Copeland surface replacement arthroplasty of the shoulder in rheumatoid arthritis.
Shoulder arthroplasty with a stemmed prosthesis is a recognized treatment for rheumatoid arthritis of the shoulder. The humeral component of the Copeland cementless surface replacement arthroplasty consists of a cup for surface replacement with a short central peg for primary fixation to the bone. We hypothesized that surface replacement may offer some advantages over stemmed prostheses. Between 1986 and 1998, seventy-five shoulders underwent surface replacement arthroplasty (thirty-three hemiarthroplasties and forty-two total shoulder arthroplasties) for the treatment of rheumatoid arthritis. The results of these procedures were reviewed after an average duration of follow-up of 6.5 years. Patients were assessed with use of the Constant score, a patient satisfaction score, and radiographs. The average Constant score was 47.9 points (age and sex-adjusted score, 71%) in the hemiarthroplasty group and 53.4 points (age and sex-adjusted score, 76%) in the total shoulder replacement group. The mean range of active flexion improved from 50 degrees in the hemiarthroplasty group and 47 degrees in the total shoulder replacement group to 101 degrees and 104 degrees, respectively. Seventy-two of the seventy-five shoulders were considered by the patients to be much better or better at the time of the review. Of the sixty-eight humeral implants that were evaluated radiographically, fifty-six (82%) showed no lucencies, eleven (16%) showed localized lucencies of <1 mm in width, and one was definitely loose. Of the thirty-nine glenoid implants that were evaluated radiographically, nineteen (49%) showed no lucencies, nineteen showed localized lucencies of <1 mm, and one was definitely loose. No lucencies were observed adjacent to the hydroxyapatite-coated implants. Thirty-nine (57%) of the sixty-eight shoulders showed some degree of superior subluxation. Three patients required a major reoperation: two required a revision because of loosening of both components, and one patient with pain at the site of a hemiarthroplasty had a revision to a total shoulder arthroplasty to provide relief. The indications for this surface replacement are the same as those for the conventional stemmed prostheses, but the surface replacement has the advantage of bone preservation as well as avoidance of the potential complications associated with a long humeral stem in rheumatoid bone. This procedure is not suitable for severely damaged joints in which the humeral head is insufficient or too soft. Therapeutic study, Level IV (case series [no, or historical, control group]). See Instructions to Authors for a complete description of levels of evidence.


Oral EBV and KSHV infection in HIV.
The gamma herpesviruses, Kaposi's-sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), are tightly associated with the development of AIDS-associated oral disease and malignancy during immune suppression. The objective of this investigation was to characterize oral infection and pathogenesis in healthy and immune-suppressed individuals. To characterize oral EBV and KSHV infection, we examined throat washings and oral epithelial cells from HIV-positive and HIV-negative individuals. Quantitative/real-time polymerase-chain-reaction (PCR) assays, transmission electronmicroscopy, immunostaining, and sequence analysis were used to identify viral infection. Virus was isolated from throat-wash samples and was used to infect epithelial and lymphoid cell lines. We detected EBV and KSHV in the oral cavity in healthy and immune-suppressed individuals. Viral strain analysis of KSHV K1 in multiple clones from the oral cavities of healthy persons and immunosuppressed patients detected several strains previously detected in KS lesions, with minor strain variation within individuals. Immunoelectron microscopy for multiple viral antigens detected consistent expression of viral proteins and oral epithelial specimens. In oral epithelial cells infected with wild-type KSHV in vitro, the K8.1 glycoprotein associated with lytic KSHV infection was detected in both primary and telomerase immortalized oral epithelial cultures by 24 hours post-infection. Virions were detected, subsequent to infection, by scanning electron microscopy. Oral epithelial cells were also infected in vitro with wild-type EBV originating from throat washes. Analysis of these data suggests that, like EBV, KSHV infection is present in the oropharynx of healthy individuals, is transmissible in vitro, and may be transmitted by saliva.


Specific mesoderm subset derived from human pluripotent stem cells ameliorates microvascular pathology in type 2 diabetic mice.
Human induced pluripotent stem cells (hiPSCs) were differentiated into a specific mesoderm subset characterized by KDR+CD56+APLNR+ (KNA+) expression. KNA+ cells had high clonal proliferative potential and specification into endothelial colony-forming cell (ECFCs) phenotype. KNA+ cells differentiated into perfused blood vessels when implanted subcutaneously into the flank of nonobese diabetic/severe combined immunodeficient mice and when injected into the vitreous of type 2 diabetic mice (db/db mice). Transcriptomic analysis showed that differentiation of hiPSCs derived from diabetics into KNA+ cells was sufficient to change baseline differences in gene expression caused by the diabetic status and reprogram diabetic cells to a pattern similar to KNA+ cells derived from nondiabetic hiPSCs. Proteomic array studies performed on retinas of db/db mice injected with either control or diabetic donor-derived KNA+ cells showed correction of aberrant signaling in db/db retinas toward normal healthy retina. These data provide "proof of principle" that KNA+ cells restore perfusion and correct vascular dysfunction in db/db mice.


Effect of Manuka Honey on Eyelid Wound Healing: A Randomized Controlled Trial.
To report outcomes of a randomized trial on the role of "active" Manuka honey on eyelid surgical wound healing. Prospective, randomized, single-blinded study was performed for patients undergoing bilateral upper blepharoplasty. Vaseline was applied 4 times a day to both sides for 6 weeks and in addition, one eyelid was randomized to receive Manuka honey twice daily. Postoperative wounds were graded by a masked observer at 1 week, 1 month, and 4 months using Manchester scar scale and a modified eyelid scar grading scale. Patients scored symptoms, expressed preferred side, and of any problems they experienced using honey. Standard photographs were graded by 2 independent assessors. Fifty-five patients were randomized. One week after surgery, 46 (29 women, 17 men, mean age 68 years, median 69, range 49-85) were available for analysis. There was a trend toward distortion of the surrounding skin being less (1.6 vs. 1.8, p = 0.07) and the scar being less palpable (1.8 vs. 2.0, p = 0.08) on the Manuka-treated side. Patients reported the scar on the Manuka side to have less stiffness (1.3 vs. 1.6, p = 0.058). At 1 month, all 3 grading scales showed no difference between the 2 sides. At 4 months, scar grading scales showed no differences; however, patients reported scar pain to be significantly less on the Manuka-treated side than control (0.48 vs. 1.9, p = 0.005). Thirty-one of 46 patients believed the scars were similar on both sides, 11 preferred the honey-treated side, and 4 preferred the control. Upper eyelid scars treated with or without Manuka honey heal well, without significant difference when assessed by validated scar grading scales; however, honey may provide subjective benefits early, postoperatively.


Endogenous, tissue-specific short interfering RNAs silence the chalcone synthase gene family in glycine max seed coats.
Two dominant alleles of the I locus in Glycine max silence nine chalcone synthase (CHS) genes to inhibit function of the flavonoid pathway in the seed coat. We describe here the intricacies of this naturally occurring silencing mechanism based on results from small RNA gel blots and high-throughput sequencing of small RNA populations. The two dominant alleles of the I locus encompass a 27-kb region containing two perfectly repeated and inverted clusters of three chalcone synthase genes (CHS1, CHS3, and CHS4). This structure silences the expression of all CHS genes, including CHS7 and CHS8, located on other chromosomes. The CHS short interfering RNAs (siRNAs) sequenced support a mechanism by which RNAs transcribed from the CHS inverted repeat form aberrant double-stranded RNAs that become substrates for dicer-like ribonuclease. The resulting primary siRNAs become guides that target the mRNAs of the nonlinked, highly expressed CHS7 and CHS8 genes, followed by subsequent amplification of CHS7 and CHS8 secondary siRNAs by RNA-dependent RNA polymerase. Most remarkably, this silencing mechanism occurs only in one tissue, the seed coat, as shown by the lack of CHS siRNAs in cotyledons and vegetative tissues. Thus, production of the trigger double-stranded RNA that initiates the process occurs in a specific tissue and represents an example of naturally occurring inhibition of a metabolic pathway by siRNAs in one tissue while allowing expression of the pathway and synthesis of valuable secondary metabolites in all other organs/tissues of the plant.


Quantification and confocal imaging of protein specific molecularly imprinted polymers.
We have employed FITC--albumin as the protein template molecule in an aqueous phase molecular imprinted polymer (HydroMIP) strategy. For the first time, the use of a fluorescently labeled template is reported, with subsequent characterization of the smart material to show that the HydroMIP possesses a significant molecular memory in comparison to that of the nonimprinted control polymer (HydroNIP). The imaging of the FITC--albumin imprinted HydroMIP using confocal microscopy is described, with the in situ removal of the imprinted protein displayed in terms of observed changes in the fluorescence of the imprinted polymer, both before and after template elution (using a 10% SDS/10% AcOH (w/v) solution). We also report the imaging of a bovine hemoglobin (BHb) imprinted HydroMIP using two-photon confocal microscopy and describe the effects of template elution upon protein autofluorescence. The findings further contribute to the understanding of aqueous phase molecular imprinting protocols and document the use of fluorescence as a useful tool in template labeling/detection and novel imaging strategies.


Lipid metabolic reprogramming in cancer cells.
Many human diseases, including metabolic, immune and central nervous system disorders, as well as cancer, are the consequence of an alteration in lipid metabolic enzymes and their pathways. This illustrates the fundamental role played by lipids in maintaining membrane homeostasis and normal function in healthy cells. We reviewed the major lipid dysfunctions occurring during tumor development, as determined using systems biology approaches. In it, we provide detailed insight into the essential roles exerted by specific lipids in mediating intracellular oncogenic signaling, endoplasmic reticulum stress and bidirectional crosstalk between cells of the tumor microenvironment and cancer cells. Finally, we summarize the advances in ongoing research aimed at exploiting the dependency of cancer cells on lipids to abolish tumor progression.


Occupational class and exposure to job stressors among employed men and women in Japan.
The relationship between occupational class and exposure to job stressors among employed men and women in Japan remains unclear. Data of 16,444 men and 3,078 women were analyzed. The information was obtained from answers to a questionnaire distributed among employees of nine companies in Japan between 1996 and 1998 (average response rate, 85%). The International Standardized Classification of Occupations was used to classify respondents into eight occupational categories. The Job Content Questionnaire was used to measure job demands, job control, worksite support, and job insecurity. The associations between occupational class and job stressors, as well as job strain, were examined controlling for age, education, marital status, chronic medical condition, and personality traits, such as neuroticism and extraversion. Men and women in high-class occupations (e.g., managers and professionals) had significantly greater job control, while job demands and worksite social support were not greatly different among occupations. A clear occupational class gradient in job insecurity was observed in women. A greater prevalence of high job strain was observed in low-class occupations compared to high-class occupations in both men and women. The occupational class gradient in job strain was greater for women. These patterns did not change after controlling for other covariates. The present study suggests an occupational class gradient in job strain for employed men and women in Japan. Japanese women workers may have a greater occupational class gradient in job strain and job insecurity than men.


Search for pair production of a heavy up-type quark decaying to a W boson and a b quark in the lepton + jets channel with the ATLAS detector.
A search is presented for production of a heavy up-type quark (t') together with its antiparticle, assuming subsequent decay to a W boson and a b quark, t't[over ¯]'→W(+)bW(-)b[over ¯]. The search is based on 1.04 fb(-1) of proton-proton collisions at √[s]=7 TeV collected by the ATLAS detector at the CERN Large Hadron Collider. Data are analyzed in the lepton+jets final state, characterized by a high transverse momentum isolated electron or muon, high missing transverse momentum, and at least three jets. No significant excess of events above the background expectation is observed. A 95% C.L. lower limit of 404 GeV is set for the mass of the t' quark.


Use of Mental Health Services by Youths and Young Adults Before and During Correctional Custody: A Population-Based Study.
The authors measured use of mental health services among young people before and during incarceration. Administrative data were used to describe mental health services received by 13,919 youths and young adults (ages 12-24) while incarcerated in Ontario, Canada, correctional centers (physician visits, April 1, 2010-March 31, 2012) and, for a subset of the population, during the five years prior to incarceration. Forty-two percent had a mental health-related visit during incarceration. Thirty-five percent had no mental health contact for five years before the beginning of the correctional episode. Forty percent of individuals with schizophrenia had a psychiatric hospitalization in the year before entering custody. For one-third of young people with a mental health visit while incarcerated, the visit was the first mental health contact in at least five years. Yet high use of psychiatric services before entering custody among individuals with schizophrenia may indicate gaps in continuity of mental health care.


Revised consensus statement on the preventive and symptomatic care of patients with leukodystrophies.
Leukodystrophies are a broad class of genetic disorders that result in disruption or destruction of central myelination. Although the mechanisms underlying these disorders are heterogeneous, there are many common symptoms that affect patients irrespective of the genetic diagnosis. The comfort and quality of life of these children is a primary goal that can complement efforts directed at curative therapies. Contained within this report is a systems-based approach to management of complications that result from leukodystrophies. We discuss the initial evaluation, identification of common medical issues, and management options to establish a comprehensive, standardized care approach. We will also address clinical topics relevant to select leukodystrophies, such as gallbladder pathology and adrenal insufficiency. The recommendations within this review rely on existing studies and consensus opinions and underscore the need for future research on evidence-based outcomes to better treat the manifestations of this unique set of genetic disorders.


Updated recommendation for the benign stand-alone ACMG/AMP criterion.
The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group set out to refine the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists (ACMG/AMP) variant pathogenicity recommendations for stand-alone rule BA1 (a variant with minor allele frequency [MAF] > 0.05 is benign), by clarifying how it should be used and specifying a set of variants that should be exempted from this rule. We cross-referenced ClinVar and Exome Aggregation Consortium data to identify variants for which there was a plausible argument for pathogenicity and the variant exists in one or more population data sets at MAF > 0.05. We identified nine such variants that were present in these data sets that may not be benign. The ACMG/AMP criteria were applied to these variants that resulted in four pathogenic and five variants of uncertain significance. We have refined benign rule BA1 by clarifying terms used to describe its use, which databases we recommend using, and assumptions made about this rule. We also recognized an initial list of nine variants for which there was some evidence of pathogenicity even though the MAF was high for these variants. We specify processes whereby individuals can petition ClinGen for amendments to our variant-specific assertions and the criteria experts should use when setting a numerically lower threshold for BA1 for specific genes.


Child behaviors associated with childhood obesity and parents' self-efficacy to handle them: confirmatory factor analysis of the Lifestyle Behavior Checklist.
The development of family-based programs for child weight management requires an understanding of parents' difficulties in managing children's eating and physical activity behaviors; however, knowledge about the specific behaviors that parents find most difficult to address is still limited. The Lifestyle Behavior Checklist (LBC) is an Australian instrument that assesses parents' perceptions of children's obesity-related behaviors (the Problem scale), and parents' self-efficacy in dealing with these behaviors (the Confidence scale). Our aims were 1) to examine the psychometric properties (the factor structure, internal reliability, construct and discriminative validity) of the LBC in parents of preschoolers in Sweden, using the Child Feeding Questionnaire (CFQ) as a criterion measure, 2) to study associations between the LBC and socio-demographic factors. The LBC and the CFQ (measuring parental feeding practices) were distributed to parents from 25 schools/preschools and to parents starting a childhood obesity intervention. To test the fit of the original four-factor model (misbehavior in relation to food, overeating, emotional correlates of being overweight, physical activity (24 items)) to the data, confirmatory factor analysis (CFA) was performed. Structural equation modelling was used to examine associations between the LBC and the CFQ and socio-demographic factors. In a sample of 478 parents, a five-factor structure proved best fit to data, after excluding 6 items and allowing two pairs of error terms to correlate (TLI = 0.899; CFI = 0.918; RMSEA = 0.042; SRMR = 0.055). The Confidence scale indicated unidimensionality, therefore a hierarchical CFA with 5 first order factors and one second order factor was tested showing good fit. The validity of the LBC was proven by relevant associations with the CFQ and child weight status; parental responses differed depending on child weight status. The Confidence scale was not associated with any child or parent variables. In a large sample of Swedish parents of preschoolers, the LBC showed good psychometric properties, with relevant correlations to similar constructs. A five-factor structure showed best fit to data with moderate to high internal reliability. The LBC was shown to discriminate effectively between parents of normal weight children and parents of overweight/obese children.


Cultural transmission in a food preparation task: The role of interactivity, innovation and storytelling.
Interactive conversation drives the transmission of cultural information in small groups and large networks. In formal (e.g. schools) and informal (e.g. home) learning settings, interactivity does not only allow individuals and groups to faithfully transmit and learn new knowledge and skills, but also to boost cumulative cultural evolution. Here we investigate how interactivity affects performance, teaching, learning, innovation and chosen diffusion mode (e.g. instructional discourse vs. storytelling) of previously acquired information in a transmission chain experiment. In our experiment, participants (n = 288) working in 48 chains with three generations of pairs had to learn and complete a collaborative food preparation task (ravioli-making), and then transmit their experience to a new generation of participants in an interactive and non-interactive condition. Food preparation is a real-world task that it is taught and learned across cultures and transmitted over generations in families and groups. Pairs were defined as teachers or learners depending on their role in the transmission chain. The number of good exemplars of ravioli each pair produced was taken as measurement of performance. Contrary to our expectations, the results did not reveal that (1) performance increased over generations or that (2) interactivity in transmission sessions promoted increased performance. However, the results showed that (3) interactivity promoted the transmission of more information from teachers to learners; (4) increased quantity of information transmission from teachers led to higher performance in learners; (5) higher performance generations introduced more innovations in transmission sessions; (6) learners applied those transmitted innovations to their performance which made them persist over generations; (7) storytelling was specialized for the transmission of non-routine, unexpected information. Our findings offer new insights on how interactivity, innovation and storytelling affect the cultural transmission of complex collaborative tasks.


Nucleotide variation at Msn and Alas2, two genes flanking the centromere of the X chromosome in humans.
The centromeric region of the X chromosome in humans experiences low rates of recombination over a considerable physical distance. In such a region, the effects of selection may extend to linked sites that are far away. To investigate the effects of this recombinational environment on patterns of nucleotide variability, we sequenced 4581 bp at Msn and 4697 bp at Alas2, two genes situated on either side of the X chromosome centromere, in a worldwide sample of 41 men, as well as in one common chimpanzee and one orangutan. To investigate patterns of linkage disequilibrium (LD) across the centromere, we also genotyped several informative sites from each gene in 120 men from sub-Saharan Africa. By studying X-linked loci in males, we were able to recover haplotypes and study long-range patterns of LD directly. Overall patterns of variability were remarkably similar at these two loci. Both loci exhibited (i) very low levels of nucleotide diversity (among the lowest seen in the human genome); (ii) a strong skew in the distribution of allele frequencies, with an excess of both very-low and very-high-frequency derived alleles in non-African populations; (iii) much less variation in the non-African than in the African samples; (iv) very high levels of population differentiation; and (v) complete LD among all sites within loci. We also observed significant LD between Msn and Alas2 in Africa, despite the fact that they are separated by approximately 10 Mb. These observations are difficult to reconcile with a simple demographic model but may be consistent with positive and/or purifying selection acting on loci within this large region of low recombination.


A study of the knowledge and attitude towards pulse polio immunization in semi urban areas of South India.
The government of India launched the pulse polio immunization (PPI) programme in 1995 with the aim of eradicating poliomyelitis by the end of 2000. Despite this, 733 children with polio were reported in 2009 alone. Therefore, there is a need to understand the reason underlying such high numbers of cases after so many years of programme implementation. This study was performed to assess the knowledge of the general population about poliomyelitis and PPI and their attitude and practice towards PPI. This cross-sectional study was undertaken in two semi- urban areas of Mangalore city. Only houses in which children under five lived were included in the study. Data was collected by interviewing any adult member of the household using a pretested questionnaire. The literacy rate of study participants was 99%. Only 35(10.9%) participants knew the correct mode of transmission of polio. More than one quarter of the study population were under the misconception that polio is a curable disease. The primary source of information about PPI in majority of participants was the television (n = 192; 60%). Two-hundred and eighty eight (90%) participants knew that the purpose of PPI was to eradicate polio. Only 128 (40%) participants knew that polio drops can be given to children with mild illnesses and an identical number of participants knew that hot food stuff should not be given for at least half an hour following vaccination administration. Misconceptions such as PPI causing vaccine overdose was identified among 7 (2.2%) participants, it is a substitute for routine immunization was believed among 30 (9.4%) participants and that oral polio vaccine prevents other diseases was seen among 76 (23.7%) participants. The educational status of the participants was significantly associated with their awareness level (χ(2) =13.668, DF=6, P=0.033). This study identified a few important misconceptions associated with polio and PPI which need to be addressed by large scale awareness campaigns in order to achieve polio eradication in the near future.


The influence of the NOD Nss1/Idd5 loci on sialadenitis and gene expression in salivary glands of congenic mice.
The nonobese diabetic (NOD) Nss1 and Idd5 loci have been associated with sialadenitis development in mice. In this study the NOD Nss1 and Idd5 loci were backcrossed onto the healthy control strain B10.Q by using the speed congenic breeding strategy, resulting in three congenic strains: B10.Q.Nss1, B10.Q.Nss1/Idd5 heterozygous and B10.Q.Nss1/Idd5 homozygous. We investigated the effects of the Nss1 and Idd5 loci on sialadenitis and gene expression in NOD congenic mice. One submandibular salivary gland from each mouse was used for histological analysis of sialadenitis, whereas the contralateral salivary gland was used for gene expression profiling with the Applied Biosystems Mouse Genome Survey chip v.1.0. The results were validated using quantitative reverse transcriptase PCR. The NOD Nss1 and Idd5 loci had clear influence on the onset and progression of sialadenitis in congenic mice. Double congenic mice exhibited the most severe phenotype. We successfully identified several genes that are located in the NOD congenic regions to be differentially expressed between the congenic strains and the control strain. Several of these were found to be co-regulated, such as Stat1, complement component C1q genes and Tlr12. Also, a vast contingency of interferon-regulated genes (such as Ltb, Irf7 and Irf8) and cytokine and chemokine genes (such as Ccr7 and Ccl19) were differentially expressed between the congenic strains and the control strain. Over-representation of inflammatory signalling pathways was observed among the differentially expressed genes. We have found that the introgression of the NOD loci Nss1 and Idd5 on a healthy background caused sialadenitis in NOD congenic mouse strains, and we propose that genes within these loci are important factors in the pathogenesis. Furthermore, gene expression profiling has revealed several differentially expressed genes within and outside the NOD loci that are similar to genes found to be differentially expressed in patients with Sjögren's syndrome, and as such are interesting candidates for investigation to enhance our understanding of disease mechanisms and to develop future therapies.


Antidepressant use and risk of adverse outcomes in people aged 20-64 years: cohort study using a primary care database.
Antidepressants are one of the most commonly prescribed medications in young and middle-aged adults, but there is relatively little information on their safety across a range of adverse outcomes in this age group. This study aimed to assess associations between antidepressant treatment and several adverse outcomes in people aged 20-64 years diagnosed with depression. We conducted a cohort study in 238,963 patients aged 20-64 years registered with practices across the UK contributing to the QResearch primary care database. Only patients with a first diagnosis of depression were included. Outcomes were falls, fractures, upper gastrointestinal bleed, road traffic accidents, adverse drug reactions and all-cause mortality recorded during follow-up. Cox proportional hazards models were used to estimate hazard ratios associated with antidepressant exposure adjusting for potential confounding variables. During 5 years of follow-up, 4651 patients had experienced a fall, 4796 had fractures, 1066 had upper gastrointestinal bleeds, 3690 had road traffic accidents, 1058 had experienced adverse drug reactions, and 3181 patients died. Fracture rates were significantly increased for selective serotonin reuptake inhibitors (adjusted hazard ratio 1.30, 95% CI 1.21-1.39) and other antidepressants (1.28, 1.11-1.48) compared with periods when antidepressants were not used. All antidepressant drug classes were associated with significantly increased rates of falls. Rates of adverse drug reactions were significantly higher for tricyclic and related antidepressants (1.54, 1.25-1.88) and other antidepressants (1.61, 1.22-2.12) compared with selective serotonin reuptake inhibitors. Trazodone was associated with a significantly increased risk of upper gastrointestinal bleed. All-cause mortality rates were significantly higher for tricyclic and related antidepressants (1.39, 1.22-1.59) and other antidepressants (1.26, 1.08-1.47) than for selective serotonin reuptake inhibitors over 5 years but not 1 year, and were significantly reduced after 85 or more days of treatment with selective serotonin reuptake inhibitors. Mirtazapine was associated with significantly increased mortality rates over 1 and 5 years of follow-up. Selective serotonin reuptake inhibitors had higher rates of fracture than tricyclic and related antidepressants but lower mortality and adverse drug reaction rates than the other antidepressant drug classes. The association between mirtazapine and increased mortality merits further investigation. These risks should be carefully considered and balanced against potential benefits for individual patients when the decision to prescribe an antidepressant is made.


Nematode Community Response to Green Infrastructure Design in a Semiarid City.
Urbanization affects ecosystem function and environmental quality through shifts in ecosystem fluxes that are brought on by features of the built environment. Green infrastructure (GI) has been suggested as a best management practice (BMP) to address urban hydrologic and ecological impacts of the built environment, but GI practice has only been studied from a limited set of climatic conditions and disciplinary approaches. Here, we evaluate GI features in a semiarid city from the perspective of soil ecology through the application of soil nematode community analysis. This study was conducted to investigate soil ecological interactions in small-scale GI as a means of assessing curb-cut rain garden basin design in a semiarid city. We looked at the choice of mulching approaches (organic vs. rock) and how this design choice affects the soil ecology of rain basins in Tucson, AZ. We sampled soils during the monsoon rain season and assessed the soil nematode community as a bioindicator of soil quality and biogeochemical processes. We found that the use of organic mulch in GI basins promotes enhanced soil organic matter contents and larger nematode populations. Nematode community indices point to enhanced food web structure in streetscape rain garden basins that are mulched with organic material. Results from this study suggest that soil management practices for GI can help promote ecological interactions and ecosystem services in urban ecosystems.


Population norms for the EQ-5D-3L in China derived from the 2013 National Health Services Survey.
EQ-5D-3L is one of the most commonly used instruments for assessing health-related quality of life and cost-utility analyses, but it is not yet available in China. This study aims to develop population norms for the EQ-5D-3L in China in order to encourage appropriate use and interpretation of the EQ-5D-3L instrument. Data were extracted from the 2013 National Health Services Survey on a nationally representative sample of 188 720 participants. The utility index based on the 2018 Chinese preference-based value sets were calculated for the participants with different demographic and socio-economic characteristics. Differences in reported problems and visual analogue scale (VAS) and utility index scores were tested using a logistic, linear and tobit regression model, respectively. The Chinese respondents were less likely to report problems on the EQ-5D dimensions compared with most populations in other countries. Pain/discomfort was the most commonly reported problem (12.6%). This resulted in a high ceiling effect (84.19%) on the utility index and high mean scores for the utility index (0.985 ± 0.056) and VAS (80.91 ± 13.74) in the Chinese population. Those who were younger, better educated, employed, married, had no illness condition, lived in a more developed region and had a higher income obtained higher scores in both VAS and utility index. The VAS and utility index scores were also associated with gender, residency and lifestyles, but not always in a consistent way. Male and rural residents had a higher VAS score but not in the utility index compared with their female and urban counterparts. This study provides national population norms for the EQ-5D-3L based on the 2018 Chinese preference-based value sets. The norms can be used as a reference for health evaluation studies. Cautions need to be taken for presenting and interpreting the utility index results given the high ceiling effect of the EQ-5D-3L instrument.


Serum NfL and GFAP are associated with incident dementia and dementia mortality in older adults: The cardiovascular health study.
Circulating neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have been independently associated with dementia risk. Their additive association, and their associations with dementia-specific mortality, have not been investigated. We associated serum NfL, GFAP, total tau ,and ubiquitin carboxyl-terminal hydrolase-L1, measured in 1712 dementia-free adults, with 19-year incident dementia and dementia-specific mortality risk, and with 3-year cognitive decline. In adjusted models, being in the highest versus lowest tertile of NfL or GFAP associated with a hazard ratio (HR) of 1.49 (1.20-1.84) and 1.38 (1.15-1.66) for incident dementia, and 2.87 (1.79-4.61) and 2.76 (1.73-4.40) for dementia-specific mortality. Joint third versus first tertile exposure further increased risk; HR = 2.06 (1.60-2.67) and 9.22 (4.48-18.9). NfL was independently associated with accelerated cognitive decline. Circulating NfL and GFAP may, independently and jointly, provide useful clinical insight regarding dementia risk and prognosis.


Achieving high quality standards in laparoscopic colon resection for cancer: A Delphi consensus-based position paper.
To investigate the rate of laparoscopic colectomies for colon cancer using registries and population-based studies. To provide a position paper on mini-invasive (MIS) colon cancer surgery based on the opinion of experts leader in this field. A systematic review of the literature was conducted using PRISMA guidelines for the rate of laparoscopy in colon cancer. Moreover, Delphi methodology was used to reach consensus among 35 international experts in four study rounds. Consensus was defined as an agreement ≥75.0%. Domains of interest included nosology, essential technical/oncological requirements, outcomes and MIS training. Forty-four studies from 42 articles were reviewed. Although it is still sub-optimal, the rate of MIS for colon cancer increased over the years and it is currently >50% in Korea, Netherlands, UK and Australia. The remaining European countries are un-investigated and presented lower rates with highest variations, ranging 7-35%. Using Delphi methodology, a laparoscopic colectomy was defined as a "colon resection performed using key-hole surgery independently from the type of anastomosis". The panel defined also the oncological requirements recognized essential for the procedure and agreed that when performed by experienced surgeons, it should be marked as best practice in guidelines, given the principles of oncologic surgery be respected (R0 procedure, vessel ligation and mesocolon integrity). The rate of MIS colectomies for cancer in Europe should be further investigated. A panel of leaders in this field defined laparoscopic colectomy as a best practice procedure when performed by an experienced surgeon respecting the standards of surgical oncology.


Normal to abnormal ItBu·AlH3 isomerization in solution and in the solid state.
A complex of an N-heterocyclic carbene ItBu (1,3-di-tert-butylimidazolin-2-ylidene) and aluminum hydride was observed to isomerize into an abnormal carbene complex aItBu·AlH3 (aItBu = 1,3-di-tert-butylimidazolin-4-ylidene) in a polar solvent, and, for the first time, in the solid state. ItBu·AlH3 and aItBu·AlH3 were structurally characterized by single crystal X-ray diffraction analysis. NMR studies and DFT computations indicate that the polarity of the solvent promotes the isomerization process. The possible pathways for the isomerization are discussed on the basis of the DFT computational studies.


Peer assessment of resuscitation skills.
Peer tuition has been identified as a useful tool for delivering undergraduate healthcare training in basic life support. The aim of this study was to test the expansion of the peer tuition model to include peer assessment of performance. The study also sought to establish the attitudes towards peer assessment among the course students and tutors. Students undergoing an end-of-course test in basic life support were simultaneously assessed by peer and faculty assessors, and the reliability of assessment results was measured. Students' and peer assessors' attitudes to peer assessment were also measured, by questionnaire. In all 162 candidates were assessed by 9 sets of peers and faculty examiners. Inter-observer agreement was high (>95%) for all assessment domains apart from chest compressions (93%). Agreement on the final pass/fail decision was less consistent at 86%, because of the lower pass rate of 71% (115/162) afforded by peer assessors compared with 82% (132/162) by faculty assessors (p=0.0008). Peer assessor sensitivity and specificity were 85% was 90%, respectively, with positive predictive value of 97% and negative predictive value of 57%. Senior healthcare students can make reliable assessments of their peers' performance during an end-of-course test in basic life support. Students preferred peer assessment, and the peer assessment process was acceptable to the majority of students and peer assessors.


Chemical Makeup and Hydrophilic Behavior of Graphene Oxide Nanoribbons after Low-Temperature Fluorination.
Here we investigated the fluorination of graphene oxide nanoribbons (GONRs) using H2 and F2 gases at low temperature, below 200 °C, with the purpose of elucidating their structure and predicting a fluorination mechanism. The importance of this study is the understanding of how fluorine functional groups are incorporated in complex structures, such as GONRs, as a function of temperature. The insight provided herein can potentially help engineer application-oriented materials for several research and industrial sectors. Direct (13)C pulse magic angle spinning (MAS) nuclear magnetic resonance (NMR) confirmed the presence of epoxy, hydroxyl, ester and ketone carbonyl, tertiary alkyl fluorides, as well as graphitic sp(2)-hybridized carbon. Moreover, (19)F-(13)C cross-polarization MAS NMR with (1)H and (19)F decoupling confirmed the presence of secondary alkyl fluoride (CF2) groups in the fluorinated graphene oxide nanoribbon (FGONR) structures fluorinated above 50 °C. First-principles density functional theory calculations gained insight into the atomic arrangement of the most dominant chemical groups. The fluorinated GONRs present atomic fluorine percentages in the range of 6-35. Interestingly, the FGONRs synthesized up to 100 °C, with 6-19% of atomic fluorine, exhibit colloidal similar stability in aqueous environments when compared to GONRs. This colloidal stability is important because it is not common for materials with up to 19% fluorine to have a high degree of hydrophilicity.


Ethics Consultation Quality Assessment Tool: A Novel Method for Assessing the Quality of Ethics Case Consultations Based on Written Records.
Although ethics consultation is offered as a clinical service in most hospitals in the United States, few valid and practical tools are available to evaluate, ensure, and improve ethics consultation quality. The quality of ethics consultation is important because poor quality ethics consultation can result in ethically inappropriate outcomes for patients, other stakeholders, or the health care system. To promote accountability for the quality of ethics consultation, we developed the Ethics Consultation Quality Assessment Tool (ECQAT). ECQAT enables raters to assess the quality of ethics consultations based on the written record. Through rigorous development and preliminary testing, we identified key elements of a quality ethics consultation (ethics question, consultation-specific information, ethical analysis, and conclusions and/or recommendations), established scoring criteria, developed training guidelines, and designed a holistic assessment process. This article describes the development of the ECQAT, the resulting product, and recommended future testing and potential uses for the tool.


Production and characterization of monoclonal antibodies to human interleukin 2: strategy and tactics.
The unique hormonal characteristics of human interleukin 2 (IL 2), primarily the high affinity of the IL 2-receptor interaction, created several impediments to the generation of monoclonal antibodies to this lymphokine. Because normal cell sources produce only a few micrograms of IL 2 per liter, it was necessary to utilize high producer clones and subclones of a human T leukemia cell line to obtain immunogenic amounts of IL 2 protein. Moreover, assays that required antibody-mediated intervention of the high affinity IL 2-receptor binding were ineffectual in the identification of anti-IL 2-producing hybridomas, thus necessitating the development of immunoassays. Two of three initially derived antibodies detected by enzyme-linked immunoassay were found to react specifically with IL 2 as demonstrated by antibody concentration-dependent neutralization of IL 2 activity. The neutralization of cellular proliferation was specific for IL 2-reactive cells, coincided with an inhibition of IL 2 receptor binding, could be completely overcome by affinity-purified IL 2 and was species-specific; human and murine IL 2 were neutralized, whereas rat IL 2 activity remained unaffected. A third antibody, although much less effective in neutralizing IL 2 activity, bound to IL 2 more avidly and functioned as an efficient immunoabsorbent. IL 2 could be concentrated and purified by immunoabsorption from crude conditioned medium in a single step. The purified product, which retained biologic activity, was made up of a single protein (Mr = 15,500) as determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis, reversed-phase liquid chromatography, and amino-terminal amino acid sequence analysis. These results indicate that the distinctive biochemical and functional properties of individual lymphokines may well determine the efficiency with which antibodies may be elicited and detected. However, once produced, anti-lymphokines are uniquely suited for the exploration of the molecular and biologic properties of these immunoregulatory molecules.


Points-Based Reward Systems in Gamification Impact Children's Physical Activity Strategies and Psychological Needs.
Gamification is an increasingly popular form of health intervention but its efficacy remains elusive due to a lack of clarity in its conceptualization and operationalization. This study aimed to isolate and determine the direct causal effect of one of the most popular game elements used in gamified interventions, the points-based reward system, on physical activity (PA) in children. A 72-hour field study with children aged 9 to 13 ( N = 67) was conducted using a digital PA intervention featuring a virtual dog, with and without a points-based reward system. PA was assessed with an activity monitor, and overall PA, three levels of PA intensity, and PA strategies during the 3-day intervention were measured. Guided by self-determination theory, the impact of the points-based reward system on children's basic psychological needs was also investigated. Results indicated that the points-based reward system briefly increased PA engagement but did not significantly affect overall PA over time. When given equal number of points regardless of intensity, children approached the PA intervention strategically by engaging in significantly more light intensity and significantly less vigorous intensity PA than children who did not receive points. Results also suggested that the points-based reward system might promote perceptions of relatedness with the virtual agent featured in the gamified intervention.


Elimination of the differential chemoresistance between the murine B-cell lymphoma LY-ar and LY-as cell lines after arsenic (As2O3) exposure via the overexpression of gsto1 (p28).
Arsenic, in the form of As(2)O(3), has gained therapeutic importance because it has been shown to be very effective clinically in the treatment of acute promyelocytic leukemia (APL). Via numerous pathways arsenic induces cellular alterations such as induction of apoptosis, inhibition of cellular proliferation, stimulation of differentiation, and inhibition of angiogenesis. Responses vary depending on cell type, dose and the form of arsenic. GSTO1, a member of the glutathione S-transferase superfamily omega, has recently been shown to be identical to the rate-limiting enzyme, monomethyl arsenous (MMA(V)) reductase which catalyzes methylarsonate (MMA(V)) to methylarsenous acid (MMA(III)) during arsenic biotransformation. In this study, we investigated whether arsenic trioxide (As(2)O(3)) induces apoptosis in both chemosensitive and chemoresistant cell lines that varied in their expression of p28 (gsto1), the mouse homolog of GSTO1. The cytotoxicity of arsenic in the gsto1- and bcl-2-expressing chemoresistant and radioresistant LY-ar mouse lymphoma cell line, was compared with that of the LY-ar's parental cell line, LY-as. LY-as cells are radiosensitive, apoptotically permissive, and do not express gsto1 or bcl-2. Cell survival, glutathione (GSH) levels, mitochondrial membrane potential, and stress-activated kinase status after arsenic treatment were examined in these cell lines. As(2)O(3) induced an equivalent dose- and time-dependent increase in apoptosis in these cell lines. Cellular survival, as measured after a 24-h exposure, was also the same in each cell line. Reduced GSH was modulated in a similar time- and dose-dependent manner. Apoptosis was preceded by loss of mitochondrial membrane potential that triggered caspase-mediated pathways associated with apoptosis. With a prolonged exposure of As(2)O(3), both cell lines showed decreased activation of ERK family members, ERK1, ERK2 and ERK5. As(2)O(3) enhanced the death signals in LY-ar cells through a decrease in GSH, loss of mitochondrial membrane potential, and abatement of survival signals. This effect is similar to that seen when LY-ar cells are treated with thiol-depleting agents or by the removal of methionine and cysteine (GSH precursor) from the growth medium. This response is also completely contrary to that seen for radiation, actinomycin D, VP-16 and other agents, where LY-ar cells do not succumb to apoptosis. The overexpression of gsto1 in normally chemoresistant and radioresistant LY-ar cells renders them vulnerable to the cytotoxic effects of As(2)O(3), despite the 30-fold overexpression of the survival factor bcl-2. Gsto1 and its human homolog, GSTO1, may serve as a marker for arsenic sensitivity, particularly in cells that are resistant to other chemotherapeutic agents.


Pacpaint: a histology-based deep learning model uncovers the extensive intratumor molecular heterogeneity of pancreatic adenocarcinoma.
Two tumor (Classical/Basal) and stroma (Inactive/active) subtypes of Pancreatic adenocarcinoma (PDAC) with prognostic and theragnostic implications have been described. These molecular subtypes were defined by RNAseq, a costly technique sensitive to sample quality and cellularity, not used in routine practice. To allow rapid PDAC molecular subtyping and study PDAC heterogeneity, we develop PACpAInt, a multi-step deep learning model. PACpAInt is trained on a multicentric cohort (n = 202) and validated on 4 independent cohorts including biopsies (surgical cohorts n = 148; 97; 126 / biopsy cohort n = 25), all with transcriptomic data (n = 598) to predict tumor tissue, tumor cells from stroma, and their transcriptomic molecular subtypes, either at the whole slide or tile level (112 µm squares). PACpAInt correctly predicts tumor subtypes at the whole slide level on surgical and biopsies specimens and independently predicts survival. PACpAInt highlights the presence of a minor aggressive Basal contingent that negatively impacts survival in 39% of RNA-defined classical cases. Tile-level analysis ( > 6 millions) redefines PDAC microheterogeneity showing codependencies in the distribution of tumor and stroma subtypes, and demonstrates that, in addition to the Classical and Basal tumors, there are Hybrid tumors that combine the latter subtypes, and Intermediate tumors that may represent a transition state during PDAC evolution.


Polymorphic tandem repeats within gene promoters act as modifiers of gene expression and DNA methylation in humans.
Despite representing an important source of genetic variation, tandem repeats (TRs) remain poorly studied due to technical difficulties. We hypothesized that TRs can operate as expression (eQTLs) and methylation (mQTLs) quantitative trait loci. To test this we analyzed the effect of variation at 4849 promoter-associated TRs, genotyped in 120 individuals, on neighboring gene expression and DNA methylation. Polymorphic promoter TRs were associated with increased variance in local gene expression and DNA methylation, suggesting functional consequences related to TR variation. We identified >100 TRs associated with expression/methylation levels of adjacent genes. These potential eQTL/mQTL TRs were enriched for overlaps with transcription factor binding and DNaseI hypersensitivity sites, providing a rationale for their effects. Moreover, we showed that most TR variants are poorly tagged by nearby single nucleotide polymorphisms (SNPs) markers, indicating that many functional TR variants are not effectively assayed by SNP-based approaches. Our study assigns biological significance to TR variations in the human genome, and suggests that a significant fraction of TR variations exert functional effects via alterations of local gene expression or epigenetics. We conclude that targeted studies that focus on genotyping TR variants are required to fully ascertain functional variation in the genome.


Transcranial Direct Current Stimulation Does Not Influence the Speed-Accuracy Tradeoff in Perceptual Decision-making: Evidence from Three Independent Studies.
In perceptual decision-making tasks, people balance the speed and accuracy with which they make their decisions by modulating a response threshold. Neuroimaging studies suggest that this speed-accuracy tradeoff is implemented in a corticobasal ganglia network that includes an important contribution from the pre-SMA. To test this hypothesis, we used anodal transcranial direct current stimulation (tDCS) to modulate neural activity in pre-SMA while participants performed a simple perceptual decision-making task. Participants viewed a pattern of moving dots and judged the direction of the global motion. In separate trials, they were cued to either respond quickly or accurately. We used the diffusion decision model to estimate the response threshold parameter, comparing conditions in which participants received sham or anodal tDCS. In three independent experiments, we failed to observe an influence of tDCS on the response threshold. Additional, exploratory analyses showed no influence of tDCS on the duration of nondecision processes or on the efficiency of information processing. Taken together, these findings provide a cautionary note, either concerning the causal role of pre-SMA in decision-making or on the utility of tDCS for modifying response caution in decision-making tasks.


A woman's history of vaginal orgasm is discernible from her walk.
Research has demonstrated the association between vaginal orgasm and better mental health. Some theories of psychotherapy assert a link between muscle blocks and disturbances of both character and sexual function. In Functional-Sexological therapy, one focus of treatment is amelioration of voluntary movement. The present study examines the association of general everyday body movement with history of vaginal orgasm. The objective was to determine if appropriately trained sexologists could infer women's history of vaginal orgasm from observing only their gait. Women with known histories of either vaginal orgasm or vaginal anorgasmia were videotaped walking on the street, and their orgasmic status was judged by sexologists blind to their history. The concordance between having had orgasms triggered by penile-vaginal intercourse (not orgasm from direct clitoral stimulation) and raters' inferences of vaginal orgasm history based on observation of the woman's walk was the main outcome measure. In the sample of healthy young Belgian women (half of whom were vaginally orgasmic), history of vaginal orgasm (triggered solely by penile-vaginal intercourse) was diagnosable at far better than chance level (81.25% correct, Fisher's Exact Test P < 0.05) by appropriately trained sexologists. Clitoral orgasm history was unrelated to both ratings and to vaginal orgasm history. Exploratory analyses suggest that greater pelvic and vertebral rotation and stride length might be characteristic of the gait of women who have experienced vaginal orgasm (r = 0.51, P < 0.05). The discerning observer may infer women's experience of vaginal orgasm from a gait that comprises fluidity, energy, sensuality, freedom, and absence of both flaccid and locked muscles. Results are discussed with regard to previous research on gait, the effect of the musculature on sexual function, the special nature of vaginal orgasm, and implications for sexual therapy.


Dietary Fibre May Mitigate Sarcopenia Risk: Findings from the NU-AGE Cohort of Older European Adults.
Sarcopenia is characterised by a progressive loss of skeletal muscle mass and physical function as well as related metabolic disturbances. While fibre-rich diets can influence metabolic health outcomes, the impact on skeletal muscle mass and function is yet to be determined, and the moderating effects by physical activity (PA) need to be considered. The aim of the present study was to examine links between fibre intake, skeletal muscle mass and physical function in a cohort of older adults from the NU-AGE study. In 981 older adults (71 ± 4 years, 58% female), physical function was assessed using the short-physical performance battery test and handgrip strength. Skeletal muscle mass index (SMI) was derived using dual-energy X-ray absorptiometry (DXA). Dietary fibre intake (FI) was assessed by 7-day food record and PA was objectively determined by accelerometery. General linear models accounting for covariates including PA level, protein intake and metabolic syndrome (MetS) were used. Women above the median FI had significantly higher SMI compared to those below, which remained in fully adjusted models (24.7 ± 0.2% vs. 24.2 ± 0.1%, p = 0.011, η2p = 0.012). In men, the same association was only evident in those without MetS (above median FI: 32.4 ± 0.3% vs. below median FI: 31.3 ± 0.3%, p = 0.005, η2p = 0.035). There was no significant impact of FI on physical function outcomes. The findings from this study suggest a beneficial impact of FI on skeletal muscle mass in older adults. Importantly, this impact is independent of adherence to guidelines for protein intake and PA, which further strengthens the potential role of dietary fibre in preventing sarcopenia. Further experimental work is warranted in order to elucidate the mechanisms underpinning the action of dietary fibre on the regulation of muscle mass.


Human Babesiosis Caused by Babesia duncani Has Widespread Distribution across Canada.
Human babesiosis caused by Babesia duncani is an emerging infectious disease in Canada. This malaria-like illness is brought about by a protozoan parasite infecting red blood cells. Currently, controversy surrounds which tick species are vectors of B. duncani. Since the availability of a serological or molecular test in Canada for B. duncani has been limited, we conducted a seven-year surveillance study (2011⁻2017) to ascertain the occurrence and geographic distribution of B. duncani infection country-wide. Surveillance case data for human B. duncani infections were collected by contacting physicians and naturopathic physicians in the United States and Canada who specialize in tick-borne diseases. During the seven-year period, 1119 cases were identified. The presence of B. duncani infections was widespread across Canada, with the highest occurrence in the Pacific coast region. Patients with human babesiosis may be asymptomatic, but as this parasitemia progresses, symptoms range from mild to fatal. Donors of blood, plasma, living tissues, and organs may unknowingly be infected with this piroplasm and are contributing to the spread of this zoonosis. Our data show that greater awareness of human babesiosis is needed in Canada, and the imminent threat to the security of the Canadian blood supply warrants further investigation. Based on our epidemiological findings, human babesiosis should be a nationally notifiable disease in Canada. Whenever a patient has a tick bite, health practitioners must watch for B. duncani infections, and include human babesiosis in their differential diagnosis.


Radical anterior segment surgery for epithelial invasion of the anterior chamber: report of three cases.
Three patients who developed epithelial invasion of the anterior chamber were treated by radical anterior segment surgery. Two adults had typical epithelial downgrowth of the anterior chamber, while the third patient, an 8-year-old child, developed large serous cysts following evacuation of a traumatic hyphema. In all three patients, the invading epithelium involved the iris, cornea, and angle, while the two adults had epithelium on the vitreous face as well. The operation consisted of an en bloc excision of cornea and sclera with contiguous iris, ciliary body, and vitreous when necessary. A free-hand corneoscleral graft was fashioned and sewn into the bed using interrupted 9-0 nylon sutures on the scleral side and continuous 10-0 nylon sutures on the corneal side. The patients all developed transitory glaucoma in the early post-operative period. The glaucoma was controlled with acetazolamide. A mild anterior uveitis usually was present for several months and was suppressed with topical applications of corticosteroids. Histopathologic study of the excised tissue showed complete removal of the epithelium.


Apoptotic cell death dynamics of HL60 cells studied using a microfluidic cell trap device.
This paper presents the design, fabrication and first results of a microfluidic cell trap device for analysis of apoptosis. The microfluidic silicon-glass chip enables the immobilization of cells and real-time monitoring of the apoptotic process. Induction of apoptosis, either electric field mediated or chemically induced with tumour necrosis factor (TNF-alpha), in combination with cycloheximide (CHX), was addressed. Exposure of cells to the appropriate fluorescent dyes, FLICA and PI, allows one to discriminate between viable, apoptotic and necrotic cells. The results showed that the onset of apoptosis and the transitions during the course of the cell death cascade were followed in chemically induced apoptotic HL60 cells. For the case of electric field mediated cell death, the distinction between apoptotic and necrotic stage was not clear. This paper presents the first results to analyse programmed cell death dynamics using this apoptosis chip and a first step towards an integrated apoptosis chip for high-throughput drug screening on a single cellular level.


Demonstration of antihistamine properties with AST-1: a bioactive extract from garden slugs (Diplosolenodes occidentalis).
Parched and ground whole garden slugs are claimed in rural Jamaican folklore practices to have useful effects in the treatment of bronchial asthma. Since this claim may be associated with respiratory dysfunction due to histamine from allergic sensitization, the authors investigated the effects of a semi-pure alcoholic extract (AST-1) on histamine-induced contraction of the guinea pig in vitro tracheal muscle preparation and cutaneous allergic responses in ovalbumin sensitized guinea pigs. Chemical analysis of AST-1 by column chromatography and thin layer chromatography indicated two compounds in the composition, but the molecular structures were not determined Pharmacological evaluation of AST-1 produced a concentration-dependent inhibition of histamine-induced contraction of the guinea pig tracheal muscle preparation. AST-1 also inhibited contraction of the tracheal muscle produced by selective H1 receptor stimulation with HTMT dimaleate. H2 receptors were not involved, as indicated by the absence of contraction with dimaprit hydrochloride, a selective H2 agonist. Also, in ovalbumin sensitized guinea pigs, AST-1 and diphenhydramine, a selective H1 antagonist, inhibited the cutaneous responses due to intradermal injection of histamine and ovalbumin. These results suggest that AST-1 has H1 anti-histamine properties which can inhibit histamine-induced tracheobronchial muscle contraction and cutaneous responses due to allergy.


Intervention Packages for Early Visceral Leishmaniasis Case Detection and Sandfly Control in Bangladesh: A Comparative Analysis.
We compared the efficacy of three intervention packages for active case detection (ACD) of visceral leishmaniasis (VL)/post-kala-azar dermal leishmaniasis (PKDL) combined with sandfly control around an index case. The packages were 1) no kala-azar transmission activity involving indoor residual spraying (IRS) with deltamethrin, peri-domestic deployment of larvicide with temephos, and house-to-house search for cases; 2) fever camp (FC) plus durable wall lining (DWL) with deltamethrin; and 3) FC plus insecticide (deltamethrin) impregnated bed-nets (ITN) around an index case. Fever camp includes 1-day campaign at the village level to screen and diagnose VL, PKDL, leprosy, malaria, and tuberculosis among residents with chronic fever or skin disease. Efficacy was measured through yield of new cases, vector density reduction, and mortality at 1, 3, 6, 9, and 12 months following intervention. Fever camp + DWL was the most efficacious intervention package with 0.5 case detected per intervention, 79% reduction in vector density (incidence rate ratio [IRR] = 0.21, P = 0.010), and 95.1% (95% confidence interval: 93.4%, 96.8%) sandfly mortality at 12 months. No kala-azar transmission activity was efficacious for vector control (74% vector reduction, IRR = 0.26, P < 0.0001 at 9 months; and 84% sandfly mortality at 3 months), but not for case detection (0 case per intervention). Fever camp + ITN was efficacious in detection of VL/PKDL cases (0.43 case per intervention), but its efficacy for vector control was inconsistent. We recommend index case-based FC for ACD combined with DWL or IRS plus larvicide for sandfly control during the consolidation and maintenance phases of the VL elimination program of the Indian subcontinent.


Survival and Competitiveness of Bradyrhizobium japonicum Strains 20 Years after Introduction into Field Locations in Poland.
It was previously demonstrated that there are no indigenous strains of Bradyrhizobium japonicum forming nitrogen-fixing root nodule symbioses with soybean plants in arable field soils in Poland. However, bacteria currently classified within this species are present (together with Bradyrhizobium canariense) as indigenous populations of strains specific for nodulation of legumes in the Genisteae tribe. These rhizobia, infecting legumes such as lupins, are well established in Polish soils. The studies described here were based on soybean nodulation field experiments, established at the Poznań University of Life Sciences Experiment Station in Gorzyń, Poland, and initiated in the spring of 1994. Long-term research was then conducted in order to study the relation between B. japonicum USDA 110 and USDA 123, introduced together into the same location, where no soybean rhizobia were earlier detected, and nodulation and competitive success were followed over time. Here we report the extra-long-term saprophytic survival of B. japonicum strains nodulating soybeans that were introduced as inoculants 20 years earlier and where soybeans were not grown for the next 17 years. The strains remained viable and symbiotically competent, and molecular and immunochemical methods showed that the strains were undistinguishable from the original inoculum strains USDA 110 and USDA 123. We also show that the strains had balanced numbers and their mobility in soil was low. To our knowledge, this is the first report showing the extra-long-term persistence of soybean-nodulating strains introduced into Polish soils and the first analyzing the long-term competitive relations of USDA 110 and USDA 123 after the two strains, neither of which was native, were introduced into the environment almost 2 decades ago.


Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein.
Leukotrienes are proinflammatory products of arachidonic acid oxidation by 5-lipoxygenase that have been shown to be involved in respiratory and cardiovascular diseases. The integral membrane protein FLAP is essential for leukotriene biosynthesis. We describe the x-ray crystal structures of human FLAP in complex with two leukotriene biosynthesis inhibitors at 4.0 and 4.2 angstrom resolution, respectively. The structures show that inhibitors bind in membrane-embedded pockets of FLAP, which suggests how these inhibitors prevent arachidonic acid from binding to FLAP and subsequently being transferred to 5-lipoxygenase, thereby preventing leukotriene biosynthesis. This structural information provides a platform for the development of therapeutics for respiratory and cardiovascular diseases.


Direct and cytokine-mediated activation of protein kinase C induces human immunodeficiency virus expression in chronically infected promonocytic cells.
The chronically infected promonocytic clone U1 expresses low-to-undetectable constitutive levels of human immunodeficiency virus (HIV). Virus replication in these cells can be increased up to 25-fold by phorbol esters (phorbol-12-myristate-13-acetate), recombinant cytokines such as tumor necrosis factor-alpha, and cytokine-enriched mononuclear cell supernatants. We have tested specific activators of protein kinases (PK) and PK inhibitors (isoquinolinesulfonamide derivatives), as well as calcium-mobilizing agents, for their effect on constitutive and induced virus expression in U1 cells. Virus expression was measured by reverse transcriptase, Western blot, and nuclear run-on analysis. Activation of PKC by 1-oleyl,2-acetylglycerol, a synthetic analog of the natural ligand 1,2-diacylglycerol, and bryostatin 1 (a recently described specific PKC activator) resulted in a two- to eightfold increase in virus production. In contrast, activators of cyclic-nucleotide-dependent PKs were not effective in inducing virus expression. PK inhibitors were tested for their effect on HIV upregulation by cytokines and other inducing agents. The isoquinolinesulfonamide derivative H7, a potent inhibitor of PKC activation, effectively blocked (70 to 90%) HIV induction by cytokines and phorbol-12-myristate-13-acetate. The derivative HA1004, which is more selective for cyclic-nucleotide-dependent kinases, did not suppress viral induction. In addition, increases in intracellular calcium levels dramatically enhanced HIV production induced by both specific PKC activators and cytokines. These results indicate that activation of PKC is a common pathway involved in the upregulation of HIV expression in chronically infected cells stimulated by cytokines and other inducing agents.


Changes in Ocean Heat, Carbon Content, and Ventilation: A Review of the First Decade of GO-SHIP Global Repeat Hydrography.
Global ship-based programs, with highly accurate, full water column physical and biogeochemical observations repeated decadally since the 1970s, provide a crucial resource for documenting ocean change. The ocean, a central component of Earth's climate system, is taking up most of Earth's excess anthropogenic heat, with about 19% of this excess in the abyssal ocean beneath 2,000 m, dominated by Southern Ocean warming. The ocean also has taken up about 27% of anthropogenic carbon, resulting in acidification of the upper ocean. Increased stratification has resulted in a decline in oxygen and increase in nutrients in the Northern Hemisphere thermocline and an expansion of tropical oxygen minimum zones. Southern Hemisphere thermocline oxygen increased in the 2000s owing to stronger wind forcing and ventilation. The most recent decade of global hydrography has mapped dissolved organic carbon, a large, bioactive reservoir, for the first time and quantified its contribution to export production (∼20%) and deep-ocean oxygen utilization. Ship-based measurements also show that vertical diffusivity increases from a minimum in the thermocline to a maximum within the bottom 1,500 m, shifting our physical paradigm of the ocean's overturning circulation.


Are early growth and nutrition related to bone health in adolescence? The Copenhagen Cohort Study of infant nutrition and growth.
It is generally accepted that peak bone mass affects later fracture risk in the elderly. The extent to which early nutrition and growth can program later bone health has been examined in only a few studies. In the Copenhagen Cohort Study we showed that breastfed infants had significantly higher serum (s)-osteocalcin concentration than did formula-fed infants. We investigated whether early nutrition and early growth are associated with later bone mass in adolescence. Participants were examined at birth; at ages 2, 6, and 9 mo (n = 143); and at age 17 y (n = 109) with anthropometric and s-osteocalcin measures and whole-body dual-energy X-ray absorptiometry (DXA) scanning (age 17 y only). Total body (T) and lumbar spine (LS) DXA values were used. The duration of exclusive breastfeeding was positively correlated with the sex-adjusted LS bone mineral content (BMC), LS bone area (BA), and LS bone mineral density (BMD) (all P < 0.03) and with size-adjusted LS-BMC (P = 0.075) at 17 y of age. s-Osteocalcin at 6 mo was positively correlated with sex-adjusted LS-BMC and LS-BMD (both P < 0.04) and with size-adjusted LS-BMC (P = 0.047) at 17 y of age. Weight and length at 9 mo and increase in weight and length during the first 9 mo of life were positively correlated with sex-adjusted T-BMC and T-BA at age 17 y (all P < 0.04). Early body size and growth in infancy are related to bone mass in late adolescence. Furthermore, the duration of exclusive breastfeeding and the markers of bone turnover at 6 mo seem to be positively related to LS bone mass at age 17 y.


Muscle-derived hematopoietic stem cells are hematopoietic in origin.
It has recently been shown that mononuclear cells from murine skeletal muscle contain the potential to repopulate all major peripheral blood lineages in lethally irradiated mice, but the origin of this activity is unknown. We have fractionated muscle cells on the basis of hematopoietic markers to show that the active population exclusively expresses the hematopoietic stem cell antigens Sca-1 and CD45. Muscle cells obtained from 6- to 8-week-old C57BL/6-CD45.1 mice and enriched for cells expressing Sca-1 and CD45 were able to generate hematopoietic but not myogenic colonies in vitro and repopulated multiple hematopoietic lineages of lethally irradiated C57BL/6-CD45.2 mice. These data show that muscle-derived hematopoietic stem cells are likely derived from the hematopoietic system and are a result not of transdifferentiation of myogenic stem cells but instead of the presence of substantial numbers of hematopoietic stem cells in the muscle. Although CD45-negative cells were highly myogenic in vitro and in vivo, CD45-positive muscle-derived cells displayed only very limited myogenic activity and only in vivo.


The effect of smoking on outcomes following primary total hip and knee arthroplasty: a population-based cohort study of 117,024 patients.
Background and purpose - Smoking is a modifiable risk factor that may adversely affect postoperative outcomes. Healthcare providers are increasingly denying smokers access to total hip and knee arthroplasty (THA and TKA) until they stop smoking. Evidence supporting this is unclear. We assessed the effect of smoking on outcomes following arthroplasty.Patients and methods - We identified THAs and TKAs from the Clinical Practice Research Datalink, which were linked with datasets from Hospital Episode Statistics and the Office for National Statistics to identify outcomes. The effect of smoking on postoperative outcomes (complications, medications, revision, mortality, patient-reported outcome measures [PROMs]) was assessed using adjusted regression models.Results - We studied 60,812 THAs and 56,212 TKAs (11% smokers, 33% ex-smokers, 57% non-smokers). Following THA, smokers had an increased risk of lower respiratory tract infection (LRTI) and myocardial infarction compared with non-smokers and ex-smokers. Following TKA, smokers had an increased risk of LRTI compared with non-smokers. Compared with non-smokers (THA relative risk ratio [RRR] = 0.65; 95% CI = 0.61-0.69; TKA RRR = 0.82; CI = 0.78-0.86) and ex-smokers (THR RRR = 0.90; CI = 0.84-0.95), smokers had increased opioid usage 1-year postoperatively. Similar patterns were observed for weak opioids, paracetamol, and gabapentinoids. 1-year mortality rates were higher in smokers compared with non-smokers (THA hazard ratio [HR] = 0.37, CI = 0.29-0.49; TKA HR = 0.52, CI = 0.34-0.81) and ex-smokers (THA HR = 0.53, CI = 0.40-0.70). Long-term revision rates were not increased in smokers. Smokers had improvement in PROMs compared with preoperatively, with no clinically important difference in postoperative PROMs between smokers, non-smokers, and ex-smokers.Interpretation - Smoking is associated with more medical complications, higher analgesia usage, and increased mortality following arthroplasty. Most adverse outcomes were reduced in ex-smokers, therefore smoking cessation should be encouraged before arthroplasty.


Pharmacology of a constitutively active muscarinic receptor generated by random mutagenesis.
We have isolated a mutant m5 muscarinic receptor that mediates robust functional responses in the absence of agonists. This constitutively active receptor was isolated from a library of receptors containing randomly introduced mutations in the sixth transmembrane domain and contains the substitutions serine 465 for tyrosine and threonine 486 for proline. Although these individual residues are not conserved in other G-protein-coupled receptors, they are predicted to be at the junction between the sixth transmembrane domain and the last extracellular loop. The mutant receptor (CAm5) was subjected to detailed pharmacological analysis. All of the antagonists tested (atropine, quinuclidinyl benzilate, N-methyl scopolamine, 4-diphenylacetoxy-N-methylpiperidine and pirenzepine) fully suppressed both the constitutive and agonist-induced activities of CAm5 revealing that these ligands are negative antagonists (inverse agonists). The potency of these ligands was similar at the mutant and wild-type receptors, suggesting that the antagonist binding site of this receptor is unchanged. The mutant had increased sensitivity to the agonists carbachol, arecoline, and McN-A-343 as measured both by functional response and by radioligand binding. These effects are explained and predicted by a model in which the primary effect of the mutations is to alter a spontaneous equilibrium existing between the active and inactive states of the receptor.


Involvement of residues of the 29 terminal protein intermediate and priming domains in the formation of a stable and functional heterodimer with the replicative DNA polymerase.
Bacteriophage Φ29 genome consists of a linear double-stranded DNA with a terminal protein (TP) covalently linked to each 5' end (TP-DNA) that together with a specific sequence constitutes the replication origins. To initiate replication, the DNA polymerase forms a heterodimer with a free TP that recognizes the origins and initiates replication using as primer the hydroxyl group of TP residue Ser232. The 3D structure of the DNA polymerase/TP heterodimer allowed the identification of TP residues that could be responsible for interaction with the DNA polymerase. Here, we examined the role of TP residues Arg158, Arg169, Glu191, Asp198, Tyr250, Glu252, Gln253 and Arg256 by in vitro analyses of mutant derivatives. The results showed that substitution of these residues had an effect on either the stability of the TP/DNA polymerase complex (R158A) or in the functional interaction of the TP at the polymerization active site (R169A, E191A, Y250A, E252A, Q253A and R256A), affecting the first steps of Φ29 TP-DNA replication. These results allow us to propose a role for these residues in the maintenance of the equilibrium between TP-priming domain stabilization and its gradual exit from the polymerization active site of the DNA polymerase as new DNA is being synthesized.


Presence of Calcium-Like Tissue Composition in Carotid Plaque is Indicative of Significant Coronary Artery Disease in High-Risk Patients.
Grayscale pixel ranges from ultrasound images, indicating differences in atherosclerotic plaque echogenicity, have been shown to represent different tissue types. Our objective was to determine whether carotid plaque composition was correlated with severity of coronary artery disease (CAD) and risk of cardiovascular (CV) events. A focused carotid ultrasound was performed in 522 participants who had recently undergone coronary angiography. In 468 participants found to have atherosclerotic plaque in at least one carotid artery, plaque composition was assessed for tissue-like types: grayscale ranges 0-4 (blood), 8-26 (fat), 41-76 (muscle), 112-196 (fibrous), and 211-255 (calcium). Logistic regression was used to evaluate correlations with significant CAD (≥50% stenosis). Cox proportional hazards models were used to determine risk for 5-year CV outcomes. Carotid plaque percent fibrous and percent calcium increased with severity of CAD (P < .02). When adjusted for age, sex, body mass index, estimated glomerular filtration rate, and traditional cardiac risk factors, maximum plaque height and percent calcium remained independent contributors of significant CAD (P < .01). Plaque height (≥2.74 mm), percent calcium (≥0.11%), and percent fat (11.6%) were associated with increased risk for CV events. Combined plaque height and percent fat gave the highest risk for events (risk ratio = 2.02; CI, 1.41-2.94, P = .0002). Carotid plaque fibrous and calcium-like tissues are correlated with increased CAD. Increased percent fat or percent calcium is associated with risk for CV events; however, a combination of plaque height, percent calcium, and/or percent fat increases risk for CV events. Incorporating ultrasound carotid plaque composition into screening practice may improve patient risk stratification for heart disease.


Analysis of clonality of atypical cutaneous lymphoid infiltrates associated with drug therapy by PCR/DGGE.
Atypical lymphocytic infiltrates that mimic cutaneous lymphoma (ie, pseudolymphoma) are often observed in skin biopsy specimens from patients with altered immune function. The latter may reflect systemic immune dysregulatory states such as collagen vascular disease or human immunodeficiency virus infection. Among the iatrogenic causes are drug therapy with agents that abrogate lymphocyte function. These drugs encompass the anticonvulsants, antidepressants, phenothiazines, calcium channel blockers, and angiotensin-converting enzyme inhibitors. The appellation of lymphomatoid hypersensitivity reaction has been applied to cases of drug-associated pseudolymphoma. Pathologically and clinically, the distinction of such cases from cutaneous lymphoma is difficult. We employed the polymerase chain reaction (PCR) on archival material of proven drug-associated lymphomatoid hypersensitivity reactions both to explore its utility as an adjunct in diagnosis and to investigate the genotypic aberrations induced by drug therapy. Formalin-fixed, paraffin-embedded biopsy specimens from seven cutaneous T-cell lymphomas (CTCL), one nodal T-cell lymphoma, two cutaneous B-cell lymphomas, three typical hypersensitivity reactions, one tonsil, and 14 lymphomatoid hypersensitivity reactions were studied. Control cases for which DNA derived from fresh tissue was used include the Jurkat T-cell tumor line, placenta, one nodal B-cell lymphoma, and one case of reactive lymph node hyperplasia. DNA was obtained and purified by standard methods, then amplified with oligonucleotide primers specific for the T-cell receptor gamma locus and the immunoglobulin heavy chain genes. T-cell amplicons were analyzed by denaturing gradient gel electrophoresis (DGGE) and B-cell amplicons by either nondenaturing polyacrylamide or agarose gel electrophoresis. The nodal and Jurkat T-cell lymphomas, six of seven CTCL, one cutaneous B-cell lymphoma, and 2 of 14 lymphomatoid hypersensitivity reactions showed dominant ("monoclonal") T-cell gene rearrangement patterns, and the remainder of cases were polyclonal. A causal relationship between drug therapy and skin eruption was ascertained in the two patients showing T-cell rearrangements, and both experienced complete and sustained lesional resolution on discontinuation of the implicated drug. The only immunoglobulin heavy chain gene rearrangements detected by PCR were in two of the three B-cell lymphomas. We conclude that PCR/DGGE is a powerful method for assaying T-cell clonality in archival tissue and can aid in the discrimination of reactive from malignant cutaneous infiltrates with appropriate clinicopathologic correlation. Recognition that a monoclonal TCRgamma rearrangement can be observed in cases of drug-associated lymphomatoid hypersensitivity may help in avoiding a misdiagnosis of malignant lymphoma.


Changing essay writing in undergraduate nursing education through action research: a Swedish example.
This article describes the development of literature-based models for bachelor degree essays in Swedish undergraduate nursing education. Students' experiences in a course with literature-based models for bachelor degree essays are discussed. The ever-growing body of nursing research and specialized and complex health care practices make great demands on nursing education in terms of preparing students to be both skilled practitioners and users of research. Teaching to help students understand evidence-based practice is a challenge for nursing education. Action research was used to generate knowledge of and practical solutions to problems in everyday locations. Six models were developed: concept analysis, contributing to evidence-based nursing by means of quantitative research, contributing to evidence-based nursing by means of qualitative research, discourse analysis, analysis of narratives, and literature review. Action research was found to be a relevant procedure for changing ways of working with literature-based, bachelor degree essays. The models that were developed increased students' confidence in writing essays and preparedness for the nursing role.


Incidence of human papillomavirus type 33 in premalignant and malignant skin lesions from organ transplant recipients.
Human papillomavirus (HPV) type 33 belongs to potentially oncogenic types in genital cancers, but its infection corresponds to an intermediate risk for progression towards malignancy. We studied by in situ hybridization with biotinylated probes the incidence of HPV 33 infection in a series of 106 skin lesions and 12 mucosal lesions from heart and renal transplant recipients, 34 skin lesions and 17 mucosal lesions from normal population. We have shown that skin lesions from both populations could harbor HPV 33. In transplant recipients, HPV 33 was identified in 12/77 premalignant and malignant lesions and one oral leukoplakia; in the normal population, HPV 33 was detected in 2/13 warts and 2/15 mucosal lesions. The analysis of in sial hybridization signal pattern of the 17 HPV 33 positive samples suggests that a strong viral DNA signal was uniformly distributed in the nuclei of positive cell foci in 11 cases and punctate signals were seen in the nuclei of dispersed cells of 6 skin biopsies. The significance of the presence of HPV 33 DNA in skin lesions is not clear; the hybridization signal pattern may be important, mainly in premalignant actinic keratodses of organ transplant recipients although other factors are most likely involved to change the epithelial environment.


RD Lawrence Lecture 2009. Old genes, new tricks: learning about blood glucose regulation from naturally occurring genetic variation in humans.
The study of rare monogenic forms of diabetes and pancreatic B-cell dysfunction provides an unrivalled opportunity to link a specific change in gene function with precise cellular consequences and clinical phenotype in humans. Over the past 20 years there has been considerable success in determining the genetic aetiology of a number of rare monogenic forms of diabetes, which has had a significant impact on both our understanding of normal physiology and on translational medicine. The impact of these discoveries has been substantial, with insights into both developmental biology and normal physiology. There are clear examples where determining the genetic aetiology for individuals with rare monogenic subtypes of diabetes has led to improved treatment. Although formerly in the shadow of the monogenic diabetes field, over the past 3 years there has been staggering progress in our understanding of the genetic basis of Type 2 diabetes. This has been largely as a result of genome-wide association studies and has seen the list of 'diabetes susceptibility genes' increase from three to close to 20. There is now encouraging evidence to support a potential role for genetics in determining the response of individuals with Type 2 diabetes to different therapeutic options. One of the challenges that lies ahead is determining how the non-coding genetic variants exert their pathogenicity. It is possible that parallels can be drawn from functional work on rare regulatory mutations causing monogenic forms of diabetes. However, it is more likely that comprehensive approaches will be necessary.


[Brain development and plasticity].
Neurodevelopmental disorders are associated to functional anomalies of the brain that become manifest early on in life. Traditionally, they have been related almost exclusively to the appearance of intellectual disability and delayed psychomotor development. The causes of these disorders have been partially described, and include anomalies due to genetic causes (Down syndrome, fragile X syndrome, etc.), exposure to toxic factors during pregnancy (foetal alcohol syndrome), infections (cytomegalovirus, toxoplasmosis, etc.) or other alterations, including a status of great immaturity at birth (very preterm). Epidemiological data based on a better knowledge of the diseases affecting the central nervous system suggest that some mental disorders, which appear in adolescence or early adulthood, also have their origin in anomalies in brain development. This review aims to offer an overview of brain development. Some of the cellular and molecular processes that may account for the similarities and differences in the phenotypes that generate alterations affecting normal development are also analysed. The study is conducted with a view to clearly identifying processes that are susceptible to modification by means of therapeutic intervention consisting in an early care programme.


Core-Shell Au@Metal-Oxide Nanoparticle Electrocatalysts for Enhanced Oxygen Evolution.
Enhanced catalysis for electrochemical oxygen evolution is essential for the efficacy of many renewable energy technologies, including water electrolyzers and metal-air batteries. Recently, Au supports have been shown to enhance the activity of many 3d transition metal-oxide thin films for the oxygen evolution reaction (OER) in alkaline media. Herein, we translate the beneficial impact of Au supports to high surface area, device-ready core-shell nanoparticles consisting of a Au-core and a metal-oxide shell (Au@MxOy where M = Ni, Co, Fe, and CoFe). Through a systematic evaluation, we establish trends in performance and illustrate the universal activity enhancement when employing the Au-core in the 3d transition metal-oxide nanoparticles. The highest activity particles, Au@CoFeOx, demonstrate an overpotential of 328 ± 3 mV over a 2 h stability test at 10 mA cm-2, illustrating that strategically coupling Au support and mixed metal-oxide effects in a core-shell nanoparticle morphology is a promising avenue to achieve device-ready, high-performance OER catalysts.


Clinical, genetic and pathological heterogeneity of frontotemporal dementia: a review.
Frontotemporal dementia (FTD) is the second most common young-onset dementia and is clinically characterised by progressive behavioural change, executive dysfunction and language difficulties. Three clinical syndromes, behavioural variant FTD, semantic dementia and progressive non-fluent aphasia, form part of a clinicopathological spectrum named frontotemporal lobar degeneration (FTLD). The classical neuropsychological phenotype of FTD has been enriched by tests exploring Theory of Mind, social cognition and emotional processing. Imaging studies have detailed the patterns of atrophy associated with different clinical and pathological subtypes. These patterns offer some diagnostic utility, while measures of progression of atrophy may be of use in future trials. 30-50% of FTD is familial, and mutations in two genes, microtubule associated protein tau and Progranulin (GRN), account for about half of these cases. Rare defects in VCP, CHMP2B, TARDP and FUS genes have been found in a small number of families. Linkage to chromosome 9p13.2-21.3 has been established in familial FTD with motor neuron disease, although the causative gene is yet to be identified. Recent developments in the immunohistochemistry of FTLD, and also in amyotrophic lateral sclerosis (ALS), have led to a new pathological nomenclature. The two major groups are those with tau-positive inclusions (FTLD-tau) and those with ubiquitin-positive and TAR DNA-binding protein of 43 kDa (TDP-43) positive inclusions (FTLD-TDP). Recently, a new protein involved in familial ALS, fused in sarcoma (FUS), has been found in FTLD patients with ubiquitin-positive and TDP-43-negative inclusions. In this review, the authors discuss recent clinical, neuropsychological, imaging, genetic and pathological developments that have changed our understanding of FTD, its classification and criteria. The potential to establish an early diagnosis, predict underlying pathology during life and quantify disease progression will all be required for disease-specific therapeutic trials in the future.


Aeromonas-Acanthamoeba interaction and early shift to a viable but nonculturable state of Aeromonas by Acanthamoeba.
To investigate the hypothesis that amoeba may comprise a significant environmental reservoir for Aeromonas, Acanthamoeba-Aeromonas interaction experiments were performed. Acanthamoeba were grown in monoculture and co-cultures with three different species of Aeromonas. Survival, invasion and viable but nonculturable state experiments were performed. We showed that at a low initial bacterial cell density, growth of Aeromonas spp. was inhibited by Acanthamoeba castellanii, while A. castellanii growth was unaffected. In contrast, a high initial bacterial cell density, Aeromonas hydrophila AEW44 and Aeromonas veronii biovar sobria AEW104 suppressed the growth of A. castellanii. Fluorescent and phase-contrast microscopic observations of GFP tagged Aer. hydrophila AEW44 demonstrated that the bacterial cells aggregated on A. castellanii cells after 15 min of incubation and internalized. Aeromonas hydrophila AEW44 cells were found to be actively moving. Interestingly, Aer. hydrophila AEW44 cells shifted more rapidly to a viable but nonculturable form when co-cultured with A. castellanii than in monoculture. We demonstrated that Aeromonas spp. are able to interact with and to infect the protozoan A. castellanii under laboratory conditions. Free-living amoeba might play a role as reservoir for Aeromonas, and thus may increase the transmission of Aeromonas by acting as a vehicle.


Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4⁺ T cell tolerance.
Dendritic cells (DCs), and more recently lymph node stromal cells (LNSCs), have been described to tolerize self-reactive CD8(+) T cells in LNs. Although LNSCs express MHCII, it is unknown whether they can also impact CD4(+) T cell functions. We show that the promoter IV (pIV) of class II transactivator (CIITA), the master regulator of MHCII expression, controls endogenous MHCII expression by LNSCs. Unexpectedly, LNSCs also acquire peptide-MHCII complexes from DCs and induce CD4(+) T cell dysfunction by presenting transferred complexes to naive CD4(+) T cells and preventing their proliferation and survival. Our data reveals a novel, alternative mechanism where LN-resident stromal cells tolerize CD4(+) T cells through the presentation of self-antigens via transferred peptide-MHCII complexes of DC origin.


Head start participation and school readiness: evidence from the Early Childhood Longitudinal Study-Birth Cohort.
Using data from the Early Childhood Longitudinal Study-Birth Cohort (n ≈ 6,950), a nationally representative sample of children born in 2001, we examined school readiness (academic skills and socioemotional well-being) at kindergarten entry for children who attended Head Start compared with those who experienced other types of child care (prekindergarten, other center-based care, other nonparental care, or parental care). Using propensity score matching methods and ordinary least squares regressions with rich controls, we found that Head Start participants had higher early reading and math scores than children in other nonparental care or parental care but also higher levels of conduct problems than those in parental care. Head Start participants had lower early reading scores compared with children in prekindergarten and had no differences in any outcomes compared with children in other center-based care. Head Start benefits were more pronounced for children who had low initial cognitive ability or parents with low levels of education or who attended Head Start for more than 20 hr per week.


A unified framework integrating parent-of-origin effects for association study.
Genetic imprinting is the most well-known cause for parent-of-origin effect (POE) whereby a gene is differentially expressed depending on the parental origin of the same alleles. Genetic imprinting is related to several human disorders, including diabetes, breast cancer, alcoholism, and obesity. This phenomenon has been shown to be important for normal embryonic development in mammals. Traditional association approaches ignore this important genetic phenomenon. In this study, we generalize the natural and orthogonal interactions (NOIA) framework to allow for estimation of both main allelic effects and POEs. We develop a statistical (Stat-POE) model that has the orthogonal estimates of parameters including the POEs. We conducted simulation studies for both quantitative and qualitative traits to evaluate the performance of the statistical and functional models with different levels of POEs. Our results showed that the newly proposed Stat-POE model, which ensures orthogonality of variance components if Hardy-Weinberg Equilibrium (HWE) or equal minor and major allele frequencies is satisfied, had greater power for detecting the main allelic additive effect than a Func-POE model, which codes according to allelic substitutions, for both quantitative and qualitative traits. The power for detecting the POE was the same for the Stat-POE and Func-POE models under HWE for quantitative traits.