Post-cranial skeletons of hypothyroid cretins show a similar anatomical mosaic as Homo floresiensis.
Human remains, some as recent as 15 thousand years, from Liang Bua (LB) on the Indonesian island of Flores have been attributed to a new species, Homo floresiensis. The definition includes a mosaic of features, some like modern humans (hence derived: genus Homo), some like modern apes and australopithecines (hence primitive: not species sapiens), and some unique (hence new species: floresiensis). Conversely, because only modern humans (H. sapiens) are known in this region in the last 40 thousand years, these individuals have also been suggested to be genetic human dwarfs. Such dwarfs resemble small humans and do not show the mosaic combination of the most complete individuals, LB1 and LB6, so this idea has been largely dismissed. We have previously shown that some features of the cranium of hypothyroid cretins are like those of LB1. Here we examine cretin postcrania to see if they show anatomical mosaics like H. floresiensis. We find that hypothyroid cretins share at least 10 postcranial features with Homo floresiensis and unaffected humans not found in apes (or australopithecines when materials permit). They share with H. floresiensis, modern apes and australopithecines at least 11 postcranial features not found in unaffected humans. They share with H. floresiensis, at least 8 features not found in apes, australopithecines or unaffected humans. Sixteen features can be rendered metrically and multivariate analyses demonstrate that H. floresiensis co-locates with cretins, both being markedly separate from humans and chimpanzees (P<0.001: from analysis of similarity (ANOSIM) over all variables, ANOSIM, global R>0.999). We therefore conclude that LB1 and LB6, at least, are, most likely, endemic cretins from a population of unaffected Homo sapiens. This is consistent with recent hypothyroid endemic cretinism throughout Indonesia, including the nearby island of Bali.


Characterization of avian H5N1 influenza viruses from poultry in Hong Kong.
The transmission of avian H5N1 influenza viruses to 18 humans in Hong Kong in 1997 with six deaths established that avian influenza viruses can transmit to and cause lethal infection in humans. This report characterizes the antigenic and biological properties of the H5N1 influenza viruses isolated from chickens, ducks, and geese from farms and poultry markets in Hong Kong during 1997 and compares them with those of virus isolated from the index human case. Each of the H5N1 viruses from Hong Kong poultry markets that were tested were lethal in chickens, possessed polybasic amino acids at the carboxy-terminus of HA1, and by definition were highly pathogenic in poultry. The available nonpathogenic H5 influenza viruses and the pathogenic H5N1 virus from Hong Kong were analyzed with monoclonal antibodies prepared to A/chicken/Pennsylvania/1370/83 (H5N2). The analysis revealed limited antigenic drift in 15 years and established that monoclonal antibodies are useful reagents for identification and antigenic analysis of avian strains that may transmit to humans in the future. One of the monoclonal antibodies permitted separation of the H5N1 influenza viruses from poultry into two groups that correlated with the presence or absence of a carbohydrate at residue 158 adjacent to the receptor binding site on HA. The H5N1 viruses examined replicated in geese, pigs, rats, and mice, but to only a very limited extent in ducks. It is noteworthy that all infected geese shed virus and that the H5N1 viruses caused disease signs and death in a portion (3 of 16) of the geese, with evidence of systemic spread to the brain. The tropism for geese is unusual and may provide insight into the origin of these viruses. In mice, the H5N1 virus caused lethal pneumonia and spread systemically to the brain. Mice would thus provide an ideal model system for studying immune responses and pathogenesis. Transmission experiments in chickens revealed that the H5N1 viruses are spread by fecal-oral transmission rather than by aerosol, and that the viruses are inactivated by drying of feces at ambient temperature. However, infectivity is maintained for at least 4 days in wet feces at 25 degreesC. There were differences in the morphology of the H5N1 viruses isolated from birds and humans. The perpetuation of H5N1 influenza viruses in the poultry markets in Hong Kong and the transmission of these viruses to humans emphasize the importance of these markets in the epidemiology of influenza. The poultry markets are of critical importance in the perpetuation and transmission of influenza viruses to other avian species and to mammals, including humans.


Structural basis of thymosin-β4/profilin exchange leading to actin filament polymerization.
Thymosin-β4 (Tβ4) and profilin are the two major sequestering proteins that maintain the pool of monomeric actin (G-actin) within cells of higher eukaryotes. Tβ4 prevents G-actin from joining a filament, whereas profilin:actin only supports barbed-end elongation. Here, we report two Tβ4:actin structures. The first structure shows that Tβ4 has two helices that bind at the barbed and pointed faces of G-actin, preventing the incorporation of the bound G-actin into a filament. The second structure displays a more open nucleotide binding cleft on G-actin, which is typical of profilin:actin structures, with a concomitant disruption of the Tβ4 C-terminal helix interaction. These structures, combined with biochemical assays and molecular dynamics simulations, show that the exchange of bound actin between Tβ4 and profilin involves both steric and allosteric components. The sensitivity of profilin to the conformational state of actin indicates a similar allosteric mechanism for the dissociation of profilin during filament elongation.


Optimization of k-space trajectories for compressed sensing by Bayesian experimental design.
The optimization of k-space sampling for nonlinear sparse MRI reconstruction is phrased as a Bayesian experimental design problem. Bayesian inference is approximated by a novel relaxation to standard signal processing primitives, resulting in an efficient optimization algorithm for Cartesian and spiral trajectories. On clinical resolution brain image data from a Siemens 3T scanner, automatically optimized trajectories lead to significantly improved images, compared to standard low-pass, equispaced, or variable density randomized designs. Insights into the nonlinear design optimization problem for MRI are given.


Utilization of Body Contouring Procedures Following Weight Loss Surgery: A Study of 37,806 Patients.
Bariatric surgery has substantial health benefits; however, some patients desire body contouring (BC) procedures following rapid weight loss. There is a paucity of data regarding the true rate of BC following bariatric procedures. The purpose of our study is to examine the utilization of two common procedures, abdominoplasty, and panniculectomy, following bariatric surgery in New York State. The SPARCS longitudinal administrative database was used to identify bariatric procedures by using ICD-9 and CPT codes between 2004 and 2010. Procedures included sleeve gastrectomy, Roux-en-Y gastric bypass, and laparoscopic adjustable gastric banding. Using a unique patient identifier, we tracked those patients who subsequently underwent either abdominoplasty or panniculectomy with at least a 4-year follow-up (until 2014). Multivariable Cox proportional hazard model was used to evaluate predictors of follow-up BC surgery. 37,806 patients underwent bariatric surgery between 2004 and 2010. Only 5.58% (n = 2112) of these patients subsequently had a BC procedure, with 143 of them (6.8%) having ≥1 plastic surgery. The average time to plastic surgery after band, bypass, or sleeve was 1134.83 ± 671.09, 984.70 ± 570.53, and 903.02 ± 497.31 days, respectively (P < 0.0001). Following the multivariable Cox proportional hazard model, a female, SG patients, patients with Medicare or Medicaid, and patients in either <20 or >80%ile in yearly income were more likely to have plastic surgery after adjusting for age, race/ethnicity, comorbidities and complications (P values < 0.0001). This study shows that plastic surgery is completed by only 6% of patients following bariatric procedures. As insurance and income are associated with pursuing surgery, improved access may increase the number of patients who are able to undergo these reconstructive procedures.


Influence of grain topography on near infrared hyperspectral images.
Near infrared hyperspectral imaging (NIR-HSI) allows spatially resolved spectral information to be collected without sample destruction. Although NIR-HSI is suitable for a broad range of samples, sizes and shapes, topography of a sample affects the quality of near infrared (NIR) measurements. Single whole kernels of three cereals (barley, wheat and sorghum), with varying topographic complexity, were examined using NIR-HSI. The influence of topography (sample shape and texture) on spectral variation was examined using principal component analysis (PCA) and classification gradients. The greatest source of variation for all three grain types, despite spectral preprocessing with standard normal variate (SNV) transformation, was kernel curvature. Only 1.29% (PC5), 0.59% (PC6) and 1.36% (PC5) of the spectral variation within the respective barley, wheat and sorghum image datasets was explained within the principal component (PC) associated with the chemical change of interest (loss of kernel viability). The prior PCs explained an accumulated total of 91.18%, 89.43% and 84.39% of spectral variance, and all were influenced by kernel topography. Variation in sample shape and texture relative to the chemical change of interest is an important consideration prior to the analysis of NIR-HSI data for non-flat objects.


N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor.
Microglia provide continuous immune surveillance of the CNS and upon activation rapidly change phenotype to express receptors that respond to chemoattractants during CNS damage or infection. These activated microglia undergo directed migration towards affected tissue. Importantly, the molecular species of chemoattractant encountered determines if microglia respond with pro- or anti-inflammatory behaviour, yet the signaling molecules that trigger migration remain poorly understood. The endogenous cannabinoid system regulates microglial migration via CB2 receptors and an as yet unidentified GPCR termed the 'abnormal cannabidiol' (Abn-CBD) receptor. Abn-CBD is a synthetic isomer of the phytocannabinoid cannabidiol (CBD) and is inactive at CB1 or CB2 receptors, but functions as a selective agonist at this Gi/o-coupled GPCR. N-arachidonoyl glycine (NAGly) is an endogenous metabolite of the endocannabinoid anandamide and acts as an efficacious agonist at GPR18. Here, we investigate the relationship between NAGly, Abn-CBD, the unidentified 'Abn-CBD' receptor, GPR18, and BV-2 microglial migration. Using Boyden chamber migration experiments, yellow tetrazolium (MTT) conversion, In-cell Western, qPCR and immunocytochemistry we show that NAGly, at sub-nanomolar concentrations, and Abn-CBD potently drive cellular migration in both BV-2 microglia and HEK293-GPR18 transfected cells, but neither induce migration in HEK-GPR55 or non-transfected HEK293 wildtype cells. Migration effects are blocked or attenuated in both systems by the 'Abn-CBD' receptor antagonist O-1918, and low efficacy agonists N-arachidonoyl-serine and cannabidiol. NAGly promotes proliferation and activation of MAP kinases in BV-2 microglia and HEK293-GPR18 cells at low nanomolar concentrations - cellular responses correlated with microglial migration. Additionally, BV-2 cells show GPR18 immunocytochemical staining and abundant GPR18 mRNA. qPCR demonstrates that primary microglia, likewise, express abundant amounts of GPR18 mRNA. NAGly is the most effective lipid recruiter of BV-2 microglia currently reported and its effects mimic those of Abn-CBD. The data generated from this study supports the hypothesis that GPR18 is the previously unidentified 'Abn-CBD' receptor. The marked potency of NAGly acting on GPR18 to elicit directed migration, proliferation and perhaps other MAPK-dependent phenomena advances our understanding of the lipid-based signaling mechanisms employed by the CNS to actively recruit microglia to sites of interest. It offers a novel research avenue for developing therapeutics to elicit a self-renewing population of neuroregenerative microglia, or alternatively, to prevent the accumulation of misdirected, pro-inflammatory microglia which contribute to and exacerbate neurodegenerative disease.


Characterizing the invasion of different breast cancer cell lines with distinct E-cadherin status in 3D using a microfluidic system.
E-cadherin is a cell-cell adhesion protein that plays a prominent role in cancer invasion. Inactivation of E-cadherin in breast cancer can arise from gene promoter hypermethylation or genetic mutation. Depending on their E-cadherin status, breast cancer cells adopt different morphologies with distinct invasion modes. The tumor microenvironment (TME) can also affect the cell morphology and invasion mode. In this paper, we used a previously developed microfluidic system to quantify the three-dimensional invasion of breast cancer cells with different E-cadherin status, namely MCF-7, CAMA-1 and MDA-MB-231 with wild type, mutated and promoter hypermethylated E-cadherin, respectively. The cells migrated into a stable and reproducible microfibrous polycaprolactone mesh in the chip under a programmed stable chemotactic gradient. We observed that the MDA-MB-231 cells invaded the most, as single cells. MCF-7 cells collectively invaded into the matrix more than CAMA-1 cells, maintaining their E-cadherin expression. The CAMA-1 cells exhibited multicellular multifocal infiltration into the matrix. These results are consistent with what is seen in vivo in the cancer biology literature. In addition, comparison between complete serum and serum gradient conditions showed that the MDA-MB-231 cells invaded more under the serum gradient after one day, however this behavior was inverted after 3 days. The results showcase that the microfluidic system can be used to quantitatively assess the invasion behavior of cancer cells with different E-cadherin expression, for a longer period than conventional invasion models. In the future, it can be used to quantitatively investigate effects of matrix structure and cell treatments on cancer invasion.


Implementation of a cystic fibrosis lung transplant referral patient decision aid in routine clinical practice: an observational study.
The decision to have lung transplantation as treatment for end-stage lung disease from cystic fibrosis (CF) has benefits and serious risks. Although patient decision aids are effective interventions for helping patients reach a quality decision, little is known about implementing them in clinical practice. Our study evaluated a sustainable approach for implementing a patient decision aid for adults with CF considering referral for lung transplantation. A prospective pragmatic observational study was guided by the Knowledge-to-Action Framework. Healthcare professionals in all 23 Canadian CF clinics were eligible. We surveyed participants regarding perceived barriers and facilitators to patient decision aid use. Interventions tailored to address modifiable identified barriers included training, access to decision aids, and conference calls. The primary outcome was >80% use of the decision aid in year 2. Of 23 adult CF clinics, 18 participated (78.2%) and 13 had healthcare professionals attend training. Baseline barriers were healthcare professionals' inadequate knowledge for supporting patients making decisions (55%), clarifying patients' values for outcomes of options (58%), and helping patients handle conflicting views of others (71%). Other barriers were lack of time (52%) and needing to change how transplantation is discussed (42%). Baseline facilitators were healthcare professionals feeling comfortable discussing bad transplantation outcomes (74%), agreeing the decision aid would be easy to experiment with (71%) and use in the CF clinic (87%), and agreeing that using the decision aid would not require reorganization of the CF clinic (90%). After implementing the decision aid with interventions tailored to the barriers, decision aid use increased from 29% at baseline to 85% during year 1 and 92% in year 2 (p < 0.001). Compared to baseline, more healthcare professionals at the end of the study were confident in supporting decision-making (p = 0.03) but continued to feel inadequate ability with supporting patients to handle conflicting views (p = 0.01). Most Canadian CF clinics agreed to participate in the study. Interventions were used to target identified modifiable barriers to using the patient decision aid in routine CF clinical practice. CF clinics reported using it with almost all patients in the second year.


Alcohol industry involvement in science: A systematic review of the perspectives of the alcohol research community.
Alcohol companies have recently invested large sums of money in answering research questions to which they have clear vested interests in the outcomes. There have been extensive concerns about corporate influence on public health sciences, following the experience with the tobacco industry. This systematic review aims to investigate the perspectives of researchers on the activities of alcohol industry actors in relation to science, in order to guide future research. All data published in peer-reviewed journals (including commentaries, opinion pieces, editorials and letters as well as research reports) were eligible for inclusion. This analysis focuses on the manifest rather than latent content of the articulated views, and accordingly adopts a thematic analysis using an inductive approach to the generation of themes. There are serious concerns identified in three main areas, principally defined by where the impacts of industry scientific activities occur; on evidence informed policy making (instrumental uses of research by industry actors), on the content of the scientific evidence base itself (industry funding as a source of bias); and on the processes of undertaking research (transgressions of basic scientific norms). There are also opposing views which provide a useful critique. The evidence-base on the validity of all concerns has been slow to develop. The concerns are extensive, longstanding and unresolved and high quality investigations are needed. This study informs the detailed content of the research needed to address the concerns identified here.


Designing nanomaterials to maximize performance and minimize undesirable implications guided by the Principles of Green Chemistry.
The Twelve Principles of Green Chemistry were first published in 1998 and provide a framework that has been adopted not only by chemists, but also by design practitioners and decision-makers (e.g., materials scientists and regulators). The development of the Principles was initially motivated by the need to address decades of unintended environmental pollution and human health impacts from the production and use of hazardous chemicals. Yet, for over a decade now, the Principles have been applied to the synthesis and production of engineered nanomaterials (ENMs) and the products they enable. While the combined efforts of the global scientific community have led to promising advances in the field of nanotechnology, there remain significant research gaps and the opportunity to leverage the potential global economic, societal and environmental benefits of ENMs safely and sustainably. As such, this tutorial review benchmarks the successes to date and identifies critical research gaps to be considered as future opportunities for the community to address. A sustainable material design framework is proposed that emphasizes the importance of establishing structure-property-function (SPF) and structure-property-hazard (SPH) relationships to guide the rational design of ENMs. The goal is to achieve or exceed the functional performance of current materials and the technologies they enable, while minimizing inherent hazard to avoid risk to human health and the environment at all stages of the life cycle.


Economic implications of hip fracture: health service use, institutional care and cost in Canada.
As the burden of illness associated with hip fracture extends beyond the initial hospitalization, a longitudinal 1 year cohort study was used to analyze levels of health service use, institutional care and their associated costs, and to examine patient and residency factors contributing to overall 1 year cost. Patients in the study were aged 50 year and over, and had been admitted to an acute care facility for hip fracture in the Hamilton-Wentworth region of Canada from 1 April 1995 to 31 March 1996. Health care resources assessed included initial hospitalization, rehospitalization, rehabilitation, chronic care, home care, long-term care (LTC) and informal care. Regression analysis was used to determine the effects of age, gender, residence, survival and days of follow-up on 1 year cost. The mean 1 year cost of hip fracture for the 504 study patients was 26,527 Canadian dollars (95% Cl: $24,564-$28,490). One year costs were significantly different for patients who returned to the community ($21,385), versus those who were transferred to ($44,156), or readmitted to LTC facilities ($33,729) (p < 0.001). Initial hospitalization represented 58% of 1 year cost for community-dwelling patients, compared with 27% for LTC residents. Only 59.4% of community-dwelling patients resided in the community 1 year following hip fracture, and 5.6% of patients who survived their first fracture experienced a subsequent hip fracture. Linear regression indicated place of residence, age and survival were all important contributors to 1 year cost (p < 0.001). While the average 1 year cost of care was $26,527, the overall cost varied depending on a patient's place of residence, age, and survival to 1 year. Annual economic implications of hip fracture in Canada are $650 million and are expected to rise to $2.4 billion by 2041.


Transsacral interbody fixation versus transforaminal lumbar interbody fusion at the lumbosacral junction for long fusions in primary adult scoliosis.
Achieving fusion at the lumbosacral junction poses many technical challenges. No data exist in the literature comparing radiographic or clinical outcomes between the different surgical techniques of transsacral fixation (TSF) with rods and transforaminal lumbar interbody fusion (TLIF) in conjunction with iliac fixation. The purpose of this study was to compare the clinical outcomes and radiographic fusions of TSF to TLIF in patients with adult spinal deformity undergoing long fusions across the lumbosacral junction. Patients with primary adult spinal deformity who underwent long fusions from the thoracic spine across the lumbosacral junction with different approaches of interbody fusion at the L5-S1 level were reviewed. Patients were subdivided by approach (TSF vs TLIF). Fusion status at L5-S1 was evaluated by multiple radiographs and/or CT scans. Scoliotic curve changes were also evaluated preoperatively and at final follow-up. Clinical outcomes were assessed by Scoliosis Research Society Outcome Instrument 22 and Oswestry Disability Index scores. A total of 36 patients were included in the analysis. There were 18 patients in the TSF group and 18 patients in the TLIF group. A mean of 14.00 levels were fused in the TSF group and 10.94 in the TLIF group (p = 0.01). Both groups demonstrated significant postoperative radiographic improvement in coronal parameters. The fusion rates for TSF and TLIF groups were 100% and 88.9%, respectively (p < 0.05). Eight patients in the TSF group had pelvic fixation with unilateral iliac screws, compared to 15 patients in the TLIF group (p = 0.015). No statistical differences in patients' reported outcomes were seen between groups. Despite similar clinical and radiographic outcomes between both groups, TSF required fewer iliac screws to augment stability of the lumbosacral junction while achieving a higher rate of fusion. This study suggests that TSF may decrease potential instrument-related complications requiring revision while decreasing operating room time and implant-related costs.


Intercellular adhesion molecule-1 polymorphisms, K469E and G261R and susceptibility to vasculitis and rheumatoid arthritis: a meta-analysis.
The aim of this study was to determine whether intercellular adhesion molecule-1 (ICAM-1) polymorphisms are associated with susceptibility to vasculitis or rheumatoid arthritis (RA). Meta-analyses were performed to assess the associations between K469E and G241R polymorphisms of ICAM-1 and vasculitis or RA. A total of 12 studies on 1,368 patients and 1,922 controls, which comprised 8 vasculitis studies and 4 RA studies, were included in the meta-analysis. We found no significant association between vasculitis and K469E E allele among the various subjects (OR = 1.238, 95% CI = 0.9781-1.566, p = 0.076). However, an association between vasculitis and K469E polymorphism was observed under homozygote contrast (OR = 1.443, 95% CI = 1.084-1.920, p = 0.012). Stratification by ethnicity and vasculitis type showed no association between vasculitis and 1 K469E polymorphism under heterozygote contrast. In addition, the meta-analysis revealed a significant association between the ICAM-1 G241R R allele and Behcet's disease (BD) (OR = 3.261, 95% CI = 1.653-6.434, p = 0.001), but not giant cell arteritis. Moreover, the meta-analysis indicated an association between RA and the R allele and RR+ RG genotype of the ICAM-1 G241R polymorphism (OR = 2.014, 95% CI = 1.215-3.339, p = 0.007; OR = 2.394, 95% CI = 1.354-4.235, p = 0.003). This meta-analysis suggests that the K469E polymorphism is associated with susceptibility to vasculitis, and that the G241R polymorphism is associated with susceptibility to BD and RA.


Nitropyrrole natural products: isolation, biosynthesis and total synthesis.
Nitropyrrole-containing natural products are relatively rare in nature. Known examples are limited to the β-nitropyrrole-containing pyrrolomycins and α-nitropyrrole-containing nitropyrrolins and heronapyrroles. Their unique structures and interesting bioactivity are of ongoing interest to the chemistry community. This review describes the isolation, biological activity, biosynthesis and chemical synthesis of nitropyrrole-containing natural products reported to date.


Regulation of skeletal muscle sarcomere integrity and postnatal muscle function by Mef2c.
Myocyte enhancer factor 2 (MEF2) transcription factors cooperate with the MyoD family of basic helix-loop-helix (bHLH) transcription factors to drive skeletal muscle development during embryogenesis, but little is known about the potential functions of MEF2 factors in postnatal skeletal muscle. Here we show that skeletal muscle-specific deletion of Mef2c in mice results in disorganized myofibers and perinatal lethality. In contrast, neither Mef2a nor Mef2d is required for normal skeletal muscle development in vivo. Skeletal muscle deficient in Mef2c differentiates and forms normal myofibers during embryogenesis, but myofibers rapidly deteriorate after birth due to disorganized sarcomeres and a loss of integrity of the M line. Microarray analysis of Mef2c null muscles identified several muscle structural genes that depend on MEF2C, including those encoding the M-line-specific proteins myomesin and M protein. We show that MEF2C directly regulates myomesin gene transcription and that loss of Mef2c in skeletal muscle results in improper sarcomere organization. These results reveal a key role for Mef2c in maintenance of sarcomere integrity and postnatal maturation of skeletal muscle.


Upregulated microRNA‑671‑3p promotes tumor progression by suppressing forkhead box P2 expression in non‑small‑cell lung cancer.
In the present study, the expression of microRNA (miR)‑671‑3p in non‑small‑cell lung cancer (NSCLC) was detected via reverse transcription‑quantitative polymerase chain reaction analysis, and its role in cell proliferation, apoptosis, migration and invasion was investigated via Cell Counting Kit‑8, colony formation, flow cytometry, Transwell and scratch assays, respectively. It was observed that the expression of miR‑671‑3p was upregulated in NSCLC tissues and cell lines (A549 and H1975). Treatment with miR‑671‑3p inhibitors suppressed cell proliferation, migration and invasion, and increased apoptosis in vitro, suggesting that miR‑671‑3p functions as an oncogene in NSCLC. In addition, forkhead box P2 (FOXP2) has been reported to be a tumor suppressor that is downregulated in several types of cancer, and its low expression was confirmed in NSCLC tissues and cell lines in the current study via western blotting. The results of the luciferase reporter assay also demonstrated that miR‑671‑3p targeted directly the 3'‑untranslated region of FOXP2. Furthermore, overexpression of FOXP2 in A549 and H1975 cell lines suppressed the growth, migration and invasion, and promoted apoptosis, whereas these effects were reversed by transfection with miR‑671‑3p mimics, suggesting that miR‑671‑3p promoted tumor progression via regulating FOXP2. Taken together, the results reported in the present study implied that miR‑671‑3p may be a potential therapeutic target in NSCLC.


Seroprevalence and Associated Risk Factors of Toxocariasis among College Students in Taipei City, Taiwan.
Infection by Toxocara spp. is known to be significantly associated with partial epilepsy. It has become popular for people to raise dogs/cats as pets and consume roasted meat/viscera, and the status of Toxocara spp. infection, epilepsy awareness, and associated risk factors among the general population are currently unknown in Taiwan. A seroepidemiological investigation among 203 college students (CSs), consisting of 110 males and 93 females with an average age of 21.5 ± 1.2 years, was conducted in 2009 in Taipei City. A Western blot analysis based on excretory-secretory antigens derived from Toxocara canis larvae (TcESs) was applied to determine the positivity of serum immunoglobulin G antibodies. A self-administered questionnaire was also given to obtain information about demographic characteristics, epilepsy awareness, and risk factors. A logistic regression model was applied for the statistical analysis using SPSS software. The overall seropositive rate of Toxocara spp. infection was 8.4% (17/203). As to epilepsy awareness, a non-significantly higher seroprevalence was found in CSs who claimed to "know" about epilepsy compared to those who did not know (P > 0.05). It appears that appropriate educational programs are urgently needed to provide correct knowledge related to the prevention and control measures against Toxocara spp. infections to avoid potential threats by this parasite to the general population in Taiwan.


Association of Interleukin 6 Receptor Variant With Cardiovascular Disease Effects of Interleukin 6 Receptor Blocking Therapy: A Phenome-Wide Association Study.
Electronic health record (EHR) biobanks containing clinical and genomic data on large numbers of individuals have great potential to inform drug discovery. Individuals with interleukin 6 receptor (IL6R) single-nucleotide polymorphisms (SNPs) who are not receiving IL6R blocking therapy have biomarker profiles similar to those treated with IL6R blockers. This gene-drug pair provides an example to test whether associations of IL6R SNPs with a broad range of phenotypes can inform which diseases may benefit from treatment with IL6R blockade. To determine whether screening for clinical associations with the IL6R SNP in a phenome-wide association study (PheWAS) using EHR biobank data can identify drug effects from IL6R clinical trials. Diagnosis codes and routine laboratory measurements were extracted from the VA Million Veteran Program (MVP); diagnosis codes were mapped to phenotype groups using published PheWAS methods. A PheWAS was performed by fitting logistic regression models for testing associations of the IL6R SNPs with 1342 phenotype groups and by fitting linear regression models for testing associations of the IL6R SNP with 26 routine laboratory measurements. Significance was reported using a false discovery rate of 0.05 or less. Findings were replicated in 2 independent cohorts using UK Biobank and Vanderbilt University Biobank data. The Million Veteran Program included 332 799 US veterans; the UK Biobank, 408 455 individuals from the general population of the United Kingdom; and the Vanderbilt University Biobank, 13 835 patients from a tertiary care center. IL6R SNPs (rs2228145; rs4129267). Phenotypes defined by International Classification of Diseases, Ninth Revision codes. Of the 332 799 veterans included in the main cohort, 305 228 (91.7%) were men, and the mean (SD) age was 66.1 (13.6) years. The IL6R SNP was most strongly associated with a reduced risk of aortic aneurysm phenotypes (odds ratio, 0.87-0.90; 95% CI, 0.84-0.93) in the MVP. We observed known off-target effects of IL6R blockade from clinical trials (eg, higher hemoglobin level). The reduced risk for aortic aneurysms among those with the IL6R SNP in the MVP was replicated in the Vanderbilt University Biobank, and the reduced risk for coronary heart disease was replicated in the UK Biobank. In this proof-of-concept study, we demonstrated application of the PheWAS using large EHR biobanks to inform drug effects. The findings of an association of the IL6R SNP with reduced risk for aortic aneurysms correspond with the newest indication for IL6R blockade, giant cell arteritis, of which a major complication is aortic aneurysm.


Specialization patterns across various youth sports and relationship to injury risk.
Current trends among young athletes towards earlier specialization age and year-round training on multiple teams has raised concern for increased injury risk. Our previous analyses showed higher risk for injury in highly specialized young athletes. The goal of this research was to determine whether sports specialization and injury patterns vary by sports type. In this clinical case-control study, injured athletes (aged 7-18 years) were recruited from sports medicine clinics and compared to similarly aged uninjured athletes recruited from primary care clinics. Participants completed a survey reporting age, gender, sport type, specialization patterns, and details regarding sports-related injuries in the previous 6 months. Clinical diagnoses were collected from patients' medical records. Injuries were classified as acute, overuse, or serious overuse. Of 1,190 athletes enrolled, 26% (313) were single-sport specialized (reported participation in one sport and trained >8 months/year). Sports with the highest proportion of single-sport specialized athletes were tennis (46.7%), gymnastics (30.1%), and dance (26.3%). Single-sport specialized athletes in individual sports started specializing at a younger age (11.2 ± 2.4 vs. 12.0 ± 2.7, p = 0.05) and reported higher training volumes (11.8 vs. 10.3 h/week, p = 0.04) than those in team sports. Sports with the youngest specialization age were gymnastics (8.9 ± 1.7), dance (10.8 ± 3.0), and soccer (10.9 ± 2.4). Single-sport specialized athletes in individual sports accounted for a higher proportion of overuse injuries (44.3% vs 32.2%, OR = 1.67, p = 0.037) and serious overuse injuries (23.4% vs 11.6%, OR = 2.38, p = 0.011), but a lower proportion of acute injuries (28.8% vs 13.8%, OR = 0.37, p = 0.001) compared to single-sport specialized athletes involved in team sports. Athletes in individual sports may be more likely to specialize in a single sport than team sport athletes. Single-sport specialized athletes in individual sports also reported higher training volumes and greater rates of overuse injuries than single-sport specialized athletes in team sports.


Cell Death Inducing Microbial Protein Phosphatase Inhibitors--Mechanisms of Action.
Okadaic acid (OA) and microcystin (MC) as well as several other microbial toxins like nodularin and calyculinA are known as tumor promoters as well as inducers of apoptotic cell death. Their intracellular targets are the major serine/threonine protein phosphatases. This review summarizes mechanisms believed to be responsible for the death induction and tumor promotion with focus on the interdependent production of reactive oxygen species (ROS) and activation of Ca(2+)/calmodulin kinase II (CaM-KII). New data are presented using inhibitors of specific ROS producing enzymes to curb nodularin/MC-induced liver cell (hepatocyte) death. They indicate that enzymes of the arachidonic acid pathway, notably phospholipase A2, 5-lipoxygenase, and cyclooxygenases, may be required for nodularin/MC-induced (and presumably OA-induced) cell death, suggesting new ways to overcome at least some aspects of OA and MC toxicity.


Efficient Generation of Genome-wide Libraries for Protein-ligand Screens Using Gibson Assembly.
Genome-wide screens using yeast or phage displays are powerful tools for identifying protein-ligand interactions, including drug or vaccine targets, ligand receptors, or protein-protein interactions. However, assembling libraries for genome-wide screens can be challenging and often requires unbiased cloning of 10 5 -10 7 DNA fragments for a complete representation of a eukaryote genome. A sub-optimal genomic library can miss key genomic sequences and thus result in biased screens. Here, we describe an efficient method to generate genome-wide libraries for yeast surface display using Gibson assembly. The protocol entails genome fragmentation, ligation of adapters, library cloning using Gibson assembly, library transformation, library DNA recovery, and a streamlined Oxford nanopore library sequencing procedure that covers the length of the cloned DNA fragments. We also describe a computational pipeline to analyze the library coverage of the genome and predict the proportion of expressed proteins. The method allows seamless library transfer among multiple vectors and can be easily adapted to any expression system.


Translationally optimal codons associate with aggregation-prone sites in proteins.
We analyze the relationship between codon usage bias and residue aggregation propensity in the genomes of four model organisms, Escherichia coli, yeast, fly, and mouse, as well as the archaeon Halobacterium species NRC-1. Using the Mantel-Haenszel procedure, we find that translationally optimal codons associate with aggregation-prone residues. Our results are qualitatively and quantitatively similar to those of an earlier study where we found an association between translationally optimal codons and buried residues. We also combine the aggregation-propensity data with solvent-accessibility data. Although the resulting data set is small, and hence statistical power low, results indicate that the association between optimal codons and aggregation-prone residues exists both at buried and at exposed sites. By comparing codon usage at different combinations of sites (exposed, aggregation-prone sites versus buried, non-aggregation-prone sites; buried, aggregation-prone sites versus exposed, non-aggregation-prone sites), we find that aggregation propensity and solvent accessibility seem to have independent effects of (on average) comparable magnitude on codon usage. Finally, in fly, we assess whether optimal codons associate with sites at which amino acid substitutions lead to an increase in aggregation propensity, and find only a very weak effect. These results suggest that optimal codons may be required to reduce the frequency of translation errors at aggregation-prone sites that coincide with certain functional sites, such as protein-protein interfaces. Alternatively, optimal codons may be required for rapid translation of aggregation-prone regions.


[Cancer-related fatigue as a thematic issue in oncology nursing].
This study aims at investigating how scientific production in Oncology Nursing has approached fatigue, associating such production with the defining characteristics set forth by NANDA; and identifying those Nursing interventions performed for its prevention and/or treatment in those publications, correlating them with those interventions mentioned by NIC. It is a reflection on the theme of "fatigue" in the area of Oncology Nursing, which used the narrative bibliographical review as its method. The LILACS and MEDLINE bases were used for data access. Similarities were found between the defining characteristics for the NANDA diagnosis of "fatigue" and the description of fatigue found in the researched articles. In light of the NANDA Diagnosis Taxonomy's lack of validation in oncology care environments, there is a need for studies that articulate the validated characteristics with the evidenced ones. Intervention strategies in the case of fatigue may be educational and pharmacological or not. There is, however, a need for research in order to develop an evidence-based clinical practice.


Generation of single-frequency tunable green light in a coupled ring tapered diode laser cavity.
We report the realization of a tapered diode laser operated in a coupled ring cavity that significantly improves the coherence properties of the tapered laser and efficiently generates tunable light at the second harmonic frequency. The tapered diode laser is tunable with single-frequency output in the broad wavelength range from 1049 nm to 1093 nm and the beam propagation factor is improved from M(2) = 2.8 to below 1.1. The laser frequency is automatically locked to the cavity resonance frequency using optical feedback. Furthermore, we show that this adaptive external cavity approach leads to efficient frequency doubling. More than 500 mW green output power is obtained by placing a periodically poled LiNbO(3) crystal in the external cavity. The single frequency green output from the laser system is tunable in the 530 nm to 533 nm range limited by the LiNbO(3) crystal. The optical to optical conversion efficiency exceeds 30%.


Inhibition of cell cycle progression by the alternatively spliced integrin beta 1C.
Integrins regulate cell growth, differentiation, and behavior in many systems. Integrin beta 1C (beta 1S) is an alternatively spliced variant of integrin beta 1 with a specific cytoplasmic domain and is expressed in several human tissues. Human beta 1c transiently expressed in mouse 10T1/2 fibroblasts showed a diffuse pattern of cell surface staining, whereas beta1 localized to focal adhesions. Moderate concentrations of beta 1C had no effect on actin stress fibers or focal adhesions, but markedly inhibited DNA synthesis. Inhibition by beta 1C mapped to the late G1 phase of the cell cycle, near the G1-S boundary. Thus, alternative splicing of beta1 results in transmission of distinct signals that may regulate growth in vivo.


Culture, ethics, and respect: the bottom line is understanding.
As the world becomes smaller, there is increasing recognition that the world is more culturally diverse. People within a particular group share customs, habits, and values; however, these individuals may share few, if any, beliefs and practices with people from other cultural groups. This increasing cultural diversity raises questions about ways to deliver appropriate and respectful health care to patients from other cultures. This article discusses culture, culture and health care, and respect for culture. There is a description of means that nurses can use to provide culturally relevant care. Ethical practice requires a recognition of one's biases, a sensitivity to cultural differences, the avoidance of generalizations about cultures, and the provision of culturally relevant care.


Evidence for a prepore stage in the action of Clostridium perfringens epsilon toxin.
Clostridium perfringens epsilon toxin (ETX) rapidly kills MDCK II cells at 37°C, but not 4°C. The current study shows that, in MDCK II cells, ETX binds and forms an oligomeric complex equally well at 37°C and 4°C but only forms a pore at 37°C. However, the complex formed in MDCK cells treated with ETX at 4°C has the potential to form an active pore, since shifting those cells to 37°C results in rapid cytotoxicity. Those results suggested that the block in pore formation at 4°C involves temperature-related trapping of ETX in a prepore intermediate on the MDCK II cell plasma membrane surface. Evidence supporting this hypothesis was obtained when the ETX complex in MDCK II cells was shown to be more susceptible to pronase degradation when formed at 4°C vs. 37°C; this result is consistent with ETX complex formed at 4°C remaining present in an exposed prepore on the membrane surface, while the ETX prepore complex formed at 37°C is unaccessible to pronase because it has inserted into the plasma membrane to form an active pore. In addition, the ETX complex rapidly dissociated from MDCK II cells at 4°C, but not 37°C; this result is consistent with the ETX complex being resistant to dissociation at 37°C because it has inserted into membranes, while the ETX prepore readily dissociates from cells at 4°C because it remains on the membrane surface. These results support the identification of a prepore stage in ETX action and suggest a revised model for ETX cytotoxicity, i) ETX binds to an unidentified receptor, ii) ETX oligomerizes into a prepore on the membrane surface, and iii) the prepore inserts into membranes, in a temperature-sensitive manner, to form an active pore.


Parental perceptions regarding healthy behaviours for preventing overweight and obesity in young children: a systematic review of qualitative studies.
Evidence is increasingly pointing towards the importance of early life strategies to prevent childhood overweight and obesity. This systematic review synthesizes qualitative research concerning parental perceptions regarding behaviours for preventing overweight and obesity in young children. During May and June 2008, a range of electronic databases were searched and together with lateral searching techniques 21 studies were identified for review. Data extraction and synthesis using thematic content analysis revealed six organizing and 32 finer level themes. These related to child factors, family dynamics, parenting, knowledge and beliefs, extra-familial influences and resources and environment. Themes were mapped to a socioecological model which illustrated how factors at individual, interpersonal, community, organizational and societal levels interact in complex ways to impact on parental perceptions about healthy behaviours for preventing child overweight. Although parents suggested several ideas to promote healthy child weight-related behaviours, many of their views concerned perceived barriers, some of which may be amenable to practical intervention. Furthermore, intergenerational influences on parental health beliefs and knowledge suggest that health promotion strategies may be more effective if directed at the wider family, rather than parents alone. Significantly, many parents believed strategies to promote healthy weight should start early in a child's life.


Effects of script training on the peer-to-peer communication of children with autism spectrum disorder.
A multiple baseline design across participants was used to demonstrate the effects of a script-training procedure on the peer-to-peer communication of 3 children with autism spectrum disorder during group play with peers. Both scripted and unscripted initiations as well as responses to peers increased for all 3 participants. Stimulus generalization across novel toys, settings, and peers was observed. Novel unscripted initiations, responses, and appropriate changes in topics during peer-to-peer exchanges were analyzed by considering the cumulative frequency of these behaviors across phases of the study. Treatment gains were maintained during 4-week follow-up sessions. Results are discussed in terms of recommendations for practitioners, response variability, and potential future avenues of research.


Elevated urinary IL-18 levels at the time of ICU admission predict adverse clinical outcomes.
Urine IL-18 (uIL-18) has demonstrated moderate capacity to predict acute kidney injury (AKI) and adverse outcomes in defined settings. Its ability to predict AKI and provide prognostic information in broadly selected, critically ill adults remains unknown. The study prospectively evaluated the capacity of uIL-18 measured within 24 hours of intensive care unit (ICU) admission to predict AKI, death, and receipt of acute dialysis in a large mixed-adult ICU population. Of 451 patients, 86 developed AKI within 48 hours of enrollment and had higher median uIL-18 levels [426 (interquartile range [IQR]: 152 to 1183) pg/mg creatinine] compared with those without AKI [248 (IQR: 120 to 559) pg/mg]. The area under the receiver operating characteristic curve for uIL-18 predicting subsequent AKI within 24 hours was 0.62 (95% CI: 0.54 to 0.69) and improved modestly to 0.67 (95% CI: 0.53 to 0.81) in patients whose enrollment eGFR was >or=75 ml/min per 1.73 m(2). The highest median uIL-18 levels were observed in patients with sepsis at enrollment [508 (IQR: 230 to 1281) pg/mg], those receiving acute dialysis [571 (IQR: 161 to 1614) pg/mg] or dying [532 (IQR: 210 to 1614) pg/mg] within 28 days of ascertainment. After adjustment for a priori selected clinical predictors, uIL-18 remained independently predictive of composite outcome of death or acute dialysis within 28 days of ascertainment (odds ratio, 1.86 [95% CI: 1.31 to 2.64]). uIL-18 did not reliably predict AKI development, but did predict poor clinical outcomes in a broadly selected, critically ill adult population.


One of these things is not like the others: Testing trajectories in drinking frequency, drinking quantity, and alcohol-related problems in undergraduate women.
Alcohol misuse is an increasingly common problem in undergraduate women. Building upon research suggesting that maturing out of risky patterns of alcohol use can occur, our study tested how three facets of alcohol use change differentially over time in undergraduate women. A sample of 218 undergraduate women (M age=20.6years) participated in a four-wave, 18-month longitudinal study measuring frequency of alcohol consuming occasions, quantity of alcohol consumed per occasion, and alcohol-related problems. Growth curve analyses showed that alcohol frequency remained stable over 18months, whereas alcohol quantity and problems decreased over time. Results indicate undergraduate women are drinking with similar frequency over time, but they are drinking a smaller quantity of alcohol per drinking occasion and they are experiencing fewer alcohol-related problems. Findings help clarify the maturity principle by showing a different pattern of drinking as undergraduate women age that involves lower quantities of alcohol per drinking occasion and less problematic alcohol use, but not necessarily less frequent drinking.


Sedation effects by dexmedetomidine versus propofol in decreasing duration of mechanical ventilation after open heart surgery.
: The objective of this study was to compare the suitability (efficacy and safety) of dexmedetomidine versus propofol for patients admitted to the intensive care unit (ICU) after the cardiovascular surgery for the postoperative sedation before weaning from mechanical ventilation. Sedation is prescribed in patients admitted to the ICU after cardiovascular surgery to reduce the patient discomfort, ventilator asynchrony, to make mechanical ventilation tolerable, prevent accidental device removal, and to reduce metabolic demands during respiratory and hemodynamic instability. Careful drug selection for sedation by the ICU team, postcardiovascular surgery should be done so that patients can be easily weaned from mechanical ventilation after sedation is stopped to achieve a shorter duration of mechanical ventilation and decreased the length of stay in ICU. A total of 50 patients admitted to the ICU after cardiovascular surgery, aged from 18 to 55 years and requiring mechanical ventilation on arrival to the ICU were enrolled in a prospective and comparative study. They were randomly divided into two groups as follows: Group D patients (n = 25) received dexmedetomidine in a maintenance infusion dose of 0.8 μg/kg/h and Group P patients (n = 25) received propofol in a maintenance infusion dose of 1.5 mg/kg/h. The patients were assessed for 12 h postoperatively, and dosing of the study drug was adjusted based on sedation assessment performed with the Richmond Agitation-Sedation Scale (RASS). The patients were required to be within the RASS target range of -2 to +1 at the time of study drug initiation. At every 4 h, the following information was recorded from each patient such as heart rate (HR), mean arterial pressure (MAP), arterial blood gases (ABG), tidal volume (TV), exhaled TV, maximum inspiratory pressure, respiratory rate and the rapid shallow breathing index, duration of mechanical ventilation, midazolam and fentanyl dose requirements, and financial costs. The study results showed no statistically significant difference between both groups with regard to age and body mass index. Group P patients were more associated with lower MAP and HR than Group D patients. There was no statistically significant difference between groups with regard to ABG findings, oxygenation, ventilation, and respiratory parameters. There was significant difference between both the groups in midazolam and fentanyl dose requirement and financial costs with a value of P < 0.05. Dexmedetomidine is safer and equally effective agent for the sedation of mechanically ventilated patients admitted to the ICU after cardiovascular surgery compared to the patients receiving propofol, with good hemodynamic stability, and equally rapid extubation time.


Topical antimicrobial agents for the treatment of chronic wounds.
Chronic wounds are commonly observed in acute and community settings. The management of chronic wounds represents a significant proportion of health-care resources and makes up a substantial amount of contact time with community-based nurses spending approximately 25% to 50% of their time treating wounds. Chronic wounds often exhibit increased bacterial burden that can negatively impact upon patients, reduce their quality of life and substantially increase treatment costs for health care providers. Antibiotic resistance has become a major medical and public health problem, and interest has been generated in the use of topical therapies to manage wound infection. This article presents an overview of the historical use of honey, silver and iodine for the treatment of infected wounds progressing through to modern day use and the current evidence base for the use of these antimicrobial agents in the management of infected wounds.


Type I neuregulin1α is a novel local mediator to suppress hepatic gluconeogenesis in mice.
Neuregulin1 is an epidermal growth factor (EGF)-like domain-containing protein that has multiple isoforms and functions as a local mediator in the control of various cellular functions. Here we show that type I isoform of neuregulin1 with an α-type EGF-like domain (Nrg1α) is the major isoform in mouse liver and regulates hepatic glucose production. Forced expression of Nrg1α in mouse liver enhanced systemic glucose disposal and decreased hepatic glucose production with reduced fasting blood glucose levels. Nuclear forkhead box protein O1 (FoxO1) and its downstream targets, PEPCK and G6Pase, were suppressed in liver and isolated hepatocytes by Nrg1α overexpression. In contrast, silencing of Nrg1α enhanced glucose production with increased PEPCK and G6Pase expressions in cAMP/dexamethasone-stimulated hepatocytes. Mechanistically, the recombinant α-type EGF-like domain of NRG1α (rNRG1α) stimulated the ERBB3 signalling pathway in hepatocytes, resulting in decreased nuclear FoxO1 accumulation via activation of both the AKT and ERK pathways. In addition, acute treatment with rNRG1α also suppressed elevation of blood glucose levels after both glucose and pyruvate challenge. Although a liver-specific deletion of Nrg1 gene in mice showed little effect on systemic glucose metabolism, these results suggest that NRG1α have a novel regulatory function in hepatic gluconeogenesis by regulating the ERBB3-AKT/ERK-FoxO1 cascade.


Lifestyle modifications to prevent and control hypertension. 4. Recommendations on physical exercise training. Canadian Hypertension Society, Canadian Coalition for High Blood Pressure Prevention and Control, Laboratory Centre for Disease Control at Health Canada, Heart and Stroke Foundation of Canada.
To provide updated, evidence-based recommendations for health care professionals concerning the effects of regular physical activity on the prevention and control of hypertension in otherwise healthy adults. People may engage in no, sporadic or regular physical activity that may be of low, moderate or vigorous intensity. For sedentary people with hypertension, the options are to undertake or maintain regular physical activity and to avoid or moderate medication use; to use another lifestyle modification technique; to commence or continue antihypertensive medication; or to take no action and remain at increased risk of cardiovascular disease. The health outcomes considered were changes in blood pressure and in morbidity and mortality rates. Because of insufficient evidence, no economic outcomes were considered. A MEDLINE search was conducted for the period 1966-1997 with the terms exercise, exertion, physical activity, hypertension and blood pressure. Both reports of trials and review articles were obtained. Other relevant evidence was obtained from the reference lists of these articles, from the personal files of the authors and through contacts with experts. The articles were reviewed, classified according to study design and graded according to level of evidence. A high value was placed on avoidance of cardiovascular morbidity and premature death caused by untreated hypertension. Physical activity of moderate intensity involving rhythmic movements with the lower limbs for 50-60 minutes, 3 or 4 times per week, reduces blood pressure and appears to be more effective than vigorous exercise. Harm is uncommon and is generally restricted to the musculoskeletal injuries that may occur with any repetitive activity. Injury occurs more often with jogging than with walking, cycling or swimming. The costs include the costs of appropriate shoes, garments and equipment, but these were not specifically measured. (1) People with mild hypertension should engage in 50-60 minutes of moderate rhythmic exercise of the lower limbs, such as brisk walking or cycling, 3 or 4 times per week to reduce blood pressure, (2) Exercise should be prescribed as an adjunctive therapy for people who require pharmacologic therapy for hypertension, especially those who are not receiving beta-blockers. (3) People who do not have hypertension should participate in regular exercise as it will decrease blood pressure and reduce the risk of coronary artery disease, although there is no direct evidence that it will prevent hypertension. These recommendations agree with those of the World Hypertension League, the American College of Sports Medicine, the report of the US Surgeon General on physical activity and health, and the US National Institutes of Health Consensus Development Panel on Physical Activity and Cardiovascular Health. These guidelines have not been clinically tested. The Canadian Hypertension Society, the Canadian Coalition for High Blood Pressure Prevention and Control, the Laboratory Centre for Disease Control at Health Canada, and the Heart and Stroke Foundation of Canada.


Carrier peak isolation from single interferogram using spectrum shift technique.
This paper presents a new method to obtain a wrapped phase distribution from a single interferogram with a spatial carrier modulation. The Fourier transform of the interferogram has three peaks: one is a dc peak around the origin in the Fourier domain, and the other two are carrier peaks that have information of phase modulation by an object placed in the interferometer. Since the wrapped phase can be evaluated by one of the two carrier peaks, the dc peak and the adjoint peak that is the other peak of two carrier peaks should be removed by filters. The proposed filtering process consists of two stages: dc peak filtering and adjoint peak filtering. A spectrum shift filter based on symmetrical characteristics of the spectrum is applied in both stages as a basic filter that can remove most of the undesired spectrum. An additional two filters are applied to remove the remaining spectrum. The new method can automatically isolate the carrier peak, even when the boundary of peaks is not very clear. Numerical evaluations of simulation data and experimental data demonstrate that the proposed method can successfully isolate the carrier peak.


Morning Plasma Melatonin Differences in Autism: Beyond the Impact of Pineal Gland Volume.
While low plasma melatonin, a neuro-hormone synthesized in the pineal gland, has been frequently associated with autism, our understanding of the mechanisms behind it have remained unclear. In this exploratory study, we hypothesized that low melatonin levels in ASD could be linked to a decrease of the pineal gland volume (PGV). PGV estimates with magnetic resonance imaging (MRI) with a voxel-based volumetric measurement method and early morning plasma melatonin levels were evaluated for 215 participants, including 78 individuals with ASD, 90 unaffected relatives, and 47 controls. We first found that both early morning melatonin level and PGV were lower in patients compared to controls. We secondly built a linear model and observed that plasma melatonin was correlated to the group of the participant, but also to the PGV. To further understand the relationship between PGV and melatonin, we generated a normative model of the PGV relationship with melatonin level based on control participant data. We found an effect of PGV on normalized melatonin levels in ASD. Melatonin deficit appeared however more related to the group of the subject. Thus, melatonin variations in ASD could be mainly driven by melatonin pathway dysregulation.


Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: implications for HIV-associated neurological disease.
Mononuclear phagocytes (monocytes, macrophages, and dendritic cells) play major roles in human immunodeficiency virus (HIV) persistence and disease pathogenesis. Macrophage antigen presentation and effector cell functions are impaired by HIV-1 infection. Abnormalities of macrophage effector cell function in bone marrow, lung, and brain likely result as a direct consequence of cellular activation and HIV replication. To further elucidate the extent of macrophage dysfunction in HIV-1 disease, a critical activation-specific regulatory molecule, nitric oxide (NO.), which may contribute to diverse pathology, was studied. Little, if any, NO. is produced by uninfected human monocytes. In contrast, infection with HIV-1 increases NO. production to modest, but significant levels (2-5 microM). Monocyte activation (with lipopolysaccharide, tumor necrosis factor alpha, or through interactions with astroglial cells) further enhances NO. production in HIV-infected cells, whereas its levels are diminished by interleukin 4. These results suggest a possible role for NO. in HIV-associated pathology where virus-infected macrophages are found. In support of this hypothesis, RNA encoding the inducible NO synthase (iNOS) was detected in postmortem brain tissue from one pediatric AIDS patient with advanced HIV encephalitis. Corresponding iNOS mRNA was not detected in brain tissue from five AIDS patients who died with less significant brain disease. These results demonstrate that HIV-1 can influence the expression of NOS in both cultured human monocytes and brain tissue. This newly described feature of HIV-macrophage interactions suggests previously unappreciated mechanisms of tissue pathology that result from productive viral replication.


Differences in activity limitation, pain intensity, and global health in patients with rheumatoid arthritis in Sweden and the USA: a 5-year follow-up.
In this study we compared activity limitations, pain intensity, and global health in patients with rheumatoid arthritis (RA) in Sweden and the USA and aimed to determine whether nationality is associated with these outcomes. We used longitudinal data from the 'Swedish TIRA project' (n = 149) and the University of California, San Francisco (UCSF) RA panel study (n = 85). Data were collected annually concerning use of medications [disease-modifying anti-rheumatic drugs (DMARDs), biologics, and corticosteroids], morning stiffness, number of swollen joints, and number of painful joints. Three self-reported outcome measures were examined: pain intensity measured on a 0-100 visual analogue scale (VAS), activity limitation according to the Health Assessment Questionnaire (HAQ), and global health. To analyse the data, the Student's t-test, the χ(2)-test, and the generalized estimating equation (GEE) method were used. Nationality was significantly related to HAQ score and pain intensity, even after adjustment for covariates. The patients in the TIRA cohort reported a lower HAQ score and a higher pain intensity than the patients in the UCSF cohort. Nationality was not related to global health. Patients with RA should be assessed with awareness of the psychosocial and cultural context because disability seems to be affected by nationality. Further knowledge to clarify how a multinational setting affects disability could improve the translation of interventions for patients with RA across nationalities.


Modulation of the behavioral effects of chlordiazepoxide by methylxanthines and analogs of adenosine in squirrel monkeys.
The effects of chlordiazepoxide (CDAP) on suppressed behavior of squirrel monkeys were determined alone and in combination with selected methylxanthines (caffeine, theophylline, 8-phenyltheophylline, theobromine, 3-isobutyl-1-methylxanthine) and analogs of adenosine (L-PIA, N6-cyclohexyladenosine, NECA). Monkeys responded under a fixed-interval schedule of food presentation in which responding was suppressed by a concurrent fixed-ratio schedule of response-produced electric shock. Dose-effect curves were determined by administering cumulative doses i.v. during timeout periods that preceded sequential components of the schedule. When administered alone, CDAP produced dose-related increases in the rate of suppressed responding at doses up to 17.8 mg/kg and decreased responding at a higher dose of 32.0 mg/kg. Under the same conditions, the methylxanthines usually had only small effects on responding over the range of doses studied, whereas L-PIA and NECA usually decreased responding in a dose-related manner. After presession treatment with intermediate doses of caffeine, 8-phenyltheophylline or 3-isobutyl-1-methylxanthine, the increases is suppressed responding produced by CDAP often were larger than those produced by CDAP alone. In contrast, after presession treatment with low doses of L-PIA, NECA or N6-cyclohexyladenosine the increases in suppressed responding normally produced by CDAP were either reduced or eliminated. Although L-PIA, NECA and N6-cyclohexyladenosine attenuated the rate-increasing effects of CDAP, there was no indication that they produced an overall rightward shift in the CDAP dose-effect curve, suggesting that the adenosine analogs did not act simply as competitive antagonists of CDAP.(ABSTRACT TRUNCATED AT 250 WORDS)


Are differences in population prevalence of alcohol's harm to others related to survey administration mode?
This study assessed the comparability of estimates of alcohol's harm to others across different administration modes in Swedish general population surveys. Harm was categorised as harm from strangers' drinking and harm from heavy drinkers known to the respondent. Three surveys were conducted in 2011/2012 (n = 6841), including identical questions. One was based on self-administered postal or Web questionnaires, and two were based on computer-assisted telephone interviews of which one included a more ambitious procedure in terms of for example monetary incentives to the respondents. Pearson χ2 -tests were used to compare differences in the prevalence of harm. To estimate potential effects of survey mode, the samples were pooled, and multivariate Poisson regression models with mode as explanatory variable were used, adjusting for socio-demographic and behavioural factors. Respondents in the two computer-assisted telephone interviews were more likely to report harm from strangers' drinking compared with respondents in the self-administered postal or Web questionnaires. However, no significant differences were found between survey modes concerning reports of harm from known people's drinking. A survey mode based on interviews seems to facilitate reports of harm from strangers' drinking. This does not apply to reports of harm from known people's drinking. Therefore, the comparability of estimates of alcohol's harm to others between survey modes depends on the type of harm being studied. [Sundin E, Landberg J, Galanti MR, Room R, Ramstedt M. Are differences in population prevalence of alcohol's harmto others related to survey administration mode?


Bortezomib-resistant mutant proteasomes: structural and biochemical evaluation with carfilzomib and ONX 0914.
Inhibition of the 20S proteasome by bortezomib (Velcade) constitutes a successfully applied therapy for blood cancer. However, emerging resistance restricts its medicinal use. For example, mutations in the proteolytically active β5-subunit of the proteasome, the main target of inhibitors, were reported to impair drug binding and thus to reduce therapeutic efficacy. Using yeast as a model system, we describe here a systematic evaluation of these mutations by cell growth analysis, proteasome inhibition assays, and X-ray crystallography. The 11 mutants examined display decreased proliferation rates, impaired proteolytic activity, and marked resistance to bortezomib as well as the α',β'-epoxyketone inhibitors carfilzomib (Kyprolis) and ONX 0914, while the second-generation compound carfilzomib was the least affected. In total, 49 proteasome X-ray structures, including structural data on proteasome-carfilzomib complexes, reveal three distinct molecular mechanisms that hamper both drug binding and natural substrate turnover to an extent that is still compatible with cell survival.


Use of Hormone Replacement Therapy and Risk of Dementia: A Nationwide Cohort Study.
Estrogen has the potential to influence brain physiology implicated in dementia pathogenesis. Hormone replacement therapy (HRT) might be expected to influence the risk of dementia. Observational data indicated that HRT was associated with reductions in dementia risk, but experimental evidence demonstrates that HRT increases the incidence of dementia. To determine the effect of HRT on risk of dementia, a retrospective cohort study was performed using a nationwide claims dataset in Taiwan. A population-base longitudinal study was performed using data from the Longitudinal Health Insurance Database in Taiwan. A total of 35,024 women with HRT were enrolled as the exposed cohort and 70,048 women without HRT were selected on the basis of propensity matching as the comparison cohort. All of the subjects were followed up until the diagnosis of dementia, death, or at the end of December 31, 2013, whichever occurred first. Overall, the average duration of follow-up (±SD) in the HT and comparison cohort was 12.3(±2.3) and 12.2 (±2.4), respectively. The Cox proportional hazards regression models were conducted to produce hazard ratios (HRs) with 95% confidence intervals (CIs) to evaluate the association of HRT with the risk of dementia. In the follow-up period, the cumulative incidence of dementia for the HRT cohort (20.04 per 1,000) was significantly higher than the corresponding cumulative incidence for the comparison cohort (15.79 per 1,000), resulting in an adjusted hazard ratio of 1.35 (95% CI, 1.13-2.62). There was an increased risk of dementia with a higher cumulative dose of HRT prescription (p for trend <0.0001). This cohort study documented that HRT was associated with an increased risk of dementia. The clinical implications of this study merit further investigations.


The Perfect Stage of Powdery Mildew of Grapevine Caused by Erysiphe necator Found in Peru.
Grapevine (Vitis vinifera L.) has been cultivated in Peru since the sixteenth century to produce wine and grape brandy called "Pisco". Grapevine powdery mildew caused by Erysiphe necator (Schwein.) (formerly Uncinula necator [Schw.] Burr.; anamorph Oidium tuckeri) is currently the most important disease of grapevine in Peru. Table grape producers rely heavily on fungicide applications to manage powdery mildew infections. In Peru, the pathogen is normally found in the anamorphic state, except for one report of the teleomorphic state in 1972 (2) on wine grape varieties. In July 2011, ascomata were observed on table grapevine leaves cv. Sugraone in a commercial field near Huaral in the central coast of Peru. Abundant, mature (black) and immature (brown), globose ascocarps were visible on the abaxial leaf surfaces covered by the anamorphic state of the fungus. The chasmothecia were epiphyllous and ranged from 93.3 to 157.5 μm in diameter. The appendages were hyaline, variable in number (9 to 17), septate, with the apex helicoid when mature, and measuring 310 to 480 μm long. Each ascocarp contained four to seven subglobose asci (55.3 to 76.7 × 36.3 to 52.0 μm) with two to six (mostly three) ascospores. The ascospores were elliptical, hyaline, and measured 20.2 to 25.0 μm long by 11.1 to 17.3 μm wide. The pathogen was identified as E. necator on the basis of the host genus and morphology of the teleomorph (1). The teleomorphic state of E. necator could be a source of primary inoculum before infection by anamorphic conidia occurs, provide the basis for genetic recombination, and lead to more frequent appearance of new races. This could have serious implications for managing fungicide resistance in the pathogen population and may also result in the development of virulence to the resistance of some grape varieties tolerant to powdery mildew infections. In South America, the teleomorph of E. necator has been recently detected in Chile (3), and has caused great concern among grape producers. To our knowledge, this finding represents a first record of the presence of the ascigenous state of the pathogen on table grapes in Peru. References: (1) U. Braun. A Monograph of the Erysiphales (powdery mildews). J. Cramer, Berlin-Stuttgart, 1987. (2) S. L. Dongo and M. E. Arestegui. Fitopatologia 8:35, 1973. (3) F. Riveros et al. Aconex 83:24, 2004.


Bile acids in xenogeneic ex-vivo liver perfusion: function of xenoperfused livers and compatibility with human bile salts and porcine livers.
In recent years, hepatic support systems using xenogeneic cells have been developed to support patients in fulminant hepatic failure. The extent to which xenogeneic hepatocytes metabolize and excrete human organic anions is unclear. In these studies we examined the ability of the ex vivo porcine liver to clear human bile acids during extracorporeal liver perfusion (ELP). Four patients with fulminant hepatic failure underwent extracorporeal liver perfusion with 9 porcine livers. The venovenous circuit was designed as previously described (NEJM,1994,331:234) as were the immunologic features (Transplantation 1994,58:1162). Bile from the porcine liver and serum samples were collected hourly during perfusion. Three bile acids (glycocholic, glycodeoxycholic, taurodeoxycholic acid) were selected as markers for human bile and three (glycohyocholic, glycohyodeoxycholic, and glyco-3alpha-hydroxy-6-oxo-5beta-cholanoic acid) for markers of pig bile. Bile acids from both serum and bile were processed and analyzed through high performance liquid chromatography. The Students' t test was used for statistical analysis. The mean duration of perfusions was 4.1+/-1.5 hr. The mean total bile acid clearance from serum (243+/-44 micromol/h) was similar to the total bile acid biliary excretion (286+/-84 micromol/hr, P = 0.06). After 1 hr of perfusion, bile samples demonstrated a predominance of pig bile salts (65%). After 3 hr of perfusion, human bile acids made up 85% of total biliary bile acids. Pig bile acids appeared in patients' sera after 1 hr of perfusion, and after 3 hr, 35% of serum bile salts were pig-specific. Porcine livers perfused with human blood can clear the serum of potentially toxic human bile acids and excrete them into bile. Simultaneously, the percentage of pig-specific bile acids in patient serum increases during xenogeneic perfusion for unknown reasons. The relative hepatic uptake of bile acid from serum is similar to bile acid excretion in bile. Further development of systems using porcine livers or hepatocytes is warranted.


Results of the anatomic medullary locking total hip arthroplasty at a minimum of twenty years. A concise follow-up of previous reports.
Between October 1982 and December 1984, the senior author performed 223 total hip arthroplasties in 215 patients with use of the anatomic medullary locking hip stem and TriSpike cup. We now report on 119 of these hips at a mean of 22.0 years (range, 20.0 to 25.0 years) after surgery. Of the fifty-six hips with minimum twenty-year follow-up radiographs and the original acetabular component, seventeen (30.4%) had pelvic osteolytic lesions measuring larger than 1.5 cm(2). Of the sixty-eight hips with twenty-year radiographs and the original anatomic medullary locking stem, twenty-five (36.8%) had femoral osteolytic lesions measuring larger than 1.5 cm(2). Acetabular osteolysis was significantly associated with cup loosening (p = 0.006), but the presence of femoral osteolysis was not associated with stem loosening. Kaplan-Meier analysis, with revision for any reason as the end point, revealed that the survival rate at twenty years was 85.8% +/- 5.2% for the acetabular shell and 97.8% +/- 2.2% for the stem. The most common reoperation was polyethylene exchange because of wear or osteolysis.


The safety evaluation of food flavouring substances: the role of metabolic studies.
The safety assessment of a flavour substance examines several factors, including metabolic and physiological disposition data. The present article provides an overview of the metabolism and disposition of flavour substances by identifying general applicable principles of metabolism to illustrate how information on metabolic fate is taken into account in their safety evaluation. The metabolism of the majority of flavour substances involves a series both of enzymatic and non-enzymatic biotransformation that often results in products that are more hydrophilic and more readily excretable than their precursors. Flavours can undergo metabolic reactions, such as oxidation, reduction, or hydrolysis that alter a functional group relative to the parent compound. The altered functional group may serve as a reaction site for a subsequent metabolic transformation. Metabolic intermediates undergo conjugation with an endogenous agent such as glucuronic acid, sulphate, glutathione, amino acids, or acetate. Such conjugates are typically readily excreted through the kidneys and liver. This paper summarizes the types of metabolic reactions that have been documented for flavour substances that are added to the human food chain, the methodologies available for metabolic studies, and the factors that affect the metabolic fate of a flavour substance.


Analysis of the genetic loci of pigment pattern evolution in vertebrates.
Vertebrate pigmentation patterns are amongst the best characterised model systems for studying the genetic basis of adaptive evolution. The wealth of available data on the genetic basis for pigmentation evolution allows for analysis of trends and quantitative testing of evolutionary hypotheses. We employed Gephebase, a database of genetic variants associated with natural and domesticated trait variation, to examine trends in how cis-regulatory and coding mutations contribute to vertebrate pigmentation phenotypes, as well as factors that favour one mutation type over the other. We found that studies with lower ascertainment bias identified higher proportions of cis-regulatory mutations, and that cis-regulatory mutations were more common amongst animals harbouring a higher number of pigment cell classes. We classified pigmentation traits firstly according to their physiological basis and secondly according to whether they affect colour or pattern, and identified that carotenoid-based pigmentation and variation in pattern boundaries are preferentially associated with cis-regulatory change. We also classified genes according to their developmental, cellular, and molecular functions. We found a greater proportion of cis-regulatory mutations in genes implicated in upstream developmental processes compared to those involved in downstream cellular functions, and that ligands were associated with a higher proportion of cis-regulatory mutations than their respective receptors. Based on these trends, we discuss future directions for research in vertebrate pigmentation evolution.


A homozygous nonsense variant in IFT52 is associated with a human skeletal ciliopathy.
Intraflagellar transport (IFT) is vital for the functioning of primary cilia. Defects in several components of IFT complexes cause a spectrum of ciliopathies with variable involvement of skeleton, brain, eyes, ectoderm and kidneys. We examined a child from a consanguineous family who had short stature, narrow thorax, short hands and feet, postaxial polydactyly of hands, pigmentary retinopathy, small teeth and skeletal dysplasia. The clinical phenotype of the child shows significant overlap with cranioectodermal dysplasia type I (Sensenbrenner syndrome). Whole-exome sequencing revealed a homozygous nonsense variant p.R142* in IFT52 encoding an IFT-B core complex protein as the probable cause of her condition. This is the first report of a human disease associated with IFT52.


Two approaches to estimating the effect of parenting on the development of executive function in early childhood.
In the current article, we contrast 2 analytical approaches to estimate the relation of parenting to executive function development in a sample of 1,292 children assessed longitudinally between the ages of 36 and 60 months of age. Children were administered a newly developed and validated battery of 6 executive function tasks tapping inhibitory control, working memory, and attention shifting. Residualized change analysis indicated that higher quality parenting as indicated by higher scores on widely used measures of parenting at both earlier and later time points predicted more positive gain in executive function at 60 months. Latent change score models in which parenting and executive function over time were held to standards of longitudinal measurement invariance provided additional evidence of the association between change in parenting quality and change in executive function. In these models, cross-lagged paths indicated that in addition to parenting predicting change in executive function, executive function bidirectionally predicted change in parenting quality. Results were robust with the addition of covariates, including child sex, race, maternal education, and household income-to-need. Strengths and drawbacks of the 2 analytic approaches are discussed, and the findings are considered in light of emerging methodological innovations for testing the extent to which executive function is malleable and open to the influence of experience.


Medication Initiation Burden Required to Comply With Heart Failure Guideline Recommendations and Hospital Quality Measures.
Guidelines for heart failure (HF) recommend prescription of guideline-directed medical therapy before hospital discharge; some of these therapies are included in publicly reported performance measures. The burden of new medications for individual patients has not been described. We used Get With The Guidelines-HF registry data from 2008 to 2013 to characterize prescribing, indications, and contraindications for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, aldosterone antagonists, hydralazine/isosorbide dinitrate, and anticoagulants. The difference between a patient's medication regimen at hospital admission and that recommended by HF quality measures at discharge was calculated. Among 158 922 patients from 271 hospitals with a primary discharge diagnosis of HF, initiation of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was indicated in 18.1% of all patients (55.5% of those eligible at discharge were not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers at admission), β-blockers in 20.3% (50.5% of eligible), aldosterone antagonists in 24.1% (87.4% of eligible), hydralazine/isosorbide dinitrate in 8.6% (93.1% of eligible), and anticoagulants in 18.0% (58.0% of eligible). Cumulatively, 0.4% of patients were eligible for 5 new medication groups, 4.1% for 4 new medication groups, 9.4% for 3 new medication groups, 10.1% for 2 new medication groups, and 22.7% for 1 new medication group; 15.0% were not eligible for new medications because of adequate prescribing at admission; and 38.4% were not eligible for any medications recommended by HF quality measures. Compared with newly indicated medications (mean, 1.45 ± 1.23), actual new prescriptions were lower (mean, 1.16 ± 1.00). A quarter of patients hospitalized with HF need to start >1 medication to meet HF quality measures. Systems for addressing medication initiation and managing polypharmacy are central to HF transitional care.


Cyclombandakamines A1 and A2, Oxygen-Bridged Naphthylisoquinoline Dimers from a Congolese Ancistrocladus Liana.
Cyclombandakamines A1 (1) and A2 (2), both with an unprecedented pyrane-cyclohexenone-dihydrofuran sequence and six stereocenters and two chiral axes, are the first oxygen-bridged dimeric naphthylisoquinoline alkaloids. They were isolated from the leaves of an as yet unidentified Congolese Ancistrocladus species. Their stereostructures were established by spectroscopic, chemical, and chiroptical methods in combination with DFT and TDDFT calculations. They apparently originate from a cascade of oxidative cyclization reactions of "open-chain" naphthylisoquinoline dimers and exhibit significant antiprotozoal activities.


Peripheral axotomy-induced changes of motor function and histological structure of spinal anterior horn.
The aim of this study was to evaluate changes of both peripheral motor function and histology of spinal anterior horn in adult rats after unilateral sciatectomy. Ten adult healthy rats served as control group, while in the ten rat experimental group the right sciatic nerve was severed. We followed-up nerve motor function using a sciatic function index and electromyography activity of the gastrocnemious muscle. The rats of the experimental group presented the expected gross locomotor deficit and leg muscle atrophy. At 12 weeks post sciatectomy, L4 and L5 spinal cord segments were removed from the twenty rats and were analysed by istological stereological methods. In the axotomized animals volume of the anterior horn and its content of motor neurons decreased, while the content of astrocytes increased (p < 0.05). Thus, in adult rats, beside the obvious peripheral nerve disfuction, the sciatic nerve axotomy have severe consequences on the soma of the injured motor neurons in the spinal anterior horn. All these quantitative analyses may be usefull to quantify changes occurring in adult animals after axotomy and eventual management to modify the final outcomes in peripheral nerve disorders.


A Salmonella typhimurium virulence gene linked to flg.
Isogenic pairs of strains of Salmonella typhimurium which differed only in whether or not they were flagellate were found to be equally virulent in C57BL/6J mice infected orally, intravenously, or intraperitoneally. Therefore, we investigated the genetic basis for our previous observation that in this mouse model, nonflagellate delta flagABCDE25 strains were reduced in virulence compared with isogenic wild-type flagellate strains. The recombinant plasmid pMH6, which contains several flg+ genes and a segment of the S. typhimurium chromosome adjacent to the flg genes, was introduced into a delta flgABCDE25 mutant. This restored virulence in mice challenged intraperitoneally, which suggested that a virulence gene occurs adjacent to the flg genes. When plasmid pMH64, which lacks the chromosomal segment adjacent to the flg genes, was introduced into the same delta flgABCDE25 mutant, virulence was not restored. In contrast, the introduction of pMH71, a plasmid which retains the chromosomal segment adjacent to the flg genes, restored virulence. We concluded that a hitherto unknown virulence gene, which we have named mviS, occurs adjacent to the flg genes and that its absence in delta flgABCDE25 mutants, rather than the nonflagellate phenotype of the delta flgABCDE25 mutants, caused the previously reported attenuation of such mutants.


Increased expression of insulin-like growth factor-I in serum and liver after recombinant human growth hormone administration in thermally injured rats.
Recombinant human growth hormone (rhGH) has been shown to modulate the hypermetabolic response and the hepatic acute-phase response after thermal injury. In vitro studies, however, demonstrated that rhGH activates insulin-like growth factor-I (IGF-I) gene transcription and production, suggesting that rhGH may exert some of its effects indirectly through IGF-I stimulation. The purpose of this study was to determine the effects of rhGH on serum and hepatic IGF-I in thermally injured rats. Sprague-Dawley rats (56 males) receiving a 60% TBSA third-degree scald burn were randomly divided to receive either rhGH (2.5 mg/kg/day im) or saline (control). Rats were sacrificed on postburn days 1, 2, 5, and 7 and serum IGF-I, hepatic IGF-I mRNA, and IGF-I protein concentration were measured. The physiologic response to changes in IGF-I levels was evaluated by measuring hepatocyte proliferation, total liver protein concentration, and muscle dry/wet weights. Serum IGF-I was increased from postburn day 1 through day 7 in rats receiving rhGH compared to controls (P < 0.05). Hepatic IGF-I mRNA and IGF-I protein expression were increased from day 1 to 7 after burn in animals receiving rhGH when compared to controls (P < 0.05). Recombinant hGH increased hepatocyte proliferation at 5 days and total liver protein concentration at 5 and 7 days postburn compared to controls (P < 0.05). Muscle dry/wet weights increased in rats receiving rhGH at 7 days after burn compared to controls (P < 0.05). Liver and serum IGF-I levels decreased after a thermal injury. Recombinant hGH attenuated this decrease by stimulating hepatic IGF-I expression. Increases in IGF-I were associated with increases in hepatocyte proliferation and protein concentration in liver and muscle. We suggest that rhGH modulates the hypermetabolic response through IGF-I stimulation in the hepatic parenchyma.


Evaluation of the pulmonary effects of short-term nose-only cigarette smoke exposure in mice.
Much is known about the chronic effects of cigarette smoke (CS) on lung function and inflammation and development of chronic obstructive pulmonary disease. However, the underlying pathophysiological mechanisms related to the short-term exposure to CS are not fully understood. Here, we assessed the effect of CS generated by nine consecutive cigarettes per day for four days in a nose-only exposure system on airway resistance measured using forced oscillation technique, lung inflammation and oxidative stress in BALB/c mice. Control mice were exposed to air. Mice exposed to CS showed a significant increase of neutrophils and lymphocytes numbers in bronchoalveolar lavage (BAL). The total protein and endothelin levels in BAL fluid were significantly augmented suggesting an increase of alveolar-capillary barrier permeability. Similarly, airway resistance was significantly increased in the CS group compared with controls. Furthermore, reactive oxygen species and lipid peroxidation levels in lung tissue were significantly increased. The antioxidant activities of reduced glutathione, glutathione S transferase and superoxide dismutase were all significantly increased following CS exposure, indicating that CS could trigger adaptive responses that counterbalance the potentially damaging activity of oxygen radicals induced by CS exposure. In conclusion, our data indicate that short-term nose-only exposure to CS causes lung inflammation and increase of airway resistance mediated at least partly through the oxidative stress.


Prevalence, sources, and predictors of soy consumption in breast cancer.
A number of components in soy appear to have anticancer properties, including the isoflavones, genistein and daidzein. The use of soy by women with breast cancer is now being questioned because of the estrogen-like effects of isoflavones and possible interactions with tamoxifen. Clinicians providing nutrition counseling to these women are concerned because the availability of soy foods has increased dramatically in the past few years. The goal of this study was to quantify the intake of isoflavones in women with breast cancer. A cross-sectional study of 100 women with breast cancer treated at Cancer Treatment Centers of America(R) between 09/03 and 02/04. Each patient completed a soy food frequency questionnaire (FFQ) that was scored by Fred Hutchinson Cancer Research Center. Demographic and clinical predictors of soy intake were evaluated using one-way non-parametric Mann Whitney test and non-parametric spearman's rank correlation. Mean age was 50.5 years (std. dev. = 9.4; range 31-70) and mean BMI was 27.3 kg/m2 (std. dev. = 6.75; range 17-59). Genistein and Daidzein consumption was limited to 65 patients with a mean intake of 11.6 mg/day (std. dev. = 21.9; range 0-97.4) and 7.6 mg/day (std. dev. = 14.1; range 0-68.9) respectively. Soy milk (37%) and pills containing soy, isoflavones, or "natural" estrogen (24%) were the two biggest contributors to isoflavone intake. Our study suggests that the isoflavone intake of breast cancer patients at our hospital was quite variable. Thirty-five patients reported no soy intake. The mean daily intake of 11.6 mg genistein and 7.4 mg daidzein, is the equivalent of less than 1/4 cup of tofu per day. This amount is higher than what has been previously reported in non-Asian American women.


Topological aspects of charge-carrier transmission across grain boundaries in graphene.
Dislocations and grain boundaries are intrinsic topological defects of large-scale polycrystalline samples of graphene. These structural irregularities have been shown to strongly affect electronic transport in this material. Here, we report a systematic investigation of the transmission of charge carriers across the grain-boundary defects in polycrystalline graphene by means of the Landauer-Büttiker formalism within the tight-binding approximation. Calculations reveal a strong suppression of transmission at low energies upon decreasing the density of dislocations with the smallest Burgers vector b = (1,0). The observed transport anomaly is explained from the point of view of resonant backscattering due to localized states of topological origin. These states are related to the gauge field associated with all dislocations characterized by b = (n,m) with n - m ≠ 3q (q ∈ Z). Our work identifies an important source of charge-carrier scattering caused by the topological defects present in large-area graphene samples produced by chemical vapor deposition.


Predictive Value of the Cognitive Performance Test (CPT) for Staging Function and Fitness to Drive in People With Neurocognitive Disorders.
The Cognitive Performance Test (CPT) is a standardized occupational therapy assessment that examines cognitive integration with functioning in an instrumental activities of daily living context. Conventional cognitive measures provide diagnostic utility but do not fully address the functional implications. Ninety-one veterans diagnosed with cognitive impairment were evaluated. We compared the predictive value of the CPT with the Large Allen Cognitive Level Screen (LACLS), Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA) for the need to retire from driving versus ability to pass an on-road exam. Measures were also analyzed by diagnostic classification. CPT correctly classified a mild versus major neurocognitive disorder, whereas MMSE, MoCA, and LACLS did not differentiate the groups. A CPT cutoff score of <4.7/5.6 showed 89% sensitivity for failing the road exam and 75% specificity for ability to pass. CPT discriminated functional level in neurocognitive disorders and had better predictive value for fitness to drive compared with conventional cognitive measures.


Relationship between muscle strength, power and stiffness and running economy in trained male runners.
In this study, a comparison was made between muscle strength, power and muscle and tendon (km and kt respectively) stiffness of the triceps surae muscle group and running economy (RE) in trained male runners. Twelve well-trained male runners (age = 21 +/- 2.7 y, height = 178.1 +/- 7.1 cm, body mass = 66.7 +/- 3.2 kg, VO2max = 68.3 +/- 4.3 mL x kg(-1) x min(-1), 5000-m time = 15:04 min:s) underwent passive stiffness testing using a free oscillation method. Muscle strength was determined via a maximal isometric squat test and power determined via a maximal countermovement jump (CMJ). On a separate day, subjects performed an incremental treadmill test and their RE, lactate threshold, and VO2max were determined. Fingertip blood lactate was determined at the end of each 3-min stage. Lactate threshold was defined as a nonlinear increase in lactate accumulation. A statistically significant correlation was found between km and VO2 at stage 6 (r = -0.69, P = .01). In addition, statistically significant correlations were observed between CMJ peak force production and VO2 at stage 2 (r = .66, P = .02), stage 3 (r = .70, P = .01), and stage 4 (r = .58, P = .04). No other statistically significant correlations were observed. These data suggest that greater muscle stiffness and less power are associated with greater RE. Future study in this area should focus on determining the mechanisms behind this relationship and how to best apply them to a running population through training techniques.