Role of protein-protein interactions in cytochrome P450-mediated drug metabolism and toxicity.
Through their unique oxidative chemistry, cytochrome P450 monooxygenases (CYPs) catalyze the elimination of most drugs and toxins from the human body. Protein-protein interactions play a critical role in this process. Historically, the study of CYP-protein interactions has focused on their electron transfer partners and allosteric mediators, cytochrome P450 reductase and cytochrome b5. However, CYPs can bind other proteins that also affect CYP function. Some examples include the progesterone receptor membrane component 1, damage resistance protein 1, human and bovine serum albumin, and intestinal fatty acid binding protein, in addition to other CYP isoforms. Furthermore, disruption of these interactions can lead to altered paths of metabolism and the production of toxic metabolites. In this review, we summarize the available evidence for CYP protein-protein interactions from the literature and offer a discussion of the potential impact of future studies aimed at characterizing noncanonical protein-protein interactions with CYP enzymes.


Evaluating multi-purpose syndromic surveillance systems - a complex problem.
Surveillance systems need to be evaluated to understand what the system can or cannot detect. The measures commonly used to quantify detection capabilities are sensitivity, positive predictive value and timeliness. However, the practical application of these measures to multi-purpose syndromic surveillance services is complex. Specifically, it is very difficult to link definitive lists of what the service is intended to detect and what was detected. First, we discuss issues arising from a multi-purpose system, which is designed to detect a wide range of health threats, and where individual indicators, e.g. 'fever', are also multi-purpose. Secondly, we discuss different methods of defining what can be detected, including historical events and simulations. Finally, we consider the additional complexity of evaluating a service which incorporates human decision-making alongside an automated detection algorithm. Understanding the complexities involved in evaluating multi-purpose systems helps design appropriate methods to describe their detection capabilities.


Stroke: the increasing complexity of carer needs.
In Australia, more than 346,000 individuals who experience a stroke return to living in their homes with varying degrees of disability. They rely on emotional and physical support from informal carers, typically family members. Informal carers have an indispensable role in patient care poststroke, and the ability of carers to manage this role effectively is crucial for stroke survivors to be able to return home. The aim of this study was to examine the impact of the caring role on carers of stroke survivors, particularly the services provided and the levels of depression and well-being experienced. The study used a longitudinal design incorporating survey methods. Stroke survivors were assessed for functional ability, quality of life, and depression using three assessment tools: the Stroke Impact Scale, World Health Organization Quality of Life-BREF scale, and Zung Self-Rating Depression Scale. A total of 26 people were surveyed: 13 stroke survivors and their 13 carers. Carer knowledge of stroke support services was also explored. Information was collected by using survey methods and structured interviews at 3 weeks and at 3 months postdischarge. The main finding was that depression scores for carers and stroke survivors were below Australian norms at both assessment time points. The major concern identified by carers was poor follow-up procedures for initiating rehabilitation in the home. This study highlighted that a lack of appropriate discharge planning, in conjunction with early discharge of stroke survivors, can have an impact on the rehabilitation process and place increased and unrealistic demands on carers.


What differentiates method stoppers from switchers? Contraceptive discontinuation and switching among Honduran women.
Contraceptive discontinuation contributes to unplanned pregnancy and unwanted births, as well as increased maternal, neonatal and infant morbidity and mortality. Information on differences between women who stop using contraceptives and those who switch to another method would be useful for programs aimed at preventing unplanned pregnancies and their consequences. Data come from two rounds of interviews with women aged 15-44 (800 interviewed at baseline and 671 reinterviewed one year later) who were new or continuing users of injectable or oral contraceptives or an IUD. Bivariate analysis examined associations between attitudes and behaviors of women who discontinued their baseline method and side effects they experienced. Multivariate logistic regression assessed differences between women who switched methods immediately or within one month of discontinuation and those who stopped contraceptive use for one month or more. Of the 671 women who were reinterviewed, 41% (273) discontinued use of their baseline contraceptive method within the one-year follow-up; of those, 43% (117) switched to a new method, and 57% (156) stopped for one month or more. Seeking help with side effects from a health worker, urban residence, talking to a partner about the decision to discontinue, and new and recent method adoption were associated with increased odds of switching methods (odds ratios, 2.0-3.5). Access to high-quality family planning services and encouraging discussion with partners and families before stopping contraceptive use is important for women who experience side effects from contraceptive methods and are at risk of discontinuation.


Reversible cardiac disease features in an inducible CUG repeat RNA-expressing mouse model of myotonic dystrophy.
Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the DMPK gene. Expression of pathogenic expanded CUG repeat (CUGexp) RNA causes multisystemic disease by perturbing the functions of RNA-binding proteins, resulting in expression of fetal protein isoforms in adult tissues. Cardiac involvement affects 50% of individuals with DM1 and causes 25% of disease-related deaths. We developed a transgenic mouse model for tetracycline-inducible and heart-specific expression of human DMPK mRNA containing 960 CUG repeats. CUGexp RNA is expressed in atria and ventricles and induced mice exhibit electrophysiological and molecular features of DM1 disease, including cardiac conduction delays, supraventricular arrhythmias, nuclear RNA foci with Muscleblind protein colocalization, and alternative splicing defects. Importantly, these phenotypes were rescued upon loss of CUGexp RNA expression. Transcriptome analysis revealed gene expression and alternative splicing changes in ion transport genes that are associated with inherited cardiac conduction diseases, including a subset of genes involved in calcium handling. Consistent with RNA-Seq results, calcium-handling defects were identified in atrial cardiomyocytes isolated from mice expressing CUGexp RNA. These results identify potential tissue-specific mechanisms contributing to cardiac pathogenesis in DM1 and demonstrate the utility of reversible phenotypes in our model to facilitate development of targeted therapeutic approaches.


At-4/1, an interactor of the Tomato spotted wilt virus movement protein, belongs to a new family of plant proteins capable of directed intra- and intercellular trafficking.
The Tomato spotted wilt virus (TSWV) encoded NSm movement protein facilitates cell-to-cell spread of the viral genome through structurally modified plasmodesmata. NSm has been utilized as bait in yeast two-hybrid interaction trap screenings. As a result, a protein of unknown function, called At-4/1, was isolated from an Arabidopsis thaliana GAL4 activation domain-tagged cDNA library. Using polyclonal antibodies against bacterially expressed At-4/1, Western blot analysis of protein extracts isolated from different plant species as well as genome database screenings showed that homologues of At-4/1 seemed to be encoded by many vascular plants. For subcellular localization studies, At-4/1 was fused to green fluorescent protein, and corresponding expression vectors were used in particle bombardment and agroinfiltration assays. Confocal laser scannings revealed that At-4/1 assembled in punctate spots at the cell periphery. The protein accumulated intracellularly in a polarized fashion, appearing in only one-half of a bombarded epidermal cell, and, moreover, moved from cell to cell, forming twin-structured bodies seemingly located at both orifices of the plasmodesmatal pore. In coexpression studies, At-4/1 colocalized with a plant virus movement protein TGBp3 known to reside in endoplasmic reticulum-derived membrane structures located in close vicinity to plasmodesmata. Thus, At-4/1 belongs to a new family of plant proteins capable of directed intra- and intercellular trafficking.


Venous thrombotic, thromboembolic, and mechanical complications after retrievable inferior vena cava filters for major trauma.
The ideal thromboprophylaxis in patients at risk of bleeding is uncertain. This retrospective cohort study assessed the risk factors for complications after using retrievable inferior vena cava (IVC) filters for primary or secondary thromboembolism prophylaxis in patients after major trauma. Using data from radiology, trauma and death registries, the incidence of and risk factors for subsequent deep venous thrombosis (DVT), venous thromboembolism (VTE), and mechanical complications related to retrievable IVC filters in patients, admitted between 2007 and 2012, were assessed in a single trauma centre. Of the 2940 major trauma patients admitted during the study period, a retrievable IVC filter was used in 223 patients (7.6%). Thirty-six patients (16%) developed DVT or VTE subsequent to placement of IVC filters (median 20 days, interquartile range 9-33), including 27 with lower limb (DVT), 8 upper limb DVT, and 4 pulmonary embolism. A high Injury Severity Score, tibial/fibular fractures, and a delay in initiating pharmacological thromboprophylaxis after insertion of the filters (14 vs 7 days, P=0.001) were significant risk factors. Thirty patients were lost to follow-up (13%) and their filters were not retrieved. Mechanical complications-including filters adherent to the wall of IVC (4.9%), IVC thrombus (4.0%), and displaced or tilted filters (2.2%)-were common when the filters were left in situ for >50 days. A delay in initiating pharmacological thromboprophylaxis or filter removal were associated with an increased risk of subsequent DVT, VTE, and mechanical complications of retrievable IVC filters in patients after major trauma.


Social Environmental Influences on Physical Activity of Children With Autism Spectrum Disorders.
Children with Autism Spectrum Disorders (ASD) may be at greater risk for not meeting physical activity (PA) guidelines than neurotypical children (NT). The purpose of this study was to explore setting (free play versus organized) and social group composition influences on PA of children with ASD during summer camp. Data were collected on 6 ASD and 6 NT boys (aged 5 to 6 years) attending an inclusive summer camp. During free play and organized activity, research assistants observed the camp's social environment and children's PA using a modified version of the Observational System for Recording Physical Activity of Children-Preschool version. In free play, children with ASD spent significantly less time in Moderate-Vigorous PA (MVPA) while with a peer (1.2%), compared with a peer group (11.5%) or alone (13.2%). They demonstrated significantly more Light-Moderate-Vigorous PA (LMVPA) while in a solitary social context (68.2%) compared with alone with an adult (25.8%), alone with a peer (34.8%), or with a peer group (28.2%). No significant differences were noted during organized activity. Features of the social environment may influence PA levels of children with ASD. Specifically, certain social group contexts may be more PA-promoting than others depending on the setting.


Altered Gut Microbiome and Intestinal Pathology in Parkinson's Disease.
Parkinson's disease (PD) is a common neurodegenerative disorder arising from an interplay between genetic and environmental risk factors. Studies have suggested that the pathological hallmarks of intraneuronal α-synuclein aggregations may start from the olfactory bulb and the enteric nervous system of the gut and later propagate to the brain via the olfactory tract and the vagus nerve. This hypothesis correlates well with clinical symptoms, such as constipation, that may develop up to 20 years before the onset of PD motor symptoms. Recent interest in the gut-brain axis has led to vigorous research into the gastrointestinal pathology and gut microbiota changes in patients with PD. In this review, we provide current clinical and pathological evidence of gut involvement in PD by summarizing the changes in gut microbiota composition and gut inflammation associated with its pathogenesis.


Fast microfluidic temperature control for high resolution live cell imaging.
One major advantage of using genetically tractable model organisms such as the fission yeast Schizosaccharomyces pombe is the ability to construct temperature-sensitive mutations in a gene. The resulting gene product or protein behaves as wildtype at permissive temperatures. At non-permissive or restrictive temperatures the protein becomes unstable and some or all of its functions are abrogated. The protein regains its function when returning to a permissive temperature. In principle, temperature-sensitive mutation enables precise temporal control of protein activity when coupled to a fast temperature controller. Current commercial temperature control devices do not have fast switching capability over a wide range of temperatures, making repeated temperature changes impossible or impractical at the cellular timescale of seconds or minutes. Microfabrication using soft-lithography is emerging as a powerful tool for cell biological research. We present here a simple disposable polydimethylsiloxane (PDMS) based microfluidic device capable of reversibly switching between 5 °C and 45 °C in less than 10 s. This device allows high-resolution live cell imaging with an oil immersion objective lens. We demonstrate the utility of this device for studying microtubule dynamics throughout the cell cycle.


Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration.
Premutation CGG repeat expansions (55-200 CGG repeats; preCGG) within the fragile X mental retardation 1 (FMR1) gene give rise to the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), primary ovarian insufficiency and neurodevelopmental problems. Morphometric analysis of Map2B immunofluorescence reveals that neurons cultured from heterozygous female mice with preCGG repeats in defined medium display shorter dendritic lengths and fewer branches between 7 and 21 days in vitro compared with wild-type (WT) littermates. Although the numbers of synapsin and phalloidin puncta do not differ from WT, preCGG neurons possess larger puncta. PreCGG neurons display lower viability, and express elevated stress protein as they mature. PreCGG neurons have inherently different patterns of growth, dendritic complexity and synaptic architecture discernable early in the neuronal trajectory to maturation, and may reflect a cellular basis for the developmental component of the spectrum of clinical involvement in carriers of premutation alleles. The reduced viability of preCGG neurons is consistent with the mRNA toxicity and neurodegeneration associated with FXTAS.


Ganoderma carnosum and Ganoderma pfeifferi: Metal concentration, phenolic content, and biological activity.
Medicinal Ganoderma mushrooms have long tradition in Asia, and recently they began to be consumed in Europe as well. Among hundreds of Ganoderma species, only a few of them are intensively investigated, i.e., G. lucidum and G. applanatum, whereas the chemistry and bioactivities of the other species, especially of European origin, still remain unknown. This study comprises detailed chemical analysis of two Ganoderma species growing wild in Turkey, G. pfeifferi and G. carnosum. Metal composition of both species shows high concentrations of biogenic metals. Phenolic composition of the isolated extracts of G. carnosum and G. pfeifferi shows that these species are rich in simple phenolic acids, such as 2,5-dihydroxybenzoic acid and vanillic acid, but also in flavonoids. These compounds are found to be carriers of the antioxidant activity but also enzyme inhibition activity of the analyzed extracts. Overall results indicate that these two Ganoderma species have strong potential to be used for medicinal purposes.


Impact of cocoa flavanol consumption on blood pressure responsiveness to exercise.
Impaired endothelial vasodilatation may contribute to the exaggerated blood pressure (BP) responses to exercise in individuals who are overweight/obese. The present study investigated whether consumption of cocoa flavanols, which improve endothelium-dependent flow-mediated dilatation (FMD), can modify BP responsiveness to exercise. Twenty-one volunteers (eight females and thirteen males, 54.9 (se 2.2) years, BMI 31.6 (se 0.8) kg/m2, systolic BP 134 (se 2) mmHg, diastolic BP (DBP) 87 (se 2) mmHg) were randomised to consume single servings of either a high-flavanol (HF, 701 mg) or a low-flavanol (LF, 22 mg) cocoa beverage in a double-blind, cross-over design with 3-7-d washout between treatments. Two hours after cocoa consumption, FMD was measured, followed by continuous beat-to-beat assessment (Finapres) of BP before and during 10 min of cycling at 75 % of age-predicted maximum heart rate. Averaged data from two assessments on each type of beverage were compared by analysis of covariance using pre-exercise BP as the covariate. Pre-exercise BP was similar after taking LF and HF (153 (se 3)/88 (se 3) v. 153 (se 4)/87 (se 2) mmHg, respectively, P>0.05). However, the BP response to exercise (area under BP curve) was attenuated by HF compared with LF. BP increases were 68 % lower for DBP (P = 0.03) and 14 % lower for mean BP (P = 0.05). FMD measurements were higher after taking HF than after taking LF (6.1 (se 0.6) % v. 3.4 (se 0.5) %, P < 0.001). By facilitating vasodilation and attenuating exercise-induced increases in BP, cocoa flavanols may decrease cardiovascular risk and enhance the cardiovascular benefits of moderate intensity exercise in at-risk individuals.


Triple role of phenylselenonyl group enabled a one-pot synthesis of 1,3-oxazinan-2-ones from α-isocyanoacetates, phenyl vinyl selenones, and water.
Reaction of α-substituted α-isocyanoacetates with phenyl vinyl selenones in the presence of a catalytic amount of base (DBU or Et3N, 0.05-0.1 equiv) followed by addition of p-toluenesulfonic acid (PTSA, 0.1-0.2 equiv) afforded 4,4,5-trisubstituted 1,3-oxazinan-2-ones in good to excellent yields. Enantiomerically enriched heterocycles can also be prepared using a Cinchona alkaloid-derived bifunctional organocatalyst for the Michael addition step. The phenylselenonyl group served as an activator for the Michael addition, a leaving group and a latent oxidant in this integrated reaction sequence.


Identification of key peptide-specific CD4+ T cell responses to human cytomegalovirus: implications for tracking antiviral populations.
Human cytomegalovirus (CMV) infection is normally controlled effectively by the immune response, including CD4(+) T cells. Large numbers of these cells are present in healthy seropositive individuals but their loss in immunosuppression leads to reactivation and disease. Tracking such responses in vivo is hampered by poor definition of their peptide targets. In this study, we defined the key targets of the peptide-specific CD4(+) T cell responses to the CMV pp65 protein using functional assays and a peptide library. Despite a good deal of interindividual variation in the numbers of peptides recognized, responses to CMV pp65 were strikingly targeted at three key epitopes. A response to one or more of these three key peptides was seen in all individuals tested (P < 0.0001) and this finding was tested and reproduced in a second independent population. The most common response identified was that to a DR53 restricted epitope, aa281-295. HLA-DR1 restricted CMV pp65-specific populations, although reproducibly detected, were of low frequency ex vivo. However, it was possible to detect and phenotype these cells using an enrichment protocol and this revealed them to have 'effector memory' status although, in contrast to CD8(+) T cell responses, these were CD45RA(-). These data suggest that CD4(+) T cell responses to CMV can be identified reliably using a pool of just three peptides. This simple approach will provide a robust and reliable as well as economic method for tracking peptide specific populations in health and disease.


P2X7 receptor activation contributes to an initial upstream mechanism of lipopolysaccharide-induced vascular dysfunction.
Pro-inflammatory cytokines, chemokines and ROS (reactive oxygen species) are excessively produced in endotoxaemia. However, attempting to inhibit all of these inflammatory signalling pathways at the same time in order to prevent endotoxaemia is difficult. In a previous study we observed that activation of P2X7 receptors elicited the release of IL (interleukin)-1β from LPS (lipopolysaccharide)-incubated vessels. In the present study, we hypothesize that P2X7 receptor activation is the initial event leading to vascular dysfunction following LPS treatment. LPS-induced decreases in MAP (mean arterial pressure) and pressor responses to NE (noradrenaline) were attenuated in P2X7KO (P2X7-knockout) mice. Hyporeactivity in response to PE (phenylephrine) in isolated mesenteric arteries by LPS treatment was also observed in C57BL/6 [WT (wild-type)] mice, which was prevented by IL1ra (IL-1 receptor antagonist), L-NAME (N(G)-nitro-L-arginine methyl ester) and indomethacin and in P2X7KO mice. In addition, treatment with IL1ra plus L-NAME produced an additive inhibition of LPS-induced vascular hyporeactivity, suggesting different signalling pathways between IL-1β and NOS (NO synthase). LPS-induced plasma levels of IL-1β, TNFα (tumour necrosis factor α), IL-10, vascular eNOS (endothelial NOS) and COX2 (cyclo-oxygenase 2) protein expression, as determined by ELISA and Western blot, observed in WT mice were inhibited by IL1ra and in P2X7KO mice. These results suggest that P2X7 receptor activation involves an initial upstream mechanism of LPS-induced vascular dysfunction, which is associated with IL-1β-mediated eNOS, COX2 activation and TNFα release.


MicroRNA-34a upregulation during seizure-induced neuronal death.
MicroRNAs (miRNAs) are short, noncoding RNAs that function as posttranscriptional regulators of gene expression by controlling translation of mRNAs. A subset of miRNAs may be critical for the control of cell death, including the p53-regulated miRNA, miR-34a. Because seizures activate p53, and p53-deficient mice are reportedly resistant to damage caused by prolonged seizures, we investigated the role of miR-34a in seizure-induced neuronal death in vivo. Status epilepticus was induced by intra-amygdala microinjection of kainic acid in mice. This led to an early (2 h) multifold upregulation of miR-34a in the CA3 and CA1 hippocampal subfields and lower protein levels of mitogen-activated kinase kinase kinase 9, a validated miR-34a target. Immunoprecipitation of the RNA-induced silencing complex component, Argonaute-2, eluted significantly higher levels of miR-34a after seizures. Injection of mice with pifithrin-α, a putative p53 inhibitor, prevented miR-34a upregulation after seizures. Intracerebroventricular injection of antagomirs targeting miR-34a reduced hippocampal miR-34a levels and had a small modulatory effect on apoptosis-associated signaling, but did not prevent hippocampal neuronal death in models of either severe or moderate severity status epilepticus. Thus, prolonged seizures cause subfield-specific, temporally restricted upregulation of miR-34a, which may be p53 dependent, but miR-34a is probably not important for seizure-induced neuronal death in this model.


Dietary calcium and cholecalciferol modulate cyclin D1 expression, apoptosis, and tumorigenesis in intestine of adenomatous polyposis coli1638N/+ mice.
Both epidemiological and experimental findings have indicated that components of Western diets influence colonic tumorigenesis. Among dietary constituents, calcium and cholecalciferol have emerged as promising chemopreventive agents. We have demonstrated that a Western-style diet (WD) with low levels of calcium and cholecalciferol and high levels of (n-6) PUFA, increased the incidence of neoplasia in mouse intestine compared with a standard AIN-76A diet; models included wild-type mice and mice with targeted mutations. In the present study, adenomatous polyposis coli (Apc)(1638N/+) mice carrying a heterozygous Apc mutation were fed either an AIN-76A diet, a WD, or a WD supplemented with calcium and cholecalciferol (WD/Ca/VitD3). Diets were fed for 24 wk and effects on cellular and molecular events were assessed by performing immunohistochemistry in colonic epithelium along the crypt-to-surface continuum. Feeding WD to Apc(1638N/+) mice not only enhanced cyclin D1 expression in colonic epithelium compared with AIN-76A treatment as previously reported but also significantly increased the expression of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) concomitantly with a decrease in the proapoptotic Bcl2-associated X protein and the number of apoptotic epithelial cells. WD treatment enhanced mutant Apc-driven small intestinal carcinogenesis and also resulted in the formation of a small number of colonic adenomas (0.16 +/- 0.09; P < 0.05). By contrast, the WD/Ca/VitD3 diet reversed WD-induced growth, promoting changes in colonic epithelium. Importantly, Apc(1638N/+) mice fed the WD/Ca/VitD3 diet did not develop colonic tumors, further indicating that dietary calcium and cholecalciferol have a key role in the chemoprevention of colorectal neoplasia in this mouse model of human colon cancer.


The quality of general movements in infants with complex congenital heart disease undergoing surgery in the neonatal period.
Advances in diagnostic technologies, surgical management, and perioperative care have increased survival for neonates with complex congenital heart disease (CCHD). The success of these advances exposed a heightened risk of brain injury and developmental disabilities. The General Movements Assessment, a non-invasive method, may detect early neurodevelopmental impairments in high-risk infants. To examine whether infants with CCHD undergoing neonatal surgery have higher prevalence of atypical general movements (GMs) than a reference group, and whether single ventricle physiology with systemic oxygen saturations <90% increases risk for atypical GMs. Serial General Movements Assessment (GMA) in a cohort of infants with CCHD (n = 74) at writhing (term-6 weeks) and fidgety (7-17 weeks) GM-age. GMA focused on the presence of definitely abnormal GM-complexity and absent fidgety movements. Single GMAs at 3 months were available from a reference sample of Dutch infants (n = 300). Regression analyses examined relationships between cardiac characteristics and definitely abnormal GM-complexity. Higher prevalence of definitely abnormal GM-complexity in infants with CCHD compared to reference infants (adjusted OR 5.938, 95% CI 2.423-14.355), single ventricle CCHD increased the risk. Occurrence of absent fidgety movements was similar in infants with CCHD and reference infants (adjusted OR 0.475, 95% CI 0.058-3.876). Systemic postoperative oxygen saturations <90% was associated with higher risk of definitely abnormal GM-complexity at fidgety (adjusted OR 16.445 95% CI 1.149-235.281), not at writhing age. Infants with CCHD, especially those with single ventricle CCHD, are at increased risk of definitely abnormal GM-complexity. GMA at fidgety age is recommended.


[High prevalence of dyslipidemia and high atherogenic index of plasma in children and adolescents].
Dyslipidemias in childhood increase the risk of cardiovascular events in adult life. To evaluate the prevalence of dyslipidemia and risk of atherogenicity based in the atherogenic index of plasma (AIP) in a sample of school children and adolescents. Cross-sectional study of 208 children aged 10.4 ± 1.0 years (107 women). Demographic data were obtained, and a clinical evaluation was conducted, including pubertal development according to Tanner and anthropometric parameters. A fasting blood sample was obtained to measure total cholesterol (CT), HDL cholesterol (cHDL) and triglycerides (TG), glucose and insulin. LDL cholesterol (cLDL), Non-HDL cholesterol and the indices CT/cHDL, cLDL/cHDL and AIP (log[TG/cHDL]) were calculated. Risk categories according to AIP for the pediatric population were also determined (low: AIP < 0.11, intermediate: AIP 0.11-0.21, high: AIP > 0.21). Thirty eight percent of participants had dyslipidemia, without differences by gender and pubertal development. The frequency of dyslipidemia was significantly higher in children with obesity (54%, p < 0.01) and a waist circumference over percentile 90 (61%; p < 0.01). The later conditions had also higher CT/cHDL, cLDL/cHDL and AIP. According to AIP, 54% of children had a high atherogenicity risk along with alterations in anthropometric parameters and insulin resistance. All anthropometric and insulin resistance parameters were significantly correlated with the AIP. There is a high prevalence of dyslipidemia in the studied population, which is associated with an increased cardiometabolic risk. The indices of atherogenicity and particularly AIP are correlated with nutritional status, abdominal obesity and parameters of insulin resistance.


Genome-wide single nucleotide polymorphisms reveal population history and adaptive divergence in wild guppies.
Adaptation of guppies (Poecilia reticulata) to contrasting upland and lowland habitats has been extensively studied with respect to behaviour, morphology and life history traits. Yet population history has not been studied at the whole-genome level. Although single nucleotide polymorphisms (SNPs) are the most abundant form of variation in many genomes and consequently very informative for a genome-wide picture of standing natural variation in populations, genome-wide SNP data are rarely available for wild vertebrates. Here we use genetically mapped SNP markers to comprehensively survey genetic variation within and among naturally occurring guppy populations from a wide geographic range in Trinidad and Venezuela. Results from three different clustering methods, Neighbor-net, principal component analysis (PCA) and Bayesian analysis show that the population substructure agrees with geographic separation and largely with previously hypothesized patterns of historical colonization. Within major drainages (Caroni, Oropouche and Northern), populations are genetically similar, but those in different geographic regions are highly divergent from one another, with some indications of ancient shared polymorphisms. Clear genomic signatures of a previous introduction experiment were seen, and we detected additional potential admixture events. Headwater populations were significantly less heterozygous than downstream populations. Pairwise F(ST) values revealed marked differences in allele frequencies among populations from different regions, and also among populations within the same region. F(ST) outlier methods indicated some regions of the genome as being under directional selection. Overall, this study demonstrates the power of a genome-wide SNP data set to inform for studies on natural variation, adaptation and evolution of wild populations.


The patterns of drug and alcohol use and associated problems over 30 years in 397 men.
Alcohol and drug use disorders (AUDs and SUDs) and their combination are relatively common and often occur together. However, the relationships of potential early life correlates of alcohol and drug disorders to the combined diagnoses have rarely been evaluated in long-term prospective studies or in populations at high risk of one of these diagnoses but not the other. Data were analyzed from 397 males (half with an alcohol-dependent father) who had no AUDs or SUDs at age 20 and who were followed approximately every 5 years for 3 decades. Early life correlates and the course of AUDs, SUDs, and combined disorders were evaluated for 4 groups of subjects based on subsequent alcohol and/or drug diagnoses. While the overall rates of the development of AUDs and SUDs were 41 and 21%, respectively, the rates of the second substance-related diagnosis were almost 2-fold higher for individuals who had the first condition. Among potential risk factors, scores for externalizing traits were elevated for men with AUDs, SUDs, and their combination, but a low level of response (low LR) to alcohol was associated only with the risk of AUDs, even when observed in the context of SUDs. The same earlier life characteristics that related to AUDs and to SUDs also related to the combination of these diagnoses in the same person. Finally, in this prospective study, subjects with both AUDs and SUDs had a more severe course than subjects with either condition alone. This prospective evaluation of a group at high risk of AUDs confirmed the selective impact of the low LR on the risk of AUDs, the relationship of externalizing characteristics to both AUDs and SUDs and confirmed the more severe clinical course for both conditions when seen together.


The exceptional sediment load of fine-grained dispersal systems: Example of the Yellow River, China.
Sedimentary dispersal systems with fine-grained beds are common, yet the physics of sediment movement within them remains poorly constrained. We analyze sediment transport data for the best-documented, fine-grained river worldwide, the Huanghe (Yellow River) of China, where sediment flux is underpredicted by an order of magnitude according to well-accepted sediment transport relations. Our theoretical framework, bolstered by field observations, demonstrates that the Huanghe tends toward upper-stage plane bed, yielding minimal form drag, thus markedly enhancing sediment transport efficiency. We present a sediment transport formulation applicable to all river systems with silt to coarse-sand beds. This formulation demonstrates a remarkably sensitive dependence on grain size within a certain narrow range and therefore has special relevance to silt-sand fluvial systems, particularly those affected by dams.


Foods: Where Innovation, Agriculture, Molecular Biosciences and Human Nutrition Meet.
There is one commodity the world over that unites mankind-food. In 2011 the United Nations claimed that the world's population had reached the seven billion mark, a number which is set to increase dramatically in the decades to come. Food security, supply and sustainability are of paramount concern to the future economic and social progress of humanity. It is the responsibility of the food industry, together with food scientists and technologists, to shoulder the burden of ensuring an adequate supply of nutritious, safe and sensorially acceptable foods for a range of demanding consumers. In responding to this challenge, we need to understand the link between agriculture, engineering, food processing, molecular biosciences, human nutrition, commercialisation and innovation. Access to information concerning the composition and quality of foods has never been so easy for consumers and technologists alike. A plethora of research publications are made available each month to scientists and associated interested parties. The outcomes of these research manuscripts are often distilled and disseminated into messages available to everyone through bulletin boards, forums and the popular press. Newspapers and new agencies constantly report on the latest pharma-medical finding, or news regarding food safety and security concerns. We live in an age where information is so readily available to everyone that the task of finding credible and reputable data can be difficult at times. Providing sound evidenced based research is where a peer-reviewed journal can provide clarity. [...].


Selenium dependent glutathione peroxidase: a physiological regulatory system for platelet function.
In human platelets the selenoenzyme glutathione peroxidase (GSH-Px) acts as a scavenger of the peroxides generated during the burst of arachidonic acid (AA) metabolism. Such a mechanism inhibits the biosynthesis of both thromboxane A2 (TXA2) and lipoxygenase products. The same mechanism is not effective on the prostacyclin (PGI2) biosynthesis from cultured endothelial cells. In order to evaluate this effect in vivo, besides in vitro, we activated the enzyme in eight normal volunteers by increasing their daily Se intake for 8 weeks, monitoring: platelet GSH-Px activity, platelet aggregation induced by AA and U 44069, and concurrent malondialdehyde (MDA) and thromboxane B2 (TXB2) production, urinary excretion of renal and systemic TXA2 and PGI2 metabolites, platelet enzyme activities of the hexose monophosphate pathway and glutathione content, platelet adenine nucleotides, bleeding time, plasma Se concentration. We found: a) progressive platelet GSH-Px activation by Se paralleling an enhancement of platelet aggregation threshold values for AA, but not for U 44069; b) concurrent inhibition of platelet biosynthesis of TXA2 both in vitro and in vivo while the biosynthesis of systemic prostacyclin was unaffected; c) a progressive increase in the bleeding time, unmodified by aspirin. In conclusion, we believe that Se-dependent GSH-Px represents a physiological mechanism regulating the biosynthesis of prostanoids with implications in platelet function and that a Se dietary supplement might be considered in the prevention of arterial thrombosis.


Contrasting genomic consequences of anthropogenic reintroduction and natural recolonization in high-arctic wild reindeer.
Anthropogenic reintroduction can supplement natural recolonization in reestablishing a species' distribution and abundance. However, both reintroductions and recolonizations can give rise to founder effects that reduce genetic diversity and increase inbreeding, potentially causing the accumulation of genetic load and reduced fitness. Most current populations of the endemic high-arctic Svalbard reindeer (Rangifer tarandus platyrhynchus) originate from recent reintroductions or recolonizations following regional extirpations due to past overharvesting. We investigated and compared the genomic consequences of these two paths to reestablishment using whole-genome shotgun sequencing of 100 Svalbard reindeer across their range. We found little admixture between reintroduced and natural populations. Two reintroduced populations, each founded by 12 individuals around four decades (i.e. 8 reindeer generations) ago, formed two distinct genetic clusters. Compared to the source population, these populations showed only small decreases in genome-wide heterozygosity and increases in inbreeding and lengths of runs of homozygosity. In contrast, the two naturally recolonized populations without admixture possessed much lower heterozygosity, higher inbreeding and longer runs of homozygosity, possibly caused by serial population founder effects and/or fewer or more genetically related founders than in the reintroduction events. Naturally recolonized populations can thus be more vulnerable to the accumulation of genetic load than reintroduced populations. This suggests that in some organisms even small-scale reintroduction programs based on genetically diverse source populations can be more effective than natural recolonization in establishing genetically diverse populations. These findings warrant particular attention in the conservation and management of populations and species threatened by habitat fragmentation and loss.


Elastic fibers in the anulus fibrosus of the dog intervertebral disc.
A light microscopic investigation of the anulus fibrosus in cervical intervertebral discs of the dog was conducted to ascertain the arrangement and distribution of elastic fibers. Elastic fibers were observed in all lamellae of the anulus fibrosus. However, collagenous fibers were the predominant type of connective tissue fiber, and elastic fibers were randomly dispersed among them. Intralamellar (collagenous and elastic) fibers were vertically and obliquely oriented in both superficial and deep lamellae of the anulus fibrosus. All intralamellar fibers were densely and regularly arranged in superficial lamellae, but they were more loosely organized in deep lamellae. A narrow border of interlamellar, elastic fibers was observed between broader, contiguous lamellae in the superficial zone of the anulus fibrosus. Interlamellar elastic fibers wer vertically and obliquely arranged in superficial lamellae; however, they were radially oriented in deep lamellae. The deepest lamella of the anulus fibrosus consisted of a loose, three-dimensional network of intermeshing collagenous and elastic fibers. These observations suggest that elastic fibers are integral components of the articular and shock absorption mechanisms of the anulus fibrosus, and the cervical intervertebral disc of the dog is a suitable model for experimental investigation of the role of elastic fibers in intervertebral disc herniation.


Satellite cell depletion does not inhibit adult skeletal muscle regrowth following unloading-induced atrophy.
Resident muscle stem cells, known as satellite cells, are thought to be the main mediators of skeletal muscle plasticity. Satellite cells are activated, replicate, and fuse into existing muscle fibers in response to both muscle injury and mechanical load. It is generally well-accepted that satellite cells participate in postnatal growth, hypertrophy, and muscle regeneration following injury; however, their role in muscle regrowth following an atrophic stimulus remains equivocal. The current study employed a genetic mouse model (Pax7-DTA) that allowed for the effective depletion of >90% of satellite cells in adult muscle upon the administration of tamoxifen. Vehicle and tamoxifen-treated young adult female mice were either hindlimb suspended for 14 days to induce muscle atrophy or hindlimb suspended for 14 days followed by 14 days of reloading to allow regrowth, or they remained ambulatory for the duration of the experimental protocol. Additionally, 5-bromo-2'-deoxyuridine (BrdU) was added to the drinking water to track cell proliferation. Soleus muscle atrophy, as measured by whole muscle wet weight, fiber cross-sectional area, and single-fiber width, occurred in response to suspension and did not differ between satellite cell-depleted and control muscles. Furthermore, the depletion of satellite cells did not attenuate muscle mass or force recovery during the 14-day reloading period, suggesting that satellite cells are not required for muscle regrowth. Myonuclear number was not altered during either the suspension or the reloading period in soleus muscle fibers from vehicle-treated or satellite cell-depleted animals. Thus, myonuclear domain size was reduced following suspension due to decreased cytoplasmic volume and was completely restored following reloading, independent of the presence of satellite cells. These results provide convincing evidence that satellite cells are not required for muscle regrowth following atrophy and that, instead, the myonuclear domain size changes as myofibers adapt.


Motivational Interviewing to Increase Physical Activity Behavior in Cancer Patients: A Pilot Randomized Controlled Trials.
This pilot randomized controlled trial (RCT) aimed at evaluating the feasibility and potential efficacy of a motivational interviewing (MI) intervention to increase physical activity (PA) behavior in cancer patients. Participants were randomly assigned to an experimental group with standard care plus 12 MI sessions within 12 weeks or a control group with standard care only. The number of recruited participants and the modality of recruitment were recorded to describe the reach of the study. The acceptability of the study was estimated using the attrition rate during the intervention phase. The potential efficacy of the intervention was evaluated by analyzing the PA behavior. Twenty-five participants were recruited within the 16-month recruitment period (1.6 participants per month). Five participants (38.5%) from the experimental group (n = 13) and one participant (8.3%) from the control group (n = 12) dropped out of the study before the end of the intervention phase. No group by time interaction effect for PA behavior was observed at the end of the intervention. Due to the low recruitment rate and compliance, no conclusion can be drawn regarding the efficacy of MI to increase PA behavior in cancer patients. Moreover, the current literature cannot provide any evidence on the effectiveness of MI to increase PA in cancer survivors. Future RCTs should consider that the percentage of uninterested patients to join the study may be as high as 60%. Overrecruitment (30% to 40%) is also recommended to accommodate the elevated attrition rate.


Meeting national response time targets for priority 1 incidents in an urban emergency medical services system in South Africa: More ambulances won't help.
Response time is viewed as a key performance indicator in most emergency medical services (EMS) systems. To determine the effect of increased emergency vehicle numbers on response time performance for priority 1 incidents in an urban EMS system in Cape Town, South Africa, using discrete-event computer simulation. A simulation model was created, based on input data from part of the EMS operations. Two different versions of the model were used, one with primary response vehicles and ambulances and one with only ambulances. In both cases the models were run in seven different scenarios. The first scenario used the actual number of emergency vehicles in the real system, and in each subsequent scenario vehicle numbers were increased by adding the baseline number to the cumulative total. The model using only ambulances had shorter response times and a greater number of responses meeting national response time targets than models using primary response vehicles and ambulances. In both cases an improvement in response times and the number of responses meeting national response time targets was observed with the first incremental addition of vehicles. After this the improvements rapidly diminished and eventually became negligible with each successive increase in vehicle numbers. The national response time target for urban areas was never met, even with a seven-fold increase in vehicle numbers. The addition of emergency vehicles to an urban EMS system improves response times in priority 1 incidents, but alone is not capable of the magnitude of response time improvement needed to meet the national response time targets.


The Staphylococcus aureus and Staphylococcus epidermidis transferrin-binding proteins are expressed in vivo during infection.
Staphylococci express a 42 kDa cell-wall-associated protein which functions as a receptor for the mammalian iron-binding glycoprotein transferrin. To determine whether this transferrin-binding protein (TBP) is expressed during infection, Staphylococcus aureus and Staphylococcus epidermidis were grown in vivo in chambers implanted intraperitoneally in rats. SDS-PAGE and Western blotting of cell wall proteins prepared from staphylococci recovered directly from the chambers revealed the presence of both the TBP and bacterial-surface-associated rat transferrin. To obtain evidence for the in vivo expression of the staphylococcal TBPs in humans, sera and human peritoneal dialysate (HPD) from non-infected patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and sera from healthy human volunteers were screened for anti-TBP antibodies. Western immunoblots revealed that three out of ten samples from the latter group, seven out of ten HPD samples and ten of ten CAPD patient serum samples contained antibodies to the TBP of both S. aureus and S. epidermidis. To gain further insights into the appearance of TBP antibodies, HPD samples were collected over time from CAPD patients whose HPD samples taken immediately after catheter insertion lacked anti-TBP antibodies. In two of these patients, each of whom experienced an episode of peritonitis due to S. epidermidis or Staphylococcus hominis, antibodies to the TBP appeared in the HPD collected immediately post-infection. To determine whether such TBP antibodies were capable of blocking interactions between transferrin and its staphylococcal receptor, HPD immunoglobulin fractions were purified using protein A-Sepharose beads. In competition assays, these immunoglobulins blocked the binding of 125I-labelled transferrin both to whole bacteria and to the isolated 42 kDa TBPs of S. aureus and S. epidermidis. These provide evidence to show that staphylococcal TBPs are expressed in vivo during infection.


Coenzyme Q intake elevates the mitochondrial and tissue levels of Coenzyme Q and alpha-tocopherol in young mice.
The main objective of this study was to resolve the issue of whether the amounts of Coenzyme Q (CoQ), which is endogenously synthesized in cells, can be elevated in tissues and mitochondria of young mice by dietary supplementation with CoQ10. The prevalent view is that the uptake of exogenous CoQ by tissues other than plasma and liver either does not occur or is quite minimal. Mice, 6 mo of age, were fed 0, 148 or 654 mg CoQ10/(kg body x d) in their diets for 11 wk. CoQ10 intake enhanced both CoQ9 and CoQ10 homologues in the plasma, and in homogenates and mitochondria of liver, heart and skeletal muscle. CoQ was elevated in brain mitochondria, but not in the brain homogenate. The uptake of exogenous CoQ was higher in mitochondria of heart and skeletal muscle than those in liver. CoQ10 administration also elevated the alpha-tocopherol concentration in tissue homogenates and their mitochondria, thereby providing an in vivo indication of the "sparing" effect of CoQ on alpha-tocopherol. Results of this study demonstrate that, contrary to the historical view, both total and mitochondrial CoQ concentrations in the heart and skeletal muscle and in the mitochondria of brain of young mice can be augmented by dietary supplementation. Furthermore, CoQ intake enhances the antioxidative potential of tissues by elevating the endogenous amounts of alpha-tocopherol.


Pulmonary immunization using antigen 85-B polymeric microparticles to boost tuberculosis immunity.
This study aims to evaluate immunization with polymeric microparticles containing recombinant antigen 85B (rAg85B) delivered directly to the lungs to protect against tuberculosis. rAg85B was expressed in Escherichia coli and encapsulated in poly(lactic-co-glycolic acid) microparticles (P-rAg85B). These were delivered as dry powders to the lungs of guinea pigs in single or multiple doses of homologous and heterologous antigens. Bacille Calmette-Guérin (BCG) delivered subcutaneously was employed as the positive control and as part of immunization strategies. Immunized animals were challenged with a low-dose aerosol of Mycobacterium tuberculosis (MTB) H37Rv to assess the extent of protection measured as reduction in bacterial burden (CFU) in the lungs and spleens of guinea pigs. Histopathological examination and morphometric analysis of these tissues were also performed. The heterologous strategy of BCG prime-P-rAg85B aerosol boosts appeared to enhance protection from bacterial infection, as indicated by a reduction in CFU in both the lungs and spleens compared with untreated controls. Although the CFU data were not statistically different from the BCG and BCG-BCG groups, the histopathological and morphometric analyses indicated the positive effect of BCG-P-rAg85B in terms of differences in area of tissue affected and number and size of granulomas observed in tissues. P-rAg85B microparticles appeared to be effective in boosting a primary BCG immunization against MTB infection, as indicated by histopathology and morphometric analysis. These encouraging observations are relevant to boosting adults previously immunized with BCG or exposed to MTB, commonly the case in the developing world, and should be followed by further assessment of an appropriate immunization protocol for maximum protection.


Age at natural menopause genetic risk score in relation to age at natural menopause and primary open-angle glaucoma in a US-based sample.
Several attributes of female reproductive history, including age at natural menopause (ANM), have been related to primary open-angle glaucoma (POAG). We assembled 18 previously reported common genetic variants that predict ANM to determine their association with ANM or POAG. Using data from the Nurses' Health Study (7,143 women), we validated the ANM weighted genetic risk score in relation to self-reported ANM. Subsequently, to assess the relation with POAG, we used data from 2,160 female POAG cases and 29,110 controls in the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), which consists of 8 datasets with imputed genotypes to 5.6+ million markers. Associations with POAG were assessed in each dataset, and site-specific results were meta-analyzed using the inverse weighted variance method. The genetic risk score was associated with self-reported ANM (P = 2.2 × 10) and predicted 4.8% of the variance in ANM. The ANM genetic risk score was not associated with POAG (Odds Ratio (OR) = 1.002; 95% Confidence Interval (CI): 0.998, 1.007; P = 0.28). No single genetic variant in the panel achieved nominal association with POAG (P ≥0.20). Compared to the middle 80 percent, there was also no association with the lowest 10 percentile or highest 90 percentile of genetic risk score with POAG (OR = 0.75; 95% CI: 0.47, 1.21; P = 0.23 and OR = 1.10; 95% CI: 0.72, 1.69; P = 0.65, respectively). A genetic risk score predicting 4.8% of ANM variation was not related to POAG; thus, genetic determinants of ANM are unlikely to explain the previously reported association between the two phenotypes.


Hydra effects in stable communities and their implications for system dynamics.
A hydra effect occurs when the mean density of a species increases in response to greater mortality. We show that, in a stable multispecies system, a species exhibits a hydra effect only if maintaining that species at its equilibrium density destabilizes the system. The stability of the original system is due to the responses of the hydra-effect species to changes in the other species' densities. If that dynamical feedback is removed by fixing the density of the hydra-effect species, large changes in the community make-up (including the possibility of species extinction) can occur. This general result has several implications: (1) Hydra effects occur in a much wider variety of species and interaction webs than has previously been described, and may occur for multiple species, even in small webs; (2) conditions for hydra effects caused by predators (or diseases) often differ from those caused by other mortality factors; (3) introducing a specialist or a switching predator of a hydra-effect species often causes large changes in the community, which frequently involve extinction of other species; (4) harvest policies that attempt to maintain a constant density of a hydra-effect species may be difficult to implement, and, if successful, are likely to cause large changes in the densities of other species; and (5) trophic cascades and other indirect effects caused by predators of hydra-effect species can exhibit amplification of effects or unexpected directions of change. Although we concentrate on systems that are originally stable and models with no stage-structure or trait variation, the generality of our result suggests that similar responses to mortality will occur in many systems without these simplifying assumptions. In addition, while hydra effects are defined as responses to altered mortality, they also imply counterintuitive responses to changes in immigration and other parameters affecting population growth.


A Bibliometric Evaluation of Worldwide Research of the Podiatry Field from 1965 to 2017.
To identify the strengths and weaknesses in a given research area, it is necessary to analyze the published literature. International studies on podiatry research productivity are scarce. This study aimed to analyze scientific productivity in the area of podiatric medicine from 1965 to 2017. This was a retrospective, observational, bibliometric study. The MEDLINE database was used to identify research published between 1965 and 2017. Literature searches were performed in 2010 and 2017 through RefWorks, and research production per year, author, document type, country, institution, journal, and language were calculated. Podiatry's contribution to global scientific production was measured by calculating the ratio of podiatry publications to total production, and Price's law was applied to analyze the temporal evolution. Author productivity index, coauthorship, geographic distribution, and the distribution by institution type and journal (Bradford's law) were analyzed. The MEDLINE search yielded 1,256 publications, representing 4.75 articles per 100,000 publications in global scientific research. The growth rate followed Price's law after linear adjustment. The 2,229 identified authors presented a transience index of 85.73%; 0.38% were highly productive authors. The coauthorship index increased from 1.40 in 1965 to 5.80 in 2017. The most common document type was the journal article, whereas 2.1% were clinical trials. Only one document reported a controlled clinical trial. The United States led scientific production, with 77.15% of the documents; 60.5% of the publications were concentrated in four journals. Podiatry is still an emerging research field, and literature is concentrated in a small number of journals, categorized into different subjects.


Characteristics of invasion of HEp-2 cells by Providencia alcalifaciens.
Previous studies with three isolates from diarrhoeal stools suggested that Providencia alcalifaciens is an invasive enteric pathogen that also causes actin condensation in infected cells. These findings were extended in the present study with a further 14 diarrhoeal stool isolates of P. alcalifaciens and HEp-2 cell monolayers for invasion assays. Studies on invasion characteristics with two selected isolates suggested that P. alcalifaciens required prior growth at 37 degrees C for better invasion. Invasion and actin condensation were inhibited by an agent that inhibits microfilament formation, but not by agents that inhibit receptor-mediated endocytosis, microtubule formation, endosome acidification or receptor recycling. In time-course assays with HEp-2 cell monolayers maintained in medium containing gentamicin, P. alcalifaciens showed a small degree of multiplication after invasion of the cells, but viable bacteria could not be recovered over a 24-h period although the integrity of the cell monolayer was preserved during this period.


Fixed vs. variable noise in 2AFC contrast discrimination: lessons from psychometric functions.
Recent discussion regarding whether the noise that limits 2AFC discrimination performance is fixed or variable has focused either on describing experimental methods that presumably dissociate the effects of response mean and variance or on reanalyzing a published data set with the aim of determining how to solve the question through goodness-of-fit statistics. This paper illustrates that the question cannot be solved by fitting models to data and assessing goodness-of-fit because data on detection and discrimination performance can be indistinguishably fitted by models that assume either type of noise when each is coupled with a convenient form for the transducer function. Thus, success or failure at fitting a transducer model merely illustrates the capability (or lack thereof) of some particular combination of transducer function and variance function to account for the data, but it cannot disclose the nature of the noise. We also comment on some of the issues that have been raised in recent exchange on the topic, namely, the existence of additional constraints for the models, the presence of asymmetric asymptotes, the likelihood of history-dependent noise, and the potential of certain experimental methods to dissociate the effects of response mean and variance.


Improved idler beam quality via simultaneous parametric oscillation and signal-to-idler conversion.
We report on an improvement of idler beam quality in a singly resonant optical parametric oscillator (OPO), where the resonant signal is converted to the idler via an additional difference frequency generation (DFG) process. The two processes are phase matched simultaneously by a quasi-periodically poled nonlinear crystal. Whereas back-conversion of the signal and idler to the pump frequency distorts the idler beam in a standard OPO, in a quasi-periodic OPO the DFG process reduces the signal intensity, leading to suppression of back-conversion and, hence, improvement in idler beam quality. Indeed, the experimental results show under the same pump power a significant improvement in idler beam quality for the quasi-periodic OPO (1≤M2≤2.1) as compared with the standard OPO (3.2≤M2≤5.3).


The Persistence of Oral Health Disparities for African American Children: A Scoping Review.
Oral health is an important yet often neglected component of overall health, linked to heart disease, stroke, and diabetic complications. Disparities exist for many groups, including racial and ethnic minorities such as African Americans. The purpose of this study was to examine the potential factors that perpetuate oral health care disparities in African American children in the United States. A systematic search of three literature databases produced 795 articles; 23 articles were included in the final review. Articles were analyzed using a template coding approach based on the social ecological model. The review identified structural, sociocultural, and familial factors that impact the ability of African Americans to utilize oral care services, highlighting the importance of the parent/caregiver role and the patient⁻provider relationship; policy-level processes that impact access to quality care; the value of autonomy in treatment and prevention options; and the impact of sociocultural factors on food choices (e.g., food deserts, gestures of affection). In conclusion, oral health care remains an underutilized service by African American children, despite increasing access to oral care secondary to improvements in insurance coverage and community-based programs.


Location of aldosterone-producing adenomas by the determination of plasma aldosterone in adrenal vein or renal vein blood.
1. Aldosterone-producing adenomas were located before operation in eighteen patients by comparison of aldosterone concentrations in blood obtained by percutaneous catheterization of the adrenal vein or renal vein. The concentration of aldosterone in the venous effluent from the adrenal glands containing adenomas was significantly greater than in the venous effluent from contralateral glands. 2. Cathetherization of the adrenal vein is, however, technically difficult. The location of adrenal adenomas was also possible by analysis of blood from the renal vein. 3. If the concentrations of aldosterone in blood from the left renal vein were higher than those from the right, the existence of a left adrenal adenoma was suggested. A high value in plasma, obtained from the inferior vena cava above the entry of the right adrenal vein, showed a right adrenal adenoma. This procedure identified very small functional adenomas which could not be demonstrated radiographically, or seen or palpated at surgery. 4. It was concluded that differential aldosterone measurement after percutaneous bilateral adrenal vein or renal vein catheterization can be used as a definitive test for the location of an aldosterone-producing adenoma, where this is uncertain.


The Vacuolar Zinc Transporter TgZnT Protects Toxoplasma gondii from Zinc Toxicity.
Zinc (Zn2+) is the most abundant biological metal ion aside from iron and is an essential element in numerous biological systems, acting as a cofactor for a large number of enzymes and regulatory proteins. Zn2+ must be tightly regulated, as both the deficiency and overabundance of intracellular free Zn2+ are harmful to cells. Zn2+ transporters (ZnTs) play important functions in cells by reducing intracellular Zn2+ levels by transporting the ion out of the cytoplasm. We characterized a Toxoplasma gondii gene (TgGT1_251630, TgZnT), which is annotated as the only ZnT family Zn2+ transporter in T. gondii TgZnT localizes to novel vesicles that fuse with the plant-like vacuole (PLV), an endosome-like organelle. Mutant parasites lacking TgZnT exhibit reduced viability in in vitro assays. This phenotype was exacerbated by increasing zinc concentrations in the extracellular media and was rescued by media with reduced zinc. Heterologous expression of TgZnT in a Zn2+-sensitive Saccharomyces cerevisiae yeast strain partially restored growth in media with higher Zn2+ concentrations. These results suggest that TgZnT transports Zn2+ into the PLV and plays an important role in the Zn2+ tolerance of T. gondii extracellular tachyzoites.IMPORTANCEToxoplasma gondii is an intracellular pathogen of human and animals. T. gondii pathogenesis is associated with its lytic cycle, which involves invasion, replication, egress out of the host cell, and invasion of a new one. T. gondii must be able to tolerate abrupt changes in the composition of the surrounding milieu as it progresses through its lytic cycle. We report the characterization of a Zn2+ transporter of T. gondii (TgZnT) that is important for parasite growth. TgZnT restored Zn2+ tolerance in yeast mutants that were unable to grow in media with high concentrations of Zn2+ We propose that TgZnT plays a role in Zn2+ homeostasis during the T. gondii lytic cycle.


Pan-genomic perspective on the evolution of the Staphylococcus aureus USA300 epidemic.
Staphylococcus aureus USA300 represents the dominant community-associated methicillin-resistant S. aureus lineage in the USA, where it is a major cause of skin and soft tissue infections. Previous comparative genomic studies have described the population structure and evolution of USA300 based on geographically restricted isolate collections. Here, we investigated the USA300 population by sequencing genomes of a geographically distributed panel of 191 clinical S. aureus isolates belonging to clonal complex 8 (CC8), derived from the Tigecycline Evaluation and Surveillance Trial program. Isolates were collected at 12 healthcare centres across nine USA states in 2004, 2009 or 2010. Reconstruction of evolutionary relationships revealed that CC8 was dominated by USA300 isolates (154/191, 81 %), which were heterogeneous and demonstrated limited phylogeographic clustering. Analysis of the USA300 core genomes revealed an increase in median pairwise SNP distance from 62 to 98 between 2004 and 2010, with a stable pattern of above average dN/dS ratios. The phylogeny of the USA300 population indicated that early diversification events led to the formation of nested clades, which arose through cumulative acquisition of predominantly non-synonymous SNPs in various coding sequences. The accessory genome of USA300 was largely homogenous and consisted of elements previously associated with this lineage. We observed an emergence of SCCmec negative and ACME negative USA300 isolates amongst more recent samples, and an increase in the prevalence of ϕSa5 prophage. Together, the analysed S. aureus USA300 collection revealed an evolving pan-genome through increased core genome heterogeneity and temporal variation in the frequency of certain accessory elements.


Sleep across chemotherapy treatment: a growing concern for women older than 50 with breast cancer.
To conduct a metasynthesis of human sleep studies that included women aged 50 years and older with breast cancer across chemotherapy treatment. English publications were searched with the terms sleep and breast cancer via Ovid, PubMed, and EBSCO-host databases. Human studies that used sleep-specific instruments published from January 1974-May 2009 were included. Intervention studies also were included if they provided baseline sleep data. Studies that used quality-of-life or symptom instruments or in which patients were prescreened for insomnia were not included. 382 publications were found; 17 met inclusion criteria, and 3 additional studies were located from the literature on fatigue. Two articles reported on the same study, so a total of 19 studies were included in the review. In women with nonmetastatic breast cancer, subjective and objective sleep quality appear to be poor and nocturnal awakenings frequent across chemotherapy treatment. Daytime sleepiness increases in the active phase of chemotherapy, and insomnia symptoms are common before and following chemotherapy treatment. In women with recurrent or metastatic breast cancer, difficulty falling asleep, nocturnal awakenings, difficulty awakening, and daytime sleepiness are problematic at different points in chemotherapy treatment. Sleep for women, including those older than 50 years, appears to be impaired across chemotherapy treatment, although replication of findings is very limited. Future research should investigate sleep in specific age and minority groups, include daytime sleep and sleepiness, and use standard sleep nomenclature and objective measures.


Ex vivo biomechanical characteristics and effects on gap formation of using an internal fixation plate to augment primary three-loop pulley repair of canine gastrocnemius tendons.
To evaluate the effects of using an internal fixation plate to augment primary 3-loop pulley (3LP) repair of canine gastrocnemius tendons (GTs). 48 cadaveric GTs from 24 adult dogs. GTs were dissected free from other tissues, transected, and randomly assigned to 4 groups (n = 12/group). GTs were repaired with 2-0 polypropylene with a 3LP repair alone or a 3LP repair augmented with a 3-hole veterinary cuttable plate (3VCP), a 5-hole veterinary cuttable plate (5VCP), or a 7-hole veterinary cuttable plate (7VC P). Biomechanical loads, construct stiffness, gap formation, and failure modes were compared between groups. Yield, peak, and failure loads were all significantly increased for the 5VCP and 7VCP groups, compared with the 3LP alone group. Increasing plate length from 3VCP to 5VCP and from 3VCP to 7VCP increased yield, peak, and failure loads. No differences were found between the 3LP and 3VCP groups with regard to yield and peak loads, but failure load was increased in the 3VCP group. Loads to create 1-mm and 3-mm gaps were significantly greater for the 5VCP and 7VCP groups, compared with the 3LP alone and 3VCP groups. Mode of plate attachment failure differed among groups. Tendon plate augmentation may be a viable surgical option to increase the strength of the tenorrhaphy in dogs. However, in vivo studies evaluating the effects of plate augmentation on the tendon blood supply and progression of healing are needed prior to clinical application.


Infection mechanisms and putative effector repertoire of the mosquito pathogenic oomycete Pythium guiyangense uncovered by genomic analysis.
Pythium guiyangense, an oomycete from a genus of mostly plant pathogens, is an effective biological control agent that has wide potential to manage diverse mosquitoes. However, its mosquito-killing mechanisms are almost unknown. In this study, we observed that P. guiyangense could utilize cuticle penetration and ingestion of mycelia into the digestive system to infect mosquito larvae. To explore pathogenic mechanisms, a high-quality genome sequence with 239 contigs and an N50 contig length of 1,009 kb was generated. The genome assembly is approximately 110 Mb, which is almost twice the size of other sequenced Pythium genomes. Further genome analysis suggests that P. guiyangense may arise from a hybridization of two related but distinct parental species. Phylogenetic analysis demonstrated that P. guiyangense likely evolved from common ancestors shared with plant pathogens. Comparative genome analysis coupled with transcriptome sequencing data suggested that P. guiyangense may employ multiple virulence mechanisms to infect mosquitoes, including secreted proteases and kazal-type protease inhibitors. It also shares intracellular Crinkler (CRN) effectors used by plant pathogenic oomycetes to facilitate the colonization of plant hosts. Our experimental evidence demonstrates that CRN effectors of P. guiyangense can be toxic to insect cells. The infection mechanisms and putative virulence effectors of P. guiyangense uncovered by this study provide the basis to develop improved mosquito control strategies. These data also provide useful knowledge on host adaptation and evolution of the entomopathogenic lifestyle within the oomycete lineage. A deeper understanding of the biology of P. guiyangense effectors might also be useful for management of other important agricultural pests.


Clinicopathological Features and Outcomes of Endoscopic Submucosal Dissection for Superficial Cancer of the Pharynx.
The efficacy and safety of endoscopic submucosal dissection (ESD) for superficial cancer of the pharynx are still unclear. To identify clinicopathological features of superficial pharyngeal cancer, and the efficacy and safety of ESD, we retrospectively assessed 70 pharyngeal cancers in 59 patients who underwent ESD. Of these patients, 61.0% and 50.8% had a history of esophageal cancer and head and neck cancer, respectively. The median tumor size was 15 mm, and 75.7% of the lesions were located at the piriform sinus. The en bloc resection rate was 94.9%. Treatment-related adverse events occurred in 8 cases, but there was no treatment-related death. The lateral margin was positive for neoplasm in 3 lesions (4.3%) and inconclusive in 27 lesions (38.6%), but no local recurrence was observed. Cervical lymph node metastasis was observed in 6 patients, and was successfully treated by cervical lymph node dissection. The three-year overall survival rate was 91.5% (95%CI: 76.6-97.3%) and the cause-specific survival rate was 97.6% (95%CI: 84.9-99.7%). In conclusion, ESD for superficial pharyngeal cancer was safe and effective. "Resect and watch" is probably a feasible and rational strategy for treatment of patients with superficial pharyngeal cancer.


Entrustable professional activities and curricular milestones for fellowship training in pulmonary and critical care medicine: report of a multisociety working group.
This article describes the curricular milestones and entrustable professional activities for trainees in pulmonary, critical care, or combined fellowship programs. Under the Next Accreditation System of the Accreditation Council for Graduate Medical Education (ACGME), curricular milestones compose the curriculum or learning objectives for training in these fields. Entrustable professional activities represent the outcomes of training, the activities that society and professional peers can expect fellowship graduates to be able to perform unsupervised. These curricular milestones and entrustable professional activities are the products of a consensus process from a multidisciplinary committee of medical educators representing the American College of Chest Physicians (CHEST), the American Thoracic Society, the Society of Critical Care Medicine, and the Association of Pulmonary and Critical Care Medicine Program Directors. After consensus was achieved using the Delphi process, the document was revised with input from the sponsoring societies and program directors. The resulting lists can serve as a roadmap and destination for trainees, program directors, and educators. Together with the reporting milestones, they will help mark trainees' progress in the mastery of the six ACGME core competencies of graduate medical education.


Self-Optimized Biological Channels in Facilitating the Transmembrane Movement of Charged Molecules.
We consider an anisotropically two-dimensional diffusion of a charged molecule (particle) through a large biological channel under an external voltage. The channel is modeled as a cylinder of three structure parameters: radius, length, and surface density of negative charges located at the channel interior-lining. These charges induce inside the channel a potential that plays a key role in controlling the particle current through the channel. It was shown that to facilitate the transmembrane particle movement the channel should be reasonably self-optimized so that its potential coincides with the resonant one, resulting in a large particle current across the channel. Observed facilitation appears to be an intrinsic property of biological channels, regardless of the external voltage or the particle concentration gradient. This facilitation is very selective in the sense that a channel of definite structure parameters can facilitate the transmembrane movement of only particles of proper valence at corresponding temperatures. Calculations also show that the modeled channel is nonohmic with the ion conductance which exhibits a resonance at the same channel potential as that identified in the current.


Item banking: a generational change in patient-reported outcome measurement.
Patient-reported outcomes are traditionally measured with questionnaires and many have been developed to measure Vision-Related Activity Limitation (VRAL; visual disability or visual functioning), Symptoms, and Quality Of Life (QOL). These vary in quality and can be classified as First or Second Generation instruments. First generation instruments are characterized by simple summary scoring of ordinal responses, which precludes interval measurement. This problem is solved in second generation instruments where Rasch analysis is used to optimize psychometric properties. However, second generation instruments retain limitations; difficulties in comparing scores across instruments, limited applicability to populations and inability to adapt to change. A third generation approach to patient-reported outcomes measurement, item banking, can solve these problems. The aim of this project was to use Rasch analysis to calibrate all items from all instruments to form VRAL, Symptoms, and QOL Item Banks. Six hundred twenty-four people on the waiting list for cataract surgery were recruited. Each participant completed, by self-administration, a number of the 19 instruments. A total of 353 items were calibrated using Rasch analysis (Winsteps v3.67). The psychometric properties of each item bank were optimized; items fitting the Rasch model were retained (Infit and Outfit range, 0.50 to 1.50). Items were sorted into the three traits; 226 tapped VRAL, 22 symptoms, and 60 QOL. Satisfactory measurement of each latent trait occurred with person separation of 8.11 for VRAL, 2.33 for Symptoms, and 3.20 for QOL. Rasch estimates of item difficulty were highly stable with an average standard error of 0.11 logits. Item banks for the measurement of the latent traits of VRAL, symptoms, and QOL have been formed. New items can be added to enable evolution of measurement. Item banking facilitates accurate and precise measurement through computer adaptive testing. This approach provides common measurement scales, facilitating worldwide comparison of results.


Association between obesity, quality of life, physical activity and health service utilization in primary care patients with osteoarthritis.
To assess the association of obesity with quality of life, health service utilization and physical activity in a large sample of primary care patients with osteoarthritis (OA). Data were retrieved from the PraxArt project, representing a cohort of 1021 primary care patients with OA. In 978 patients, height and weight were measured and the Body Mass Index (BMI) was calculated. The AIMS2-SF was used to assess quality of life (QoL). Data about health service utilization (HSU) were retrieved by means of patients' medical files. Concomitant depression was assessed by means of the Patient Health Questionnaire (PHQ-9). Patients were grouped into normal weight, overweight and obese according to the definition of the WHO and compared by means of analysis of covariance (ANCOVA). Obese and overweight persons achieved significantly higher scores on the AIMS2-SF lower body scale, the symptom, the affect and the work scale, indicating an increased burden by OA. The PHQ-9 score increased significantly over the three weight-groups, indicating a positive association of BMI and depression. With increasing BMI, the number of comorbidities increased and physical activity decreased significantly. After controlling for covariates, contacts to orthopaedics and performed x-rays remained significantly higher in obese patients, but not contacts to general practitioners. The results display a strong association of QoL and BMI, resulting in increased use of the health care system. Thus, the study emphasizes the need for appropriate approaches in primary care to break the vicious circle of overweight, depression, decreasing physical inactivity and decreasing QoL.


A comparison between the VIPS model and the ICF for expressing nursing content in the health care record.
Multi-professional standardized terminologies are needed that cover common as well as profession-specific care content in order to obtain a full coverage and description of the contributions from different health professionals' perspectives in health care. Implementation of terminologies in clinical practice that do not cover professionals' needs for communication might jeopardize the quality of care. The aim of the study was to compare the structure and content of the Swedish VIPS model for nursing documentation and the international classification of function, disability and health (ICF). Mapping was performed between key words and prototypical examples for patient status in the VIPS model and terms in the ICF and its framework of domains, chapters and specific terms. The study had two phases. In the first phase 13 key words for patient status in the VIPS model and the 289 terms (prototypical examples) describing related content were mapped to comparable terms in the ICF. In phase two, 1424 terms on levels 2-4 in the ICF were mapped to the key words for patient status in the VIPS model. Differences in classification structures and content were found, with a more elaborated level of detail displayed in the ICF than in the VIPS model. A majority of terms could be mapped, but several essential nursing care concepts and perspectives identified in the VIPS model were missing in the ICF. Two-thirds of the content in the ICF could be mapped to the VIPS' key words for patient status; however, the remaining terms in the ICF, describing body structure and environmental factors, are not part of the VIPS model. Despite that a majority of the nursing content in the VIPS model could be expressed by terms in the ICF, the ICF needs to be developed and expanded to be functional for nursing practice. The results have international relevance for global efforts to implement unifying multi-professional terminologies. In addition, our results underline the need for sufficient coverage and level of detail to support different professional perspectives in health care terminologies.


General overview of the theories used in assessment: AMEE Guide No. 57.
There are no scientific theories that are uniquely related to assessment in medical education. There are many theories in adjacent fields, however, that can be informative for assessment in medical education, and in the recent decades they have proven their value. In this AMEE Guide we discuss theories on expertise development and psychometric theories, and the relatively young and emerging framework of assessment for learning. Expertise theories highlight the multistage processes involved. The transition from novice to expert is characterised by an increase in the aggregation of concepts from isolated facts, through semantic networks to illness scripts and instance scripts. The latter two stages enable the expert to recognise the problem quickly and form a quick and accurate representation of the problem in his/her working memory. Striking differences between experts and novices is not per se the possession of more explicit knowledge but the superior organisation of knowledge in his/her brain and pairing it with multiple real experiences, enabling not only better problem solving but also more efficient problem solving. Psychometric theories focus on the validity of the assessment - does it measure what it purports to measure and reliability - are the outcomes of the assessment reproducible. Validity is currently seen as building a train of arguments of how best observations of behaviour (answering a multiple-choice question is also a behaviour) can be translated into scores and how these can be used at the end to make inferences about the construct of interest. Reliability theories can be categorised into classical test theory, generalisability theory and item response theory. All three approaches have specific advantages and disadvantages and different areas of application. Finally in the Guide, we discuss the phenomenon of assessment for learning as opposed to assessment of learning and its implications for current and future development and research.


A quantitative study of the anatomy and distribution of coronary arteries in swine in comparison with other animals and man.
The coronary circulation of swine was studied to establish adequate baseline information for using swine in cardiovascular research. Of 65 hearts from domestic and miniature pigs, 45 were injected with a methacrylate plastic and prepared as coronary artery casts whose branches were described and measured, and 20 were injected with different coloured dyes in the right, left anterior descending, and circumflex coronary arteries so that horizontal sections of the heart showed the distribution of each artery and the source of blood supply to particular areas or structures of the heart. Like man, the swine had a left coronary artery that was larger in diameter and longer than the right coronary artery. The right coronary artery was almost always dominant (78%), supplying the posterior septum and atrioventricular node via the posterior descending coronary artery. Eight (17%) of the hearts possessed a balanced blood supply. Two (5%) hearts had a left dominant supply. The intracoronary artery dye injections showed that 72.4% of the right ventricular mass was supplied by the right coronary artery and 27.6% by the left anterior descending coronary artery. In the left ventricle 49% of the mass was supplied by the left anterior descending coronary artery, 25.5% by the right coronary artery, and 25.5% by the circumflex coronary artery. The left anterior descending coronary artery supplied 58% of the interventricular septal mass, while the posterior descending coronary artery supplied 42%. The distribution of the left anterior descending coronary artery branches to the ventricular wall varied inversely in number and size of its diagonal branches (2-9) with the obtuse marginal branches of the circumflex coronary artery which were occasionally more numerous or extended to the apex. The blood supply to the sinoatrial node was always by a branch of the right coronary artery. This analysis shows that not only the coronary anatomy but also the distribution of blood supply to particular areas or structures of the swine heart are very similar to that of humans.


An innovative method of teaching Advanced Cardiac-Life Support, or why Cosmic Osmo may someday save your life.
A demonstration and discussion of the effectiveness of an animated and interactive simulation of cardiac and/or respiratory arrest with tools to allow the user to reverse the fatal course of events. The simulation is designed to reinforce and teach the American Heart Association's course in Advanced Cardiac Life Support (ACLS). Using an animated interactive simulation allows the student to rehearse various critical events without assembling all the components typically used in the ACLS course "MegaCode." The simulation is written in a commercial authoring shell made by Authorware, Inc, and currently runs on an Apple Macintosh II platform. Cosmic Osmo (Activision) is an animated and interactive exploration game based in Hypercard that allows the user to explore and control the game by clicking on various switchs, buttons, objects, even telephones. The interactive spirit of this program has been carried over to the ACLS tutorial.


Species differences in L-tryptophan-kynurenine pathway metabolism: quantification of anthranilic acid and its related enzymes.
Anthranilic acid (AA) has attracted considerable attention as one of the L-tryptophan-kynurenine pathway metabolites in the central nervous system. In this study, a highly sensitive and accurate method for the quantification of AA has been developed using reversed-phase high-performance liquid chromatography with electrochemical detection. Serum and cerebrospinal fluid (CSF) AA concentrations in different animal species were measured. CSF AA concentrations in rabbits were 1.1 +/- 0.1 nmol/liter, which were 5. 7-33.0 times lower than those in other species studied. Serum AA concentrations, however, were slightly higher in rabbits than in other species. In contrast, the concentrations of L-kynurenine (L-KYN) in both serum and CSF were substantially higher in rabbits than in other species. Tissue kynurenine pathway enzymes, indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase, kynurenine 3-hydroxylase, and kynureninase were determined in rabbits, rats, gerbils, and mice. These enzymes varied among species, especially lung IDO activities in rabbits were 146-516 times higher than those found in other species, but rabbit liver kynurenine 3-hydroxylase activities were lower by one order of magnitude than those of the other species tested. Furthermore, brain kynurenine 3-hydroxylasae activities were 12.3-23.2 times higher in gerbils than those in the other species tested. In addition, AA concentrations in serum following intravenous administration of L-KYN (5 mg/kg) were also measured in rabbits. AA levels peaked sharply within 5 min after administration and decreased in a time-dependent manner. At 5 min after administration, CSF L-KYN and AA concentrations were also increased by 1.76- and 2.56-fold, respectively, compared with basal levels. Increased AA concentrations in CSF following L-KYN administration may reflect the entry of AA into the CSF after conversion to AA in systemic tissue and/or the local synthesis of AA from L-KYN in the CNS.


Sequential transformation for multiple traits for estimation of (co)variance components with a derivative-free algorithm for restricted maximum likelihood.
Transformation of multiple-trait records that undergo sequential selection can be used with derivative-free algorithms to maximize the restricted likelihood in estimation of covariance matrices as with derivative methods. Data transformation with appropriate parts of the Choleski decomposition of the current estimate of the residual covariance matrix results in mixed-model equations that are easily modified from round to round for calculation of the logarithm of the likelihood. The residual sum of squares is the same for transformed and untransformed analyses. Most importantly, the logarithm of the determinant of the untransformed coefficient matrix is an easily determined function of the Choleski decomposition of the residual covariance matrix and the determinant of the transformed coefficient matrix. Thus, the logarithm of the likelihood for any combination of covariance matrices can be determined from the transformed equations. Advantages of transformation are 1) the multiple-trait mixed-model equations are easy to set up, 2) the least squares part of the equations does not change from round to round, 3) right-hand sides change from round to round by constant multipliers, and 4) less memory is required. An example showed only a slight advantage of the transformation compared with no transformation in terms of solution time for each round (1 to 5%).


Robotics and neuroscience.
In the attempt to build adaptive and intelligent machines, roboticists have looked at neuroscience for more than half a century as a source of inspiration for perception and control. More recently, neuroscientists have resorted to robots for testing hypotheses and validating models of biological nervous systems. Here, we give an overview of the work at the intersection of robotics and neuroscience and highlight the most promising approaches and areas where interactions between the two fields have generated significant new insights. We articulate the work in three sections, invertebrate, vertebrate and primate neuroscience. We argue that robots generate valuable insight into the function of nervous systems, which is intimately linked to behaviour and embodiment, and that brain-inspired algorithms and devices give robots life-like capabilities.


Multicamera tracking of articulated human motion using shape and motion cues.
We present a completely automatic algorithm for initializing and tracking the articulated motion of humans using image sequences obtained from multiple cameras. A detailed articulated human body model composed of sixteen rigid segments that allows both translation and rotation at joints is used. Voxel data of the subject obtained from the images is segmented into the different articulated chains using Laplacian Eigenmaps. The segmented chains are registered in a subset of the frames using a single-frame registration technique and subsequently used to initialize the pose in the sequence. A temporal registration method is proposed to identify the partially segmented or unregistered articulated chains in the remaining frames in the sequence. The proposed tracker uses motion cues such as pixel displacement as well as 2-D and 3-D shape cues such as silhouettes, motion residue, and skeleton curves. The tracking algorithm consists of a predictor that uses motion cues and a corrector that uses shape cues. The use of complementary cues in the tracking alleviates the twin problems of drift and convergence to local minima. The use of multiple cameras also allows us to deal with the problems due to self-occlusion and kinematic singularity. We present tracking results on sequences with different kinds of motion to illustrate the effectiveness of our approach. The pose of the subject is correctly tracked for the duration of the sequence as can be verified by inspection.


Pancam multispectral imaging results from the Spirit Rover at Gusev Crater.
Panoramic Camera images at Gusev crater reveal a rock-strewn surface interspersed with high- to moderate-albedo fine-grained deposits occurring in part as drifts or in small circular swales or hollows. Optically thick coatings of fine-grained ferric iron-rich dust dominate most bright soil and rock surfaces. Spectra of some darker rock surfaces and rock regions exposed by brushing or grinding show near-infrared spectral signatures consistent with the presence of mafic silicates such as pyroxene or olivine. Atmospheric observations show a steady decline in dust opacity during the mission, and astronomical observations captured solar transits by the martian moons, Phobos and Deimos, as well as a view of Earth from the martian surface.


Long-distance retrograde effects of botulinum neurotoxin A.
Botulinum neurotoxins (designated BoNT/A-BoNT/G) are bacterial enzymes that block neurotransmitter release by cleaving essential components of the vesicle fusion machinery. BoNT/A, which cleaves SNAP-25 (synaptosomal-associated protein of 25 kDa), is extensively exploited in clinical medicine to treat neuromuscular pathologies, facial wrinkles, and various types of pain. It is widely assumed that BoNT/A remains at the synaptic terminal and its effects are confined to the injection site. Here we demonstrate that catalytically active BoNT/A is retrogradely transported by central neurons and motoneurons and is then transcytosed to afferent synapses, in which it cleaves SNAP-25. SNAP-25 cleavage by BoNT/A was observed in the contralateral hemisphere after unilateral BoNT/A delivery to the hippocampus. Appearance of cleaved SNAP-25 resulted in blockade of hippocampal activity in the untreated hemisphere. Injections of BoNT/A into the optic tectum led to the appearance of BoNT/A-truncated SNAP-25 in synaptic terminals within the retina. Cleaved SNAP-25 also appeared in the facial nucleus after injection of the toxin into rat whisker muscles. Experiments excluded passive spread of the toxin and demonstrated axonal migration and neuronal transcytosis of BoNT/A. These findings reveal a novel pathway of BoNT/A trafficking in neurons and have important implications for the clinical uses of this neurotoxin.


Contributions of severe burn and disuse to bone structure and strength in rats.
Burn and disuse results in metabolic and bone changes associated with substantial and sustained bone loss. Such loss can lead to an increased fracture incidence and osteopenia. We studied the independent effects of burn and disuse on bone morphology, composition and strength, and microstructure of the bone alterations 14days after injury. Sprague-Dawley rats were randomized into four groups: Sham/Ambulatory (SA), Burn/Ambulatory (BA), Sham/Hindlimb Unloaded (SH) and Burn/Hindlimb Unloaded (BH). Burn groups received a 40% total body surface area full-thickness scald burn. Disuse by hindlimb unloading was initiated immediately following injury. Bone turnover was determined in plasma and urine. Femur biomechanical parameters were measured by three-point bending tests and bone microarchitecture was determined by micro-computed tomography (uCT). On day 14, a significant reduction in body mass was observed as a result of burn, disuse and a combination of both. In terms of bone health, disuse alone and in combination affected femur weight, length and bone mineral content. Bending failure energy, an index of femur strength, was significantly reduced in all groups and maximum bending stress was lower when burn and disuse were combined. Osteocalcin was reduced in BA compared to the other groups, indicating influence of burn. The reductions observed in femur weight, BMC, biomechanical parameters and indices of bone formation are primarily responses to the combination of burn and disuse. These results offer insight into bone degradation following severe injury and disuse.