The Association Between Income and Life Expectancy in the United States, 2001-2014.
The relationship between income and life expectancy is well established but remains poorly understood. To measure the level, time trend, and geographic variability in the association between income and life expectancy and to identify factors related to small area variation. Income data for the US population were obtained from 1.4 billion deidentified tax records between 1999 and 2014. Mortality data were obtained from Social Security Administration death records. These data were used to estimate race- and ethnicity-adjusted life expectancy at 40 years of age by household income percentile, sex, and geographic area, and to evaluate factors associated with differences in life expectancy. Pretax household earnings as a measure of income. Relationship between income and life expectancy; trends in life expectancy by income group; geographic variation in life expectancy levels and trends by income group; and factors associated with differences in life expectancy across areas. The sample consisted of 1,408,287,218 person-year observations for individuals aged 40 to 76 years (mean age, 53.0 years; median household earnings among working individuals, $61,175 per year). There were 4,114,380 deaths among men (mortality rate, 596.3 per 100,000) and 2,694,808 deaths among women (mortality rate, 375.1 per 100,000). The analysis yielded 4 results. First, higher income was associated with greater longevity throughout the income distribution. The gap in life expectancy between the richest 1% and poorest 1% of individuals was 14.6 years (95% CI, 14.4 to 14.8 years) for men and 10.1 years (95% CI, 9.9 to 10.3 years) for women. Second, inequality in life expectancy increased over time. Between 2001 and 2014, life expectancy increased by 2.34 years for men and 2.91 years for women in the top 5% of the income distribution, but by only 0.32 years for men and 0.04 years for women in the bottom 5% (P < .001 for the differences for both sexes). Third, life expectancy for low-income individuals varied substantially across local areas. In the bottom income quartile, life expectancy differed by approximately 4.5 years between areas with the highest and lowest longevity. Changes in life expectancy between 2001 and 2014 ranged from gains of more than 4 years to losses of more than 2 years across areas. Fourth, geographic differences in life expectancy for individuals in the lowest income quartile were significantly correlated with health behaviors such as smoking (r = -0.69, P < .001), but were not significantly correlated with access to medical care, physical environmental factors, income inequality, or labor market conditions. Life expectancy for low-income individuals was positively correlated with the local area fraction of immigrants (r = 0.72, P < .001), fraction of college graduates (r = 0.42, P < .001), and government expenditures (r = 0.57, P < .001). In the United States between 2001 and 2014, higher income was associated with greater longevity, and differences in life expectancy across income groups increased over time. However, the association between life expectancy and income varied substantially across areas; differences in longevity across income groups decreased in some areas and increased in others. The differences in life expectancy were correlated with health behaviors and local area characteristics.


Identification of a novel idiopathic epilepsy locus in Belgian Shepherd dogs.
Epilepsy is the most common neurological disorder in dogs, with an incidence ranging from 0.5% to up to 20% in particular breeds. Canine epilepsy can be etiologically defined as idiopathic or symptomatic. Epileptic seizures may be classified as focal with or without secondary generalization, or as primary generalized. Nine genes have been identified for symptomatic (storage diseases) and one for idiopathic epilepsy in different breeds. However, the genetic background of common canine epilepsies remains unknown. We have studied the clinical and genetic background of epilepsy in Belgian Shepherds. We collected 159 cases and 148 controls and confirmed the presence of epilepsy through epilepsy questionnaires and clinical examinations. The MRI was normal while interictal EEG revealed abnormalities and variable foci in the clinically examined affected dogs. A genome-wide association study using Affymetrix 50K SNP arrays in 40 cases and 44 controls mapped the epilepsy locus on CFA37, which was replicated in an independent cohort (81 cases and 88 controls; combined p = 9.70×10⁻¹⁰, OR = 3.3). Fine mapping study defined a ∼1 Mb region including 12 genes of which none are known epilepsy genes or encode ion channels. Exonic sequencing was performed for two candidate genes, KLF7 and ADAM23. No variation was found in KLF7 but a highly-associated non-synonymous variant, G1203A (R387H) was present in the ADAM23 gene (p = 3.7×10⁻⁸, OR = 3.9 for homozygosity). Homozygosity for a two-SNP haplotype within the ADAM23 gene conferred the highest risk for epilepsy (p = 6.28×10⁻¹¹, OR = 7.4). ADAM23 interacts with known epilepsy proteins LGI1 and LGI2. However, our data suggests that the ADAM23 variant is a polymorphism and we have initiated a targeted re-sequencing study across the locus to identify the causative mutation. It would establish the affected breed as a novel therapeutic model, help to develop a DNA test for breeding purposes and introduce a novel candidate gene for human idiopathic epilepsies.


Projected future climate change and Baltic Sea ecosystem management.
Climate change is likely to have large effects on the Baltic Sea ecosystem. Simulations indicate 2-4 °C warming and 50-80 % decrease in ice cover by 2100. Precipitation may increase ~30 % in the north, causing increased land runoff of allochthonous organic matter (AOM) and organic pollutants and decreased salinity. Coupled physical-biogeochemical models indicate that, in the south, bottom-water anoxia may spread, reducing cod recruitment and increasing sediment phosphorus release, thus promoting cyanobacterial blooms. In the north, heterotrophic bacteria will be favored by AOM, while phytoplankton production may be reduced. Extra trophic levels in the food web may increase energy losses and consequently reduce fish production. Future management of the Baltic Sea must consider the effects of climate change on the ecosystem dynamics and functions, as well as the effects of anthropogenic nutrient and pollutant load. Monitoring should have a holistic approach, encompassing both autotrophic (phytoplankton) and heterotrophic (e.g., bacterial) processes.


Transformational leadership as a mediator between work-family conflict, nurse-reported patient safety outcomes, and job engagement.
Work-family conflict (WFC) is an important issue in nursing administration and management that is associated with reduced work effectiveness and patient safety issues. To date, very few studies have attempted to explain the mechanisms underlying these relationships. The aim of this study was to determine the influence of work-family conflict (WFC) on patient safety outcomes and job engagement via the intermediary role of transformational leadership (TL). Cross-sectional study. Seven hundred fifty-four nurses from 10 acute care hospitals in the Philippines were included in this cross-sectional study. A higher perception of WFC was associated with increased adverse events, reduced quality of care and decreased job engagement. WFC was indirectly associated with quality of care, adverse events and job engagement through the intermediary of TL. The results of this study underscore the important role of nurse managers' TL in sustaining work-family balance and, in turn, improving patient safety outcomes and enhancing job engagement among nurses. Institutional measures to foster patient safety outcomes and sustain the nursing workforce should involve enhancing nurse managers' leadership behaviors through theory-driven interventions, periodic leadership assessment, and implementation of leadership development activities. WFC may be addressed by creating empowering work conditions, providing adequate coaching and mentorship to nurses, and implementing work-family friendly policies in the workplace.


Heritability of antibody isotype and subclass responses to Plasmodium falciparum antigens.
It is important to understand the extent to which genetic factors regulate acquired immunity to common infections. A classical twin study design is useful to estimate the heritable component of variation in measurable immune parameters. This study assessed the relative heritability of different plasma antibody isotypes and subclasses (IgG1, IgG2, IgG3, IgG4, IgM, IgA and IgE) naturally acquired to P. falciparum blood stage antigens AMA1, MSP1-19, MSP2 (two allelic types) and MSP3 (two allelic types). Separate analyses were performed on plasma from 213 pairs of Gambian adult twins, 199 child twin pairs sampled in a dry season when there was little malaria transmission, and another set of 107 child twin pairs sampled at the end of the annual wet season when malaria was common. There were significantly positive heritability (h(2)) estimates for 48% (20/42) of the specific antibody assays (for the seven isotypes and subclasses to the six antigens tested) among the adults, 48% (20/42) among the children in the dry season and 31% (13/42) among the children in the wet season. In children, there were significant heritability estimates for IgG4 reactivity against each of the antigens, and this subclass had higher heritability than the other subclasses and isotypes. In adults, 75% (15/20) of the significantly heritable antigen-specific isotype responses were attributable to non-HLA class II genetic variation, whereas none showed a significant HLA contribution. Genome-wide approaches are now warranted to map the major genetic determinants of variable antibody isotype and subclass responses to malaria, alongside evaluation of their impact on infection and disease. Although plasma levels of IgG4 to malaria antigens are generally low, the exceptionally high heritability of levels of this subclass in children deserves particular investigation.


Initial experience of magnetic resonance imaging/ultrasonography fusion transperineal biopsy: Biopsy techniques and results for 75 patients.
The aim of this study is to describe the technique and to report early results of transperineal magnetic resonance imaging and ultrasonography (MRI-US) fusion biopsy. A total of 75 patients underwent MRI-US fusion transperineal biopsy. Targeted biopsy via MRI-US fusion imaging was carried out for cancer-suspicious lesions with additional systematic biopsy. Detection rates for overall and clinically significant prostate cancer (csPCa) were evaluated and compared between systematic and targeted biopsy. In addition, further investigation into the detection rate according to prostate imaging reporting and data system (PI-RADS) score was done. Results of repeat biopsies were also evaluated. Overall cancer detection rate was 61.3% (46 patients) and the detection rate for csPCa was 42.7% (32 patients). Overall detection rates for systematic and targeted biopsy were 41.3% and 57.3% (p<0.05), respectively. Detection rates for csPCa were 26.7% and 41.3%, respectively (p<0.05). The cancer detection rates via MRI fusion target biopsy were 30.8% in PI-RADS 3, 62.1% in PI-RADS 4 and 89.4% in PI-RADS 5. Rates of csPCa missed by targeted biopsy and systematic biopsy were 0.0% and 25.0%, respectively. The cancer detection rate in repeat biopsies was 61.1% (11 among 18 patients) in which 55.5% of cancer suspected lesions were located in the anterior portion. Transperineal MRI-US fusion biopsy is useful for improving overall cancer detection rate and especially detection of csPCa. Transperineal MRI-US targeted biopsy show potential benefits to improve cancer detection rate in patients with high PI-RADS score, tumor located at the anterior portion and in repeat biopsies.


Blood and urine metal ion levels in young and active patients after Birmingham hip resurfacing arthroplasty: four-year results of a prospective longitudinal study.
This is a longitudinal study of the daily urinary output and the concentrations in whole blood of cobalt and chromium in patients with metal-on-metal resurfacings over a period of four years. Twelve-hour urine collections and whole blood specimens were collected before and periodically after a Birmingham hip resurfacing in 26 patients. All ion analyses were carried out using a high-resolution inductively-coupled plasma mass spectrometer. Clinical and radiological assessment, hip function scoring and activity level assessment revealed excellent hip function. There was a significant early increase in urinary metal output, reaching a peak at six months for cobalt and one year for chromium post-operatively. There was thereafter a steady decrease in the median urinary output of cobalt over the following three years, although the differences are not statistically significant. The mean whole blood levels of cobalt and chromium also showed a significant increase between the pre-operative and one-year post-operative periods. The blood levels then decreased to a lower level at four years, compared with the one-year levels. This late reduction was statistically significant for chromium but not for cobalt. The effects of systemic metal ion exposure in patients with metal-on-metal resurfacing arthroplasties continue to be a matter of concern. The levels in this study provide a baseline against which the in vivo wear performance of newer bearings can be compared.


NTP technical report on the toxicity studies of 1-Nitropyrene (CAS No. 5522-43-0) Administered by Inhalation to F344/N Rats.
1-Nitropyrene is a by-product of combustion. It is the predominant nitrated polycyclic aromatic hydrocarbon emitted in diesel engine exhaust and has been found at concentrations of up to 57 pg/m(3) in the air over urban and suburban areas. 1-Nitropyrene is detoxified mainly to 1-aminopyrene by nitro reduction. 1-Nitropyrene can also undergo ring oxidation, depending on the concentration of oxygen. Aryl nitrenium ions generated by nitro reduction or K-region nitropyrene epoxides generated by ring oxidation can react with DNA, forming adducts. 1-Nitropyrene was nominated for toxicity study because it is mutagenic, it is found in the environment, and it has potential for human exposure. Administration by inhalation was chosen because humans are exposed to 1-nitropyrene mainly by inhalation. Nose-only inhalation was chosen because whole-body inhalation exposure would require a large quantity of purified 1-nitropyrene that is expensive and difficult to procure. The study was performed in rats because of technical problems with conducting nose-only inhalation studies in mice and because mice are known to be more resistant to 1-nitropyrene toxicity. In the base study, groups of 10 male and 10 female 7-week-old F344/N rats were exposed to 0, 0.5, 2, 8, 20, or 50 mg/m(3) 1-nitropyrene aerosol, 6 hours per day, 5 days per week, for 13 weeks. At 13 weeks, rats were evaluated for histopathology, clinical pathology, and reproductive system effects. In a supplemental evaluation, toxicokinetic effects were assessed in male F344/N rats exposed to 1-nitropyrene for 13 weeks. All rats survived to the end of the 13-week exposure. For all groups, body weight gains of exposed rats were similar to those of concurrent controls (but lower than those of historical whole body inhalation study control rats); however, liver weights of exposed male rats were higher than those of the controls. There were slight variations in certain hematology and clinical chemistry parameters for some groups, but these were not considered related to 1-nitropyrene exposure. Squamous metaplasia of the respiratory mucosa was observed in the larynx of male rats exposed to 1-nitropyrene at a concentration of 2 mg/m(3) or greater and of female rats at all exposure concentrations. Squamous metaplasia of the bronchial epithelium also occurred in male and female rats in the higher exposure groups. Cytoplasmic alteration of the nasal respiratory epithelium was observed in both sexes exposed to 1-nitropyrene at a concentration of 8 mg/m(3)or greater. No treatment-related effects on sperm motility or vaginal cytology were noted. However, testicular atrophy was observed in all male rats and was considered a secondary effect resulting from the daily confinement within the exposure tubes. The elimination half-life of 1-nitropyrene in the lungs was about 1 hour for rats exposed to 8 mg/m(3)and 6 hours for rats exposed to 50 mg/m(3). Lung burdens of 1-nitropyrene in rats exposed to 8 mg/m(3) remained the same for the 13-week duration; however, lung burdens in rats exposed to 50 mg/m(3) increased with time indicating that the rats were unable to clear the 1-nitropyrene between exposures. The half-life of 1-nitropyrene in the plasma of rats exposed to 50 mg/m(3) was about 1 hour. Based on data contained in this report and previously published reports on the genetic toxicity, carcinogenicity, and toxicokinetics of 1-nitropyrene, it is the opinion of the National Toxicology Program (NTP) that 1-nitropyrene has a high likelihood of being carcinogenic to the respiratory tract, particularly under exposure conditions that lead to significant accumulations of 1-nitropyrene in the lungs, and perhaps other organs of F344/N rats. In summary, nose-only inhalation exposure to 1-nitropyrene for 13 weeks induced squamous metaplasia of the laryngeal and bronchial respiratory epithelium in male and female rats. Cytoplasmic alteration in the nasal respiratory epithelium were also induced in male and female rats. The no-observed-adverse-effect level (NOAEL) for male rats was 0.5 mg/m(3). A NOAEL for female rats could not be determined from these studies. Synonyms: 3-Nitropyrene; Pyrene, 1-nitro.


Temperature-strain discrimination in distributed optical fiber sensing using phase-sensitive optical time-domain reflectometry.
A method based on coherent Rayleigh scattering distinctly evaluating temperature and strain is proposed and experimentally demonstrated for distributed optical fiber sensing. Combining conventional phase-sensitive optical time-domain domain reflectometry (ϕOTDR) and ϕOTDR-based birefringence measurements, independent distributed temperature and strain profiles are obtained along a polarization-maintaining fiber. A theoretical analysis, supported by experimental data, indicates that the proposed system for temperature-strain discrimination is intrinsically better conditioned than an equivalent existing approach that combines classical Brillouin sensing with Brillouin dynamic gratings. This is due to the higher sensitivity of coherent Rayleigh scatting compared to Brillouin scattering, thus offering better performance and lower temperature-strain uncertainties in the discrimination. Compared to the Brillouin-based approach, the ϕOTDR-based system here proposed requires access to only one fiber-end, and a much simpler experimental layout. Experimental results validate the full discrimination of temperature and strain along a 100 m-long elliptical-core polarization-maintaining fiber with measurement uncertainties of ~40 mK and ~0.5 με, respectively. These values agree very well with the theoretically expected measurand resolutions.


Export of hepatitis B virus RNA on a Rev-like pathway: inhibition by the regenerating liver inhibitory factor IkappaB alpha.
Nuclear export of hepatitis B virus (HBV) RNA is mediated by a specific RNA element but, in contrast to lentivirus genomic RNA, does not depend on viral proteins. We show that nonetheless, the export of HBV RNA can be blocked by competitive inhibitors of Rev-mediated lentivirus RNA export, suggesting that the export pathways of both viral species share components and might be driven by the same nuclear export machinery. HBV RNA export is also inhibited by overexpression of IkappaB alpha, as reported previously for the export of human immunodeficiency virus RNA. Since IkappaB alpha is strongly overexpressed during liver regeneration, its inhibition of HBV RNA export might contribute to elimination or silent persistence of HBV.


Limitations on quantum key repeaters.
A major application of quantum communication is the distribution of entangled particles for use in quantum key distribution. Owing to noise in the communication line, quantum key distribution is, in practice, limited to a distance of a few hundred kilometres, and can only be extended to longer distances by use of a quantum repeater, a device that performs entanglement distillation and quantum teleportation. The existence of noisy entangled states that are undistillable but nevertheless useful for quantum key distribution raises the question of the feasibility of a quantum key repeater, which would work beyond the limits of entanglement distillation, hence possibly tolerating higher noise levels than existing protocols. Here we exhibit fundamental limits on such a device in the form of bounds on the rate at which it may extract secure key. As a consequence, we give examples of states suitable for quantum key distribution but unsuitable for the most general quantum key repeater protocol.


Strong evidence against platelet-rich plasma injections for chronic lateral epicondylar tendinopathy: a systematic review.
Chronic lateral epicondylar tendinopathy is frequent in athletes, and platelet-rich plasma (PRP) is being used increasingly in its treatment. To systematically review the literature on the efficacy of PRP injections for chronic lateral epicondylar tendinopathy. The databases of PubMed, EMBASE, CINAHL, Medline OvidSP, Scopus, Google Scholar, Web of Science and Cochrane Library were searched in October 2013. Inclusion criteria were a clinical diagnosis of chronic lateral epicondylar tendinopathy, a randomised controlled trial, an intervention with a PRP injection and the outcome measures described in terms of pain and/or function. One author screened the search results and two authors independently assessed the study quality using the Physiotherapy Evidence Database (PEDro) score. A study was considered to be of high quality if its PEDro score was ≥6. A best evidence synthesis was used to identify the level of evidence. 6 studies were included, of which four were considered to be of high quality. Three high-quality studies (75%) and two low-quality studies showed no significant benefit at the final follow-up measurement or predefined primary outcome score when compared with a control group. One high-quality study (25%) showed a beneficial effect of a PRP injection when compared with a corticosteroid injection (corticosteroid injections are harmful in tendinopathy). Based on the best evidence synthesis, there is strong evidence that PRP injections are not efficacious in chronic lateral epicondylar tendinopathy. There is strong evidence that PRP injections are not efficacious in the management of chronic lateral elbow tendinopathy.


Use of automated imaging and analysis technology for the detection of aneuploidy in human sperm.
To determine the precision and accuracy of an automated cell counting system when applied to counting aneuploidies in sperm samples. Prospective pilot study. Andrology clinic and research laboratory in a university teaching hospital. Ten anonymous sperm donors of known fertility and two patients seeking infertility treatment. Semen samples were processed for detection of aneuploidies for chromosomes 13, 18, 21, X, and Y with use of fluorescent in situ hybridization. The detection of chromosome aneuploidy was performed both by manual counting and by the use of an automated cell counting system with manual review of aneuploid sperm. Semen samples were judged for the percent aneuploidy for chromosomes 13, 18, 21, X, and Y when counted manually or with the use of the automated cell counting system and review by a technician. The sperm aneuploidy rates determined by the automated cell counting system and careful review were comparable with those obtained by manual counting by a trained technician. These preliminary data demonstrate that automated cell counting devices may be useful in increasing productivity in aneuploidy detection in sperm and may become an alternative to the labor-intensive manual counting by technicians.


Dynamic variation in cycling of hematopoietic stem cells in steady state and inflammation.
Hematopoietic stem cells (HSCs) maintain blood production. How often mouse HSCs divide and whether each HSC contributes simultaneously, sequentially, or repetitively to hematopoiesis remains to be determined. We track division of 5-(and-6)-carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled HSC in vivo. We found that, in steady-state mice, bone marrow cells capable of reconstituting lifelong hematopoiesis are found within both fast-cycling (undergoing five or more divisions in 7 wk) and quiescent (undergoing zero divisions in 12-14 wk) lineage marker-negative c-Kit(+) Sca-1(+) populations. The contribution of each population to hematopoiesis can fluctuate with time, and cells with extensive proliferative history are prone to return to quiescence. Furthermore, injection of the bacterial component lipopolysaccharide increased the proliferation and self-renewal capacity of HSCs. These findings suggest a model in which all HSCs undergo dynamic and demand-adapted entry into and exit out of the cell cycle over time. This may facilitate a similar degree of turnover of the entire HSC pool at the end of life.


Phase I study of oral cyclophosphamide and oral topotecan for children with recurrent or refractory solid tumors.
To determine the maximum-tolerated duration and dose-limiting toxicity of a daily schedule of orally administered cyclophosphamide and topotecan in pediatric patients with recurrent or refractory malignant solid tumors. Patients received oral cyclophosphamide (50 mg/m2/dose) in the morning followed by topotecan (0.8 mg/m2/dose) 8-12 hr later for an escalating number of consecutive days (10, 14, and 17 days). Seventeen pediatric patients were treated with oral cyclophosphamide and topotecan for durations of 10-17 days for a total of 58 treatment courses. Reversible hematologic toxicity (neutropenia and thrombocytopenia) was the dose-limiting toxicity. Nonhematologic toxicities of greater than grade 3 were not observed. A partial response (neuroblastoma following myeloablative chemotherapy and stem cell rescue) and prolonged stable disease (medulloblastoma) were each observed in one patient. The recommended duration of therapy with a daily schedule of both oral cyclophosphamide (50 mg/m2/day) and topotecan (0.8 mg/m2/day) for previously treated pediatric patients with recurrent or refractory solid tumors is 14 consecutive days. The observed dose limiting toxicity (DLT) was reversible neutropenia. This regimen was well tolerated in heavily pretreated patients and demonstrated activity against recurrent pediatric solid tumors.


Dietary fish oil ameliorates adipose tissue dysfunction in insulin-resistant rats fed a sucrose-rich diet improving oxidative stress, peroxisome proliferator-activated receptor γ and uncoupling protein 2.
This work aims to assess the possible beneficial effects of dietary fish oil (FO) on the pre-existing adipose tissue dysfunction through the improvement or reversion of the mechanisms underlying oxidative stress and pro-inflammatory cytokines in dyslipemic insulin-resistant rats. Wistar rats were fed a sucrose rich diet (SRD) for 6 months. After that half of the animals continued with the SRD until month 8 while in the other half corn oil was replaced by FO for 2 months (SRD + FO). A reference group consumed a control diet all the time. In an epididymal fat pad, we analyzed antioxidant and oxidant enzyme activities, ROS content, glutathione redox state, the protein level of peroxisome proliferator-activated receptor gamma (PPARγ) and the expression and protein levels of uncoupling protein 2 (UCP2) as well as oxidative stress biomarkers and TNF-α and IL-6 plasma levels. Besides these, insulin sensitivity and the composition of fatty acid phospholipids of adipose tissue were measured. Compared with the SRD the SRD + FO fed group showed a decrease of fat pad weight and the antioxidant and oxidant enzyme activities and ROS content returned to control values along with normal plasma TNF-α and IL-6 levels. FO normalized both the decrease of PPARγ protein and the increase of protein and expression of UCP2. Furthermore, FO increased the n-3/n-6 fatty acid ratio in the adipose tissue phospholipids and normalized dyslipidemia and insulin resistance. Finally, these findings reinforce the view that dietary FO may exert a beneficial effect in ameliorating the dyslipidemia and insulin resistance in this animal model.


Effect of Timing and Duration of Soil Saturation on Soilborne Pythium Diseases of Common Bean (Phaseolus vulgaris).
Understanding combined abiotic (waterlogging) and biotic (Pythium spp.) stress resistance remains an important challenge to improving common bean (Phaseolus vulgaris) productivity in disease-prone regions with irregular but intensive rainfall patterns. This study documented the effects of timing (1, 3, 5, 7, and 9 days after sowing) and duration (3, 6, 12, and 24 h) of soil saturation (waterlogging) on damping-off, as well as hypocotyl and root diseases of common bean caused by Pythium irregulare. There were significant effects of timing of waterlogging as well as the presence or absence of the pathogen on emergence of the three bean varieties tested; namely, 'Gourmet Delight', 'Brown Beauty', and 'Pioneer'. The interaction between time of waterlogging and variety was significant for both root and hypocotyl disease severities. In the presence of P. irregulare, waterlogging 1 day after sowing resulted in the least emergence (55.2 ± 5.6%), although plants that survived after 5 weeks had less hypocotyl and root disease (percent hypocotyl disease index [%HDI] ± standard deviation [SD] = 42.0 ± 2.1% and percent root disease index [%RDI] ± SD = 42.4 ± 2.1%, respectively) than nonwaterlogged plants (%HDI = 50.8 ± 2.1% and %RDI = 48.0 ± 2.1%, respectively). The most severe disease assessed 5 weeks after sowing occurred when plants were subjected to waterlogging 9 days after sowing (%HDI = 61.3 ± 2.1% and %RDI = 56.0 ± 2.1%). In general, both hypocotyl and root disease severity increased as the duration of waterlogging increased from 1 to 24 h, with %HDI increasing from 53.9 ± 3.2% to 70.9 ± 3.2%, while %RDI increased from 57.2 ± 1.5% to 73.7 ± 1.5%. Varieties responded differentially in terms of disease development after waterlogging, with the least hypocotyl and root disease on Gourmet Delight (%HDI = 51.4 ± 3.2 and %RDI = 60.1 ± 1.5, respectively) and greatest on Pioneer (%HDI = 66.2 ± 3.2 and %RDI = 64.9 ± 1.5, respectively). Despite being susceptible to hypocotyl and root disease, Pioneer had the greatest emergence and shoot dry weight overall among the three varieties, suggesting that this variety has a degree of tolerance to waterlogging, P. irregulare infection, and the combination of these two stresses. Although the resistance of Gourmet Delight could be exploited to breed bean varieties that exhibit less hypocotyl and root disease when waterlogging occurs, the tolerance to both P. irregulare infection and waterlogging observed for Pioneer could also be exploited to breed varieties that incur less damage from hypocotyl or root disease or waterlogging. Furthermore, this study demonstrated what appears to be independent resistance to hypocotyl versus root infection by P. irregulare, which offers an opportunity to combine resistance to both stresses to reduce the impact of damping-off and root rot in conditions conducive for P. irregulare.


Disaccharidase activity in the small intestine of susceptible and resistant mice after primary and challenge infections with Giardia muris.
The activities of four disaccharidases were examined in resistant (C57Bl/6) and susceptible (C3H/HeN) mice during the primary infection with Giardia muris and after challenge with either trophozoite extract or cysts. Significant decreases in lactase, sucrase, trehalase, and maltase activities in C57Bl/6 mice and lactase and sucrase activities in C3H/HeN mice in the anterior 25% of the small intestine were observed on day 10 after infection. The activities of maltase, sucrase, trehalase, and lactase in the jejunum of C3H/HeN mice were significantly reduced after challenge with trophozoite extract, when compared with the uninfected or infected, but not challenged animals. Decreases in enzyme activities of C3H/HeN mice were evident as early as 12 hours after challenge with the extract. The resistant C57Bl/6 mice showed little change in disaccharidase activity after challenge with trophozoite extract. On the other hand, challenge with cysts resulted in a few decreases in disaccharidase activities in both strains of mice: C57Bl/6 mice showed decreases in the duodenum, while disaccharidases of C3H/HeN mice had lower activity more posteriorly. Thus, challenge with parasite antigen results in a more severe disaccharidase deficiency in susceptible hosts when compared with resistant ones.


Elderberry flavonoids bind to and prevent H1N1 infection in vitro.
A ionization technique in mass spectrometry called Direct Analysis in Real Time Mass Spectrometry (DART TOF-MS) coupled with a Direct Binding Assay was used to identify and characterize anti-viral components of an elderberry fruit (Sambucus nigra L.) extract without either derivatization or separation by standard chromatographic techniques. The elderberry extract inhibited Human Influenza A (H1N1) infection in vitro with an IC(50) value of 252+/-34 microg/mL. The Direct Binding Assay established that flavonoids from the elderberry extract bind to H1N1 virions and, when bound, block the ability of the viruses to infect host cells. Two compounds were identified, 5,7,3',4'-tetra-O-methylquercetin (1) and 5,7-dihydroxy-4-oxo-2-(3,4,5-trihydroxyphenyl)chroman-3-yl-3,4,5-trihydroxycyclohexanecarboxylate (2), as H1N1-bound chemical species. Compound 1 and dihydromyricetin (3), the corresponding 3-hydroxyflavonone of 2, were synthesized and shown to inhibit H1N1 infection in vitro by binding to H1N1 virions, blocking host cell entry and/or recognition. Compound 1 gave an IC(50) of 0.13 microg/mL (0.36 microM) for H1N1 infection inhibition, while dihydromyricetin (3) achieved an IC(50) of 2.8 microg/mL (8.7 microM). The H1N1 inhibition activities of the elderberry flavonoids compare favorably to the known anti-influenza activities of Oseltamivir (Tamiflu; 0.32 microM) and Amantadine (27 microM).


Engaging a chemical disaster community: lessons from Graniteville.
Community engagement remains a primary objective of public health practice. While this approach has been adopted with success in response to many community health issues, it is rarely adopted in chemical disaster response. Empirical research suggests that management of chemical disasters focuses on the emergency response with almost no community engagement for long-term recovery. Graniteville, an unincorporated and medically underserved community in South Carolina was the site of one of the largest chlorine exposures by a general US population. Following the immediate response, we sought community participation and partnered with community stakeholders and representatives in order to address community-identified health and environmental concerns. Subsequently, we engaged the community through regular town hall meetings, harnessing community capacity, forming coalitions with existing local assets like churches, schools, health centers, and businesses, and hosting community-wide events like health picnics and screenings. Information obtained from these events through discussions, interviews, and surveys facilitated focused public health service which eventually transitioned to community-driven public health research. Specific outcomes of the community engagement efforts and steps taken to ensure sustainability of these efforts and outcomes will be discussed.


PhoP-PhoQ activates transcription of pmrAB, encoding a two-component regulatory system involved in Salmonella typhimurium antimicrobial peptide resistance.
Antimicrobial cationic peptides are a host defense mechanism of many animal species including mammals, insects, and amphibians. Salmonella typhimurium is an enteric and intracellular pathogen that interacts with antimicrobial peptides within neutrophil and macrophage phagosomes and at intestinal mucosal surfaces. The Salmonella spp. virulence regulators, PhoP and PhoQ, activate the transcription of genes (pag) within macrophage phagosomes necessary for resistance to cationic antimicrobial peptides. One PhoP-activated gene, pagB, forms an operon with pmrAB (5' pagB-pmrA-pmrB 3'), a two-component regulatory system involved in resistance to the antimicrobial peptides polymyxin, azurocidin (CAP37), bactericidal/permeability-increasing protein (BPI or CAP57), protamine, and polylysine. Expression of pmrAB increased transcription of pagB-pmrAB by activation of a promoter 5' to pagB. pmrAB is also expressed from a second promoter, not regulated by PhoP-PhoQ or PmrA-PmrB, located within the pagB coding sequence. S. typhimurium strains with increased pag locus expression were demonstrated to be polymyxin resistant because of induction of pagB-pmrAB; however, PmrA-PmrB was not responsible for the increased sensitivity of PhoP-null mutants to NP-1 defensin. Therefore, PhoP regulates at least two separate networks of genes responsible for cationic antimicrobial peptide resistance. These data suggest that resistance to the polymyxin-CAP family is controlled by a cascade of regulatory protein expression that activates transcription upon environmental sensing.


Pathogen-sugar interactions revealed by universal saturation transfer analysis.
Many pathogens exploit host cell-surface glycans. However, precise analyses of glycan ligands binding with heavily modified pathogen proteins can be confounded by overlapping sugar signals and/or compounded with known experimental constraints. Universal saturation transfer analysis (uSTA) builds on existing nuclear magnetic resonance spectroscopy to provide an automated workflow for quantitating protein-ligand interactions. uSTA reveals that early-pandemic, B-origin-lineage severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer binds sialoside sugars in an "end-on" manner. uSTA-guided modeling and a high-resolution cryo-electron microscopy structure implicate the spike N-terminal domain (NTD) and confirm end-on binding. This finding rationalizes the effect of NTD mutations that abolish sugar binding in SARS-CoV-2 variants of concern. Together with genetic variance analyses in early pandemic patient cohorts, this binding implicates a sialylated polylactosamine motif found on tetraantennary N-linked glycoproteins deep in the human lung as potentially relevant to virulence and/or zoonosis.


A Literature Review of Social and Economic Leader-Member Exchange.
Leader-member exchange (LMX) research has increasingly relied upon the social exchange theory (SET) as a theoretical foundation, but the dominating way of measuring LMX has not followed this theoretical development (Gottfredson et al., 2020). With the aim of developing a measure that more coherently reflects SET, Kuvaas et al. (2012) conceptualized LMX as two qualitatively different relationships, labeled economic LMX and social LMX. Since the most applied LMX measures are under scrutiny for not being sufficiently grounded in theory (Gottfredson et al., 2020), it may be especially important to expose alternative measures. Therefore, we provide a comprehensive review of the research to date applying a two-dimensional approach to LMX, while also adding to interpretation and suggestions for how we can progress the field even further.


Statistical support for the hypothesis of developmental constraint in marsupial skull evolution.
In contrast to placental neonates, in which all cranial bones are ossified, marsupial young have only the bones of the oral region and the exoccipital ossified at birth, in order to facilitate suckling at an early stage of development. In this study, we investigated whether this heterochronic shift in the timing of cranial ossification constrains cranial disparity in marsupials relative to placentals. We collected three-dimensional (3D) landmark data about the crania of a wide range of extant placentals and marsupials, and from six fossil metatherians (the clade including extant marsupials and their stem relatives), using a laser scanner and a 3D digitizer. Principal components analysis and delta variance tests were used to investigate the distribution and disparity of cranial morphology between different landmark sets (optimizing either number of landmarks or number of taxa) of the whole skull and of individual developmental or functional regions (neurocranium, viscerocranium, oral region) for extant placentals and marsupials. Marsupial and placental data was also compared based on shared ecological aspects including diet, habitat, and time of peak activity. We found that the extant marsupial taxa investigated here occupy a much smaller area of morphospace than the placental taxa, with a significantly (P<0.01) smaller overall variance. Inclusion of fossil taxa did not significantly increase the variance of metatherian cranial shape. Fossil forms generally plotted close to or within the realm of their extant marsupial relatives. When the disparities of cranial regions were investigated separately, significant differences between placentals and marsupials were seen for the viscerocranial and oral regions, but not for the neurocranial region. These results support the hypothesis of developmental constraint limiting the evolution of the marsupial skull, and further suggest that the marsupial viscerocranium as a whole, rather than just the early-ossifying oral region, is developmentally constrained.


Endoplasmic reticulum stress decreases intracellular thyroid hormone activation via an eIF2a-mediated decrease in type 2 deiodinase synthesis.
Cells respond rapidly to endoplasmic reticulum (ER) stress by blocking protein translation, increasing protein folding capacity, and accelerating degradation of unfolded proteins via ubiquitination and ER-associated degradation pathways. The ER resident type 2 deiodinase (D2) is normally ubiquitinated and degraded in the proteasome, a pathway that is accelerated by enzyme catalysis of T(4) to T(3). To test whether D2 is normally processed through ER-associated degradation, ER stress was induced in cells that endogenously express D2 by exposure to thapsigargin or tunicamycin. In all cell models, D2 activity was rapidly lost, to as low as of 30% of control activity, without affecting D2 mRNA levels; loss of about 40% of D2 activity and protein was also seen in human embryonic kidney 293 cells transiently expressing D2. In primary human airway cells with ER stress resulting from cystic fibrosis, D2 activity was absent. The rapid ER stress-induced loss of D2 resulted in decreased intracellular D2-mediated T(3) production. ER stress-induced loss of D2 was prevented in the absence of T(4), by blocking the proteasome with MG-132 or by treatment with chemical chaperones. Notably, ER stress did not alter D2 activity half-life but rather decreased D2 synthesis as assessed by induction of D2 mRNA and by [(35)S]methionine labeling. Remarkably, ER-stress-induced loss in D2 activity is prevented in cells transiently expressing an inactive eukaryotic initiation factor 2, indicating that this pathway mediates the loss of D2 activity. In conclusion, D2 is selectively lost during ER stress due to an eukaryotic initiation factor 2-mediated decrease in D2 synthesis and sustained proteasomal degradation. This explains the lack of D2 activity in primary human airway cells with ER stress resulting from cystic fibrosis.


ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases.
Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) is a rare and heterogeneous subtype of SM and few studies on this specific entity have been reported. Sixty two patients with Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) were presented. Myeloid AHNMD was the most frequent (82%) cases. This subset of patients were older, had more cutaneous lesions, splenomegaly, liver enlargement, ascites; lower bone mineral density and hemoglobin levels and higher tryptase level than lymphoid AHNMD. Defects in KIT, TET2, ASXL1 and CBL were positive in 87%, 27%, 14%, and 11% of cases respectively. The overall survival of patients with SM-AHNMD was 85.2 months. Within the myeloid group, SM-MPN fared better than SM-MDS or SM-AML (p = 0.044,). In univariate analysis, the presence of C-findings, the AHNMD subtypes (SM-MDS/CMML/AML versus SM-MPN/hypereosinophilia) (p = 0.044), Neutropenia (p = 0.015), high monocyte level (p = 0.015) and the presence of ASXL1 mutation had detrimental effects on OS (p = 0.007). In multivariate analysis and penalized Cox model, only the presence of ASXL1 mutation remained an independent prognostic factor that negatively affected OS (p = 0.035). SM-AHNMD is heterogeneous with variable prognosis according to the type of the AHNMD. ASXL1 is mutated in a subset of myeloid AHNMD and adversely impact on OS.


Naturally occurring amino acid polymorphisms in human immunodeficiency virus type 1 (HIV-1) Gag p7(NC) and the C-cleavage site impact Gag-Pol processing by HIV-1 protease.
Human immunodeficiency virus type 1 (HIV-1) protease activity is targeted at nine cleavage sites comprising different amino acid sequences in the viral Gag-Pol polyprotein. Amino acid polymorphisms in protease and in regions of Gag, particularly p7(NC) and the C-cleavage site between p2 and p7(NC), occur in natural variants of HIV-1 within infected patients. Studies were designed to examine the role of natural polymorphisms in protease and to identify determinants in Gag that modulate protease processing activity. Closely related Gag-Pol regions from an HIV-1-infected mother and two children were evaluated for processing in an inducible expression system, for protease activity on cleavage-site analogues, and for impact on replication by recombinant viruses. Gag-Pol regions displayed one of three processing phenotypes based on the appearance of Gag intermediates and accumulation of mature p24(CA). Gag-Pol regions that were processed rapidly to produce p24(CA) resulted in high-level replication by recombinant viruses, while slow-processing Gag-Pol variants resulted in recombinant viruses that replicated with reduced kinetics in both T cell lines and peripheral blood mononuclear cells. Direct impact by Gag sequences on processing by protease was assessed by construction of chimeric Gag-Pol regions and by site-directed mutagenesis. Optimal protease activity occurred when Gag and Pol regions were derived from the same gag-pol allele. Heterologous Gag regions generally diminished rates and extent of protease processing. Natural polymorphisms in novel positions in p7(NC) and the C-cleavage site have a dominant effect on protease processing activity. Accumulation of Gag products after processing at the C site appears to delay subsequent cleavage and production of mature p24(CA).


The two-receptor model of lipoprotein clearance: tests of the hypothesis in "knockout" mice lacking the low density lipoprotein receptor, apolipoprotein E, or both proteins.
Apolipoprotein E (apoE) is hypothesized to mediate lipoprotein clearance by binding to two receptors: (i) the low density lipoprotein receptor (LDLR) and (ii) a chylomicron remnant receptor. To test this hypothesis, we have compared plasma lipoproteins in mice that are homozygous for targeted disruptions of the genes for apoE [apoE(-/-)], the LDLR [LDLR(-/-)], and both molecules [poE(-/-); LDLR(-/-)]. On a normal chow diet, apoE(-/-) mice had higher mean plasma cholesterol levels than LDLR(-/-) mice (579 vs. 268 mg/dl). Cholesterol levels in the apoE(-/-); LDLR(-/-) mice were not significantly different from those in the apoE(-/-) mice. LDLR(-/-) mice had a relatively isolated elevation in plasma LDL, whereas apoE(-/-) mice had a marked increase in larger lipoproteins corresponding to very low density lipoproteins and chylomicron remnants. The lipoprotein pattern in apoE(-/-); LDLR(-/-) mice resembled that of apoE(-/-) mice. The LDLR(-/-) mice had a marked elevation in apoB-100 and a modest increase in apoB-48. In contrast, the apoE(-/-) mice had a marked elevation in apoB-48 but not in apoB-100. The LDLR(-/-); apoE(-/-) double homozygotes had marked elevations of both apolipoproteins. The observation that apoB-48 increases more dramatically with apoE deficiency than with LDLR deficiency supports the notion that apoE binds to a second receptor in addition to the LDLR. This conclusion is also supported by the observation that superimposition of a LDLR deficiency onto an apoE deficiency [apoE(-/-); LDLR(-/-) double homozygotes] does not increase hypercholesterolemia beyond the level observed with apoE deficiency alone.


Thermal evolution of MnxOy nanofibres as catalysts for the oxygen reduction reaction.
Manganese oxides (MnxOy) are considered as a promising catalyst alternative to platinum in fuel cell applications. In fact, a proper catalyst is needed in order to facilitate the oxygen reduction reaction (ORR) at the cathode, and platinum is considered the best material due to its low overpotential for this reaction. Contrary to platinum, MnxOy is inexpensive, environmentally friendly and can be shaped into several nanostructures; furthermore, most of them show significant electro-catalytic performance. Several strategies have been carried out in order to increase their efficiency, by preparing light and high-surface area materials. In this framework, nanofibres are among the most promising nanostructures that can be used for this purpose. In this work, a study of the thermal, morphological and catalytic behavior of MnxOy nanofibres obtained through the electrospinning technique is proposed. Emphasis is given to the thermal evolution of the precursors, proposing a possible crystallization mechanism of the different manganese oxides obtained. It turns out that manganese oxide nanofibres exhibit good catalytic performance for the ORR, comparable to those obtained by using Pt-based catalysts.


Transforming the Information System for Research in Primary Care (SIDIAP) in Catalonia to the OMOP Common Data Model and Its Use for COVID-19 Research.
The primary aim of this work was to convert the Information System for Research in Primary Care (SIDIAP) from Catalonia, Spain, to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). Our second aim was to provide a descriptive analysis of COVID-19-related outcomes among the general population. We mapped patient-level data from SIDIAP to the OMOP CDM and we performed more than 3,400 data quality checks to assess its readiness for research. We established a general population cohort as of the 1st March 2020 and identified outpatient COVID-19 diagnoses or tested positive for, hospitalised with, admitted to intensive care units (ICU) with, died with, or vaccinated against COVID-19 up to 30th June 2022. After verifying the high quality of the transformed dataset, we included 5,870,274 individuals in the general population cohort. Of those, 604,472 had either an outpatient COVID-19 diagnosis or positive test result, 58,991 had a hospitalisation, 5,642 had an ICU admission, and 11,233 died with COVID-19. A total of 4,584,515 received a COVID-19 vaccine. People who were hospitalised or died were more commonly older, male, and with more comorbidities. Those admitted to ICU with COVID-19 were generally younger and more often male than those hospitalised and those who died. We successfully transformed SIDIAP to the OMOP CDM. From this dataset, a general population cohort of 5.9 million individuals was identified and their COVID-19-related outcomes over time were described. The transformed SIDIAP database is a valuable resource that can enable distributed network research in COVID-19 and beyond.


Adiposity Measures and Plasma Adipokines in Females with Rheumatoid and Osteoarthritis.
The objective of this study was to examine the relationship between adipokines and adiposity in individuals with rheumatoid and osteoarthritis in the Atlantic PATH cohort. Using a nested case-control analysis, participants in the Atlantic PATH cohort with rheumatoid or osteoarthritis were matched for measures of adiposity with participants without a history of arthritis. Both measured and self-reported data were used to examine disease status, adiposity, and lifestyle factors. Immunoassays were used to measure plasma markers. BMI was positively correlated with percentage body fat, fat mass index (FMI), and a change in BMI from 18 years of age in all 3 groups. There were no statistical differences between levels of plasma adipokines; adiponectin levels were 6.6, 7.9, and 8.2 μg/ml, leptin levels were 10.3, 13.7, and 11.5 ng/ml, and resistin levels were 10.0, 12.1, and 10.8 ng/ml in participants without arthritis, with rheumatoid arthritis, and with osteoarthritis, respectively. Those with higher levels of adiponectin were more likely to have osteoarthritis (but not rheumatoid arthritis). No association was found between arthritis types and leptin or resistin. This study demonstrates differences in measures of adiposity and adipokines in specific types of arthritis and highlights the need for more research targeting specific adipokines during arthritic disease progression.


First dating of a recombination event in mammalian tick-borne flaviviruses.
The mammalian tick-borne flavivirus group (MTBFG) contains viruses associated with important human and animal diseases such as encephalitis and hemorrhagic fever. In contrast to mosquito-borne flaviviruses where recombination events are frequent, the evolutionary dynamic within the MTBFG was believed to be essentially clonal. This assumption was challenged with the recent report of several homologous recombinations within the Tick-borne encephalitis virus (TBEV). We performed a thorough analysis of publicly available genomes in this group and found no compelling evidence for the previously identified recombinations. However, our results show for the first time that demonstrable recombination (i.e., with large statistical support and strong phylogenetic evidences) has occurred in the MTBFG, more specifically within the Louping ill virus lineage. Putative parents, recombinant strains and breakpoints were further tested for statistical significance using phylogenetic methods. We investigated the time of divergence between the recombinant and parental strains in a Bayesian framework. The recombination was estimated to have occurred during a window of 282 to 76 years before the present. By unravelling the temporal setting of the event, we adduce hypotheses about the ecological conditions that could account for the observed recombination.


Premature ventricular complexes and the risk of incident stroke: the Atherosclerosis Risk In Communities (ARIC) Study.
Premature ventricular complexes (PVCs) on a 2-minute electrocardiogram are a common, largely asymptomatic finding associated with increased risk of coronary heart disease and death. They may reflect atherosclerosis or other pathogenic pathways that predispose to arrhythmias and stroke. We conducted a prospective evaluation of the Atherosclerosis Risk In Communities Study cohort (n=14,783) of middle-aged men and women to assess whether the presence of PVCs at study baseline (1987 to 1989) influenced the risk of incident stroke through December 31, 2004. PVCs were seen in 6.1% of the participants at baseline, and 729 (4.9%) had incident stroke. The unadjusted cumulative proportion of incident stroke in individuals with any PVC was 6.6% compared with 4.1% in those without PVC. The unadjusted hazard ratio of incident stroke in individuals with any PVC compared with those without any PVCs was 1.71 (95% CI, 1.33 to 2.20). Among individuals without hypertension and diabetes at baseline, PVCs were independently associated with incident stroke (hazard ratio: 1.72; 95% CI: 1.14 to 2.59). Among those with either diabetes or hypertension, the presence of any PVCs did not increase the risk of stroke. The association was stronger for noncarotid embolic stroke than for thrombotic stroke and its magnitude increased with higher frequency of PVCs. Frequent PVCs are associated with risk of incident stroke in participants free of hypertension and diabetes. This suggests that PVCs may contribute to atrioventricular remodeling or may be a risk marker for incident stroke, particularly embolic stroke.


Coupled long-term summer warming and deeper snow alters species composition and stimulates gross primary productivity in tussock tundra.
Climate change is expected to increase summer temperature and winter precipitation throughout the Arctic. The long-term implications of these changes for plant species composition, plant function, and ecosystem processes are difficult to predict. We report on the influence of enhanced snow depth and warmer summer temperature following 20 years of an ITEX experimental manipulation at Toolik Lake, Alaska. Winter snow depth was increased using snow fences and warming was accomplished during summer using passive open-top chambers. One of the most important consequences of these experimental treatments was an increase in active layer depth and rate of thaw, which has led to deeper drainage and lower soil moisture content. Vegetation concomitantly shifted from a relatively wet system with high cover of the sedge Eriophorum vaginatum to a drier system, dominated by deciduous shrubs including Betula nana and Salix pulchra. At the individual plant level, we observed higher leaf nitrogen concentration associated with warmer temperatures and increased snow in S. pulchra and B. nana, but high leaf nitrogen concentration did not lead to higher rates of net photosynthesis. At the ecosystem level, we observed higher GPP and NEE in response to summer warming. Our results suggest that deeper snow has a cascading set of biophysical consequences that include a deeper active layer that leads to altered species composition, greater leaf nitrogen concentration, and higher ecosystem-level carbon uptake.


Change management with the electronic health record.
Many medical organizations have already changed to, are implementing, or are contemplating implementing an electronic health record (EHR) system. As in all change, some people accept the switch from paper to EHRs much easier and with more enthuiasm than others. It is common for organizations to overlook the importance of including change management properties as they create the overall plan for the change from paper to paperless. Often the result of this is anger, frustration, and lack of cooperation or even sabotage from physicians and office staff who are the recipients of the training on the EHR system. This article examines the steps for, opportunities for, and positive results from incorporating change management principles from the very beginning, and the benefits accrued by understanding and utilizing the concepts of good choices, relationships, planning, and feedback.


Biomechanical evaluation of an injectable radiopaque polypropylene fumarate cement for kyphoplasty in a cadaveric osteoporotic vertebral compression fracture model.
Vertebral compression fractures cause pain, deformity, and disability. Polypropylene fumarate (PPF) has shown promise as an injectable cement for bone defects but little is known about its performance for kyphoplasty. The purpose of this study was to evaluate the biomechanical performance of PPF for kyphoplasty in simulated anterior compression fractures in cadaveric vertebral bodies. Thirty-one vertebral bodies (T9 to L4) from osteoporotic cadaveric spines were disarticulated, stripped of soft tissue and compressed on a materials testing machine to determine pretreatment strength and stiffness. All fractures were repaired with inflatable balloon tamps and either polymethylmethacrylate or PPF-30 (containing 30% barium sulfate by dry weight) cement and then retested. Strength restoration with PMMA and PPF-30 were 120% and 104%, respectively, of the pretreatment strengths. For stiffness, PMMA and PPF-30 restored vertebral bodies to 69% and 53%, respectively, of the initial values. There was no significant difference in treatment with either PMMA or PPF-30. The biopolymer PPF-30 exhibits mechanical properties similar to PMMA in a cadaveric kyphoplasty model. PPF biopolymer may be a suitable alternative for kyphoplasty.


Expression of dihydrodiol dehydrogenase in the resected stage I non-small cell lung cancer.
Recently, by using differential display on specimens of non-small cell lung cancer (NSCLC), we detected overexpression of dihydrodiol dehydrogenase (DDH) that was rarely expressed in the corresponding normal lung tissue. DDH overexpression was correlated with poor prognosis of patients with advanced NSCLC. Because DDH could metabolize polycyclic aromatic hydrocarbons (PAH) in the liver, DDH overexpression in NSCLC would suggest an association with carcinogenesis and disease progression. In this study, we investigated DDH expression in 103 patients with resected stage I NSCLC. Expression of DDH was detected by using immunohistochemistry. Relation between DDH expression and clinicopathological parameter (age, gender, smoking habit, tumor status, histological type, cell differentiation, local recurrence, distant metastasis or survival) was analyzed by statistical analysis. DDH overexpression was detected in 39 (37.9%) of 103 pathological sections. Frequency of DDH overexpression was significantly higher in male patients (p=0.043) and patients with squamous cell carcinoma (p<0.005). Among 103 patients, 14 patients had local recurrence and 28 patients had distant metastasis during follow-up examination. The 5-year survival rate of these patients was poorer than those who did not have local recurrence or distant metastasis (both were p<0.005, respectively). Although patients with low DDH expression had more favorable outcome than those with DDH overexpression, in terms of survival rate no statistical significance was detected (p=0.889). The results suggest that DDH expression may serve as an early but not prognostic biomarker for patients with resectable stage I NSCLC.


Depression treatment in assisted living settings: is an innovative approach feasible?
Depression is a common, disabling, and underrecognized problem among older adults in assisted living (AL) settings. The purpose of this study was to evaluate stakeholder perceptions of using a blended model of depression care that combines essential features of evidence-based collaborative care and older adult outreach for use in AL settings. A descriptive mixed-methods design was used to assess perceptions of the three main components of the depression model: onsite depression care management, staff development activities, and AL nurses as staff resources and liaisons to primary care providers. Quantitative and narrative responses were consistently positive and supportive of depression care approaches. Potential barriers included time constraints for staff and costs for residents. These data provide strong support for further evaluation of the blended depression model. Staff development activities may be implemented independent of the model to enhance depression recognition, assessment, and daily care approaches in AL.


Liver fibrosis stage and HCV genotype distribution in HIV-HCV coinfected patients with persistently normal transaminases.
Hepatitis C virus (HCV)-infected patients with normal transaminases may show significant liver damage. The proportion of subjects with alanine aminotransferase (ALT) levels within normal limits was examined in HIV-infected patients never exposed to interferon and with detectable plasma HCV-RNA on regular follow-up at one single institution. Liver fibrosis was evaluated using transient elastography (FibroScan). Out of 281 coinfected patients, 25 (8.9%) had persistently normal ALT levels. Patients with HCV genotypes 2 (1/5; 20%) and 4 (10/50; 20%), more often had significantly normal ALT than patients with HCV-1 (13/158; 8%) (p = 0.01) and HCV-3 (1/49; 2%) (p = 0.01). Liver fibrosis stages in these patients were as follows: F0-F1 in 13 (59.1%), F2 in 4 (18.2%), F3 in 2 (9.1%), and F4 in 3 (13.6%). Advanced liver fibrosis (F3-F4) tended to be more frequent in patients infected with HCV-4 than HCV-1 (33.3% versus 9.1%; p = 0.2). Of HIV-infected patients with chronic hepatitis C 8.9% show persistently normal ALT levels. Nearly 25% of HIV-HCV-coinfected patients with persistently normal ALT show advanced liver fibrosis. Therefore, HCV-HIV-coinfected patients with normal ALT levels should be closely monitored.


The evolution of alternative parasitic life histories in large blue butterflies.
Large blue (Maculinea) butterflies are highly endangered throughout the Palaearctic region, and have been the focus of intense conservation research. In addition, their extraordinary parasitic lifestyles make them ideal for studies of life history evolution. Early instars consume flower buds of specific host plants, but later instars live in ant nests where they either devour the brood (predators), or are fed mouth-to-mouth by the adult ants (cuckoos). Here we present the phylogeny for the group, which shows that it is a monophyletic clade nested within Phengaris, a rare Oriental genus whose species have similar life histories. Cuckoo species are likely to have evolved from predatory ancestors. As early as five million years ago, two Maculinea clades diverged, leading to the different parasitic strategies seen in the genus today. Contrary to current belief, the two recognized cuckoo species show little genetic divergence and are probably a single ecologically differentiated species. On the other hand, some of the predatory morphospecies exhibit considerable genetic divergence and may contain cryptic species. These findings have important implications for conservation and reintroduction efforts.


The ion channel transient receptor potential melastatin-2 does not play a role in inflammatory mouse models of chronic obstructive pulmonary diseases.
There is strong evidence that oxidative stress is associated with the pathogenesis of chronic obstructive pulmonary disease (COPD). The transient receptor potential melastatin-2 (TRPM2) is an oxidative stress sensing channel that is expressed in a number of inflammatory cells and therefore it has been suggested that inhibition of TRPM2 could lead to a beneficial effect in COPD patients. In this study, we have investigated the role of TRPM2 in a variety of mouse models of oxidative stress and COPD using TRPM2-deficent mice. Mice were exposed to ozone (3 ppm for 4 h) or lipopolysaccharide (LPS, 0.3 mg/kg, intranasaly). In another model, mice were exposed to tobacco smoke (750 μg/l total wet particulate matter) for 30 min twice a day on three consecutive days. For the exacerbation model, the smoke exposure on the morning of day 3 animals was replaced with intranasal administration of LPS (0.3 mg/kg). Animals were killed 3 and 24 h after the challenge (ozone and LPS model) or 18 h after the last tobacco smoke exposure. In vitro neutrophil chemotaxis and monocyte activation were also studied using cells isolated from wild type and TRPM2-deficient animals. Statistical significance for the in vivo data (P < 0.05) was determined using analysis of variance with Kruskal-Wallis and Dunns multiple comparison test. In all models studied, no difference in the bronchoalveolar lavage inflammation could be evidenced when comparing wild type and TRPM2-deficient mice. In addition, no difference could be seen in the lung inflammation as assessed by the measurement of various cytokines/chemokines. Similarly in various in vitro cellular activation assays using isolated neutrophils and monocytes no significant differences could be observed when comparing wild type and TRPM2-deficient mice. We have shown, in all the models tested, no difference in the development of airway inflammation or cell activation between TRPM2-deficient mice and their wild type counterparts. These results would suggest that inhibiting TRPM2 activity in COPD would have no anti-inflammatory effect.


Nature reserve selection problem: a tight approximation algorithm.
The Nature Reserve Selection Problem is a problem that arises in the context of studying biodiversity conservation. Subject to budgetary constraints, the problem is to select a set of regions to conserve so that the phylogenetic diversity of the set of species contained within those regions is maximized. Recently, it was shown in a paper by Moulton et al. that this problem is NP-hard. In this paper, we establish a tight polynomial-time approximation algorithm for the Nature Reserve Section Problem. Furthermore, we resolve a question on the computational complexity of a related problem left open in Moulton et al.


The shape of posterior corneal surface in normal, post-LASIK, and post-epi-LASIK eyes.
PURPOSE. To evaluate the shape of the posterior corneal surface in eyes with normal myopia or myopic astigmatism and the changes after LASIK and epi-LASIK. METHODS. A total of 152 eyes were included in the study. The posterior corneal elevation was measured with Scheimpflug imaging (Pentacam; Oculus, Wetzlar, Germany), before LASIK or epi-LASIK and at 1 and 6 months after surgery, along the four optical zones (center and 2-, 4-, and 6-mm diameters) as a function of the meridian. RESULTS. In normal eyes, the heights were lower in the vertical meridian than in the horizontal meridian and were also lower in the superior hemisphere than in the inferior hemisphere. In post-LASIK eyes, almost all regions protruded 1 month after surgery, except for the 6-mm diameter, which exhibited a slight but not significant (P = 0.731) backward displacement. The various elevations returned to original levels 6 months after LASIK. In the post-epi-LASIK group, there was a significant backward displacement in the center and 2-mm regions after surgery. Moreover, there was no shift at the 4-mm diameter, and the 6-mm diameter showed a progressive forward shift. CONCLUSIONS. The shape of the normal posterior corneal surface exhibited obvious regional disparities and radial asymmetry. The displacement after LASIK was observed as time-dependent changes that protruded at an early stage but then returned to original levels 6 months after surgery. On the other hand, the displacement after epi-LASIK appeared as region-dependent changes that could be divided into central and peripheral parts that displayed backward and forward shift trends, respectively.


Subsidence in impaction grafting: the effect of adding a ceramic bone graft extender to bone.
The incidence of revision total hip arthroplasty is increasing dramatically and the associated demand for allograft bone is likely to exceed the available supply. In addition, allograft presents potential problems with regard to infection, antigenicity, availability, reproducibility and cost. It is therefore desirable to develop an alternative to allograft. This study investigated BoneSave, a porous tricalcium phosphate-hydroxyapatite ceramic for use in impaction grafting of the femur at revision total hip arthroplasty. The findings of an in vitro mechanical study comparing the initial stability of pure allograft, a volume mixture of 50 per cent allograft and 50 per cent BoneSave, and a volume mixture of 10 per cent allograft and 90 per cent BoneSave are reported. The BoneSave-allograft mixtures exhibit both much greater mechanical stability and reproducibility than the pure allograft (p < 0.05) at all tested loads (200-800 N). At high peak loads the high volume (90%, v/v) BoneSave mix also provided higher mechanical stability than the medium volume (50 per cent BoneSave-50 per cent allograft) mix (p < 0.05). These results demonstrate thatfrom a mechanical standpoint the tested ceramic provides adequate initial stability to be used as a bone graft extender with allograft in impaction grafting of the femur.


High-resolution array CGH and gene expression profiling of alveolar soft part sarcoma.
Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis, and little molecular evidence exists for its origin, initiation, and progression. The aim of this study was to elucidate candidate molecular pathways involved in tumor pathogenesis. We employed high-throughput array comparative genomic hybridization (aCGH) and cDNA-Mediated Annealing, Selection, Ligation, and Extension Assay to profile the genomic and expression signatures of primary and metastatic ASPS from 17 tumors derived from 11 patients. We used an integrative bioinformatics approach to elucidate the molecular pathways associated with ASPS progression. FISH was performed to validate the presence of the t(X;17)(p11.2;q25) ASPL-TFE3 fusion and, hence, confirm the aCGH observations. FISH analysis identified the ASPL-TFE3 fusion in all cases. aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify consistent alterations in either group. Gene expression analysis highlighted 1,063 genes that were differentially expressed between the two groups. Gene set enrichment analysis identified 16 enriched gene sets (P < 0.1) associated with differentially expressed genes. Notable among these were several stem cell gene expression signatures and pathways related to differentiation. In particular, the paired box transcription factor PAX6 was upregulated in the primary tumors, along with several genes whose mouse orthologs have previously been implicated in Pax6 DNA binding during neural stem cell differentiation. In addition to suggesting a tentative neural line of differentiation for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS.


A case of renovascular hypertension with incidental primary bilateral macronodular adrenocortical hyperplasia.
Renovascular hypertension (RVHT) is an important and potentially treatable form of resistant hypertension. Hypercortisolemia could also cause hypertension and diabetes mellitus. We experienced a case wherein adrenalectomy markedly improved blood pressure and plasma glucose levels in a patient with RVHT and low-level autonomous cortisol secretion. A 62-year-old Japanese man had been treated for hypertension and diabetes mellitus for 10 years. He was hospitalized because of a disturbance in consciousness. His blood pressure (BP) was 236/118 mmHg, pulse rate was 132 beats/min, and plasma glucose level was 712 mg/dL. Abdominal CT scanning revealed the presence of bilateral adrenal masses and left atrophic kidney. Abdominal magnetic resonance angiography demonstrated marked stenosis of the left main renal artery. The patient was subsequently diagnosed with atherosclerotic RVHT with left renal artery stenosis. His left adrenal lobular mass was over 40 mm and it was clinically suspected the potential for cortisol overproduction. Therefore, laparoscopic left nephrectomy and adrenalectomy were simultaneously performed, resulting in improved BP and glucose levels. Pathological studies revealed the presence of multiple cortisol-producing adrenal nodules and aldosterone-producing cell clusters in the adjacent left adrenal cortex. In the present case, the activated renin-angiotensin-aldosterone system and cortisol overproduction resulted in severe hypertension, which was managed with simultaneous unilateral nephrectomy and adrenalectomy. Concomitant activation of the renin-angiotensin-aldosterone system and cortisol overproduction may contribute to the development of severe hypertension and lead to lethal cardiovascular complications. Treatment with simultaneous unilateral nephrectomy and adrenalectomy markedly improves BP and blood glucose levels. CYP11B2 immunohistochemistry staining revealed the existence of aldosterone-producing cell clusters (APCCs) in the adjacent non-nodular adrenal gland, suggesting that APCCs may contribute to aldosterone overproduction in patients with RVHT.


Medullary thyroid carcinoma in children with multiple endocrine neoplasia types 2A and 2B.
Recently it has become possible to identify persons who have multiple endocrine neoplasia (MEN) syndrome types 2A and 2B based on the presence of missense mutations in the RET protooncogene. Kindred members who have inherited these syndromes can be identified before clinical or biochemical evidence of medullary thyroid carcinoma (MTC) develops, the malignancy that occurs in all affected patients. It is not known whether prophylactic removal of the thyroid gland early in childhood, based on a positive genetic test result, has a better clinical outcome than that associated with thyroidectomy after MTC is diagnosed clinically or biochemically. The authors' goal was to determine the long-term outcome for patients with MEN 2A and 2B who had thyroidectomy for MTC during childhood. These results were compared with those of patients who had prophylactic removal of the thyroid gland after the genetic diagnosis of MEN 2A was established. The hospital records of 49 children with MEN 2A or 2B were reviewed. Each patient had thyroidectomy for MTC before 16 years of age. The mean age at the time of operation was 10 years, and the mean follow-up period for those who had surgery before the availability of direct DNA genetic testing was 9.8 years. The indications for surgery included an elevated basal or stimulated plasma calcitonin level, a positive genetic test result, a thyroid mass, family history of MTC, or a phenotype diagnostic of MEN 2B. All children for whom the diagnosis of MEN 2A was established by direct genetic testing had thyroidectomy within the last 2 years. Of the 11 patients with MEN 2B who underwent thyroidectomy during childhood, 10 had MTC, and only 3 (27%) remain free of disease after the mean follow-up period of 11 years. One patient died, and seven are alive with persistent MTC. Among the 24 patients with MEN 2A who had their thyroid glands removed because of a family history of MTC or because of biochemical evidence of the disease, 5 (21%) have persistent or recurrent MTC after the mean follow-up period of 9.3 years. In four of these, the MTC was confined to the thyroid gland at the time of thyroidectomy. Of the 14 children who had thyroidectomy based on direct DNA testing, MTC was present in 11. Only four had elevated levels of stimulated plasma calcitonin before surgery. None had lymph node metastasis or surgical complications. The authors conclude that a significant number of patients with MEN 2A or 2B who undergo thyroidectomy in childhood for MTC have persistent or recurrent disease long-term. The genetic diagnosis of patients with these syndromes may allow for prophylactic surgery before the development of biochemical or clinical evidence of MTC. This approach is safe, but longer clinical follow-up will be necessary to confirm that MTC has been cured.


E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx- ECOG-ACRIN Cancer Research Group.
Purpose Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) is treatment-responsive. Definitive chemoradiation results in high cure rates but causes long-term toxicity and may represent overtreatment of some patients. This phase II trial evaluated whether complete clinical response (cCR) to induction chemotherapy (IC) could select patients with HPV-associated OPSCC for reduced radiation dose as a means of sparing late sequelae. Methods Patients with HPV16 and/or p16-positive, stage III-IV OPSCC received three cycles of IC with cisplatin, paclitaxel, and cetuximab. Patients with primary-site cCR to IC received intensity-modulated radiation therapy (IMRT) 54 Gy with weekly cetuximab; those with less than cCR to IC at the primary site or nodes received 69.3 Gy and cetuximab to those regions. The primary end point was 2-year progression-free survival. Results Of the 90 patients enrolled, 80 were evaluable. Their median age was 57 years (range, 35 to 73 years), with the majority having stage T1-3N0-N2b OPSCC and a history of ≤ 10 pack-years of cigarette smoking. Three cycles of IC were delivered to 77 of the 80 patients. Fifty-six patients (70%) achieved a primary-site cCR to IC and 51 patients continued to cetuximab with IMRT 54 Gy. After median follow-up of 35.4 months, 2-year progression-free survival and overall survival rates were 80% and 94%, respectively, for patients with primary-site cCR treated with 54 Gy of radiation (n = 51); 96% and 96%, respectively, for patients with < T4, < N2c, and ≤ 10 pack-year smoking history who were treated with ≤ 54 Gy of radiation (n = 27). At 12 months, significantly fewer patients treated with a radiation dose ≤ 54 Gy had difficulty swallowing solids (40% v 89%; P = .011) or had impaired nutrition (10% v 44%; P = .025). Conclusion For IC responders, reduced-dose IMRT with concurrent cetuximab is worthy of further study in favorable-risk patients with HPV-associated OPSCC. Radiation dose reduction resulted in significantly improved swallowing and nutritional status.


Persistence and transmission of tick-borne viruses: Ixodes ricinus and louping-ill virus in red grouse populations.
The population dynamics of tick-borne disease agents and in particular the mechanisms which influence their persistence are examined with reference to the flavivirus that causes louping-ill in red grouse and sheep. Pockets of infection cause heavy mortality and the infection probably persists as a consequence of immigration of susceptible hosts. Seroprevalence is positively associated with temporal variations in vectors per host, although variation between areas is associated with the abundance of mountain hares. The presence of alternative tick hosts, particularly large mammals, provides additional hosts for increasing tick abundance. Grouse alone can not support the vectors and the pathogen but both can persist when a non-viraemic mammalian host supports the tick population and a sufficiently high number of nymphs bite grouse. These alternative hosts may also amplify virus through non-viraemic transmission by the process of co-feeding, although the relative significance of this has yet to be determined. Another possible route of infection is through the ingestion of vectors when feeding or preening. Trans-ovarial transmission is a potentially important mechanism for virus persistence but has not been recorded with louping-ill and Ixodes ricinus. The influence of non-viraemic hosts, both in the multiplication of vectors and the amplification of virus through non-viraemic transmission are considered significant for virus persistence.


An experimental and theoretical investigation of the C(1D) + D2 reaction.
In a previous joint experimental and theoretical study of the barrierless chemical reaction C(1D) + H2 at low temperatures (300-50 K) [K. M. Hickson, J.-C. Loison, H. Guo and Y. V. Suleimanov, J. Phys. Chem. Lett., 2015, 6, 4194], excellent agreement was found between experimental thermal rate constants and theoretical estimates based on ring polymer molecular dynamics (RPMD) over the two lowest singlet potential energy surfaces (PESs). Here, we extend this work to one of its isotopologues, C(1D) + D2, over the same temperature range. Experimental and RPMD results are in good agreement when contributions from both PESs to this chemical reaction are included in the RPMD simulations. The deviation between experiment and the RPMD calculations does not exceed 25% and both results exhibit a slight negative temperature dependence. The first excited 1A'' PES plays a more important role than the ground 1A' PES as the temperature is decreased, similar to our previous studies of the C(1D) + H2 reaction but with a more pronounced effect. The small differences in temperature dependence between the earlier and present experimental studies of C(1D) + H2/D2 reactions are discussed in terms of the use of non-equilibrium populations of ortho/para-H2/D2. We argue that RPMD provides a very convenient and reliable tool to study low-temperature chemical reactions.


Nutritional factors in ovarian cancer prevention: what have we learned in the past 5 years?
The recommendation of the American Cancer Society Nutrition and Physical Activity 2001 Guidelines regarding ovarian cancer prevention was that "there are no firmly established nutritional risk factors for ovarian cancer, though vegetable and fruit consumption may lower risk." Since then, a number of studies have been published including several large cohort studies. The main objective of this review was to evaluate the literature from the past 5 yr and determine whether any more firm recommendations could be made at this point. Searches were conducted from 2000 to July 2006, and relevant citations were reviewed. Although population-based case-control studies have fairly consistently shown an increased risk with increase body mass, cohort data are inconclusive. The role of physical activity is also unclear. The current epidemiologic evidence for dietary factors is generally inconsistent to warrant public health recommendations regarding any of these factors.


An antibody-free microfluidic paper-based analytical device for the determination of tear fluid lactoferrin by fluorescence sensitization of Tb3+.
An inkjet-printed microfluidic paper-based analytical device (μPAD) for the detection of lactoferrin has been developed. The analyte concentration dependent fluorescence emission, caused by the sensitization of pre-deposited terbium (Tb(3+)) upon complexation with lactoferrin on the paper device, is captured using a digital camera. The dynamic response range (0.5-3 mg mL(-1)) and the limit of detection (0.30 mg mL(-1)) of the μPAD are suitable for the analysis of normal human tears and the detection of eye disorders. Finally, lactoferrin concentrations in human tear samples were analyzed by the μPADs and the assay results corresponded within 6% error to those obtained by an immunoassay (ELISA). The μPADs provide a simple, rapid and accurate method for lactoferrin detection in tear fluid. Results are obtained within 15 min of a single application of 2.5 μL of sample. To the best of our knowledge, this is the first report of a device for lactoferrin quantification relying neither on an immunoassay nor on high cost analytical instrumentation.


Is specific IgE antibody analysis feasible for the diagnosis of methylenediphenyl diisocyanate-induced occupational asthma?
Early recognition improves the prognosis of isocyanate asthma. A major unanswered question is whether IgE-dependent mechanisms are of diagnostic value? Our objective was to appraise serological methods using various methylenediphenyl diisocyanate (MDI)-albumin conjugates and weigh up the data versus the outcome of standardized comprehensive clinical diagnostics to evaluate the viability of immunological analysis in supportive MDI-asthma diagnosis (OAI). Specific IgE (sIgE) and IgG (sIgG) binding was measured with fluorescence enzyme immunoassay in 43 study subjects (using conjugates prepared in-vapor, in-solution and commercial preparations). The differential clinical diagnosis included standardized measurement of pulmonary function, non-specific bronchial hyper-responsiveness, specific MDI-prick test (MDI-SPT) and specific inhalation challenge (MDI-SIC). Detailed diagnostic scheme allows the differential OAI and MDI-induced hypersensitivity pneumonitis (PI). The presumed OAI diagnoses were confirmed in 84 % (45 % cases having demonstrable sIgE antibodies) with RR 5.7, P > 0.001, when OAI diagnosis is correlated with MDI-SIC/MDI-SPT (RR 1.28 for MDI-SIC alone); sIgG antibodies were clinically relevant for PI and not for the OA diagnosis. MDI-specific IgE data generated with commercial ImmunoCAP preparations show high correlation with our in-vapor generated MDI conjugates. Isocyanate-specific IgE antibodies are not always detectable but their presence is strongly predictive of OAI and supportive for the diagnosis. MDI-SPT can be a valuable parameter differentiating OAI and PI. We have confirmed and extended published data showing that isocyanate-albumin conjugates perform better in specific antibody assays when prepared with volatile phase formulations and would like to stress additionally the necessity for further refinements and standardization in clinical diagnostics procedures.


Acute poisoning: understanding 90% of cases in a nutshell.
The acutely poisoned patient remains a common problem facing doctors working in acute medicine in the United Kingdom and worldwide. This review examines the initial management of the acutely poisoned patient. Aspects of general management are reviewed including immediate interventions, investigations, gastrointestinal decontamination techniques, use of antidotes, methods to increase poison elimination, and psychological assessment. More common and serious poisonings caused by paracetamol, salicylates, opioids, tricyclic antidepressants, selective serotonin reuptake inhibitors, benzodiazepines, non-steroidal anti-inflammatory drugs, and cocaine are discussed in detail. Specific aspects of common paediatric poisonings are reviewed.


Look Who's Pointing Now: Cautions Related to the Clinical Use of Facilitated Communication.
This article focuses on three factors related to the use of facilitated communication (FC), all of which constitute possible reasons for caution by speech-language pathologists who are considering this technique for individuals with severe communication impairments. First, problems with the theoretical bases of FC are discussed, especially those attributing the success of this method to its ability to target individuals' underlying difficulties with apraxia, word finding, and social-emotional challenges. A case is made that there is insufficient evidence to support claims that FC overrides such problems. The notion of the method unlocking communication and related skills from otherwise competent individuals is also questioned. Next, the subject of candidacy is discussed. Special attention is called to the absence of criteria for initiating, maintaining, modifying, and terminating this approach. Finally, outcomes of the method are summarized. Discrepancies between qualitative and experimental investigations are summarized, along with some possible explanations for these differences. Suggested parameters for evaluating individuals' uses of FC are discussed, along with the continuing need for speech-language pathologists to make informed decisions concerning the role FC will play in their interventions with individuals who exhibit severe communication impairments.


A dominant negative form of the AAA ATPase SKD1/VPS4 impairs membrane trafficking out of endosomal/lysosomal compartments: class E vps phenotype in mammalian cells.
SKD1 is a member of the family of ATPases associated with cellular activities whose yeast homologue Vps4p has been implicated in endosomal/vacuolar membrane transports. When a mutant of SKD1 that lacks ATPase activity [SKD1(E235Q)] was overexpressed in mammalian cells, it induced a dominant negative phenotype characterized by aberrant endosomal structures (denoted as E235Q compartments). Expression of SKD1(E235Q) caused an accumulation of basolateral recycling receptors, such as asialoglycoprotein receptor and low-density lipoprotein in polarized hepatocytes and Madin-Darby canine kidney cells, respectively, in E235Q compartments. In addition, SKD1(E235Q) also abrogated, via endosomes, transport to the trans-Golgi network, as indicated by an accumulation of TGN38 in E235Q compartments. Three lines of evidence further demonstrated that SKD1 participates in the membrane transport from early endosomes to late endosomes/lysosomes: (1) a redistribution of a late endosomal and lysosomal membrane protein endolyn in E235Q compartments; (2) an inhibition of epidermal growth factor receptor degradation, due to an accumulation of the receptors in E235Q compartments; and (3) a mis-sorting of and defect in the proteolytic processing of newly synthesized cathepsin D. An intriguing finding was that the expression of SKD1(E235Q) caused the number of lysosomes to decrease (to one-sixth of control numbers) but their size to increase (2.4-fold larger in diameter than control lysosomes). Indeed, an ultrastructural analysis revealed that the expression of SKD1(E235Q) causes an accumulation of hybrid organelles formed by direct fusion between late endosomes and lysosomes. We conclude that SKD1 regulates multiple steps of membrane transport out of early endosomes and the reformation of lysosomes from a hybrid organelle.


A new class of multimerization selective inhibitors of HIV-1 integrase.
The quinoline-based allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are promising candidates for clinically useful antiviral agents. Studies using these compounds have highlighted the role of IN in both early and late stages of virus replication. However, dissecting the exact mechanism of action of the quinoline-based ALLINIs has been complicated by the multifunctional nature of these inhibitors because they both inhibit IN binding with its cofactor LEDGF/p75 and promote aberrant IN multimerization with similar potencies in vitro. Here we report design of small molecules that allowed us to probe the role of HIV-1 IN multimerization independently from IN-LEDGF/p75 interactions in infected cells. We altered the rigid quinoline moiety in ALLINIs and designed pyridine-based molecules with a rotatable single bond to allow these compounds to bridge between interacting IN subunits optimally and promote oligomerization. The most potent pyridine-based inhibitor, KF116, potently (EC50 of 0.024 µM) blocked HIV-1 replication by inducing aberrant IN multimerization in virus particles, whereas it was not effective when added to target cells. Furthermore, KF116 inhibited the HIV-1 IN variant with the A128T substitution, which confers resistance to the majority of quinoline-based ALLINIs. A genome-wide HIV-1 integration site analysis demonstrated that addition of KF116 to target or producer cells did not affect LEDGF/p75-dependent HIV-1 integration in host chromosomes, indicating that this compound is not detectably inhibiting IN-LEDGF/p75 binding. These findings delineate the significance of correctly ordered IN structure for HIV-1 particle morphogenesis and demonstrate feasibility of exploiting IN multimerization as a therapeutic target. Furthermore, pyridine-based compounds present a novel class of multimerization selective IN inhibitors as investigational probes for HIV-1 molecular biology.


Extracting insights from electronic health records: case studies, a visual analytics process model, and design recommendations.
Current electronic health record (EHR) systems facilitate the storage, retrieval, persistence, and sharing of patient data. However, the way physicians interact with EHRs has not changed much. More specifically, support for temporal analysis of a large number of EHRs has been lacking. A number of information visualization techniques have been proposed to alleviate this problem. Unfortunately, due to their limited application to a single case study, the results are often difficult to generalize across medical scenarios. We present the usage data of Lifelines2 (Wang et al. 2008), our information visualization system, and user comments, both collected over eight different medical case studies. We generalize our experience into a visual analytics process model for multiple EHRs. Based on our analysis, we make seven design recommendations to information visualization tools to explore EHR systems.


Imaging out-of-plane polarized emission patterns on gap mode SERS substrates: from high molecular coverage to the single molecule regime.
Gap mode surface-enhanced Raman scattering (SERS) substrates are created when a single nanoparticle is deposited on a thin metal film, creating a region of significant electromagnetic field enhancement in the gap between the nanoparticle and the film due to excitation of a vertically-oriented, out-of-plane dipole plasmon mode, e.g. the gap plasmon. When molecules are located in the gap and couple to the gap plasmon mode, the resulting emission is polarized perpendicular to the thin film, generating SERS emission patterns that have a characteristic donut shape. We analyze these SERS emission patterns using a dipole emission model and extract out-of-plane and in-plane emission angles associated with the gap plasmon mode. Fluctuations in both of these angles reveal dynamic heterogeneity due to molecular motion within the hot spot that changes as a function of molecular coverage. We also reveal static heterogeneity associated with structural defects in the thin film component of the gap mode substrates, indicating that even nanometer-scale surface roughness can impact the quality of gap mode emission.