14 of these addressed program-based strategies to increase cessation among pregnant women through relapse prevention programs. Although there is much information on the rationale and strategies for smoking cessation for pregnant women, fewer studies exist on how to prevent relapse. Maintaining and accelerating progress in cessation during pregnancy and postpartum requires more research that focuses on relapse prevention and cessation. Programs should incorporate stresses particular to postpartum women, should be part of routine health care, and should involve the woman's social support network, including her partner, to maximize effectiveness.


Asynchronous steady-state visual evoked potential based BCI control of a 2-DoF artificial upper limb.
A brain-computer interface (BCI) provides a direct connection between the human brain and a computer. One type of BCI can be realized using steady-state visual evoked potentials (SSVEPs), resulting from repetitive stimulation. The aim of this study was the realization of an asynchronous SSVEP-BCI, based on canonical correlation analysis, suitable for the control of a 2-degrees of freedom (DoF) hand and elbow neuroprosthesis. To determine whether this BCI is suitable for the control of 2-DoF neuroprosthetic devices, online experiments with a virtual and a robotic limb feedback were conducted with eight healthy subjects and one tetraplegic patient. All participants were able to control the artificial limbs with the BCI. In the online experiments, the positive predictive value (PPV) varied between 69% and 83% and the false negative rate (FNR) varied between 1% and 17%. The spinal cord injured patient achieved PPV and FNR values within one standard deviation of the mean for all healthy subjects.


Pegylated liposomal doxorubicin for relapsed epithelial ovarian cancer.
Ovarian cancer is the eighth most common cancer in women and it is usually diagnosed at an advanced stage. The majority of ovarian tumours are epithelial in origin. Women with relapsed epithelial ovarian cancer (EOC) often have a reduced performance status with a limited life expectancy, therefore maintaining quality of life with effective symptom control is the main purpose of treatment. Drug treatment of relapsed disease is directed by the platinum-free interval: relapsed platinum-sensitive disease is usually re-treated with platinum-based therapy and platinum-resistant disease challenged with non-platinum drugs. However, the side-effects of chemotherapy agents may be severe and optimal treatment regimens are unclear. Pegylated liposomal doxorubicin (PLD), which contains a cytotoxic drug called doxorubicin hydrochloride is one of several treatment modalities that may be considered for single-agent treatment of relapsed EOC, or used in combination with other drugs. To assess the efficacy and safety of PLD in women with relapsed epithelial ovarian cancer (EOC). We searched the Cochrane Gynaecological Cancer Group (CGCG) trials register, CENTRAL, MEDLINE and EMBASE from 1990 to February 2013. We also searched online registers of clinical trials, abstracts of scientific meetings and reference lists of included studies. Randomised controlled trials (RCTs) that evaluated PLD in women diagnosed with relapsed epithelial ovarian cancer. Two review authors independently abstracted data to a pre-designed data collection form and assessed the risk of bias according to the Cochrane Handbook for Systematic Reviews of Interventions guidelines. Where possible, we pooled collected data in meta-analyses using RevMan 5.2 software. We included 14 RCTs that evaluated PLD alone or in combination with other drugs. Four RCTs contributed no data to the meta-analyses. Two studies compared PLD plus carboplatin (carbo) to paclitaxel (PAC)/carbo in women with platinum-sensitive relapsed EOC. Overall survival (OS) was similar for these treatments, however progression-free survival (PFS) was longer with PLD/carbo (1164 participants; hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.74 to 0.97; I² = 7%; P value 0.01). PLD/carbo was associated with significantly more anaemia and thrombocytopenia than PAC/carbo, whereas PAC/carbo was associated with significantly more alopecia, neuropathies, hypersensitivity reactions and arthralgias/myalgias. PLD/carbo was well-tolerated and women receiving this treatment were significantly less likely to discontinue treatment than those receiving PAC/carbo (two studies, 1150 participants; risk ratio (RR) 0.38, 95% CI 0.26 to 0.57; I² = 0%; P < 0.00001).Five studies compared other agents to PLD alone. None of these agents were associated with significantly better survival or severe adverse-event profiles than PLD. Topotecan and gemcitabine were associated with significantly more haematological severe adverse events than PLD, and patupilone was associated with significantly more severe neuropathies and diarrhoea. Severe hand-foot syndrome (HFS) occurred consistently more frequently with PLD than the other drugs.Three studies compared PLD combination treatment to PLD alone. Two combinations resulted in a significantly longer PFS compared with PLD alone: trabectedin (TBD)/PLD (one study, 672 women; HR 0.79, 95% CI 0.65 to 0.96; P value 0.02) and vintafolide (EC145)/PLD (one study, 149 women; HR 0.63, 95% CI 0.41 to 0.97; P value 0.04). TBD/PLD appeared to benefit the partially platinum-sensitive subgroup only. Further studies are likely to have an important impact on our confidence in these estimates. TBD/PLD was associated with significantly more haematological and gastrointestinal severe adverse events than PLD alone, whereas EC145/PLD appeared to be well-tolerated.For platinum-resistant relapsed EOC, the median PFS and OS for single-agent PLD across seven included studies was 15 weeks and 54 weeks, respectively. Severe HFS occurred significantly more frequently in women receiving a 50 mg/m² dose of PLD than those receiving less than 50 mg/m² (17% versus 2%, respectively; P value 0.01). In platinum-sensitive relapsed epithelial ovarian cancer, PLD/carbo is more effective than PAC/carbo and is better tolerated; PLD/carbo should therefore be considered as first-line treatment in women with platinum-sensitive relapsed EOC. PLD alone is a useful agent for platinum-resistant relapsed EOC, however it remains unclear how it compares with other single agents for this subgroup and in what order these agents should be used. There is insufficient evidence to support the use of PLD in combination with other agents in platinum-resistant relapsed EOC.


Retroviral vectors for liver-directed gene therapy.
Retroviruses are popular gene therapy vectors because they stably integrate the DNA copy of their genome into the host chromosome during their replication cycle. The widely used murine retroviral vector systems have two components: the transfer vector for the transgene carries all the cis-acting elements necessary for the replication and efficient integration of the viral DNA; and the packaging cell line produces all the trans-acting proteins necessary for both structural and catalytic functions of the virus. Advances in design of retroviral vectors have resulted in greater degree of biosafety, expanded host range, and increased stability of the virus particles. Retroviral vectors have been widely used in the ex vivo gene therapy protocols to correct the liver diseases in a wide variety of species. In a limited number of applications, in vivo gene therapy has been achieved after the liver cells have been stimulated to regenerate. One major limitation of murine retroviral vectors is their inability to infect nondividing cells. This problem has been overcome by deriving vectors from lentiviruses (a class of retroviruses) that have the ability to infect both dividing and nondividing cells. The lentiviral vectors are derived from human immunodeficiency virus type 1 (HIV-1). Initial studies using lentiviral vectors for gene delivery to the liver in vivo show promising results. A highly crippled version of lentivirus has been generated by using producer cells in which the trans-acting components are expressed by several different coding elements and vectors that incorporate features of self-inactivation. These improvements should ensure biosafety of lentiviruses and make them useful in efficient delivery of therapeutic genes to nondividing differentiated tissues such as the liver.


Neural correlates of partial lexical activation.
As a spoken word unfolds over time, it is temporarily consistent with the acoustic forms of multiple words. Previous behavioral research has shown that, in the face of temporary ambiguity about how a word will end, multiple candidate words are briefly activated. Here, we provide neural imaging evidence that lexical candidates only temporarily consistent with the input activate perceptually based semantic representations. An artificial lexicon and novel visual environment were used to target human MT/V5 and an area anterior to it which have been shown to be recruited during the reading of motion words. Participants learned words that referred to novel objects and to motion or color/texture changes that the objects underwent. The lexical items corresponding to the change events were organized into phonologically similar pairs differing only in the final syllable. Upon hearing spoken scene descriptions in a posttraining verification task, participants showed greater activation in the left hemisphere anterior extent of MT/V5 when motion words were heard than when nonmotion words were heard. Importantly, when a nonmotion word was heard, the level of activation in the anterior extent of MT/V5 was modulated by whether there was a phonologically related competitor that was a motion word rather than another nonmotion word. These results provide evidence of activation of a perceptual brain region in response to the semantics of a word while lexical competition is in process and before the word is fully recognized.


Methamphetamine and driving impairment.
Following a review of the effects of methamphetamine on human performance, actual driving and behavior were evaluated in 28 cases in which drivers arrested or killed in traffic accidents had tested positive for methamphetamine. The circumstances surrounding the arrest or accident were examined, together with any observations by the arresting officer regarding behavioral irregularities. The investigators also made a determination of culpability. Most of the arrests resulted from accidents in which the driver was determined to be culpable. Typical driving behaviors included drifting out of the lane of travel, erratic driving, weaving, speeding, drifting off the road, and high speed collisions. Behavioral manifestations of methamphetamine use in arrestees included rapid or confused speech, rapid pulse, agitation, paranoia, dilated pupils, violet or aggressive attitude. Combined alcohol and methamphetamine use was uncommon, however use of marijuana was evident in about one third of the cases. In addition to impairing judgment and increasing risk taking, the effects of withdrawal from methamphetamine use including fatigue, hypersomnnolence, and depression are likely contributors to many of these accidents. A consideration of the literature and the cases discussed here, leads to the conclusion that methamphetamine at any concentration is likely to produce symptoms that are inconsistent with safe driving.


Association of socioeconomic deprivation with opioid prescribing in primary care in England: a spatial analysis.
The increasing trends in opioid prescribing and opioid-related deaths in England are concerning. A greater understanding of the association of deprivation with opioid prescribing is needed to guide policy responses and interventions. The 2018/2019 English national primary care prescribing data were analysed spatially. Prescribing of opioids in general practice was quantified by defined daily doses (DDD) and attributed to 32 844 lower layer super output areas (LSOAs), the geographical units representing ~1500 people. Linear regression was used to model the effect of socioeconomic deprivation (quintiles) on opioid prescribing while accounting for population demographics and the prevalence of specific health conditions. Adjusted DDD estimates were compared at each deprivation level within higher organisational areas (Clinical Commissioning Groups, CCGs). In total, 624 411 164 DDDs of opioids were prescribed. LSOA-level prescribing varied between 1.7 and 121.04 DDD/1000 population/day. Prescribing in the most deprived areas in the North of England was 1.2 times higher than the national average for areas with similar deprivation levels and 3.3 times higher than the most deprived areas in London. Prescribing in the most deprived areas was on average 9.70 DDD/1000 people/day (95% CI 9.41 to 10.00) higher than the least deprived areas. Deprivation-driven disparities varied between individual CCGs. In the most unequal CCG, prescribing in the most deprived areas was twice that in the least deprived areas. Opioid prescribing varied substantially across England and deprivation was strongly associated with prescribing. This paper provides evidence for guiding policy interventions and allocation of resources to areas with the highest levels of opioid prescribing.


[Post-Normal Pandemics: why CoViD-19 requires a new approach to science.]
In addressing pandemics, science has never seemed more needed and useful, while at the same time limited and powerless. The existing contract between science and society is falling apart. A new covenant is urgently needed to navigate the days ahead.


Site-specific integration and expression of an anti-malarial gene in transgenic Anopheles gambiae significantly reduces Plasmodium infections.
Diseases transmitted by mosquitoes have a devastating impact on global health and this is worsening due to difficulties with existing control measures and climate change. Genetically modified mosquitoes that are refractory to disease transmission are seen as having great potential in the delivery of novel control strategies. Historically the genetic modification of insects has relied upon transposable elements which have many limitations despite their successful use. To circumvent these limitations the Streptomyces phage phiC31 integrase system has been successfully adapted for site-specific transgene integration in insects. Here, we present the first site-specific transformation of Anopheles gambiae, the principal vector of human malaria. Mosquitoes were initially engineered to incorporate the phiC31 targeting site at a defined genomic location. A second phase of genetic modification then achieved site-specific integration of Vida3, a synthetic anti-malarial gene. Expression of Vida3, specifically in the midgut of bloodfed females, offered consistent and significant protection against Plasmodium yoelii nigeriensis, reducing average parasite intensity by 85%. Similar protection was observed against Plasmodium falciparum in some experiments, although protection was inconsistent. In the fight against malaria, it is imperative to establish a broad repertoire of both anti-malarial effector genes and tissue-specific promoters for their expression, enabling those offering maximum effect with minimum fitness cost to be identified. In the future, this technology will allow effective comparisons and informed choices to be made, potentially leading to complete transmission blockade.


Dynamic mimicry in an Indo-Malayan octopus.
During research dives in Indonesia (Sulawesi and Bali), we filmed a distinctive long-armed octopus, which is new to science. Diving over 24 h periods revealed that the 'mimic octopus' emerges during daylight hours to forage on sand substrates in full view of pelagic fish predators. We observed nine individuals of this species displaying a repertoire of postures and body patterns, several of which are clearly impersonations of venomous animals co-occurring in this habitat. This 'dynamic mimicry' avoids the genetic constraints that may limit the diversity of genetically polymorphic mimics but has the same effect of decreasing the frequency with which predators encounter particular mimics. Additionally, our observations suggest that the octopus makes decisions about the most appropriate form of mimicry to use, allowing it to enhance further the benefits of mimicking toxic models by employing mimicry according to the nature of perceived threats.


A CROC stronger than ROC: measuring, visualizing and optimizing early retrieval.
The performance of classifiers is often assessed using Receiver Operating Characteristic ROC [or (AC) accumulation curve or enrichment curve] curves and the corresponding areas under the curves (AUCs). However, in many fundamental problems ranging from information retrieval to drug discovery, only the very top of the ranked list of predictions is of any interest and ROCs and AUCs are not very useful. New metrics, visualizations and optimization tools are needed to address this 'early retrieval' problem. To address the early retrieval problem, we develop the general concentrated ROC (CROC) framework. In this framework, any relevant portion of the ROC (or AC) curve is magnified smoothly by an appropriate continuous transformation of the coordinates with a corresponding magnification factor. Appropriate families of magnification functions confined to the unit square are derived and their properties are analyzed together with the resulting CROC curves. The area under the CROC curve (AUC[CROC]) can be used to assess early retrieval. The general framework is demonstrated on a drug discovery problem and used to discriminate more accurately the early retrieval performance of five different predictors. From this framework, we propose a novel metric and visualization-the CROC(exp), an exponential transform of the ROC curve-as an alternative to other methods. The CROC(exp) provides a principled, flexible and effective way for measuring and visualizing early retrieval performance with excellent statistical power. Corresponding methods for optimizing early retrieval are also described in the Appendix. Datasets are publicly available. Python code and command-line utilities implementing CROC curves and metrics are available at http://pypi.python.org/pypi/CROC/ CONTACT: email@example.com


Examining the Relationship Between Traumatic Brain Injury and Substance Use Outcomes in the Canadian Population.
The literature has opposing views regarding the magnitude of the association between substance use and TBI. Most studies have examined clinical samples which are not representative of the entire head injured population. Clinical samples provide very limited insight into TBI patients whom do not seek care. This paper examines the associations between TBI and substance use/misuse. Its primary aim is to test whether or not individuals with a past-year TBI have higher rates of substance use/misuse than Canadians without a TBI or back and/or spine injury controls drawing on self-report population level data. Using the 2009-2010 Canadian Community Health Survey, a nationally representative cross-sectional survey of Canadians 12 years and older, this paper assessed substance use (i.e., illicit drug use; drinking and binge drinking; current smoking) among those with a TBI, as compared to two control groups: (1) individuals with a back or spinal injury (BSI); and (2) healthy noninjured controls. Multivariate regressions (logistic and multinomial), both unadjusted and adjusting for a range of injury and sociodemographic covariates, were used in hypothesis testing. Those with a past-year TBI demonstrated significantly elevated rates of illicit drug use relative to non-injured Canadians. Relative to the BSI group those with a TBI were less likely to drink alcohol, did not differ in binge drinking, cigarette smoking and illicit drug use. Health care professionals working with the TBI population should integrate screening, brief intervention, and referral programming as a means to reduce future harm related to substance misuse.


The effect of rare variants in TREM2 and PLD3 on longitudinal cognitive function in the Wisconsin Registry for Alzheimer's Prevention.
Recent studies have found an association between functional variants in TREM2 and PLD3 and Alzheimer's disease (AD), but their effect on cognitive function is unknown. We examined the effect of these variants on cognitive function in 1449 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of initially asymptomatic adults, aged 36-73 years at baseline, enriched for a parental history of AD. A comprehensive cognitive test battery was performed at up to 5 visits. A factor analysis resulted in 6 cognitive factors that were standardized into z scores (∼N [0, 1]); the mean of these z scores was also calculated. In linear mixed models adjusted for age, gender, practice effects, and self-reported race/ethnicity, PLD3 V232M carriers had significantly lower mean z scores (p = 0.02) and lower z scores for story recall (p = 0.04), visual learning and memory (p = 0.049), and speed and flexibility (p = 0.02) than noncarriers. TREM2 R47H carriers had marginally lower z scores for speed and flexibility (p = 0.06). In conclusion, a functional variant in PLD3 was associated with significantly lower cognitive function in individuals carrying the variant than in noncarriers.


Coronary artery stent geometry and in-stent contrast attenuation with 64-slice computed tomography.
We aimed at assessing stent geometry and in-stent contrast attenuation with 64-slice CT in patients with various coronary stents. Twenty-nine patients (mean age 60 +/- 11 years; 24 men) with 50 stents underwent CT within 2 weeks after stent placement. Mean in-stent luminal diameter and reference vessel diameter proximal and distal to the stent were assessed with CT, and compared to quantitative coronary angiography (QCA). Stent length was also compared to the manufacturer's values. Images were reconstructed using a medium-smooth (B30f) and sharp (B46f) kernel. All 50 stents could be visualized with CT. Mean in-stent luminal diameter was systematically underestimated with CT compared to QCA (1.60 +/- 0.39 mm versus 2.49 +/- 0.45 mm; P < 0.0001), resulting in a modest correlation of QCA versus CT (r = 0.49; P < 0.0001). Stent length as given by the manufacturer was 18.2 +/- 6.2 mm, correlating well with CT (18.5 +/- 5.7 mm; r = 0.95; P < 0.0001) and QCA (17.4 +/- 5.6 mm; r = 0.87; P < 0.0001). Proximal and distal reference vessel diameters were similar with CT and QCA (P = 0.06 and P = 0.03). B46f kernel images showed higher image noise (P < 0.05) and lower in-stent CT attenuation values (P < 0.001) than images reconstructed with the B30f kernel. 64-slice CT allows measurement of coronary artery in-stent density, and significantly underestimates the true in-stent diameter compared to QCA.


Prostaglandin concentrations in cerebrospinal fluid of rabbits under normal and ischemic conditions.
Clinical studies have demonstrated elevated levels of both arachidonic acid and prostaglandins in the cerebrospinal fluid of humans after ischemic stroke and subarachnoid hemorrhage. Such increases in free fatty acid, arachidonic acid, and prostaglandin concentrations suggest excessive production and accumulation of these substances in the ischemic brain. We used a rabbit model of ischemic infarction to examine the relation between controlled central nervous system ischemia and cerebrospinal fluid prostaglandin levels. We found that following stroke PGF2 alpha and not PGD2 was the predominant prostaglandin present in the cerebrospinal fluid. PGF2 alpha also underwent the largest percent increase over control prostaglandin concentrations. This is similar to human and dog cerebrospinal fluid studies, which demonstrate PGF2 alpha as the predominant prostaglandin following ischemic injury. The lack of PGD2 elevation under ischemic conditions may suggest that the rabbit model is more like stroke in humans than the rat or gerbil models. Our preliminary work demonstrates that it is practical to study postischemic prostaglandin changes in cerebrospinal fluid rather than in brain tissue in a rabbit model of central nervous system ischemia.


Implanting inequality: empirical evidence of social and ethical risks of implantable radio-frequency identification (RFID) devices.
The aim of this study was to assess empirically the social and ethical risks associated with implantable radio-frequency identification (RFID) devices. Qualitative research included observational studies in twenty-three U.S. hospitals that have implemented new patient identification systems and eighty semi-structured interviews about the social and ethical implications of new patient identification systems, including RFID implants. The study identified three primary social and ethical risks associated with RFID implants: (i) unfair prioritization of patients based on their participation in the system, (ii) diminished trust of patients by care providers, and (iii) endangerment of patients who misunderstand the capabilities of the systems. RFID implants may aggravate inequalities in access to care without any clear health benefits. This research underscores the importance of critically evaluating new healthcare technologies from the perspective of both normative ethics and empirical ethics.


Mechanisms of acupuncture-electroacupuncture on persistent pain.
In the last decade, preclinical investigations of electroacupuncture mechanisms on persistent tissue injury (inflammatory), nerve injury (neuropathic), cancer, and visceral pain have increased. These studies show that electroacupuncture activates the nervous system differently in health than in pain conditions, alleviates both sensory and affective inflammatory pain, and inhibits inflammatory and neuropathic pain more effectively at 2 to 10 Hz than at 100 Hz. Electroacupuncture blocks pain by activating a variety of bioactive chemicals through peripheral, spinal, and supraspinal mechanisms. These include opioids, which desensitize peripheral nociceptors and reduce proinflammatory cytokines peripherally and in the spinal cord, and serotonin and norepinephrine, which decrease spinal N-methyl-D-aspartate receptor subunit GluN1 phosphorylation. Additional studies suggest that electroacupuncture, when combined with low dosages of conventional analgesics, provides effective pain management which can forestall the side effects of often-debilitating pharmaceuticals.


Busulfan dosing in children with BMIs ≥ 85% undergoing HSCT: a new optimal strategy.
Childhood obesity has more than tripled in the past 30 years. The prevalence of overweight and obese children has also increased in the pediatric cancer setting, causing substantial concern over proper chemotherapeutic dosing in this population. The purpose of this study was to determine if children with an increased body mass index (BMI) have an alteration in busulfan pharmacokinetics during hematopoietic stem cell transplant (HSCT) conditioning. We retrospectively reviewed data on busulfan pharmacokinetics (PK) on HSCT subjects (subjects were part of a prospective study previously reported by our group at Children's Memorial Hospital) to determine appropriateness of dosing. Subjects were divided into appropriate BMI categories (<25th percentile, 25th-85th percentile, ≥ 85th percentile) and busulfan PK dosing was analyzed (test dose, regimen dose, area under the curve [AUC], and clearance). The dosing based on PK test dose data of children with BMI ≥ 85% was compared against the package insert dosing recommendations of using adjusted ideal body weight (AIBW) in obese patients to determine which dosing schema was most accurate. Children with high BMIs had higher AUCs when dosing on actual weight then their normal or low BMI counterparts. This indicates that children with a high BMI require less drug (2.9 mg/kg using actual body weight) to achieve the same AUC as children with normal BMI (4.0 mg/kg) or low BMI (3.6 mg/kg). Using the recommended AIBW dosing schema, 53% of the patients with high BMIs would have had regimen dose AUCs ≥ 20% over/under the target; whereas with the PK test dose method, only 16% of the patients with high BMIs had regimen dose AUCs ≥ 20% over/under the target. PK testing continues to be the gold standard for busulfan dosing in children. Particular vigilance should be paid to PK monitoring in high BMI categories because of the potential risk of imprecise dosing when using the AIBW schema.


Hypovitaminosis D, neighborhood poverty, and progression of chronic kidney disease in disadvantaged populations.
In the United States, there are significant racial disparities in the incidence and prevalence of end-stage renal disease. The disparities are greatest for the Blacks and the magnitude of disparity is significantly greater than is evident from the incidence and prevalence data of end-stage renal disease - early stage chronic kidney disease is less common in Blacks and during that stage, mortality rate is significantly higher for that racial group. Recent studies have identified a genetic predisposition for non-diabetic renal disease among Blacks. However, genetic factors explain only part of the higher risk and the racial disparities are a result of a complex interplay of biology and sociology. Herein we focus on two factors and their role in explaining the higher risk for progression of chronic kidney disease among Blacks - one biologic (vitamin D deficiency) and one sociologic (neighborhood poverty). A greater Understanding of these factors is important in order to reduce the racial disparities in the United States.


Lactate dehydrogenase (LDH) isoenzymes patterns in ocular tumours.
Estimation of lactate dehydrogenase (LDH) isoenzymes in the serum and aqueous humor was carried out in 15 cases of benign ocular tumour, 15 cases of malignant tumor and 15 normal cases. Cases of both sexes aged between 1 year and 75 years were included. LDH, isoenzymes specially LDH4 and LDH5 are higher and LDH1 and LDH2 lower in sera of patients with malignant tumor specially retinoblastoma as compared to benign tumor cases and control cases. LDH isoenzymes in aqueous humor are significantly higher and show a characteristic pattern in retinoblastoma cases, the concentration was presumably too low in the control, malignant tumor other than retinoblastoma and benign tumor cases as its fractionation was not possible.


Inability of dimethyl sulfoxide and 5-fluorouracil to open the blood-brain barrier.
The inability of most chemotherapeutic agents to adequately penetrate the blood-brain barrier (BBB), in either normal brain or tumor-infiltrated brain, is a major factor limiting the use of chemotherapy in central nervous system malignancy. This barrier, however, can be opened in a reversible manner by the intra-arterial administration of hyperosmotic agents such as mannitol. It has been suggested that the intravenous administration of dimethyl sulfoxide (DMSO) or 5-fluorouracil (5-FU) can accomplish the same thing in a less invasive manner. We have not been able to confirm these findings. DMSO was administered to 25 rats intravenously at concentrations ranging from 25 to 90% or into the internal carotid artery at a concentration of 30%. The penetration of methotrexate, Evans blue-albumin, and hexosaminidase A was then evaluated at intervals ranging from 1.5 to 3.5 hours after administration. Significant barrier opening was not observed in animals receiving intravenous DMSO. Barrier modification, albeit generally modest, was obtained in animals receiving intracarotid DMSO, but this may have been the result of grand mal seizures, inasmuch as 5 of 6 of these animals had such seizures. Several of the animals receiving i.v. DMSO also had seizures, and all animals developed varying degrees of hematuria. Similarly, 5-FU was administered at a dose of 30 mg/kg i.v. and the permeability of the BBB to either Evans blue-albumin or methotrexate was evaluated. No increased permeability of the BBB to these two markers was observed. In summary, osmotic BBB opening in our hands remains the most consistent and reliable means available to open the BBB in a reversible fashion. Neither intravenous DMSO nor 5-FU seems to increase the delivery of chemotherapy or protein tracer to the central nervous system, and the use of DMSO can result in seizures and hematuria.


A randomized open-label study of 3- versus 5-drug combination antiretroviral therapy in newly HIV-1-infected individuals.
To understand whether combination antiretroviral therapy (cART) has been optimized, we asked whether 3-drug protease inhibitor (PI)-based cART intensified with raltegravir and maraviroc and initiated during early infection would improve outcomes when compared with similarly applied 3-drug PI-based cART. Forty newly HIV-1-infected patients were randomized 1:2 to receive 3-drug (N = 14) or 5-drug (N = 26) therapy. The primary end point was the percent of subjects with undetectable plasma viremia using standard reverse transcriptase-polymerase chain reaction and the single copy assay after 48 weeks. Secondary end points included levels of cell-associated HIV-1 DNA and RNA and levels of infectious virus in resting CD4 T cells at week 96 and quantitative and qualitative immunologic responses. At 48 weeks, 34 subjects remained on study and are included in the as-treated analysis. Three of 11 (27.3%) in the 3-drug arm and 9 of 21 (42.9%) in the 5-drug arm had plasma HIV-1 RNA levels below detection by both standard reverse transcriptase-polymerase chain reaction and single copy assay (P = 0.46, Fisher exact test). No significant differences in absolute levels of proviral DNA or changes in cell-associated RNA were seen during 96 weeks of therapy. Mean levels of infectious HIV-1 in resting CD4 T cells at week 96 in 7 subjects treated with 3-drugs and 13 with 5-drugs were 0.67 and 0.71 infectious units per million, respectively (P = 0.81). No differences were seen in quantitative or qualitative immunologic determinations including markers of immune activation. Intensified 5-drug cART initiated during early infection fails to significantly further impact virologic or immunologic responses beyond those achieved with standard 3-drug PI-based cART.


A Two-Layer Method for Sedentary Behaviors Classification Using Smartphone and Bluetooth Beacons.
Among the factors that outline the health of populations, person's lifestyle is the more important one. This work focuses on the caracterization and prevention of sedentary lifestyles. A sedentary behavior is defined as "any waking behavior characterized by an energy expenditure of 1.5 METs (Metabolic Equivalent) or less while in a sitting or reclining posture". To propose a method for sedentary behaviors classification using a smartphone and Bluetooth beacons considering different types of classification models: personal, hybrid or impersonal. Following the CRISP-DM methodology, a method based on a two-layer approach for the classification of sedentary behaviors is proposed. Using data collected from a smartphones' accelerometer, gyroscope and barometer; the first layer classifies between performing a sedentary behavior and not. The second layer of the method classifies the specific sedentary activity performed using only the smartphone's accelerometer and barometer data, but adding indoor location data, using Bluetooth Low Energy (BLE) beacons. To improve the precision of the classification, both layers implemented the Random Forest algorithm and the personal model. This study presents the first available method for the automatic classification of specific sedentary behaviors. The layered classification approach has the potential to improve processing, memory and energy consumption of mobile devices and wearables used.


High-sensitivity cardiac troponin I and B-type natriuretic Peptide as predictors of vascular events in primary prevention: impact of statin therapy.
Cardiac troponin and B-type natriuretic peptide (BNP) concentrations are associated with adverse cardiovascular outcome in primary prevention populations. Whether statin therapy modifies this association is poorly understood. We measured high-sensitivity cardiac troponin I (hsTnI) in 12 956 and BNP in 11 076 participants without cardiovascular disease in the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial before randomization to rosuvastatin 20 mg/d or placebo. Nearly 92% of participants had detectable circulating hsTnI, and 2.9% of men and 4.1% of women had levels above proposed sex-specific reference limits of 36 and 15 ng/L, respectively. hsTnI concentrations in the highest tertile were associated with a first major cardiovascular event (adjusted hazard ratio [aHR], 2.19; 95% confidence interval, 1.56-3.06; P for trend <0.001). BNP levels in the highest tertile were also associated a first cardiovascular event (aHR, 1.94; 95% confidence interval, 1.41-2.68; P for trend <0.001). The risk of all-cause mortality was elevated for the highest versus the lowest tertiles of hsTnI (aHR, 2.61; 95% confidence interval, 1.81-3.78; P for trend <0.001) and BNP (aHR, 1.45; 95% confidence interval, 1.03-2.04; P for trend 0.02). Rosuvastatin was equally effective in preventing a first cardiovascular event across categories of hsTnI (aHR range, 0.50-0.60) and BNP (aHR range, 0.42-0.67) with no statistically significant evidence of interaction (P for interaction=0.53 and 0.20, respectively). In a contemporary primary prevention population, baseline cardiac troponin I and BNP were associated with the risk of vascular events and all-cause mortality. The benefits of rosuvastatin were substantial and consistent regardless of baseline hsTnI or BNP concentrations. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.


Transfer function analysis of dynamic cerebral autoregulation: A white paper from the International Cerebral Autoregulation Research Network.
Cerebral autoregulation is the intrinsic ability of the brain to maintain adequate cerebral perfusion in the presence of blood pressure changes. A large number of methods to assess the quality of cerebral autoregulation have been proposed over the last 30 years. However, no single method has been universally accepted as a gold standard. Therefore, the choice of which method to employ to quantify cerebral autoregulation remains a matter of personal choice. Nevertheless, given the concept that cerebral autoregulation represents the dynamic relationship between blood pressure (stimulus or input) and cerebral blood flow (response or output), transfer function analysis became the most popular approach adopted in studies based on spontaneous fluctuations of blood pressure. Despite its sound theoretical background, the literature shows considerable variation in implementation of transfer function analysis in practice, which has limited comparisons between studies and hindered progress towards clinical application. Therefore, the purpose of the present white paper is to improve standardisation of parameters and settings adopted for application of transfer function analysis in studies of dynamic cerebral autoregulation. The development of these recommendations was initiated by (but not confined to) theCerebral Autoregulation Research Network(CARNet -www.car-net.org).


Arabidopsis jasmonate signaling pathway.
Jasmonates control defense gene expression and male fertility in the model plant Arabidopsis thaliana. In both cases, the involvement of the jasmonate pathway is complex, involving large-scale transcriptional reprogramming. Additionally, jasmonate signaling is hard-wired into the auxin, ethylene, and salicylate signal networks, all of which are under intense investigation in Arabidopsis. In male fertility, jasmonic acid (JA) is the essential signal intervening both at the level of anther elongation and in pollen dehiscense. A number of genes potentially involved in jasmonate-dependent anther elongation have recently been discovered. In the case of defense, at least two jasmonates, JA and its precursor 12-oxo-phytodienoic acid (OPDA), are necessary for the fine-tuning of defense gene expression in response to various microbial pathogens and arthropod herbivores. However, only OPDA is required for full resistance to some insects and fungi. Other jasmonates probably affect yet more physiological responses. A series of breakthroughs have identified the SKP/CULLIN/F-BOX (SCF), CORONATINE INSENSITIVE (COI1) complex, acting together with the CONSTITUTIVE PHOTOMORPHOGENIC 9 (COP9) signalosome, as central regulatory components of jasmonate signaling in Arabidopsis. The studies, mostly involving mutational approaches, have paved the way for suppressor screens that are expected to further extend our knowledge of jasmonate signaling. When these and other new mutants affecting jasmonate signaling are characterized, new nodes will be added to the Arabidopsis Jasmonate Signaling Pathway Connections Map, and the lists of target genes regulated by jasmonates in Arabidopsis will be expanded.


Staphylococcal SSL5-induced platelet microparticles provoke proinflammatory responses via the CD40/TRAF6/NFκB signalling pathway in monocytes.
Pathogens-induced platelet activation contributes to inflammation in cardiovascular diseases, but underlying mechanisms remain elusive. Staphylococcal superantigen-like protein 5 (SSL5) is a known activator of platelets. Here we examined whether SSL5 is implicated in Staphylococcus aureus (S. aureus)-induced inflammation and potential mechanisms involved. As expected, we show that SSL5 activates human platelets and induces generation of platelet microparticles (PMPs). Flow cytometry and scanning electron microscopy studies demonstrate that SSL5-induced PMPs (SSL5-PMPs) bind to monocytes, causing aggregate formation. In addition, SSL5-PMPs provoke monocyte expression and release of inflammatory mediators, including interleukin-1β (IL-1β), tumour necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1) and matrix metalloproteinase-9 (MMP-9) in a dose- and time-dependent manner. SSL5-PMPs also enhance MCP-1-induced monocyte migration. Blockade of CD40 and CD40 ligand (CD40L) interactions with neutralising antibodies significantly reduce monocyte release of inflammatory mediators and migration induced by SSL5-PMPs. SiRNA-mediated silencing of CD40 or TNF receptor (TNFR)-associated factor 6 (TRAF6) gene largely abrogates phosphorylation and nuclear translocation of NFκB (p65). In conclusion, SSL5 provokes the release of inflammatory mediators in monocytes, at least in part, via PMPs-mediated activation of the CD40/TRAF6/NFκB signalling pathway, though it normally inhibits leukocyte function. Our findings thus reveal a novel mechanism by which S. aureus induces inflammation.


Posture Detection Based on Smart Cushion for Wheelchair Users.
The postures of wheelchair users can reveal their sitting habit, mood, and even predict health risks such as pressure ulcers or lower back pain. Mining the hidden information of the postures can reveal their wellness and general health conditions. In this paper, a cushion-based posture recognition system is used to process pressure sensor signals for the detection of user's posture in the wheelchair. The proposed posture detection method is composed of three main steps: data level classification for posture detection, backward selection of sensor configuration, and recognition results compared with previous literature. Five supervised classification techniques-Decision Tree (J48), Support Vector Machines (SVM), Multilayer Perceptron (MLP), Naive Bayes, and k-Nearest Neighbor (k-NN)-are compared in terms of classification accuracy, precision, recall, and F-measure. Results indicate that the J48 classifier provides the highest accuracy compared to other techniques. The backward selection method was used to determine the best sensor deployment configuration of the wheelchair. Several kinds of pressure sensor deployments are compared and our new method of deployment is shown to better detect postures of the wheelchair users. Performance analysis also took into account the Body Mass Index (BMI), useful for evaluating the robustness of the method across individual physical differences. Results show that our proposed sensor deployment is effective, achieving 99.47% posture recognition accuracy. Our proposed method is very competitive for posture recognition and robust in comparison with other former research. Accurate posture detection represents a fundamental basic block to develop several applications, including fatigue estimation and activity level assessment.


Vaccine preventable diseases and vaccination coverage in Aboriginal and Torres Strait Islander people, Australia 2003 to 2006.
This, the second report on vaccine preventable diseases and vaccination coverage in Aboriginal and Torres Strait Islander people, brings together the relevant sources of routinely collected data on vaccine preventable diseases--notifications, hospitalisations, deaths, and childhood and adult vaccination coverage. As a result of continued improvements in the collection of data on Indigenous status, this second report is considerably more comprehensive, with data available from more jurisdictions, and more detailed presentation, including time trends and vaccination coverage by jurisdiction. Vaccination coverage data provide evidence of successful program delivery and highlight some areas for improvement. For universally funded vaccines in children, coverage is similar in Indigenous and non-Indigenous children by 24 months of age. However, delayed vaccination is more common in Indigenous children, with 6%-8% fewer children fully vaccinated at 12 months of age. More timely vaccination, particularly within the first six months of life, is particularly important in reducing the disproportionate burdens of disease due to pertussis and Haemophilus influenzae type b (Hib). For vaccination programs targeted specifically at Aboriginal and Torres Strait Islander children and adults, coverage is substantially lower than for those programs targeted at all Australians. This is true for hepatitis A and polysaccharide pneumococcal vaccine for children, and influenza and polysaccharide pneumococcal vaccine for adults. Targeted vaccination programs present a particular challenge for health services in urban areas. Nevertheless, the impact of vaccination programs in preventing disease and reducing the disparity of disease burden between Aboriginal and Torres Strait Islander and non-Indigenous people has been substantial. This is evident in data on notifications, hospitalisations and deaths. Diseases which, in the past, have had devastating and often disproportionately high impact on Indigenous people, such as diphtheria, measles, poliomyelitis, smallpox and tetanus, are now completely or almost completely absent from Australia. Hepatitis B infection, another disease responsible for high levels of infection and substantial serious illness and death in the pre-vaccine era, is also now well controlled in age groups eligible for vaccination. Although invasive Hib disease is now rare in Australia since the introduction of vaccination in 1993, higher rates of disease persist in Aboriginal and Torres Strait Islander children. More research is needed into the contribution of environmental factors, delayed vaccination and vaccine failure to this continued disparity. Hepatitis A has disproportionately affected Aboriginal and Torres Strait Islander children in the past. Vaccination programs in north Queensland and in various other countries have been very successful in reducing the burden of hepatitis A. It is too early to assess the impact of the vaccination program for Aboriginal and Torres Strait Islander children that commenced in regions outside north Queensland in November 2005. For some other diseases the situation is more complicated. The substantial impact of the national meningococcal C vaccination program since 2003 is evident in this report, although the higher proportion of non-vaccine preventable serotype B disease in Aboriginal and Torres Strait Islander people underlines the need for a new vaccine to cover this serotype. Pneumonia remains the most important communicable disease contributor to premature mortality in Aboriginal and Torres Strait Islander people of all ages. In young Indigenous adults, the eightfold higher rate of hospitalisation compared with their non-Indigenous peers, and the 11-fold higher rate of invasive pneumococcal disease, suggest the need for more widespread use of influenza and pneumococcal vaccines in this age group. Current coverage for Indigenous 15-49 year olds, where influenza and pneumococcal vaccines are funded only for those with risk factors, is low even though some 70% of this age group have one or more risk factors. Overall, the data presented in this report provide powerful evidence for the impact of vaccines in reducing disease in Aboriginal and Torres Strait Islander people, and also point to areas for further improvement. Immunisation programs are an example of how preventive health programs in general can be enhanced to close the gap in morbidity and mortality between Indigenous and non-Indigenous Australians.


A randomized controlled pilot study of home-based step training in older people using videogame technology.
Stepping impairments are associated with physical and cognitive decline in older adults and increased fall risk. Exercise interventions can reduce fall risk, but adherence is often low. A new exergame involving step training may provide an enjoyable exercise alternative for preventing falls in older people. To assess the feasibility and safety of unsupervised, home-based step pad training and determine the effectiveness of this intervention on stepping performance and associated fall risk in older people. Single-blinded two-arm randomized controlled trial comparing step pad training with control (no-intervention). Thirty-seven older adults residing in independent-living units of a retirement village in Sydney, Australia. Intervention group (IG) participants were provided with a computerized step pad system connected to their TVs and played a step game as often as they liked (with a recommended dose of 2-3 sessions per week for 15-20 minutes each) for eight weeks. In addition, IG participants were asked to complete a choice stepping reaction time (CSRT) task once each week. CSRT, the Physiological Profile Assessment (PPA), neuropsychological and functional mobility measures were assessed at baseline and eight week follow-up. Thirty-two participants completed the study (86.5%). IG participants played a median 2.75 sessions/week and no adverse events were reported. Compared to the control group, the IG significantly improved their CSRT (F31,1 = 18.203, p<.001), PPA composite scores (F31,1 = 12.706, p = 0.001), as well as the postural sway (F31,1 = 4.226, p = 0.049) and contrast sensitivity (F31,1 = 4.415, p = 0.044) PPA sub-component scores. In addition, the IG improved significantly in their dual-task ability as assessed by a timed up and go test/verbal fluency task (F31,1 = 4.226, p = 0.049). Step pad training can be safely undertaken at home to improve physical and cognitive parameters of fall risk in older people without major cognitive and physical impairments. Australian New Zealand Clinical Trials Registry ACTRN12611001081909.


Foxa1 and Foxa2 interact with the androgen receptor to regulate prostate and epididymal genes differentially.
Previous studies from our group have shown that Foxa1 is expressed in the prostate and interacts with the androgen receptor (AR) to regulate prostate-specific genes such as prostate-specific antigen (PSA) and probasin (PB). We report here that Foxa2 but not Foxa1 is expressed in the epididymis. Further, Foxa2 interacts with the AR to regulate the mouse epididymal retinoic acid binding protein (mE-RABP) gene, an epididymis-specific gene. Binding of Foxa2 to the mE-RABP promoter was confirmed by gel-shift and chromatin immunoprecipitation (ChIP) assays. Overexpression of Foxa2 suppresses androgen activation of the mE-RABP promoter while overexpression of Foxa2 with prostate-specific promoters activates gene expression in an androgen-independent manner. GST pull-down assays determined that both Foxa1 and Foxa2 physically interact with the DNA binding domain of the AR. The interaction between Foxa proteins and AR was further confirmed by gel-shift assays where Foxa protein was recruited to AR binding oligomers even when Foxa binding sites were not present, and AR was recruited to Foxa binding oligomers even in the absence of an AR binding site. Given that Foxa1 and Foxa2 proteins are expressed differentially in the prostate and epididymis, these data suggest that the Foxa proteins have distinct effects on AR-regulated genes in different male reproductive accessory organs.


Evaluation of pulmonary and systemic toxicity following lung exposure to graphite nanoplates: a member of the graphene-based nanomaterial family.
Graphene, a monolayer of carbon, is an engineered nanomaterial (ENM) with physical and chemical properties that may offer application advantages over other carbonaceous ENMs, such as carbon nanotubes (CNT). The goal of this study was to comparatively assess pulmonary and systemic toxicity of graphite nanoplates, a member of the graphene-based nanomaterial family, with respect to nanoplate size. Three sizes of graphite nanoplates [20 μm lateral (Gr20), 5 μm lateral (Gr5), and <2 μm lateral (Gr1)] ranging from 8-25 nm in thickness were characterized for difference in surface area, structure,, zeta potential, and agglomeration in dispersion medium, the vehicle for in vivo studies. Mice were exposed by pharyngeal aspiration to these 3 sizes of graphite nanoplates at doses of 4 or 40 μg/mouse, or to carbon black (CB) as a carbonaceous control material. At 4 h, 1 day, 7 days, 1 month, and 2 months post-exposure, bronchoalveolar lavage was performed to collect fluid and cells for analysis of lung injury and inflammation. Particle clearance, histopathology and gene expression in lung tissue were evaluated. In addition, protein levels and gene expression were measured in blood, heart, aorta and liver to assess systemic responses. All Gr samples were found to be similarly composed of two graphite structures and agglomerated to varying degrees in DM in proportion to the lateral dimension. Surface area for Gr1 was approximately 7-fold greater than Gr5 and Gr20, but was less reactive reactive per m(2). At the low dose, none of the Gr materials induced toxicity. At the high dose, Gr20 and Gr5 exposure increased indices of lung inflammation and injury in lavage fluid and tissue gene expression to a greater degree and duration than Gr1 and CB. Gr5 and Gr20 showed no or minimal lung epithelial hypertrophy and hyperplasia, and no development of fibrosis by 2 months post-exposure. In addition, the aorta and liver inflammatory and acute phase genes were transiently elevated in Gr5 and Gr20, relative to Gr1. Pulmonary and systemic toxicity of graphite nanoplates may be dependent on lateral size and/or surface reactivity, with the graphite nanoplates > 5 μm laterally inducing greater toxicity which peaked at the early time points post-exposure relative to the 1-2 μm graphite nanoplate.


A rapid dipstick antigen capture assay for the diagnosis of falciparum malaria. WHO Informal Consultation on Recent Advances in Diagnostic Techniques and Vaccines for Malaria.
Recent advances in the diagnosis of Plasmodium falciparum infections have made it possible to consider supplementing light microscopy with a standardized dipstick antigen capture assay based on the detection of a parasite-specific protein, which is secreted by the asexual blood stages and immature gametocytes but not by the other stages. Field trials indicate that this dipstick assay provides consistently reproducible results, with a threshold of detection of P. falciparum parasitaemia similar to that obtained by high quality routine malaria microscopy and a specificity and sensitivity of around 90% compared with standard thick blood film microscopy. The stability, reproducibility, and ease of use of the assay clearly indicate that it has potential for application in the management of malaria, particularly at the peripheral health care level, provided its accuracy can be assured and that it can be made affordable. Consideration should be given to its wider use where operational requirements and resources so justify, and where decisions are based on adequate evaluation of the existing health delivery systems.


Comparison of Nucleic Acid Hybridization and Fluorometry for Measurement of the Relationship between RNA/DNA Ratio and Growth Rate in a Marine Bacterium.
Continuous culture of Pseudomonas stutzeri Zobell, a marine denitrifying bacterium, was used to determine the relationship between growth rate and nucleic acid content. The trend of decreasing RNA content with decreasing growth rate, well known for enteric organisms, was found to occur in P. stutzeri Zobell as well, even at very long generation times such as those thought to occur in the oligotrophic ocean. When assayed by ethidium bromide fluorescence, the total RNA/DNA ratio was linear for generation times between 6 and 60 h. We also developed a 200-bp nucleic acid probe (with species-specific potential) for a portion of the 23S rRNA gene of P. stutzeri Zobell, which was used to quantify rRNA and rDNA by hybridization in the same continuous cultures. The rRNA/rDNA ratio also exhibited a decrease with decreasing growth rate, but the relationship, although significant, was not simply linear. The sensitivity and accuracy of the two methods are compared, and the potential for species specificity in future hybridizations is discussed.


Characterization of Complementary and Alternative Medicine-Related Consultations in an Academic Drug Information Service.
To characterize requests received through an academic drug information consultation service related to complementary and alternative medicines. A retrospective review and descriptive analysis of drug information consultations was conducted. A total of 195 consultations related to complementary and alternative medicine were evaluated. All consultation requests involved questions about dietary supplements. The most common request types were related to safety and tolerability (39%), effectiveness (38%), and therapeutic use (34%). Sixty-eight percent of the requests were from pharmacists. The most frequent consultation requests from pharmacists were questions related to drug interactions (37%), therapeutic use (37%), or stability/compatibility/storage (34%). Nearly 60% of complementary and alternative medicine-related consultation requests were able to be completely addressed using available resources. Among review sources, Natural Medicines Comprehensive Database, Clinical Pharmacology, Micromedex, and Pharmacist's Letter were the most common resources used to address consultations. Utilization of a drug information service may be a viable option for health care professionals to help answer a complementary and alternative medicine-related question. Additionally, pharmacists and other health care professionals may consider acquiring resources identified to consistently answering these questions.


Barriers to full-text publication following presentation of abstracts at annual orthopaedic meetings.
Oral presentations at national and international meetings offer an excellent forum for the dissemination of current research findings. However, publication rates of full-text articles after presentation of abstracts at international meetings have ranged from 11% to 78%, which suggests that at least 32% of the abstracts presented are never published as complete articles in peer-reviewed journals. In an effort to identify the reasons that surgeons had not had a paper published following presentation of their work at an international orthopaedic meeting, we conducted a survey of a cross section of authors of orthopaedic papers presented at a national meeting. We retrieved all abstracts from the 1996 scientific program of the sixty-third Annual Meeting of the American Academy of Orthopaedic Surgeons. A computerized Medline and PubMed search established whether the abstract had been subsequently published as a full-text article. The authors of the abstracts that had not been subsequently published were surveyed to identify the reasons for the failure to publish. A total of 465 abstracts were presented at the sixty-third Annual Meeting of the American Academy of Orthopaedic Surgeons in 1996. We surveyed the authors of 306 abstracts for which we were unable to locate a subsequent full-text publication on Medline. One hundred and ninety-nine investigators (65%) responded to the questionnaire. At the time of the survey, seventy-two manuscripts had been published, thirty-two had been submitted and rejected, fourteen were under consideration by journals, seven had been accepted for publication or were in press, and three were not recalled by the investigator. In addition, seventy-one abstracts (35.7%) of the 199 had not been submitted for publication. The authors of those abstracts were asked to indicate one or more reasons why they had not submitted a manuscript for publication. Thirty-three investigators (46.5%) indicated that they lacked sufficient time for research activities, twenty-two (31.0%) reported that the study presented at the meeting in 1996 was still in progress, fourteen (19.7%) believed that the responsibility for writing the manuscript belonged to someone else, and twelve (16.9%) reported that difficulties with co-authors who would not participate had impeded the completion of the manuscript. Nine investigators (12.7%) responded that the pursuit of publication was a low priority. In a survey of investigators who had not had a full-text article published after presenting the abstract at a national meeting, we found that the failure to publish was due to one of three main reasons: (1) they did not have enough time to prepare a manuscript for publication (the reason most frequently given); (2) almost one-third of the studies that had not been submitted for publication were ongoing; and (3) relationships with co-authors sometimes presented a barrier to final publication. Thorough preparation before the study and the establishment of stricter guidelines to limit the presentation of preliminary data at national and international meetings may improve publication rates.


Engineering stochasticity in gene expression.
Stochastic fluctuations (noise) in gene expression can cause members of otherwise genetically identical populations to display drastically different phenotypes. An understanding of the sources of noise and the strategies cells employ to function reliably despite noise is proving to be increasingly important in describing the behavior of natural organisms and will be essential for the engineering of synthetic biological systems. Here we describe the design of synthetic constructs, termed ribosome competing RNAs (rcRNAs), as a means to rationally perturb noise in cellular gene expression. We find that noise in gene expression increases in a manner proportional to the ability of an rcRNA to compete for the cellular ribosome pool. We then demonstrate that operons significantly buffer noise between coexpressed genes in a natural cellular background and can even reduce the level of rcRNA enhanced noise. These results demonstrate that synthetic genetic constructs can significantly affect the noise profile of a living cell and, importantly, that operons are a facile genetic strategy for buffering against noise.


Mast cell-derived TNF can promote Th17 cell-dependent neutrophil recruitment in ovalbumin-challenged OTII mice.
Both mast cells and IL-17 can contribute to host defense and pathology in part by orchestrating neutrophil recruitment, but the possible role of mast cells in IL-17-induced inflammation remains to be defined. We found that mast cells and IL-17, but neither IFN-gamma nor FcRgamma signaling, contributed significantly to the antigen (Ag)-dependent airway neutrophilia elicited in ovalbumin-specific T-cell receptor (TCR)-expressing C57BL/6-OTII mice, and that IFN-gamma significantly suppressed IL-17-dependent airway neutrophilia in this setting. IL-18, IL-1beta, and TNF each contributed significantly to the development of Ag- and T helper 17 (Th17 cell)-mediated airway neutrophilia. Moreover, IL-17 enhanced mast cell TNF production in vitro, and mast cell-associated TNF contributed significantly to Ag- and Th17 cell-mediated airway neutrophilia in vivo. By contrast, we detected no significant role for the candidate mediators histamine, PGD(2), LTB(4), CXCL10, or IL-16, each of which can be produced by mast cells and other cell types, in the neutrophil infiltration elicited in this model. These findings establish that mast cells and mast cell-derived TNF can significantly enhance, by FcRgamma-independent mechanisms, the Ag- and Th17 cell-dependent development of a neutrophil-rich inflammatory response at a site of Ag challenge.


Subcellular distribution of hydrolase activities for glycine and leucine homopeptides in human jejunum.
1. The subcellular distribution of peptidase activities in the normal human jejunum against glycine and leucine homopeptides has been investigated with an analytical fractionation technique. 2. An 8000 g-min supernatant was prepared from homogenates of Crosby capsule biopsy specimens and subjected to isopycnic centrifugation in a Beaufay automatic zonal rotor. 3. The distribution of subcellular organelles in the gradient was established by measurement of organelle-specific marker enzymes. 4. A sensitive fluorimetric assay for glycine peptidase was developed and used for the localization of peptidase activity with peptides composed of from two to five glycine residues as substrates. 5. Glycine peptidase activity was located in the cytosol and in the brush-border membrane but the distribution of activity varied markedly with the chain-length of substrate; the longer the peptide the greater the proportion of activity associated with the brush border. Leucine peptidase showed a similar variation in cytosol--brush border distributions. 6. The results are consistent with concepts that suggest absorption and intracellular hydrolysis of small peptides and brush-border digestion of larger peptides.


Speciation dynamics of metals in dispersion of nanoparticles with discrete distribution of charged binding sites.
We report a comprehensive theory to evaluate the kinetics of complex formation between metal ions and charged spherical nanoparticles. The latter consist of an ion-impermeable core surrounded by a soft shell layer characterized by a discrete axisymmetric 2D distribution of charged sites that bind metal ions. The theory explicitly integrates the conductive diffusion of metal ions from bulk solution toward the respective locations of the reactive sites within the particle shell volume. The kinetic constant k for outer-sphere nanoparticle-metal association is obtained from the sum of the contributions stemming from all reactive sites, each evaluated from the corresponding incoming flux of metal ions derived from steady-state Poisson-Nernst-Planck equations. Illustrations are provided to capture the basic intertwined impacts of particle size, overall particle charge, spatial heterogeneity in site distribution, type of particle (hard, core-shell or porous) and concentration of the background electrolyte on k. As a limit, k converges with predictions from previously reported analytical expressions derived for porous particles with low and high charge density, cases that correspond to coulombic and mean-field (smeared-out) electrostatic treatments, respectively. The conditions underlying the applicability of these latter approaches are rigorously identified in terms of (i) the extent of overlap between electric double layers around charged neighbouring sites, and (ii) the magnitude of the intraparticulate metal concentration gradient. For the first time, the proposed theory integrates the differentiated impact of the local potential around the charged binding sites amidst the overall particle field, together with that of the so-far discarded intraparticulate flux of metal ions.


Impact of defects on the surface chemistry of ZnO(0001 macro)-O.
Scanning tunneling microscopy and core level photoelectron spectroscopy measurements have been used to investigate the morphology of ZnO(0001 macro)-O, and its reactivity with carbon monoxide and carbon dioxide, as a function of surface preparation. Real space images of the surface indicate that increasing the substrate anneal temperature during preparation significantly reduces the surface step density. Surface defect concentration is also monitored by employing formic acid as a chemical probe, which is shown to adsorb dissociatively (HCOOH --> [HCOO](-) + H(+)) only on zinc cations at step edges. Carbon 1s X-ray photoelectron spectra show that carbon monoxide and carbon dioxide both react to form surface carbonate species. Spectra, recorded both as a function of surface preparation and following coadsorption, demonstrate that the carbonate formed from either reactant molecule is located at oxygen vacancies at step edges, evidencing the significant role that defects can play in the surface chemistry of ZnO(0001 macro)-O.


Results from a cross-sectional sexual and reproductive health study among school girls in Tanzania: high prevalence of bacterial vaginosis.
Bacterial vaginosis (BV) increases women's susceptibility to sexually transmitted infections (STIs) and HIV and may partly explain the high incidence of STI/HIV among girls and young women in East and southern Africa. The objectives of this study were to investigate the association between BV and sexual debut, to investigate other potential risk factors of BV and to estimate associations between BV and STIs. Secondary school girls in Mwanza, aged 17 and 18 years, were invited to join a cross-sectional study. Consenting participants were interviewed and samples were obtained for STI and BV testing. Factors associated with prevalent BV were analysed using multivariable logistic regression. Y-chromosome was tested as a biomarker for unprotected penile-vaginal sex. Of the 386 girls who were enrolled, 163 (42%) reported having ever had penile-vaginal sex. Ninety-five (25%) girls had BV. The prevalence of BV was 33% and 19% among girls who reported or did not report having ever had penile-vaginal sex, respectively. BV was weakly associated with having ever had one sex partner (adjusted odds ratio (aOR) 1.59;95% CI 0.93 to 2.71) and strongly associated with two or more partners (aOR = 3.67; 95% CI 1.75 to 7.72), receptive oral sex (aOR 6.38; 95% CI 1.22 to 33.4) and having prevalent human papillomavirus infection (aOR = 1.73; 95% CI 1.02 to 2.95). Of the 223 girls who reported no penile-vaginal sex, 12 (5%) tested positive for an STI and 7 (3%) tested positive for Y-chromosome. Reclassifying these positive participants as having ever had sex did not change the key results. Tanzanian girls attending school had a high prevalence of BV. Increasing number of sex partner was associated with BV; however, 19% of girls who reported no penile-vaginal sex had BV. This suggests that penile-vaginal sexual exposure may not be a prerequisite for BV. There was evidence of under-reporting of sexual debut.