Right atrial volume index to left atrial volume index ratio is associated with adverse clinical outcomes in cardiogenic shock.

BACKGROUND: Structural remodeling in chronic systolic heart failure (HF) is associated with neurohormonal and hemodynamic perturbations among HF patients presenting with cardiogenic shock (CS) and HF. Our objective was to test the hypothesis was that atrial remodeling marked by an increased right atrial volume index (RAVI) to left atrial volume index (LAVI) ratio is associated with adverse clinical outcomes in CS. METHODS: Patients in this cohort were admitted to the intensive care unit with evidence of congestion (pulmonary capillary wedge pressure > 15) and cardiogenic shock (cardiac index < 2.2, systolic blood pressure < 90 mmHg, and clinical evidence supporting CS) and had an echocardiogram at the time of admission. RAVI was measured using Simpson's method in the apical four-chamber view, while LAVI was measured using the biplane disc summation method in the four and two-chamber views by two independent observers. Cox proportional hazards regression analysis was used to assess the association of RAVI-LAVI with the combined outcome of death or left ventricular assist device (LVAD). RESULTS: Among 113 patients (mean age 59 ± 14.9 years, 29.2% female), median RAVI/LAVI was 0.84. During a median follow-up of 12 months, 43 patients died, and 65 patients had the combined outcomes of death or LVAD. Patients with RAVI/LAVI ratio above the median had a greater incidence of death or LVAD (Log-rank p ≤ 0.001), and increasing RAVI/LAVI was significantly associated with the outcomes of death or LVAD (HR 1.71 95% CI 1.11-2.64, chi square 5.91, p = 0.010) even after adjustment for patient characteristics, echocardiographic and hemodynamic variables. CONCLUSION: RAVI/LAVI is an easily assessed novel echocardiographic parameter strongly associated with the survival and or the need for mechanical circulatory support in patients with CS.

Dual targeting of the cancer antioxidant network with 1,4-naphthoquinone fused Gold(i) N-heterocyclic carbene complexes.

To achieve a systems-based approach to targeting the antioxidant pathway, 1,4-naphthoquinone annulated N-heterocyclic carbene (NHC) [bis(1,3-dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i)] [silver(i) dichloride] (1), [bis(1,3-dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i)] chloride (2), and 1,3-dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i) chloride (3)) were designed, synthesized, and tested for biological activity in a series of human cancer cell lines. The solution phase of complexes 1-3 were assigned using several spectroscopy techniques, including NMR spectroscopic analysis. Complexes 1 and 3 were further characterized by single crystal X-ray diffraction analysis. Electrochemical and spectroelectrochemical studies revealed that quinone reductions are reversible and that the electrochemically generated semiquinone and quinone dianions are stable under these conditions. Complex 1, containing two NHC-quinone moieties (to accentuate exogenous ROS via redox cycling) centered around a Au(i) center (to inactivate thioredoxin reductase (TrxR) irreversibly), was found to inhibit cancer cell proliferation to a much greater extent than the individual components (i.e., Au(i)-NHC alone or naphthoquinone alone). Treatment of A549 lung cancer cells with 1 produced a 27-fold increase in exogenous reactive oxygen species (ROS) which was found to localize to the mitochondria. The inhibition of TrxR, an essential mediator of ROS homeostasis, was achieved in the same cell line at low administrated concentrations of 1. TrxR inhibition by 1 was similar to that of auranofin, a gold(i) containing complex known to inhibit TrxR irreversibly. Complex 1 was found to induce cell death via an apoptotic mechanism as confirmed by annexin-V staining. Complex 1 was demonstrated to be efficacious in zebrafish bearing A549 xenografts. These results provide support for the suggestion that a dual targeting approach that involves reducing ROS tolerance while concurrently increasing ROS production can perturb antioxidant homeostasis, enhance cancer cell death in vitro, and reduce tumor burden in vivo, as inferred from preliminary zebra fish model studies.

Targeting Antioxidant Pathways with Ferrocenylated N-Heterocyclic Carbene Supported Gold(I) Complexes in A549 Lung Cancer Cells.

Ferrocene containing N-heterocyclic carbene (NHC) ligated gold(I) complexes of the type [Au(NHC)2]+ were prepared and found to be capable of regulating the formation of reactive oxygen species (ROS) via multiple mechanisms. Single crystal X-ray analysis of bis(1-(ferrocenylmethyl)-3-mesitylimidazol-2-ylidene)-gold(I) chloride (5) and bis(1,3-di(ferrocenylmethyl)imidazol-2-ylidene)-gold(I) chloride (6) revealed a quasi-liner geometry around the gold(I) centers, (i.e., the C-Au-C bond angle were measured to be ~177° and all the Au-Ccarbene bonds distances were in the range of 2.00 (7) - 2.03 (1) Å). A series of cell studies indicated that cell proliferation inhibition and ROS generation were directly proportional to amount of ferrocene contained within the [Au(NHC)2]+ complexes (IC50 of 6 < 5 < bis(1-benzyl-3-mesitylimidazol-2-ylidene)-gold(I) chloride (4)). Complexes 4-6 were also confirmed to inhibit thioredoxin reductase as inferred from lipoate reduction assays and increase chelatable intracellular zinc concentrations. RNA microarray gene expression assays revealed that 6 induces endoplasmic reticulum stress response pathways as a result of ROS increase.

Driving while using a smartphone-based mobility application: Evaluating the impact of three multi-choice user interfaces on visual-manual distraction.

Innovative in-car applications provided on smartphones can deliver real-time alternative mobility choices and subsequently generate visual-manual demand. Prior studies have found that multi-touch gestures such as kinetic scrolling are problematic in this respect. In this study we evaluate three prototype tasks which can be found in common mobile interaction use-cases. In a repeated-measures design, 29 participants interacted with the prototypes in a car-following task within a driving simulator environment. Task completion, driving performance and eye gaze have been analysed. We found that the slider widget used in the filtering task was too demanding and led to poor performance, while kinetic scrolling generated a comparable amount of visual distraction despite it requiring a lower degree of finger pointing accuracy. We discuss how to improve continuous list browsing in a dual-task context.

Modelling of wicking and moisture interactions of flax and viscose fibres.

Methods for assessing the wicking properties of individual fibre bundles have been developed from models based on the original Washburn equation (WE) and the modified Washburn equation (MWE), which also accounts for swelling. Both models gave indication of differences in wicking properties of flax and the viscose fibres, though MWE gave additional information that could be interpreted in terms of the physical model. Wicking of the viscose fibres is mainly via inter-fibre capillaries while that of flax is a combination of inter-fibre capillaries and lumen present in some elementary fibres. The degree of swelling and associated rotation of flax fibre in a vapour pressure range of 1-6torr were monitored using an environmental scanning electron microscope (ESEM). Viscose fibre exhibited swelling under the same conditions but did not rotate. The two techniques highlighted different mechanisms of wicking which can be used for monitoring moisture uptake/swelling of treated fibres for fabrication of composites.

Rapid analysis of purified cellulose extracted from perennial ryegrass (Lolium perenne) by instrumental analysis.

Dried, milled perennial ryegrass samples were processed using chemical and physical treatments and the extracted cellulose products were analysed for yield, crystallinity by X-ray Diffraction (XRD) and for purity using Thermogravimetric Analysis (TGA), Pyrolysis-Gas Chromatography/Mass Spectrometry (Py-GC/MS) and Fourier Transform Infrared (FTIR) spectroscopy. Extraction protocols examined the use of chemical chelation, acid and alkaline hydrolysis, along with physical degradation methods. Highest product yields were obtained using single step chemical protocols followed by physical processing, however, these products had low crystallinity and higher amorphous fraction content. Multistep chemical processing to completely remove hemicellulose and lignin with an alkali refluxing step, delivered lower yielding cellulose products of greater crystallinity and purity. In combination, the four instrumental techniques highlighted removal of amorphous fractions, providing rapid, accurate compositional data on the extracted cellulose products.

HPNS seizure risk: a role for the Golgi-associated retrograde protein complex?

Previous attempts to characterize the genetic contribution to differential risk of developing the HPNS seizure in a mouse model system are extended to additional data and an analytical mode that incorporates the set of linked resources for systems genetics in the GeneNetwork project. A quantitative trait locus (QTL) affecting HPNS seizure phenotype was mapped to a approximately 6 megabase (Mb) gene-rich region of Chr 17 based on the degree of expression covariation among genes in the region of the QTL and genes in the brains of BXD recombinant inbred mice in the same chromosomal region. Use of GeneNetwork's WebQTL analytical modules revealed that among > 220 positional candidate genes, vacuolar protein sorting gene 52 (Vps52) has highest priority. It appears that a single nearly null mutation in a distal region of Vps52 3'UTR (untranslated region) defined by a DNA probe set is associated with > 60% of the seizure risk difference between the high- and low-risk strains DBA/2 and C57BL/6, respectively. Based on the known contribution of the elements of the GARP complex--Vps52, -53 and -54--to motoneuron abnormalities, mutation-depleted Vps52 may be implicated in HPNS seizure risk variation in the mouse and, by gene homology, also with human VPS52.

Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study.

CONTEXT: Information on the use of oral bisphosphonate agents to treat pediatric osteogenesis imperfecta (OI) is limited. OBJECTIVE: The objective of the investigation was to study the efficacy and safety of daily oral alendronate (ALN) in children with OI. DESIGN AND PARTICIPANTS: We conducted a multicenter, double-blind, randomized, placebo-controlled study. One hundred thirty-nine children (aged 4-19 yr) with type I, III, or IV OI were randomized to either placebo (n = 30) or ALN (n = 109) for 2 yr. ALN doses were 5 mg/d in children less than 40 kg and 10 mg/d for those 40 kg and greater. MAIN OUTCOME MEASURES: Spine areal bone mineral density (BMD) z-score, urinary N-telopeptide of collagen type I, extremity fracture incidence, vertebral area, iliac cortical width, bone pain, physical activity, and safety parameters were measured. RESULTS: ALN increased spine areal BMD by 51% vs. a 12% increase with placebo (P < 0.001); the mean spine areal BMD z-score increased significantly from -4.6 to -3.3 (P < 0.001) with ALN, whereas the change in the placebo group (from -4.6 to -4.5) was insignificant. Urinary N-telopeptide of collagen type I decreased by 62% in the ALN-treated group, compared with 32% with placebo (P < 0.001). Long-bone fracture incidence, average midline vertebral height, iliac cortical width, bone pain, and physical activity were similar between groups. The incidences of clinical and laboratory adverse experiences were also similar between the treatment and placebo groups. CONCLUSIONS: Oral ALN for 2 yr in pediatric patients with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes.

Ultrasound for wool dyeing and finishing.

The effects of ultrasound at 35-39 kHz on several wool dyeing and finishing processes have been investigated as a way of reducing environmental impact. Ultrasound improved the effectiveness of cleaning scoured wool in water and to a lesser extent in water-nonionic surfactant. Scanning electron microscopy did not indicate any surface damage. Fluorescence microscopy revealed increased levels of sulphydryl groups on the wool surface suggesting ultrasound caused the removal of thioester-bound lipids. Ultrasound pre-treatment increased the effectiveness of subsequent oxidative-reductive bleaching, but had no effect on the uptake of acid levelling and acid milling dyes. The pre-treatment retarded the uptake of reactive dye, possibly by increasing the crystallinity of the fibre or removing surface bound lipids. Ultrasound did not improve dyeing under conditions that are currently used in industry, but did show potential to reduce the chemical and energy requirements of dyeing wool with reactive and acid milling dyes, but not acid levelling dyes.

High energy phosphate concentrations and AMPK phosphorylation in skeletal muscle from mice with inherited differences in hypoxic exercise tolerance.

The effect of chronic hypobaric hypoxia (1/2 atmospheric pressure) on high energy phosphate (HEP) compounds was investigated in slow (soleus; SOL) and fast twitch (extensor digitorum longus; EDL) muscle from 3 strains of mice with large differences in hypoxic exercise tolerance (HET). Phosphocreatine concentration ([PCr]) decreased 16-29% following hypoxia in EDL and SOL in all strains, while [ADP] and [AMP] increased. In the EDL, HET was negatively correlated with the PCr/ATP ratio and positively correlated with the ATP/P(i) ratio. The free energy of ATP hydrolysis (DeltaG(obs)) remained constant despite the substantial changes that occurred in HEP profiles. The alteration of HEP set points and preservation of DeltaG(obs) are consistent with the notion that (1) maximal rates of steady-state ATP turnover are reduced under hypoxia, and (2) HEP perturbations during rest to work transitions are reduced in skeletal muscle from hypoxia acclimated animals. We therefore expected a lower phosphorylation ratio of AMP-activated protein kinase (AMPK-P/AMPK) during stimulation in hypoxic acclimated animals. However, neither the resting nor stimulated AMPK-P/AMPK was influenced by hypoxia, although there were significant differences among strains.

Safety, pharmacokinetics and use of the novel NK-1 receptor antagonist maropitant (Cerenia) for the prevention of emesis and motion sickness in cats.

The present study characterizes the safety, pharmacokinetics, and anti-emetic effects of the selective NK-1 receptor antagonist maropitant in the cat. Safety of maropitant was determined following 15 days of subcutaneous (SC) administration at 0.5-5 mg/kg. Maropitant was well tolerated in cats at doses that exceeded the efficacious anti-emetic dose range of the drug by at least a factor of 10 and adverse clinical signs or pathological safety findings were not noted at any dose.The pharmacokinetics of maropitant in cats were determined following single dose oral (PO), intravenous (IV) and SC administration. Maropitant had a terminal half-life of 13-17 h and a bioavailability of 50 and 117% when administered PO and SC, respectively. Efficacy was determined against emesis induced either by xylazine or by motion. A dosage of 1 mg/kg maropitant administered IV, SC or PO prevented emesis elicited by xylazine. The compound had good oral antiemetic activity and a long (24 h) duration of action. Maropitant (1.0 mg/kg) was highly effective in preventing motion-induced emesis in cats. These studies indicate that the NK-1 receptor antagonist maropitant is well tolerated, safe and has excellent anti-emetic properties in cats.

The combined effects of high pressure and nisin on germination and inactivation of Bacillus spores in milk.

AIMS: The aim of this work was to investigate the germination and inactivation of spores of Bacillus species in buffer and milk subjected to high pressure (HP) and nisin. METHODS AND RESULTS: Spores of Bacillus subtilis and Bacillus cereus suspended in milk or buffer were treated at 100 or 500 MPa at 40 degrees C with or without 500 IU ml(-1) of nisin. Treatment at 500 MPa resulted in high levels of germination (4 log units) of B. subtilis spores in both milk and buffer; this increased to >6 logs by applying a second cycle of pressure. Viability of B. subtilis spores in milk and buffer was reduced by 2.5 logs by cycled HP, while the addition of nisin (500 IU ml(-1)) prior to HP treatment resulted in log reductions of 5.7 and 5.9 in phosphate buffered saline and milk, respectively. Physical damage of spores of B. subtilis following HP was apparent using scanning electron microscopy. Treating four strains of B. cereus at 500 MPa for 5 min twice at 40 degrees C in the presence of 500 IU ml(-1) nisin proved less effective at inactivating the spores of these isolates compared with B. subtilis and some strain-to-strain variability was observed. CONCLUSIONS: Although high levels of germination of Bacillus spores could be achieved by combining HP and nisin, complete inactivation was not achieved using the aforementioned treatments. SIGNIFICANCE AND IMPACT OF THE STUDY: Combinations of HP treatment and nisin may be an appealing alternative to heat pasteurization of milk.

Properties of slow- and fast-twitch skeletal muscle from mice with an inherited capacity for hypoxic exercise.

Muscle fiber type, myosin heavy chain (MHC) isoform composition, capillary density (CD) and citrate synthase (CS) activity were investigated in predominantly slow-twitch (soleus or SOL) and fast-twitch (extensor digitorum longus or EDL) skeletal muscle from mice with inherited differences in hypoxic exercise tolerance. Striking differences in hypoxic exercise tolerance previously have been found in two inbred strains of mice, Balb/cByJ (C) and C57BL/6J (B6), and their F1 hybrid following exposure to hypobaric hypoxia. Mice from the three strains were exposed for 8 weeks to either normobaric normoxia or hypobaric hypoxia (1/2 atm). Hypoxia exposure led to a slightly higher 2b fiber composition and a lower fiber area of types 1 and 2a in SOL of all mice. In the EDL, muscle fiber and MHC isoform composition remained unaffected by chronic hypoxia. Chronic hypoxia did not significantly affect CD in either muscle from any of the three strains. There were relatively larger differences in CS activity among strains and treatment, and in SOL the highest CS activity was found in the F1 mice that had been acclimated to hypoxia. In general, however, neither differences among strains nor treatment in these properties of muscle vary in a way that clearly relates to inherited hypoxic exercise tolerance.

Preclinical studies characterizing the anti-migraine and cardiovascular effects of the selective 5-HT1D receptor agonist PNU-142633.

The present study describes the preclinical pharmacology of a highly selective 5-HT1D receptor agonist PNU-142633. PNU-142633 binds with a Ki of 6 nm at the human 5-HT1D receptor and a Ki of> 18 000 nm at the human 5-HT1B receptor. The intrinsic activity of PNU-142633 at the human 5-HT1D receptor was determined to be 70% that of 5-HT in a cytosensor cell-based assay compared with 84% for that of sumatriptan. PNU-142633 was equally effective as sumatriptan and a half-log more potent than sumatriptan in preventing plasma protein extravasation induced by electrical stimulation of the trigeminal ganglion. Like sumatriptan, PNU-142633 reduced the increase in cat nucleus trigeminal caudalis blood flow elicited by electrical stimulation of the trigeminal ganglion compared with the vehicle control. The direct vasoconstrictor potential of PNU-142633 was evaluated in vascular beds. Sumatriptan increased vascular resistance in carotid, meningeal and coronary arteries while PNU-142633 failed to alter resistance in these vascular beds. These data are discussed in relation to the clinical findings of PNU-142633 in a phase II acute migraine study.

The validation of a nursing nutritional assessment tool for use on acute elderly wards.

BACKGROUND: Elderly people are at great risk of poor nutritional status. Identifying those at nutritional risk is complex owing to its multifactorial nature and highlights the need for an easily administered nutritional screening tool. AIM: To test the robustness of a tool used to identify those patients who require further dietetic assessment. METHOD: The tool was tested on an 'acute elderly' ward to assess its statistical robustness, i.e. test-retest reliability, inter-rater reliability, internal consistency and factor structure, concurrent and construct validity. The research was carried out by a dietitian and two nurses on an overall sample of 185 consecutive admissions. RESULTS: Test-retest results reflect that the tool is capable of yielding consistent assessments over time. Inter-rater reliability results revealed that when comparisons of agreement between nurses and dietitians were examined there was consistent disagreement. Internal consistency was found to be low but the rotated factor analysis suggested a relationship between the items in the tool. Concurrent validity was exhibited with body mass index, albumin and American Nutrition Risk Index only. Construct validity was not sufficiently exhibited with any of the measures used. CONCLUSION: The tool has not demonstrated reliability as determined by the statistical measures and hence validity at this stage. Issues which need to be addressed to allow this tool to be used appropriately are discussed.

Physical degradation of wheat straw by the in-vessel and windrow methods of mushroom compost production.

Mushroom compost manufacturers in Ireland are moving away from the traditional outdoor phase I windrow method, favouring in-vessel production. Composters and growers have reported better quality compost with faster spawn run and higher yields produced by this process. In the present study, physical examination of samples highlighted differences when comparing the windrow and in-vessel methods of compost production. Observations using scanning electron microscopy suggest that the cuticle of wheat straw from in-vessel production is damaged during phase I, peeling away from the surface in fragments, and exposing the epidermis. Changes in silicon levels on the straw surface acted as a marker for cuticle damage when comparing both composting systems. Cuticle damage may be important during composting and afterwards, as substrate colonisation is faster, and consequently spawn run is shorter. The phase I compost microbial community is altered by the in-vessel technique, producing a predominantly thermophilic bacterial flora in contrast to the mesophilic and thermophilic bacteria and fungi found in windrow phase I compost. These differences may be significant in mushroom compost production.

The nature and correlates of underachievement among elementary schoolchildren in Hong Kong.

This study investigated for the first time several characteristics of underachievement in a large sample of Hong Kong elementary schoolchildren. More males were identified as underachievers than females, but the ratio was substantially less than the two-to-one rate typically found in the American literature. The stability and persistence of underachievement increased during the elementary school years, and the stability of underachievement tended to be higher in subject matter that was relatively more difficult, which varied with gender. Underachievement became more specific to particular academic subjects rather than more general across the elementary grades. Parents and teachers, but not the children themselves, perceived that underachievers were more capable than same-grade nonunderachievers (who score lower on ability tests), although this awareness is more likely directed at male than female underachievers, which has been observed in other samples. In grades 1-4, teachers provided extra mentoring, communications, and support to underachievers. Thereafter, underachievers became more disruptive, impatient, and aggressive in school and perhaps at home. At that point, teachers became less supportive, offered less extra mentoring, and applied greater behavioral control over underachievers. Underachieving children also perceived that their parents became less supportive and used more discipline in grades 5-6 relative to grades 3-4. These correlates of underachievement suggests the existence of a syndrome of underachievement that separates underachievers from children who have the same grades but lower mental ability.

The future of applied child development research and public policy.

After reviewing a brief general history of applied child development research, this paper suggests that in the future we should study questions that society needs to answer as well as questions that might contribute to theory, and that our research methods need to be adjusted to match these types of questions. Further, academics are urged to broaden their audience from a nearly exclusive focus on other academics to a focus on the three ps--practitioners, policymakers, and the public--and to recognize that scholarship is packaged differently for these audiences. Finally, it is suggested that applied child development research should market as well as sell, partner with nonacademic groups, disseminate results more vigorously, and focus efforts on local as well as national issues.

Altered exercise pulmonary function after left ventricular assist device implantation.

The use of LVADs as a bridge to heart transplantation is increasing steadily as more surgical centers add this effective strategy for end-stage heart failure patients. Fundamental exercise physiology in the presence of LVADs has been described previously, and data is available that supports the safety and efficacy of exercise in this population. Variants to the expected exercise response that may be secondary to LVAD implantation, such as the pulmonary restrictive pattern that developed in the patient described in this case study, may occur. Clinicians should consider assessment and monitoring of pulmonary function in this patient population, especially in patients with exercise-induced dyspnea and perhaps patients with pre-existing pulmonary limitation.