Controller synthesis and clinical exploration of wearable gyroscopic actuators to support human balance.
Gyroscopic actuators are appealing for wearable applications due to their ability to provide overground balance support without obstructing the legs. Multiple wearable robots using this actuation principle have been proposed, but none has yet been evaluated with humans. Here we use the GyBAR, a backpack-like prototype portable robot, to investigate the hypothesis that the balance of both healthy and chronic stroke subjects can be augmented through moments applied to the upper body. We quantified balance performance in terms of each participant's ability to walk or remain standing on a narrow support surface oriented to challenge stability in either the frontal or the sagittal plane. By comparing candidate balance controllers, it was found that effective assistance did not require regulation to a reference posture. A rotational viscous field increased the distance healthy participants could walk along a 30mm-wide beam by a factor of 2.0, compared to when the GyBAR was worn but inactive. The same controller enabled individuals with chronic stroke to remain standing for a factor of 2.5 longer on a narrow block. Due to its wearability and versatility of control, the GyBAR could enable new therapy interventions for training and rehabilitation.


Aspiration of the asymptomatic metatarsophalangeal joint in gout patients and hyperuricemic controls.
Asymptomatic metatarsophalangeal joints were aspirated in a group of patients with gout, in 2 control groups with hyperuricemia, and in 1 normouricemic control group. Extracellular urate crystals were present in 70% of gout patients, in 1 of 19 patients with asymptomatic hyperuricemia, and in 2 of 9 patients with renal failure and hyperuricemia but no history of joint disease. Crystals were not found in the 10 normouricemic patients who had other types of arthritis. The presence of crystals in the subjects with gout was not correlated with a history of podagra, duration of gout, presence of tophi, or degree of control of hyperuricemia. Though crystals were found on rare occasions in joint fluid of asymptomatic hyperuricemic subjects, the presence of these crystals in asymptomatic joints was more common in subjects with gout.


Understanding child-based effects on parenting: temperament as a moderator of genetic and environmental contributions to parenting.
The degree to which child temperament moderates genetic and environmental contributions to parenting was examined. Participants were drawn from the Nonshared Environment and Adolescent Development project and included 720 sibling pairs, ages 13.5 + 2.0 years (Sibling 1) to 12.1 + 1.3 years (Sibling 2). The sample consisted of 6 sibling types: 93 monozygotic twin pairs, 99 dizygotic twin pairs, and 95 full sibling pairs from never-divorced families and 182 full-sibling, 109 half-sibling, and 130 unrelated-sibling pairs residing in stepfamilies. Composite child temperament ratings (negative emotionality, activity, shyness, and sociability) were derived from mothers' and fathers' reports. Composite parenting ratings (negativity, warmth) for mothers and fathers were generated from children's and parents' reports. Analyses indicated that at higher levels of negative emotionality and sociability, child-based genetic contributions to mothers' and fathers' negativity increased, whereas the contributions of environmental factors declined. The opposite pattern was observed for child shyness. These same characteristics had less impact on parental warmth. For fathers only, nonshared environmental contributions to fathers' warmth increased in the presence of high child activity and sociability but declined when children were very shy. Overall these findings indicate that child-based effects on negative parenting are enhanced when children demonstrate potentially challenging characteristics but are weaker in the absence of such characteristics.


The role of the spiral ligament in cochlear mechanics.
Maximum deflection of the basilar membrane (BM) in fresh guinea pig cochlea preparations attains values attaining roughly half the width of the membrane. Displacement of the BM is made possible by the elastic spiral ligament, which participates directly in dynamic processes of cochlear mechanics. That the movement is transmitted to the spiral ligament during experimental deformation of the BM by an instrument is borne out also by structural changes in the lateral wall epithelium in acoustic trauma and by vascular changes produced by chronic acoustic stress.


An MR-Safe Endovascular Robotic Platform: Design, Control, and Ex-Vivo Evaluation.
Cardiovascular diseases are the most common cause of global death. Endovascular interventions, in combination with advanced imaging technologies, are promising approaches for minimally invasive diagnosis and therapy. More recently, teleoperated robotic platforms target improved manipulation accuracy, stabilisation of instruments in the vasculature, and reduction of patient recovery times. However, benefits of recent platforms are undermined by a lack of haptics and residual patient exposure to ionising radiation. The purpose of this research was to design, implement, and evaluate a novel endovascular robotic platform, which accommodates emerging non-ionising magnetic resonance imaging (MRI). We proposed a pneumatically actuated MR-safe teleoperation platform to manipulate endovascular instrumentation remotely and to provide operators with haptic feedback for endovascular tasks. The platform task performance was evaluated in an ex vivo cannulation study with clinical experts ( N = 7) under fluoroscopic guidance and haptic assistance on abdominal and thoracic phantoms. The study demonstrated that the robotic dexterity involving pneumatic actuation concepts enabled successful remote cannulation of different vascular anatomies with success rates of 90%-100%. Compared to manual cannulation, slightly lower interaction forces between instrumentation and phantoms were measured for specific tasks. The maximum robotic interaction forces did not exceed 3N. This research demonstrates a promising versatile robotic technology for remote manipulation of endovascular instrumentation in MR environments. The results pave the way for clinical translation with device deployment to endovascular interventions using non-ionising real-time 3D MR guidance.


Substance use and symptomatology among adolescent children of alcoholics.
This study assessed the magnitude and specificity of parental alcoholism as a risk factor for internalizing symptomatology, externalizing symptomatology, and alcohol and drug use in adolescence. We evaluated parents' and children's reports of symptomatology and children's reports of alcohol and drug use in a community sample of 454 adolescents. The results showed that parental alcoholism was a moderate to strong risk factor, with stronger risk associated with recent (rather than remitted) parental alcoholism. Multivariate analyses showed that the specificity of risk varied with the outcome measure. In predicting externalizing symptomatology, the risk associated with parental alcoholism was mediated by co-occurring parental psychopathology and environmental stress. However, in predicting alcohol use, the father's alcoholism was a specific risk factor above and beyond the more generalized effects of stress and family disruption.


Gallic acid metabolites are markers of black tea intake in humans.
Gallic acid is one of the main phenolic components of black tea. The objective of this study was to identify urinary gallic acid metabolites with potential for use as markers of black tea intake. In an initial study, nine compounds, assessed by using gas chromatography-mass spectrometry, were found to increase in concentration in urine after 3 cups of black tea over 3 h. A subsequent study employed a controlled crossover design in which 10 subjects consumed 5 cups per day of black tea or water for 4 weeks in random order. Twenty-four hour urine samples were collected at the end of each period. Of the 9 candidate compounds identified in the initial study, only 3 were present at higher concentrations in urine of all 10 subjects during tea-drinking in comparison to water-drinking periods. These compounds were identified as 4-O-methylgallic acid, 3-O-methylgallic acid, and 3, 4-O-dimethylgallic acid, all methyl ether derivatives of gallic acid. It is suggested that these compounds have the potential to be used as markers of black tea intake.


Significantly higher polybrominated diphenyl ether levels in young U.S. children than in their mothers.
While young children are rarely included in biomonitoring studies, they are presumed to be at greater risk of ingesting environmental contaminants-particularly those that accumulate in foods or shed from consumer products. The widely used fire retardants polybrominated diphenyl ethers (PBDEs) are ubiquitous contaminants in the indoor environment and are widely detected at higher levels in Americans than in individuals from other countries. However, there are only three studies of PBDEs in U.S. children. We hypothesized that PBDEs are present in higher concentrations in young children than their mothers. PBDEs were assessed in blood samples collected concurrently from 20 mothers and their children, ages 1.5 to 4 years. The chemical analyses were performed by GC/MS applying selected ion monitoring. The samples were analyzed for 20 PBDE congeners; 11 were detected. SigmaPBDEs for children were typically 2.8 times higher than for mothers, with median child:mother ratios varying from 2 to 4 for individual congeners. In 19 of 20 families studied, children had higher SigmaPBDE concentrations than their mothers with significant (p < 0.01) concentration differences for five of the PBDE congeners. Decabromodiphenyl ether (BDE-209) was quantitated in 13 children and 9 mothers. Other studies indicate PBDEs are not elevated at birth, suggesting that early life is an intense period of PBDE intake. Children's increased hand-to-mouth activity, dietary preferences, and exposures from breast milk may result in greater ingestion of PBDEs than adults. These findings suggest that measurements from adults likely do not reflect exposures to young children despite sharing homes and similar diets.


Sequence and transcriptional analysis of the genes responsible for curdlan biosynthesis in Agrobacterium sp. ATCC 31749 under simulated dissolved oxygen gradients conditions.
Expression at the mRNA level of ten selected genes in Agrobacterium sp. ATCC 31749 under various dissolved oxygen (DO) levels during curdlan fermentation related to electron transfer chain (ETC), tricarboxylic acid (TCA) cycle, peptidoglycan/lipopolysaccharide biosynthesis, and uridine diphosphate (UDP)-glucose biosynthesis were determined by qRT-PCR. Experiments were performed at DO levels of 30%, 50%, and 75%, as well as under low-oxygen conditions. The effect of high cell density on transcriptional response of the above genes under low oxygen was also studied. Besides cytochrome d (cyd A), the transcription levels of all the other genes were increased at higher DO and reached maximum at 50% DO. Under 75% DO, the transcriptional levels of all the genes were repressed. In addition, transcription levels of icd, sdh, cyo A, and fix N genes did not exhibit significant fluctuation with high cell density culture under low oxygen. These results suggested a mechanism for DO regulation of curdlan synthesis through regulation of transcriptional levels of ETCs, TCA, and UDP-glucose synthesis genes during curdlan fermentation. To our knowledge, this is the first report that DO concentration apparently regulates curdlan biosynthesis in Agrobacterium sp. ATCC 31749 providing essential lead for the optimization of the fermentation at the industrial scale.


The effect of standard and high-fluence corneal cross-linking (CXL) on cornea and limbus.
When treating peripheral ectatic disease-like pellucid marginal degeneration (PMD), corneal cross-linking with UV-A and riboflavin (CXL) must be applied eccentrically to the periphery of the lower cornea, partly irradiating the corneal limbus. Here, we investigated the effect of standard and double-standard fluence corneal cross-linking with riboflavin and UV-A (CXL) on cornea and corneal limbus in the rabbit eye in vivo. Epithelium-off CXL was performed in male New Zealand White rabbits with two irradiation diameters (7 mm central cornea, 13 mm cornea and limbus), using standard fluence (5.4 J/cm(2)) and double-standard fluence (10.8 J/cm(2)) settings. Controls were subjected to epithelial removal and riboflavin instillation, but were not irradiated with UV-A. Following CXL, animals were examined daily until complete closure of the epithelium, and at 7, 14, 21, and 28 days. Animals were killed and a corneoscleral button was excised and processed for light microscopy and immunohistochemistry. For both irradiation diameters and fluences tested, no signs of endothelial damage or limbal vessel thrombosis were observed, and time to re-epithelialization was similar to untreated controls. Histological and immunohistochemical analysis revealed no differences in the p63 putative stem cell marker expression pattern. Even when using fluence twice as high as the one used in current clinical CXL settings, circumferential UV-A irradiation of the corneal limbus does not alter the regenerative capacity of the limbal epithelial cells, and the expression pattern of the putative stem cell marker p63 remains unchanged. This suggests that eccentric CXL may be performed safely in PMD.


Contribution of the self-regulation model to understanding the health related quality of life of rheumatoid arthritis patients.
This study examined a comprehensive model that integrates the interrelationships among health-related-quality-of-life (HRQoL), disease duration, disease severity, illness representations, and coping resources regarding patients with Rheumatoid arthritis (RA), based on the Self-regulation model. A convenience sample of 164 patients with RA completed measures of disease's characteristics (disease duration, disease status), illness representations (timeline, consequences, self-control, treatment control, symptom burden, concern about RA, understanding RA, emotional representations), coping resources (resilience, social support), HRQoL, and socio-demographic questionnaires. The research model was assessed through path analysis. Perceptions of higher treatment control, lower consequences of RA and lower symptom burden were directly related to HRQoL. The perceptions of higher self-control, higher treatment control, less concern about RA, and lower emotional representations were associated with higher resilience, which in turn was associated with higher HRQoL. The perceptions of higher treatment control, greater understanding of RA, and lower emotional representations were associated with higher perceived social support; however, social support was not associated with HRQoL. This study contributes to a better understanding of the determinants of HRQoL among RA patients. The findings indicate that clinical interventions targeting RA patients' illness representations and resilience may assist patients with RA to improve their HRQoL.


ML segmentation strategies for object interference compensation in FDG-PET lesion quantification.
Quantification of lesion activity by FDG uptake in oncological PET is severely limited by partial volume effects. A maximum likelihood (ML) expectation maximization (EM) algorithm considering regional basis functions (AWOSEM-region) had been previously developed. Regional basis functions are iteratively segmented and quantified, thus identifying the volume and the activity of the lesion. Improvement of AWOSEM-region when analyzing proximal interfering hot objects is addressed by proper segmentation initialization steps and models of spill-out and partial volume effects. Conditions relevant to lung PET-CT studies are considered: 1) lesion close to hot organ (e.g. chest wall, heart and mediastinum), 2) two close lesions. CT image was considered for pre-segmenting hot anatomical structures, never for lesion identification, solely defined by iterations on PET data. Further resolution recovery beyond the smooth standard clinical image was necessary to start lesion segmentation. A watershed algorithm was used to separate two close lesions. A subtraction of the spill-out from a nearby hot organ was introduced to enhance a lesion for the initial segmentation and start the further quantification steps. Biograph scanner blurring was modeled from phantom data in order to implement the procedure for 3D clinical lung studies. In simulations, the procedure was able to separate structures as close as one pixel-size (2.25 mm). Robustness against the input segmentation errors defining the addressed objects was tested showing that convergence was not sensitive to initial volume overestimates up to 130%. Poor robustness was found against underestimates. A clinical study of a small lung lesion close to chest wall displayed a good recovery of both lesion activity and volume. With proper initialization and models of spill-out from hot organs, AWOSEM-region can be successfully applied to lung oncological studies.


Multi-state modeling of biomolecules.
Multi-state modeling of biomolecules refers to a series of techniques used to represent and compute the behavior of biological molecules or complexes that can adopt a large number of possible functional states. Biological signaling systems often rely on complexes of biological macromolecules that can undergo several functionally significant modifications that are mutually compatible. Thus, they can exist in a very large number of functionally different states. Modeling such multi-state systems poses two problems: the problem of how to describe and specify a multi-state system (the "specification problem") and the problem of how to use a computer to simulate the progress of the system over time (the "computation problem"). To address the specification problem, modelers have in recent years moved away from explicit specification of all possible states and towards rule-based formalisms that allow for implicit model specification, including the κ-calculus, BioNetGen, the Allosteric Network Compiler, and others. To tackle the computation problem, they have turned to particle-based methods that have in many cases proved more computationally efficient than population-based methods based on ordinary differential equations, partial differential equations, or the Gillespie stochastic simulation algorithm. Given current computing technology, particle-based methods are sometimes the only possible option. Particle-based simulators fall into two further categories: nonspatial simulators, such as StochSim, DYNSTOC, RuleMonkey, and the Network-Free Stochastic Simulator (NFSim), and spatial simulators, including Meredys, SRSim, and MCell. Modelers can thus choose from a variety of tools, the best choice depending on the particular problem. Development of faster and more powerful methods is ongoing, promising the ability to simulate ever more complex signaling processes in the future.


[Gene expression specific for heart atria and ventricles].
The data on the chamber-specific expression of cardiac genes in the animal and human heart are reviewed. The positional specification of atrial and ventricular gene expression observed in adults is initiated early during embryogenesis. The existence of a cascade of genes is assumed, beginning with genes whose products form an anterior-posterior gradient along the heart-forming regions or along the linear heart tube derived from these regions, and ending with genes that encode the contractile proteins and display chamber-specific expression.


Statistics of normalized Stokes polarization parameters.
The normalized Stokes parameters are formed from the ratio of the polarization components to the intensity component of light. Such ratio distributions are known to have an undefined mean and variance, and yet researchers in the polarization community work with these normalized parameters all the time. We show that while in theory the normalized parameters have a pathological probability density, in practice they are quite well-behaved. We provide expressions for their approximate densities and confirm the results with laboratory measurements.


Psychological and Physical Intimate Partner Aggression Are Associated with Broad and Specific Internalizing Symptoms during Pregnancy.
Intimate partner violence (IPV) has serious consequences, particularly during high-risk periods such as pregnancy, which poses a significant risk to maternal mental health. However, it is unclear whether IPV presents a broad risk for psychopathology or is specific to distinct diagnoses or symptom dimensions (e.g., panic, social anxiety). Further, the relative impact of physical versus psychological aggression remains unclear. One hundred and fifty-nine pregnant couples completed surveys assessing psychological and physical intimate partner aggression unfolding in the couple relationship, as well as a range of internalizing symptoms. Psychological and physical aggression were each associated with broad negative affectivity, which underlies mood and anxiety disorders; however, only psychological aggression demonstrated a unique association. Further, for pregnant women, aggression was uniquely associated with several symptom dimensions characteristic of PTSD. In contrast, men demonstrated a relatively heterogeneous symptom presentation in relation to aggression. The present study identifies unique symptom manifestations associated with IPV for couples navigating pregnancy and suggests psychological aggression can be more detrimental to mental health than physical aggression. To promote maternal perinatal mental health, clinicians should screen for covert forms of psychological aggression during pregnancy (e.g., raised voices, insults), trauma-related distress, and symptom elevations in women and their partners.


Doping with Graphitic Nitrogen Triggers Ferromagnetism in Graphene.
Nitrogen doping opens possibilities for tailoring the electronic properties and band gap of graphene toward its applications, e.g., in spintronics and optoelectronics. One major obstacle is development of magnetically active N-doped graphene with spin-polarized conductive behavior. However, the effect of nitrogen on the magnetic properties of graphene has so far only been addressed theoretically, and triggering of magnetism through N-doping has not yet been proved experimentally, except for systems containing a high amount of oxygen and thus decreased conductivity. Here, we report the first example of ferromagnetic graphene achieved by controlled doping with graphitic, pyridinic, and chemisorbed nitrogen. The magnetic properties were found to depend strongly on both the nitrogen concentration and type of structural N-motifs generated in the host lattice. Graphenes doped below 5 at. % of nitrogen were nonmagnetic; however, once doped at 5.1 at. % of nitrogen, N-doped graphene exhibited transition to a ferromagnetic state at ∼69 K and displayed a saturation magnetization reaching 1.09 emu/g. Theoretical calculations were used to elucidate the effects of individual chemical forms of nitrogen on magnetic properties. Results showed that magnetic effects were triggered by graphitic nitrogen, whereas pyridinic and chemisorbed nitrogen contributed much less to the overall ferromagnetic ground state. Calculations further proved the existence of exchange coupling among the paramagnetic centers mediated by the conduction electrons.


Demographics and Outcomes of Interhospital Neurosurgical Transfer Patients Undergoing Spine Surgery.
Interhospital patient transfer (IHT) of patients is common and accounts for a significant portion of health care costs, yet the variables driving neurosurgical IHT have not been systematically described. We analyzed variables that distinguished spine surgery patients who underwent IHT from patients who did not undergo IHT to report on the effect of frailty on IHT. A retrospective chart review was performed to collect data on consecutive patients undergoing spinal procedures during 2015-2017. IHT patients were identified and compared with non-interhospital patient transfer (n-IHT) patients to identify factors that distinguished the 2 patient groups using multivariate regression analysis. Studied variables included case complexity, frailty (modified frailty index), age, insurance status, and baseline demographic variables. Postoperative outcomes affected by transfer status were identified in binary regression analysis. During 2015-2017, there were 595 n-IHT and 76 IHT spine surgery patients (N = 671). Increased frailty (modified frailty index ≥3; odds ratio = 2.4, P = 0.01) and increased spine surgery complexity (spine surgery complexity score ≥2; odds ratio = 2.57, P = 0.002) were independent risk factors associated with IHT. IHT was an independent risk factor for increased hospital length of stay and increased postoperative complications (Clavien-Dindo scale; P < 0.001). IHT patients comprise a more frail and surgically complex surgical spine population compared with n-IHT patients. IHT was also an independent risk factor for increased complications and length of stay after spine surgery. Patients' insurance status and age did not distinguish between IHT and n-IHT groups. This is the first report in any specialty to demonstrate increasing frailty is associated with IHT.


[Transplantation of mesenchymal bone marrow stromal cells as new opportunity to overcome ineffectiveness of primary anti-cytokine therapy in Crohn's disease].
Clinical observations and studies have shown that among 34 patients with Crohn's disease (CD) under infliximab (INFX) therapy in 8.8% cases was observed the loss of response to anticytokine therapy (so-called primary ineffectiveness of anti-cytokine therapy (ACT)). The increasing of INFX dosage up to 10 mg/kg of body weight failed to achieve clinical and endoscopic remission. It should be noted that, despite the long anticytokine therapy in these patients the antibodies to INFX were not observed and INFX concentration in blood serum practically was not determined. In CD patients with primary ineffectiveness of anti-cytokine therapy (ACT) was detected clinical deterioration of CD: increase of WR Best Index (CDAI), appearance of pain, fever, increase of stool frequency with blood and mucus, improving performance of acute phase of inflammation. Transplantation of mesenchymal bone marrow stromal cells (MSC) enhanced the level of INFX in the serum and overcoming the primary ineffectiveness of anti-cytokine therapy (ACT) and increase in sensitivity to Infliximab.


Guidelines to Aid in the Distinction of Endometrial and Endocervical Carcinomas, and the Distinction of Independent Primary Carcinomas of the Endometrium and Adnexa From Metastatic Spread Between These and Other Sites.
In most cases of suspected endometrial neoplasia tumor origin can be correctly assigned according to a combination of clinical, radiologic, and pathologic features, even when the latter are based upon the examination of relatively small biopsy samples. However there are well-recognized exceptions to this rule which continue to create diagnostic difficulty, and sometimes difficulties persist even after the detailed examination of resection specimens. Among the most common problems encountered in practice are the distinction of primary endometrial and primary endocervical adenocarcinomas, and the determination of tumor origin when there is synchronous, multifocal involvement of gynecologic tract sites, for example the endometrium and the ovary. However, accurate diagnosis in these cases is important because this has significant staging, management and prognostic implications. In this review we discuss the value and limitations of key morphologic, immunophenotypic and molecular findings in these diagnostic scenarios.


Caspase-dependent cleavage of c-Abl contributes to apoptosis.
The nonreceptor tyrosine kinase c-Abl may contribute to the regulation of apoptosis. c-Abl activity is induced in the nucleus upon DNA damage, and its activation is required for execution of the apoptotic program. Recently, activation of nuclear c-Abl during death receptor-induced apoptosis has been reported; however, the mechanism remains largely obscure. Here we show that c-Abl is cleaved by caspases during tumor necrosis factor- and Fas receptor-induced apoptosis. Cleavage at the very C-terminal region of c-Abl occurs mainly in the cytoplasmic compartment and generates a 120-kDa fragment that lacks the nuclear export signal and the actin-binding region but retains the intact kinase domain, the three nuclear localization signals, and the DNA-binding domain. Upon caspase cleavage, the 120-kDa fragment accumulates in the nucleus. Transient-transfection experiments show that cleavage of c-Abl may affect the efficiency of Fas-induced cell death. These data reveal a novel mechanism by which caspases can recruit c-Abl to the nuclear compartment and to the mammalian apoptotic program.


Parental experience of end-of life care in the pediatric intensive care unit.
There is a considerable variability among European countries regarding the management of end-of-life (EOL) care in the pediatric critical care setting. In Italy, recommendations on these issues are available but no study has investigated the parents' experience. The aim of this study was to explore parents' experience of EOL care in a Pediatric Intensive Care Unit (PICU) in Italy. The study was conducted in a 6-bed PICU of a university affiliated hospital in Milan. Parents of children who died between 2007-2010 after a stay of at least 24 hours were eligible to participate. Through semi-structured interviews, parents were asked to describe the story of their child's stay in the PICU, including his/her final moments. The interviews were audio-recorded, transcribed verbatim and analyzed according to the hermeneutic-phenomenology approach. Twelve parents of 8 children were interviewed. Four themes emerged that described the parents' experience: 1) loss of parental role; 2) lack of physical intimacy with their child; 3) ambivalence about end-of-life decisions; and 4) reclaiming the dying process. Our findings suggest that in order to improve pediatric EOL care we need to better integrate medical and parental priorities, in a shared process that allows parents to preserve their role and relationship with their child. The most critical aspect for parents was not related to the involvement (or not) in EOL decisions, but rather to the possibility of staying connected with their child during the hospitalization and at the time of death.


Polyphenolic extract of InsP 5-ptase expressing tomato plants reduce the proliferation of MCF-7 breast cancer cells.
In recent years, by extensive achievements in understanding the mechanisms and the pathways affected by cancer, the focus of cancer research is shifting from developing new chemotherapy methods to using natural compounds with therapeutic properties to reduce the adverse effects of synthetic drugs on human health. We used fruit extracts from previously generated human type I InsP 5-ptase gene expressing transgenic tomato plants for assessment of the anti-cancer activity of established genetically modified tomato lines. Cellular assays (MTT, Fluorescent microscopy, Flow Cytometry analysis) were used to confirm that InsP 5-ptase fruit extract was more effective for reducing the proliferation of breast cancer cells compared to wild-type tomato fruit extract. Metabolome analysis of InsP 5-ptase expressing tomato fruits performed by LC-MS identified tomato metabolites that may play a key role in the increased anti-cancer activity observed for the transgenic fruits. Total transcriptome analysis of cancer cells (MCF-7 line) exposed to an extract of transgenic fruits revealed a number of differently regulated genes in the cells treated with transgenic extract compared to untreated cells or cells treated with wild-type tomato extract. Together, this data demonstrate the potential role of the plant derived metabolites in suppressing cell viability of cancer cells and further prove the potential application of plant genetic engineering in the cancer research and drug discovery.


Apatite crystallites: effects of carbonate on morphology.
Carbonate is a substituent in the apatite structure; when present, it limits the size of the growing apatite crystals and so influences their shape that they grow more equiaxed than needle-like. The tendency for carbonate apatites to be equiaxed is related to the nature of the chemical bonds formed in the crystal. The interference of carbonate with the good crystallization of apatite, and its weakening effect on the bonds in the structure, increase the dissolution rate and the solubility, thereby presumably contributing to the susceptibility to caries of dental apatites containing carbonate.


Rigid contact lens fitting relationships in keratoconus. Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study Group.
Although the influence of flat-fitting contact lenses on corneal scarring in keratoconus is frequently debated, the current standard of care with regard to the apical fitting relationship in keratoconus remains undocumented. Patients were examined at baseline in the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study (N = 1209). Patients wearing a rigid contact lens in one or both eyes (N = 808) had their habitual rigid contact lenses analyzed, and the fluorescein patterns and base curves were compared to the first definite apical clearance lens (FDACL). The FDACL is the flattest lens in the CLEK Study trial lens set that exhibits an apical clearance fluorescein pattern. For patients wearing a rigid contact lens in both eyes, one eye was selected randomly for analysis. Twelve percent of the rigid contact lens-wearing eyes were wearing lenses fitted with apical clearance based upon the clinician's fluorescein pattern interpretation. The remainder (88%) was wearing lenses fitted with apical touch. For mild (steep keratometric reading <45 D) keratoconus corneas, the mean estimate of the base curve to cornea-fitting relationship was 1.18 D flat (SD +/- 1.84 D); moderate (steep keratometric reading: 45 to 52 D) corneas were fitted on average 2.38 D flat (SD +/- 2.56 D); and severe (steep keratometric reading > 52 D) corneas were fitted an average of 4.01 D flat (SD +/- 4.11 D). Despite the potential risk for corneal scarring imposed by flat-fitting rigid contact lenses, most CLEK Study patients wear flat-fitting lenses. Overall, rigid lenses were fitted an average of 2.86 D (SD +/- 3.31 D) flatter than the FDACL.


Protective effect of Juglans nigra on sodium arsenite-induced toxicity in rats.
Consumption of arsenic contaminated water has been implicated in metalloid-induced carcinogenesis. Dietary intake of certain plant products with chemoprotective properties may protect against the onset of diseases and promote maintenance of health. We investigated the outcome of black walnut Juglans nigra (JN) consumption on sodium arsenite (SA)-induced toxicity in rats. WISTER ALBINO RATS WERE TREATED AS FOLLOWS: Control, SA only (positive control) (2.5 mg/kg body weight), JN only (100 mg/kg weight), and JN+SA coadministered. After 5 weeks animals were sacrificed whole blood, femur, liver and testis harvested were assessed for hepatic transaminases and clastogenicity. Histology of the liver, sperm morphology and quality were also assessed. Data were analyzed (ANOVA) and expressed as means ±SD. SA treatment elevated hepatic transaminases level in serum (P < 0.05), induced histological changes in liver: fibroplasia and periportal hepatocytes infiltration by mononuclear cells. These changes were ameliorated by JN (P < 0.05) coadministration. SA induced micronuclei formation (P < 0.05). Again JN decreased (P < 0.05) micronuclei formation by 50%. Sperm count and motility decreased (P < 0.05) in all groups compared to control. JN showed no protection against arsenite effect on sperm quality. Hepatoprotective and anticlastogenic effects were apparent suggesting a chemopreventive potential active against arsenite genotoxicity and chromosomal instability which have implication for metalloid-induced carcinogenesis.


Virus particles from conidia of Penicillium species.
Virus particles and their component double-stranded ribonucleic acid (dsRNA) have been isolated from conidia and mycelia of certain Penicillium species. The conidia and mycelia of P. stoloniferum NRRL 5267 contained 75 and 85 mug of dsRNA/g (dry weight), respectively. Of the total dsRNA released from NRRL 5267 conidia, 10% was nonencapsulated. Conidia of P. brevi-compactum NRRL 5260 and P. chrysogenum Q-176 contained 2 and 120 mug of dsRNA/g (dry weight), respectively, whereas mycelium from the two species contained 3 and 95 mug of dsRNA/g (dry weight), respectively. No viruses were isolated from conidia or mycelia of P. stoloniferum NRRL 859. A method is described for disruption of both conidia and mycelia. The technique facilitates the isolation and characterization of fungal viruses and their component dsRNA and also potentiates surveying of fungal isolates for the presence of virus.


Prader-Willi syndrome and growth hormone deficiency.
Prader-Willi syndrome (PWS) is a rare multisystem genetic disorder demonstrating great variability with changing clinical features during patient's life. It is characterized by severe hypotonia with poor sucking and feeding difficulties in early infancy, followed by excessive eating and gradual development of morbid obesity in later infancy or early childhood. The phenotype is most probably due to hypothalamic dysfunction which is also responsible for growth hormone (GH) and thyroid-stimulating hormone (TSH) deficiencies, central adrenal insufficiency and hypogonadism. The multidimensional problems of patients with PWS can be managed with multidisciplinary approach. Reduced GH secretion, low peak GH response to stimulation, decreased spontaneous GH secretion and low serum IGF-1 levels in PWS patients have been documented in many studies. GH therapy has multiple beneficial effects on growth and body composition, motor and mental development in PWS patients. The recommended dosage for GH is 0.5-1 mg/m2/day. GH therapy should not be started in the presence of obstructive sleep apnea syndrome, adenotonsillar hypertrophy, severe obesity and diabetes mellitus. GH treatment should be considered for patients with genetically confirmed PWS in conjunction with dietary, environmental and life-style measures.


Emerging sensing platforms based on Cucurbit[n]uril functionalized gold nanoparticles and electrodes.
Cucurbit[n]urils (CB[n]s, n = 5-8, 10, and 14), synthetic macrocycles with unique host-guest properties, have triggered increasing research interest in recent years. Gold nanoparticles (Au NPs) and electrodes stand out as exceptional substrates for sensing due to their remarkable physicochemical characteristics. Coupling the CB[n]s with Au NPs and electrodes has enabled the development of emerging sensing platforms for various promising applications. However, monitoring the behavior of analytes at the single-molecule level is currently one of the most challenging topics in the field of CB[n]-based sensing. Constructing supramolecular junctions in a sensing platform provides an ideal structure for single-molecule analysis, which can provide insights for a fundamental understanding of supramolecular interactions and chemical reactions and guide the design of sensing applications. This feature article outlines the progress in the preparation of the CB[n] functionalized Au NPs and Au electrodes, as well as the construction and application of supramolecular junctions in sensing platforms, based on the methods of recognition tunneling (RT), surface-enhanced Raman spectroscopy (SERS), single-molecule force spectroscopy (SMFS), and electrochemical sensing (ECS). A brief perspective on the future development of and challenges in CB[n] mediated sensing platforms is also covered.


Cross-domain analogies as relating derived relations among two separate relational networks.
Contemporary behavior analytic research is making headway in analyzing analogy as the establishment of a relation of coordination among common types of trained or derived relations. Previous studies have been focused on within-domain analogy. The current study expands previous research by analyzing cross-domain analogy as relating relations among separate relational networks and by correlating participants' performance with a standard measure of analogical reasoning. In two experiments, adult participants first completed general intelligence and analogical reasoning tests. Subsequently, they were exposed to a computerized conditional discrimination training procedure designed to create two relational networks, each consisting of two 3-member equivalence classes. The critical test was a two-part analogical test in which participants had to relate combinatorial relations of coordination and distinction between the two relational networks. In Experiment 1, combinatorial relations for each network were individually tested prior to analogical testing, but in Experiment 2 they were not. Across both experiments, 65% of participants passed the analogical test on the first attempt. Moreover, results from the training procedure were strongly correlated with the standard measure of analogical reasoning.


The anticariogenic effect of sugar-free gum containing CPP-ACP nanocomplexes on approximal caries determined using digital bitewing radiography.
This study investigated, using digital bitewing radiography, the progression and regression of approximal caries in adolescent subjects chewing a sugar-free gum containing 54 mg CPP-ACP relative to the identical gum without CPP-ACP. 2,720 subjects from 29 schools were randomly assigned to one of the two gums and were instructed to chew their assigned gum for 3 x 10 min/day, with one session supervised on school days, over the 24-month study period. Standardized digital bitewing radiographs were taken at the baseline and 24-month clinical examinations for each subject. The radiographs, scored by a single examiner, were assessed for approximal surface dental caries at both the enamel and dentine level. Surface level transitions were scored using a transition matrix. Caries progression or regression was analysed using proportional-odds ordered logistic regression modelling of the transition scores at the tooth surface level. There was a statistically significant difference in the frequency distributions of the transition scores between the two gum groups (OR = 0.82, p = 0.03). For subjects chewing the CPP-ACP gum the odds of a surface experiencing caries progression were 18% less than those of a surface experiencing caries progression for subjects chewing the control gum. In conclusion, the 54 mg CPP-ACP sugar-free gum significantly slowed progression and enhanced regression of approximal caries relative to a control sugar-free gum in a 24-month clinical trial.


Effects of Fluoxetine and Visual Experience on Glutamatergic and GABAergic Synaptic Proteins in Adult Rat Visual Cortex.
Fluoxetine has emerged as a novel treatment for persistent amblyopia because in adult animals it reinstates critical period-like ocular dominance plasticity and promotes recovery of visual acuity. Translation of these results from animal models to the clinic, however, has been challenging because of the lack of understanding of how this selective serotonin reuptake inhibitor affects glutamatergic and GABAergic synaptic mechanisms that are essential for experience-dependent plasticity. An appealing hypothesis is that fluoxetine recreates a critical period (CP)-like state by shifting synaptic mechanisms to be more juvenile. To test this we studied the effect of fluoxetine treatment in adult rats, alone or in combination with visual deprivation [monocular deprivation (MD)], on a set of highly conserved presynaptic and postsynaptic proteins (synapsin, synaptophysin, VGLUT1, VGAT, PSD-95, gephyrin, GluN1, GluA2, GluN2B, GluN2A, GABAAα1, GABAAα3). We did not find evidence that fluoxetine shifted the protein amounts or balances to a CP-like state. Instead, it drove the balances in favor of the more mature subunits (GluN2A, GABAAα1). In addition, when fluoxetine was paired with MD it created a neuroprotective-like environment by normalizing the glutamatergic gain found in adult MDs. Together, our results suggest that fluoxetine treatment creates a novel synaptic environment dominated by GluN2A- and GABAAα1-dependent plasticity.


Assessment of health-promoting behavior and lifestyle of adolescents of a north Indian city.
Several health-compromising behaviors (e.g., smoking, alcohol) as well as health-enhancing behaviors (e.g., physical exercise, nutrition) are adopted in adolescence and they often persist into adulthood. Thus, there is a definite need to investigate the health behavior of adolescents rather than focus on adults since it will be far more difficult for adults to change their unhealthy habits adopted in their youth. Therefore, the present study was conducted to ascertain health-promoting behavior and lifestyle of university graduates of Chandigarh. The present cross-sectional pilot study was conducted in Chandigarh during 2009 among university graduates of Chandigarh aged 17-20 years. A semi-structured, pretested questionnaire comprising of 28 items was used to get information from students regarding their involvement in diet, physical exercise, spirituality and philanthropy. Height, weight, waist and hip circumference of the respondents were measured using standardized equipments and procedures. Mean score of health-promoting lifestyle profile of university graduates was found to be 67.5 ± 12.1 (maximum attainable score = 106). Fourteen students were found to be overweight. Frequent intake of fast food and less consumption of fruits and vegetables was reported by the students. Majority of students exercised as part of their daily routine. The result of the study showed that North Indian students had reasonably good orientations toward health behaviors, with a mean score of 67.5. The topics related to diet, physical exercise, spiritual growth and philanthropy promotion should be incorporated within the curriculum of students for their all round personality development.


Stimulation of NGF expression and secretion in 3T3-L1 adipocytes by prostaglandins PGD2, PGJ2, and Delta12-PGJ2.
Nerve growth factor (NGF) has recently been shown to be secreted from white adipocytes, its production being strongly stimulated by the proinflammatory cytokine tumor necrosis factor-alpha. In this study, we have examined whether a series of prostaglandins and other inflammation-related factors also stimulate NGF expression and secretion by adipocytes, using 3T3-L1 cells. Although interleukin (IL)-1beta, IL-10, and IL-18 each induced a small decrease in NGF mRNA level in 3T3-L1 adipocytes, there was no significant effect of these cytokines on NGF secretion. A small reduction in NGF expression and/or secretion was also observed with adiponectin and prostaglandins PGE(2), PGF(2alpha), and PGI(2). In marked contrast, prostaglandin PGD(2) induced a major, dose-dependent increase (up to 20- to 40-fold) in NGF expression and secretion. The PGD(2) metabolites, PGJ(2) and Delta(12)-PGJ(2), also induced major increases (up to 30-fold) in NGF production. A further metabolite of PGJ(2), 15-deoxy-Delta(12,14)-PGJ(2), a peroxisome proliferator-activated receptor-gamma agonist, led paradoxically to a small increase in NGF mRNA level but a fall in NGF secretion. Both PGD(2) and PGJ(2) induced significant increases in NGF gene expression by 4 h after their addition. It is concluded that PGD(2) and the J series prostaglandins, PGJ(2) and Delta(12)-PGJ(2), can play a significant role in the regulation of NGF production by white adipocytes. These results provide support for the view that NGF is an important inflammatory response protein, as well as a target-derived neurotrophin, in white adipose tissue.


The nature of chlorine-inhibition of photocatalytic degradation of dichloroacetic acid in a TiO2-based microreactor.
Photocatalytic degradation of dichloroacetic acid (DCA) was studied in a continuous-flow set-up using a titanium microreactor with an immobilized double-layered TiO2 nanoparticle/nanotube film. Chloride ions, formed during the degradation process, negatively affect the photocatalytic efficiency and at a certain concentration (approximately 0.5 mM) completely stop the reaction in the microreactor. Two proposed mechanisms of inhibition with chloride ions, competitive adsorption and photogenerated-hole scavenging, have been proposed and investigated by adsorption isotherms and electron paramagnetic resonance (EPR) measurements. The results show that chloride ions block the DCA adsorption sites on the titania surface and reduce the amount of adsorbed DCA molecules. The scavenging effect of chloride ions during photocatalysis through the formation of chlorine radicals was not detected.


Body mass index in relation to truncal asymmetry of healthy adolescents, a physiopathogenetic concept in common with idiopathic scoliosis: summary of an electronic focus group debate of the IBSE.
There is no generally accepted scientific theory for the cause of adolescent idiopathic scoliosis (AIS). As part of its mission to widen understanding of scoliosis etiology, the International Federated Body on Scoliosis Etiology (IBSE).introduced the electronic focus group (EFG) as a means of increasing debate on knowledge of important topics. This has been designated as an on-line Delphi discussion. The text for this debate was written by Dr TB Grivas. It is based on published research from Athens, Greece evaluating schoolchildren age 11-17 years for the relation of body mass index (BMI) to each of truncal asymmetry (TA) and menarcheal status. Girls with relatively lower BMI were found to have a significant excess of severe TAs and significantly later menarche confirming the well-known relation of BMI to menarche. Together with other evidence linking nutritional status to skeletal growth, the observations suggest energy balance via the hypothalamus is related to trunk asymmetry. As with a recent speculative hypothesis for the pathogenesis of AIS in girls, Grivas et al. suggest that the severe TAs involve a genetically-determined selectively increased sensitivity (up-regulation) of the hypothalamus to circulating leptin with asymmetry as an adverse response to stress (hormesis). The TA is expressed bilaterally via the sympathetic nervous system to produce left-right asymmetry in ribs and/or vertebrae leading to severe TAs when beyond the capacity of postural mechanisms of the somatic nervous system to control the shape distortion in the trunk. This EFG discusses the findings and interpretations of the paper by Grivas and colleagues as research at the borderland between the genesis of TA (physiogenesis) and AIS (pathogenesis). It is suggested that TAs, here regarded in common with AIS, result from the combination of secondary sexual development affecting body composition, adolescent skeletal growth velocity, and an asymmetry process. The possible involvement of epigenetic factors is not considered.


Tyrosine phosphatase inhibitor-3 sensitizes melanoma and colon cancer to biotherapeutics and chemotherapeutics.
Drug resistance is a major obstacle in cancer treatments and diminishes the clinical efficacy of biological, cytotoxic, or targeted therapeutics. Being an antiapoptotic mediator of chemoresistance in breast and lung cancer cells, MKP1 phosphatase might be targeted for overcoming chemoresistance and improving therapeutic efficacy. In this work, tyrosine phosphatase inhibitor-3 (TPI-3) was identified as a novel small molecule inhibitor of MKP1 and was capable of sensitizing tumors to bio- and chemotherapeutics in mice as a tolerated oral agent. Effective against recombinant MKP1, TPI-3 selectively increased MKP1 phosphosubstrates in Jurkat cells and induced cell death via apoptosis at nanomolar concentrations. TPI-3 also increased MKP1 phosphosubstrates in WM9 human melanoma cells and synergized with biotherapeutic IFN alpha 2b in the growth inhibition of melanoma cells in vitro (combination index, <1). WM9 xenografts unresponsive to individual agents were significantly inhibited (62%, P = 0.001) in mice by a tolerated combination of oral TPI-3 (10 mg/kg, 5 d/wk) and IFN alpha 2b. MKP1 expression was detected in human melanoma cell lines and tissue samples at levels up to six times higher than those in normal or nonmalignant melanocytes. TPI-3 also interacted positively with chemotherapeutics, 5-fluorouracil/leucovorin, against MC-26 colon cancer cells in vitro and in mice. Altogether, our data show the preclinical activities of TPI-3 in overcoming cancer resistance to bio- and chemotherapeutics, implicate MKP1 as a drug-resistant molecule in melanoma, and support the targeting of MKP1 for improving cancer therapeutic efficacy.


Degradation of misfolded proteins by autophagy: is it a strategy for Huntington's disease treatment?
Autophagy is a degradation pathway for long-lived cytoplasmic proteins, protein complexes, or damaged organelles. The accumulation and aggregation of misfolded proteins are hallmarks of several neurodegenerative diseases. Many researchers have reported that autophagy degrades disease-causing misfolded and aggregated proteins, including mutant huntingtin (Htt) in Huntington's disease, mutant synuclein in familial Parkingson's disease, mutant Cu, Zn-Superoxide dismutase (SOD1) in familial amyotrophic lateral sclerosis. In this review, we will bring up new evidence to elucidate the involvement of autophagy in degradation of mutant Htt, discuss the mechanisms regulating the degradation of mutant Htt by autophagy and the therapeutic effects of drugs that enhance autophagy to improve clearance of mutant Htt. We propose that enhancement of autophagy by drugs may be a strategy to treat or retard progression of Huntington's disease.


Targeting isoprenoid biosynthesis for drug discovery: bench to bedside.
The isoprenoid biosynthesis pathways produce the largest class of small molecules in Nature: isoprenoids (also called terpenoids). Not surprisingly then, isoprenoid biosynthesis is a target for drug discovery, and many drugs--such as Lipitor (used to lower cholesterol), Fosamax (used to treat osteoporosis), and many anti-infectives--target isoprenoid biosynthesis. However, drug resistance in malaria, tuberculosis, and staph infections is rising, cheap and effective drugs for the neglected tropical diseases are lacking, and progress in the development of anticancer drugs is relatively slow. Isoprenoid biosynthesis is thus an attractive target, and in this Account, I describe developments in four areas, using in each case knowledge derived from one area of chemistry to guide the development of inhibitors (or drug leads) in another, seemingly unrelated, area. First, I describe mechanistic studies of the enzyme IspH, which is present in malaria parasites and most pathogenic bacteria, but not in humans. IspH is a 4Fe-4S protein and produces the five-carbon (C5) isoprenoids IPP (isopentenyl diphosphate) and DMAPP (dimethylallyl diphosphate) from HMBPP (E-1-hydroxy-2-methyl-but-2-enyl-4-diphosphate) via a 2H(+)/2e(-) reduction (of an allyl alcohol to an alkene). The mechanism is unusual in that it involves organometallic species: "metallacycles" (η(2)-alkenes) and η(1)/η(3)-allyls. These observations lead to novel alkyne inhibitors, which also form metallacycles. Second, I describe structure-function-inhibition studies of FPP synthase, the macromolecule that condenses IPP and DMAPP to the sesquiterpene farnesyl diphosphate (FPP) in a "head-to-tail" manner. This enzyme uses a carbocation mechanism and is potently inhibited by bone resorption drugs (bisphosphonates), which I show are also antiparasitic agents that block sterol biosynthesis in protozoa. Moreover, "lipophilic" bisphosphonates inhibit protein prenylation and invasiveness in tumor cells, in addition to activating γδ T-cells to kill tumor cells, and are important new leads in oncology. Third, I describe structural and inhibition studies of a "head-to-head" triterpene synthase, dehydrosqualene synthase (CrtM), from Staphylococcus aureus. CrtM catalyzes the first committed step in biosynthesis of the carotenoid virulence factor staphyloxanthin: the condensation of two FPP molecules to produce a cyclopropane (presqualene diphosphate). The structure of CrtM is similar to that of human squalene synthase (SQS), and some SQS inhibitors (originally developed as cholesterol-lowering drugs) block staphyloxanthin biosynthesis. Treated bacteria are white and nonvirulent (because they lack the carotenoid shield that protects them from reactive oxygen species produced by neutrophils), rendering them susceptible to innate immune system clearance--a new therapeutic approach. And finally, I show that the heart drug amiodarone, also known to have antifungal activity, blocks ergosterol biosynthesis at the level of oxidosqualene cyclase in Trypanosoma cruzi, work that has led to its use in the clinic as a novel antiparasitic agent. In each of these four examples, I use information from one area (organometallic chemistry, bone resorption drugs, cholesterol-lowering agents, heart disease) to develop drug leads in an unrelated area: a "knowledge-based" approach that represents an important advance in the search for new drugs.


[Effects of treatments on serum vitamin E levels in lung cancer].
Previous evidence suggests that malignant tumours cause an decrease in the serum vitamin E level. We followed the serum alpha tocopherol in 55 lung cancer patients. The objective of the study was to evaluate the effects of treatments of lung cancer on serum vitamin E evolution. The vitamin E of patients symptomatically treated decreases from the first month and this decrease is significant (p < 0.001) in patients affected by SCLC and in those with NSCLC classified stage III and IV. The reduction of the vitamin E is also noted in the patients treated with chemotherapy (p < 0.001). Vitamin E levels improve gradually to reach standard values in the patients who followed a curative radiotherapy or benefited from the surgical ablation of the tumour. At 4 months after the surgical removal of the tumour, there was an increase in serum vitamin E concentrations and reached the normal values. This data indicates that surgical removal of lung cancer increases serum vitamin E concentrations compared to the baseline values possibly reflecting the relief of oxidative stress caused by malignant tumours.


Hair cortisol concentration in clinically healthy slaughter calves with and -without chronic bronchopneumonic -lesions.
The hypothesis of this study was that healthy calves undergo less stress and thus have lower hair cortisol concentrations than calves with chronic bronchopneumonic lesions. Fifty healthy calves (group 1) and 50 calves with chronic bronchopneumonic lesions (group 2) were used immediately after slaughter, at which time hair samples and both adrenal glands were collected. The hair samples and the left adrenal gland were used for cortisol measurement and the right adrenal gland was used for histological and morphometrical examinations. The median hair cortisol concentrations of calves in groups 1 and 2 were 1.6 and 1.9 pg/mg hair, respectively, and did not differ significantly. The same was true for the mean cortisol concentration of the adrenal gland (1.1 and 1.4 µg/g tissue) and for the adrenal cortisol content (3.7 and 4.6 µg). The weights of the cortex (3.3, mean, and 3.5 g, median) and medulla (1.7 and 1.8 g, both median) did not differ significantly between the groups. This study did not detect differences in hair and adrenal cortisol concentrations between clinically healthy slaughter calves with and without chronic bronchopneumonic lesions. In further studies, calves with clinical signs should be taken into account.


Contribution of apo CIII reduction to the greater effect of 12-week micronized fenofibrate than atorvastatin therapy on triglyceride levels and LDL size in dyslipidemic patients.
Apolipoprotein (apo) CIII plays an important role in the catabolism of triglyceride-rich lipoproteins as it is a potent inhibitor of lipoprotein lipase (LPL). A low LPL activity has been simultaneously associated with hypertriglyceridemia, low HDL cholesterol and with small LDL particles. To compare the effects of a 12-week treatment with micronized fenofibrate (200 mg) versus atorvastatin (10 mg) on apo CIII and lipoprotein-lipid levels including LDL size. After a 4-week washout period, dyslipidemic patients were randomized to either micronized fenofibrate (n = 64) or atorvastatin (n = 72). Both fenofibrate and atorvastatin significantly decreased apo CIII levels by -0.03 +/- 0.03 versus -0.01 +/- 0.03 g/l respectively, and increased LDL size by 4.9 +/- 3.3 versus 1.8 +/- 2.9 A. Improvements in these parameters were significantly greater with fenofibrate (P < 0.0001). Significant relationships were found between changes in triglycerides and changes in apo CIII (r = 0.81 and r = 0.59, P < 0.0001) as well as between changes in LDL size and changes in apo CIII (r = -0.41 and r = -0.45, P < 0.001), in both fenofibrate and atorvastatin groups. respectively. The substantial reduction in apo CIII induced by micronized fenofibrate plays an important role in the greater effect of micronized fenofibrate than atorvastatin on plasma triglycerides and LDL size.


[Devices simplifying research on the Rubin-2 thermograph].
A changed position of the mirror-reflector in the Rubin-2 thermovision unit as well as the use of an improved model of the couch-chair and a special cassette for electrochemical paper reduce the labour input and raise the information value of the method.


Transcriptional dynamics of developmental genes assessed with an FMN-dependent fluorophore in mature heterocysts of Anabaena sp. strain PCC 7120.
Anabaena sp. strain PCC 7120 is a filamentous cyanobacterium that differentiates nitrogen-fixing heterocysts when available combined nitrogen is limiting. Growth under diazotrophic conditions results in a mixture of 'new' (recently differentiated) and 'old' (mature) heterocysts. The microoxic environment present in heterocysts makes the interpretation of gene expression using oxygen-dependent fluorophores, including GFP, difficult. The work presented here evaluates the transcriptional dynamics of three developmental genes in mature heterocysts utilizing EcFbFP, a flavin mononucleotide-dependent fluorophore, as the reporter. Expression of both GFP and EcFbFP from the heterologous petE promoter showed that, although GFP and EcFbFP fluoresced in both vegetative cells and new heterocysts, only EcFbFP fluoresced in old heterocysts. A transcriptional fusion of EcFbFP to the late-stage heterocyst-specific nifB promoter displayed continued expression beyond the cessation of GFP fluorescence in heterocysts. Promoter fusions of the master regulator of differentiation, hetR, and its inhibitors, patS and hetN, to GFP and EcFbFP were visualized to determine their role(s) in heterocyst function after morphogenesis. The expression of hetR and hetN was found to persist beyond the completion of development in most heterocysts, whereas patS expression ceased. These data are consistent with a model of heterocyst patterning in which patS is involved in de novo pattern formation, hetN is required for pattern maintenance, and hetR is needed for all stages of development.


The evaluation of nurse navigators in chronic and complex care.
With increasing age and chronicity in populations, the need to reduce the costs of care while enhancing quality and hospital avoidance, is important. Nurse-led co-ordination is one such model of care that supports this approach. The aim of this research was to assess the impact that newly appointed Navigators have on service provision; social and economic impact; nurses' professional quality of life and compassion fatigue; and analysis of the change that has occurred to models of care and service delivery. A concurrent mixed-method approach was selected to address the research aims. The research project was funded in July 2018 and will conclude in December 2020. Several cohorts will be studied including; patients assigned to a navigator, patients not assigned to a navigator, family members of patients assigned a navigator; and a sample sized estimated at 140 navigators. This study provides a comprehensive international longitudinal and mixed method framework for evaluating the impact of nurse navigators on quality of care outcomes for patients with chronic conditions. IMPACT-WHAT PROBLEM WILL THE STUDY ADDRESS?: Even with specialty focused co-ordinated care, patients get lost in the system, increasing the incidence of non-compliance and exacerbation of condition. Navigators work with patients across service boundaries allowing for care that is patient responsive, and permitting variables in clinical, social and practical elements of care to be addressed in a timely manner. This novel nurse-led approach, supports hospital avoidance and patient self-management, while encouraging expansion and opportunity for the nursing and midwifery workforce.


The US Federal Tox21 Program: A strategic and operational plan for continued leadership.
The traditional approaches to toxicity testing have posed multiple challenges for evaluating the safety of commercial chemicals, pesticides, food additives/contaminants, and medical products.The challenges include number of chemicals that need to be tested, time and resource intensive nature of traditional toxicity tests, and unexpected adverse effects that occur in pharmaceutical clinical trials despite the extensive toxicological testing.Over a decade ago, the U.S. Environmental Protection Agency (EPA), National Toxicology Program (NTP), National Center for Advancing Translational Sciences (NCATS), and the Food and Drug Administration (FDA) formed a federal consortium for "Toxicology in the 21st Century" (Tox21) with a focus on developing and evaluating in vitro high-throughput screening (HTS) methods for hazard identification and providing mechanistic insights.The Tox21 consortium generated data on thousands of pharmaceuticals and datapoor chemicals, developed better understanding of the limits and applications of in vitro methods, and enabled incorporation of HTS data into regulatory decisions. To more broadly address the challenges in toxicology, Tox21 has developed a new strategic and operational plan that expands the focus of its research activities. The new focus areas include developing an expanded portfolio of alternative test systems, addressing technical limitations of in vitrotest systems, curating legacy in vivo toxicity testing data, establishing scientific confidence in the in vitrotest systems, and refining alternative methods for characterizing pharmacokinetics and in vitro assay disposition.The new Tox21 strategic and operational plan addresses key challenges to advance toxicology testing and will benefit both the organizations involved and the toxicology community.


Adsorption properties of HKUST-1 toward hydrogen and other small molecules monitored by IR.
Among microporous systems metal organic frameworks are considered promising materials for molecular adsorption. In this contribution infrared spectroscopy is successfully applied to highlight the positive role played by coordinatively unsaturated Cu2+ ions in HKUST-1, acting as specific interaction sites. A properly activated material, obtained after solvent removal, is characterized by a high fraction of coordinatively unsaturated Cu2+ ions acting as preferential adsorption sites that show specific activities towards some of the most common gaseous species (NO, CO2, CO, N2 and H2). From a temperature dependent IR study, it has been estimated that the H2 adsorption energy is as high as 10 kJ mol(-1). A very complex spectral evolution has been observed upon lowering the temperature. A further peculiarity of this material is the fact that it promotes ortho-para conversion of the adsorbed H2 species.


Arginine-rich cell penetrating peptides: design, structure-activity, and applications to alter pre-mRNA splicing by steric-block oligonucleotides.
Rerouting the splicing machinery with steric-block oligonucleotides (ON) might lead to new therapeutic strategies in the treatment of diseases such as beta-thalassemia, Duchenne muscular dystrophy, or cancers. Interfering with splicing requires the sequence-specific and stable hybridization of RNase H-incompetent ON as peptide nucleic acids (PNA) or phosphorodiamidate morpholino oligomers (PMO). Unfortunately, these uncharged DNA mimics are poorly taken up by most cell types and conventional delivery strategies that rely on electrostatic interaction do not apply. Likewise, conjugation to cell penetrating peptides (CPPs) as Tat, Arg9, Lys8, or Pen leads to poor splicing correction efficiency at low concentration essentially because PNA- and PMO-CPP conjugates remain entrapped within endocytotic vesicles. Recently, we have designed an arginine-rich peptide (R-Ahx-R)4 (with Ahx for aminohexanoic acid) and an arginine-tailed Penetratin derivative which allow sequence-specific and efficient splicing correction at low concentration in the absence of endosomolytic agents. Both CPPs are undergoing structure-activity relationship studies for further optimization as steric-block ON delivery vectors.


Right prefrontal activation during encoding, but not during retrieval, in a non-verbal paired-associates task.
Brain imaging studies have shown that episodic encoding into long-term memory preferentially activates the left prefrontal cortex and retrieval activates the right prefrontal cortex. However, it is unclear to what degree verbal analysis contributes to the left prefrontal activation during encoding. The present study was designed to avoid verbal analysis during encoding by using abstract pictures and computer-generated sounds which were difficult to code verbally. Sounds and pictures were grouped into six stimulus-stimulus pairs. When the sound from a pair was presented, the subjects were instructed to recall and visualize the associated picture. After 2.0 s the associated picture and another picture appeared on the screen and the subjects were required to identify the associated picture. Feedback about the choice was then given. Regional cerebral blood flow (rCBF) was measured with [15O]butanol and positron emission tomography (PET) in 10 subjects during initial training on the paired-associates task (encoding scan) and after 35 min of training (retrieval scan). Performance during the encoding scan was 59% correct and during the retrieval scan 98% correct, with a mean reaction time of 709 ms during retrieval. The rCBF was also measured during a control condition without any instruction to encode or retrieve. Compared with retrieval, encoding showed significant activation of the posterior part of the right middle frontal gyrus, the right inferior parietal cortex, the cingulate cortex, the left inferior parietal cortex and the left inferior and middle temporal gyri. The rCBF increase during encoding was strongly correlated with the rate of encoding. Retrieval was compared with both encoding and control. In none of these comparisons was there any prefrontal activation. The lack of prefrontal activation during near-perfect performance of the retrieval task suggests that the prefrontal cortex is not necessarily active when retrieval is fast and accurate, or what might be called automatic. Encoding was not associated with more activation of the left than the right prefrontal cortex. This result presents a limitation to the generality of left prefrontal activation during episodic encoding, which has been found in several previous brain imaging studies. Differences between studies in the relative activation of left and right prefrontal cortex during encoding and retrieval might be due to differences in paradigms, the type of stimulus used, and the demand for working memory and verbal analysis.


Esthetic outcome of immediate reconstruction with latissimus dorsi myocutaneous flap after breast-conservative surgery and skin-sparing mastectomy.
With the recent advances in oncologic breast surgery, breast reconstruction with the latissimus dorsi myocutaneous (LDM) flap without an implant has become a good option among other autologous tissue reconstructions available. However, only a few large-scale studies have so far evaluated the critical factors affecting its esthetic outcomes. We retrospectively reviewed 97 consecutive patients who underwent breast reconstruction with the LDM flap between 2001 and 2005 at our institution. The esthetic outcome in comparison with the normal breast was evaluated by means of observer assessment consisting of 7 criteria. A stratified analysis was performed to determine the factors affecting the esthetic outcomes after the breast-conservative surgery and skin-sparing mastectomy. We found that reconstruction of the lower half of the breast and exposure of the skin paddle resulted in poor esthetic outcomes after breast-conservative surgery. Large preoperative brassiere cup size, radiation history, axillary node dissection, and exposure of the skin paddle were the factors which negatively affected the overall outcomes after skin-sparing mastectomy. Age, body mass index, presence of nipple areola-complex defect, or design of skin paddle did not affect the esthetic outcomes. On the basis of these critical factors, we could determine the indications and limitations of breast reconstruction with LDM flap. In some cases, further technical modifications are still warranted, and we believe that these modifications will optimize the use of this flap in breast reconstruction.


Memory deterioration in an oxidative stress model and its correlation with cytological changes on rat hippocampus CA1.
Exposure to ozone results in an increased production of free radicals which causes oxidative stress. The purpose of this study was to determine the effects of ozone exposure on memory and its correlation with the cytology of the hippocampus. Twenty-four male Wistar rats were exposed to 1 ppm (parts per million) ozone for 4 h in a closed chamber. Control group was exposed to flowing air. After ozone exposure, the rats were given long-term (24 h) memory training which consists of a passive avoidance conditioning. After that the animals were perfused and the brains were placed in the Golgi stain. The analysis consisted in counting the dendritic spines in five secondary and five tertiary dendrites of each of the 20 pyramidal neurons of hippocampus CA1 analyzed. Our results showed alterations on long-term memory and a significant reduction of dendritic spines, and provided evidence that this deterioration in memory is probably due to the reduction in spine density in the pyramidal neurons of hippocampus.


Non-invasive assessment of barrier integrity and function of the human gut.
Over the past decades evidence has been accumulating that intestinal barrier integrity loss plays a key role in the development and perpetuation of a variety of disease states including inflammatory bowel disease and celiac disease, and is a key player in the onset of sepsis and multiple organ failure in situations of intestinal hypoperfusion, including trauma and major surgery. Insight into gut barrier integrity and function loss is important to improve our knowledge on disease etiology and pathophysiology and contributes to early detection and/or secondary prevention of disease. A variety of tests have been developed to assess intestinal epithelial cell damage, intestinal tight junction status and consequences of intestinal barrier integrity loss, i.e. increased intestinal permeability. This review discusses currently available methods for evaluating loss of human intestinal barrier integrity and function.


Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review.
Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology.


Theoretical simulations for vibrationally-resolved absorption spectra of naphthalenediimide cyclophane derivatives.
In the present work we systematically investigated the vibrationally-resolved absorption spectra of three core substituted naphthalenediimide cyclophane derivatives. It has been performed by time-dependent density functional theory calculations using three different exchange-correlation functionals, including the conventional B3LYP functional and two long-range corrected functionals: CAM-B3LYP and ωB97XD. The solvent effects were also considered with the polarizable continuum model. Calculation results showed that long range corrections are needed to correctly describe the optical properties of the three molecules because of the strong charge transfer characteristic of the excited states. The core substitution induced red shift to the first absorption band is nicely explained by the theoretical calculations. It is found that this band mainly involves the transitions within the core substituted naphthalenediimide chromophore. The high energy absorption band, on the other hand, is generated mainly from the un-substituted chromophore. These characters result in different substitution dependence for those two main absorption bands. Furthermore, the simulated vibrational profiles of the first two absorption bands nicely reproduce the observed vibrational features in the measured spectra. The accuracy of the calculated results from different functionals and basis sets has been discussed.


Trajectories of Lower Extremity Physical Performance: Effects on Fractures and Mortality in Older Women.
Prior studies have only considered one measurement of physical performance in its relationship to fractures and mortality. A single measurement is susceptible to large within-person changes over time, and thus, may not capture the true association between physical performance and the outcomes of interest. Using data from the Study of Osteoporotic Fractures, we followed 7,015 women enrolled prior to age 80 years who had outcome information beyond this age. Trajectories of walking speed (m/s) and chair stand speed (stands/s) were estimated up to the last visit prior to age 80 years using mixed-effects linear regression. Physical performance at age 80 (PF_age80) was assessed at the last visit prior to age 80 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression and multivariate models adjusted for all other covariates. Greatest walking speed decline and chair stand speed decline were both associated with higher risk of hip fracture (HR: 1.28; 95% CI: 1.03, 1.58 and HR: 1.26; 95% CI: 1.03, 1.54, respectively), but not nonspine fractures. Greatest walking speed decline and chair stand speed decline were both associated with a significant 29% (95% CI: 17-42%) and 27% (95% CI: 15-39%) increased risk of mortality, respectively. Greatest declines in walking speed and chair stand speed were both associated with an increased risk of hip fracture and mortality independent of PF_age80 and other important confounders. Both physical performance change and the single physical performance measurement should be considered in the etiology of hip fracture and mortality.


Allogeneic stem cell transplantation for Fanconi Anaemia. Severe Aplastic Anaemia Working Party of the EBMT and EUFAR. European Group for Blood and Marrow Transplantation.
Fanconi anaemia is a hereditary disorder characterised by chromosomal breaks increased by cross-linking agents. Bone marrow transplantation is the treatment of choice when a HLA identical sibling donor has been identified. The use of low-dose cyclophosphamide with thoraco-abdominal irradiation for the conditioning regimen of FA patients has lead to a dramatic improvement of survival, with a long-term survival of 75% at our institution. However, if most patients are completely cured of their haematological disease, there is concern about an increased frequency of secondary tumours, mostly head and neck squamous cell carcinomas of poor prognosis. Results of BMT using alternative donors (HLA mismatched related and unrelated donors) have also improved during the last decade. A better selection of the donor via high-resolution techniques for class-II HLA matching, and more recently the use of T cell depleted grafts are probably the main explanations. Despite a short follow-up and the small number of patients analysed, transplants using HLA matched family cord blood give some promising results. On the other hand, first results with unrelated cord blood remind that this approach is clearly an experimental one that has to be evaluated through international registries and prospective studies. New approaches including autologous stem cell transplantations and gene therapy are currently explored.


Impact of treatment completion, intolerance and adverse events on health system costs in a randomised trial of 4 months rifampin or 9 months isoniazid for latent TB.
Treatment for latent tuberculosis infection with isoniazid for 9 months (9INH) has poor completion and serious adverse events, while treatment for 4 months with daily rifampin (4RIF) has significantly higher completion and fewer adverse events. To compare the health system costs of 4RIF and 9INH. In a randomised trial conducted in five Canadian centres, one Brazilian and one Saudi Arabian centre, consenting subjects were randomised to receive 4RIF or 9INH. Health system costs were estimated from healthcare utilisation including scheduled and unscheduled visits, investigations and drugs. All activities for all subjects were evaluated using financial information from 2007 from the Montreal Chest Institute. Costs were expressed in Canadian dollars. Total health system cost per patient allocated to 4RIF was $854 compared with $970 for 9INH (p<0.0001). The average cost per patient for the 328 of 420 (78%) who completed 4RIF therapy was $1094 compared with $1625 for the 254 of 427 (60%) completing 9INH (p<0.0001). Costs were modestly increased in patients with minor intolerance and substantially increased if the treating physician stopped treatment because of possible adverse events. Total costs related to management of adverse events with 9INH were $48 142 compared with $25 684 for 4RIF (p=0.008). Using these data, incremental cost-effectiveness analyses showed that 4RIF would be cost saving and prevent more cases within 2 years if efficacy exceeded 74%, and cost saving if efficacy exceeded 65%. The 4RIF regimen was significantly cheaper per patient completing treatment because of better completion and fewer adverse events.


A methodological review of how heterogeneity has been examined in systematic reviews of diagnostic test accuracy.
To review how heterogeneity has been examined in systematic reviews of diagnostic test accuracy studies. Centre for Reviews and Dissemination's Database of Abstracts of Reviews of Effects (DARE). Systematic reviews that evaluated a diagnostic or screening test by including studies that compared a test with a reference test were identified from DARE. Reviews for which structured abstracts had been written up to December 2002 were screened for inclusion. Data extraction was undertaken using standardised data extraction forms. A total of 189 systematic reviews met the inclusion criteria. The median number of studies included was 18. Meta-analyses have a higher number with a median of 22 studies compared with 11 for narrative reviews. Graphical plots to demonstrate the spread in study results were provided in 56% of meta-analyses; in 79% these were plots of sensitivity and specificity in the receiver operating characteristic (ROC) space. Statistical tests to identify heterogeneity were used in 32% of reviews: 41% of meta-analyses and 9% of reviews using narrative syntheses. The chi-squared test and Fisher's exact test to assess heterogeneity in individual aspects of test performance were the most common. In contrast, only 16% of meta-analyses used correlation coefficients to test for a threshold effect. A narrative synthesis was used in 30% of reviews. Of the meta-analyses, 52% carried out statistical pooling alone, 18% conducted only summary receiver operator characteristic (SROC) analyses and 30% used both methods of statistical synthesis. For those undertaking SROC analyses, the main differences between the models used were the weights chosen for the regression models, although in 42% of cases the use of, or choice of, weight was not provided. The proportion of reviews using statistical pooling alone has declined from 67% in 1995 to 42% in 2001, with a corresponding increase in the use of SROC methods, from 33% to 58%. However, two-thirds of those using SROC methods also carried out statistical pooling rather than presenting only SROC models. Reviews using SROC analyses also tended to present their results as some combination of sensitivity and specificity rather than using alternative, perhaps less clinically meaningful, means of data presentation such as diagnostic odds ratios. Three-quarters of meta-analyses attempted to investigate statistically possible sources of variation, using subgroup analysis or regression analysis. The impact of clinical or socio-demographic variables was investigated in 74% of these reviews and test- or threshold-related variables in 79%. At least one quality-related variable was investigated in 63% of reviews. Within this subset, the most commonly considered variables were the use of blinding, sample size, the reference test used and the avoidance of verification bias. The emphasis on pooling individual aspects of diagnostic test performance and the under-use of statistical tests and graphical approaches to identify heterogeneity perhaps reflect the uncertainty in the most appropriate methods to use and also greater familiarity with more traditional indices of test accuracy. This indicates the difficulty and complexity of carrying out such reviews. In these cases it is strongly suggested that meta-analyses are carried out with the involvement of a statistician familiar with the field. Further methodological work on the statistical methods available for combining diagnostic test accuracy studies is needed, as are sufficiently large, prospectively designed primary studies of diagnostic test accuracy comparing two or more tests for the same target disorder. Use of individual patient data meta-analysis in diagnostic test accuracy reviews should be explored to allow heterogeneity to be considered in more detail.


Epigenetic basis of morphological variation and phenotypic plasticity in Arabidopsis thaliana.
Epigenetics is receiving growing attention in the plant science community. Epigenetic modifications are thought to play a particularly important role in fluctuating environments. It is hypothesized that epigenetics contributes to plant phenotypic plasticity because epigenetic modifications, in contrast to DNA sequence variation, are more likely to be reversible. The population of decrease in DNA methylation 1-2 (ddm1-2)-derived epigenetic recombinant inbred lines (epiRILs) in Arabidopsis thaliana is well suited for studying this hypothesis, as DNA methylation differences are maximized and DNA sequence variation is minimized. Here, we report on the extensive heritable epigenetic variation in plant growth and morphology in neutral and saline conditions detected among the epiRILs. Plant performance, in terms of branching and leaf area, was both reduced and enhanced by different quantitative trait loci (QTLs) in the ddm1-2 inherited epigenotypes. The variation in plasticity associated significantly with certain genomic regions in which the ddm1-2 inherited epigenotypes caused an increased sensitivity to environmental changes, probably due to impaired genetic regulation in the epiRILs. Many of the QTLs for morphology and plasticity overlapped, suggesting major pleiotropic effects. These findings indicate that epigenetics contributes substantially to variation in plant growth, morphology, and plasticity, especially under stress conditions.


RADseq dataset with 90% missing data fully resolves recent radiation of Petalidium (Acanthaceae) in the ultra-arid deserts of Namibia.
Deserts, even those at tropical latitudes, often have strikingly low levels of plant diversity, particularly within genera. One remarkable exception to this pattern is the genus Petalidium (Acanthaceae), in which 37 of 40 named species occupy one of the driest environments on Earth, the Namib Desert of Namibia and neighboring Angola. To contribute to understanding this enigmatic diversity, we generated RADseq data for 47 accessions of Petalidium representing 22 species. We explored the impacts of 18 different combinations of assembly parameters in de novo assembly of the data across nine levels of missing data plus a best practice assembly using a reference Acanthaceae genome for a total of 171 sequence datasets assembled. RADseq data assembled at several thresholds of missing data, including 90% missing data, yielded phylogenetic hypotheses of Petalidium that were confidently and nearly fully resolved, which is notable given that divergence time analyses suggest a crown age for African species of 3.6-1.4 Ma. De novo assembly of our data yielded the most strongly supported and well-resolved topologies; in contrast, reference-based assembly performed poorly, perhaps due in part to moderate phylogenetic divergence between the reference genome, Ruellia speciosa, and the ingroup. Overall, we found that Petalidium, despite the harshness of the environment in which species occur, shows a net diversification rate (0.8-2.1 species per my) on par with those of diverse genera in tropical, Mediterranean, and alpine environments.


A training program for elementary school teachers. Optometrist-teacher communications.
Communication between optometrists and teachers is critical to optometric involvement in interdisciplinary team approaches to learning disabilities. The classroom teacher may be a prime source of referrals to the general optometrist as well as the vision development specialist. Optometry's contribution to classroom learning cannot be fully realized without sound optometrist-teacher communication. The basic design of a training program to enhance optometrist-teacher communications is presented in this paper. The individual optometrist may modify and supplement the program to suit the special needs of the teachers involved.


Classification of noisy signals using fuzzy ARTMAP neural networks.
This paper describes an approach to classification of noisy signals using a technique based on the fuzzy ARTMAP neural network (FAMNN). The proposed method is a modification of the testing phase of the fuzzy ARTMAP that exhibits superior generalization performance compared to the generalization performance of the standard fuzzy ARTMAP in the presence of noise. An application to textured gray-scale image segmentation is presented. The superiority of the proposed modification over the standard fuzzy ARTMAP is established by a number of experiments using various texture sets, feature vectors and noise types. The texture sets include various aerial photos and also samples obtained from the Brodatz album. Furthermore, the classification performance of the standard and the modified fuzzy ARTMAP is compared for different network sizes. Classification results that illustrate the performance of the modified algorithm and the FAMNN are presented.


CSEB Student Conference 2012 abstract winners.
Chronic Diseases and Injuries in Canada (CDIC) was pleased to manage, once again, the student abstract contest for the Canadian Society for Epidemiology and Biostatistics (CSEB) Student Conference, which was held at the University of Saskatchewan in May 2012. An editorial panel from the Public Health Agency of Canada judged 42 abstract submissions and selected the top 7 to be published in this issue of the journal.


X-Ray crystallographic and mutational studies of fluoroacetate dehalogenase from Burkholderia sp. strain FA1.
Fluoroacetate dehalogenase catalyzes the hydrolytic defluorination of fluoroacetate to produce glycolate. The enzyme is unique in that it catalyzes the cleavage of a carbon-fluorine bond of an aliphatic compound: the bond energy of the carbon-fluorine bond is among the highest found in natural products. The enzyme also acts on chloroacetate, although much less efficiently. We here determined the X-ray crystal structure of the enzyme from Burkholderia sp. strain FA1 as the first experimentally determined three-dimensional structure of fluoroacetate dehalogenase. The enzyme belongs to the alpha/beta hydrolase superfamily and exists as a homodimer. Each subunit consists of core and cap domains. The catalytic triad, Asp104-His271-Asp128, of which Asp104 serves as the catalytic nucleophile, was found in the core domain at the domain interface. The active site was composed of Phe34, Asp104, Arg105, Arg108, Asp128, His271, and Phe272 of the core domain and Tyr147, His149, Trp150, and Tyr212 of the cap domain. An electron density peak corresponding to a chloride ion was found in the vicinity of the N(epsilon1) atom of Trp150 and the N(epsilon2) atom of His149, suggesting that these are the halide ion acceptors. Site-directed replacement of each of the active-site residues, except for Trp150, by Ala caused the total loss of the activity toward fluoroacetate and chloroacetate, whereas the replacement of Trp150 caused the loss of the activity only toward fluoroacetate. An interaction between Trp150 and the fluorine atom is probably an absolute requirement for the reduction of the activation energy for the cleavage of the carbon-fluorine bond.


On service differentiation in mobile Ad Hoc networks.
A network model is proposed to support service differentiation for mobile Ad Hoc networks by combining a fully distributed admission control approach and the DIFS based differentiation mechanism of IEEE802.11. It can provide different kinds of QoS (Quality of Service) for various applications. Admission controllers determine a committed bandwidth based on the reserved bandwidth of flows and the source utilization of networks. Packets are marked when entering into networks by markers according to the committed rate. By the mark in the packet header, intermediate nodes handle the received packets in different manners to provide applications with the QoS corresponding to the pre-negotiated profile. Extensive simulation experiments showed that the proposed mechanism can provide QoS guarantee to assured service traffic and increase the channel utilization of networks.


Is position in the occupational hierarchy a determinant of decline in perceived health status?
This study examines the extent to which position in the occupational hierarchy is predictive of declines in perceived health status over a 48 month period in a representative sample of the Canadian labor force. We hypothesized that the proportion of workers reporting a decline in health status would be greater among persons in lower position in the occupational hierarchy, and that these differences in risk would primarily be explained by characteristics of the psychosocial work environment and secondarily by the baseline prevalence of adverse health behaviors. The study cohort was defined as labor force participants aged 18-64 who reported good, very good or excellent health in the 1994 baseline wave of Canada's National Population Health Survey and who participated in the 1998 follow-up survey. Between 1994 and 1998, 16.6% of labor force participants reporting excellent, very good or good health status at baseline reported a decline in perceived health status. For men, the age-adjusted odds of decline in perceived health status were 1.80 (95% CI: 1.24-2.63) and 1.74 (95% CI: 1.19-2.54) for the two lowest occupational classes relative to the highest occupational class. There was no association between position in the occupational hierarchy and the prospective risk of health status decline for women. For men, the association between position in the occupational hierarchy and decline in perceived health status was moderately reduced but remained statistically significant following adjustment for baseline health, health behaviors and psychosocial work exposures. Adjustment for household income did not alter these findings. When stratified by gender, position in the occupational hierarchy was associated with the prospective risk of health status decline for men but not for women. Among men, the collective influence of health behaviors and psychosocial work exposures explained a moderate component of the decline in perceived health status. A more robust measurement of the characteristics of labor market experiences would be expected to improve understanding of the relationship between work and health in this sample.