A multicentre, clinical evaluation of a hydro-responsive wound dressing: the Glasgow experience.

OBJECTIVE: Our aim was to assess the effectiveness of hydro-responsive wound dressing (HRWD) in debridement and wound bed preparation of a variety of acute and chronic wounds that presented with devitalised tissue needing removal so that healing may proceed. METHOD: This was a non-comparative evaluation of acute and chronic wounds that required debridement as part of their normal treatment regimen. Clinicians recorded wound changes including a subjective assessment level of devitalised tissue and wound bed preparation, presence of pain, wound status (e.g., wound size) and periwound skin condition. Data was also collected from clinicians and patients to provide information on clinical performance of the dressing. RESULTS: We recruited 100 patients with a variety of wound types into the study. Over 90% of the clinicians reported removal of devitalised tissue to enable a healing response in both chronic and acute wounds. Specifically, over the course of the evaluation period, levels of devitalised tissue (necrosis and slough) reduced from 85.5% to 26.3%, and this was accompanied by an increase in wound bed granulation from 12.0% to 33.7%. Correspondingly, there was a 40% reduction in wound area, hence a clinically relevant healing response was seen upon treatment with HRWD. It is also noteworthy that this patient population included a significant proportion of chronic wounds (51.4%) that showed no signs of wound progression within <4 weeks before study inclusion. Of these chronic wounds, 93% demonstrated wound progression upon treatment with HRWD. Despite reported pain levels being low pre- and post-dressing change, overall wound pain improved (reduced) in 48% of patients. Periwound skin condition showed a tendency towards improvement, and the fluid management capabilities of the HRWD was reported as good to excellent in the majority of cases. Wound infections were reduced by at least 60% over the evaluation period. A simple cost-effective analysis demonstrated significant savings using HRWD (£6.33) over current standard practice regimens of a four-step debridement process (£8.05), larval therapy (£306.39) and mechanical pad debridement (£11.46). CONCLUSION: HRWD was well tolerated and was demonstrated to be an efficient debridement tool providing rapid, effective and pain free debridement in a variety of wound types.

The Dynamical Structure of HR 8799's Inner Debris Disk.

The HR 8799 system, with its four giant planets and two debris belts, has an architecture closely mirroring that of our Solar system where the inner, warm asteroid belt and outer, cool Edgeworth-Kuiper belt bracket the giant planets. As such, it is a valuable laboratory for examining exoplanetary dynamics and debris disk-exoplanet interactions. Whilst the outer debris belt of HR 8799 has been well resolved by previous observations, the spatial extent of the inner disk remains unknown. This leaves a significant question mark over both the location of the planetesimals responsible for producing the belt's visible dust and the physical properties of those grains. We have performed the most extensive simulations to date of the inner, unresolved debris belt around HR 8799, using UNSW Australia's Katana supercomputing facility to follow the dynamical evolution of a model inner disk comprising 300,298 particles for a period of 60 Ma. These simulations have enabled the characterisation of the extent and structure of the inner disk in detail, and will in future allow us to provide a first estimate of the small-body impact rate and water delivery prospects for possible (as-yet undetected) terrestrial planet (s) in the inner system.

Water intake, faecal output and intestinal motility in horses moved from pasture to a stabled management regime with controlled exercise.

REASONS FOR PERFORMING STUDY: A change in management from pasture to stabling is a risk factor for equine colic. OBJECTIVES: To investigate the effect of a management change from pasture with no controlled exercise to stabling with light exercise on aspects of gastrointestinal function related to large colon impaction. The hypothesis was that drinking water intake, faecal output, faecal water content and large intestinal motility would be altered by a transition from a pastured to a stabled regime. STUDY DESIGN: Within-subject management intervention trial involving changes in feeding and exercise using noninvasive techniques. METHODS: Seven normal horses were evaluated in a within-subjects study design. Horses were monitored while at pasture 24 h/day, and for 14 days following a transition to a stabling regime with light controlled exercise. Drinking water intake, faecal output and faecal dry matter were measured. Motility of the caecum, sternal flexure and left colon (contractions/min) were measured twice daily by transcutaneous ultrasound. Mean values were pooled for the pastured regime and used as a reference for comparison with stabled data (Days 1-14 post stabling) for multilevel statistical analysis. RESULTS: Drinking water intake was significantly increased (mean ± s.d. pasture 2.4 ± 1.8 vs. stabled 6.4 ± 0.6 l/100 kg bwt/day), total faecal output was significantly decreased (pasture 4.62 ± 1.69 vs. stabled 1.81 ± 0.5 kg/100 kg bwt/day) and faecal dry matter content was significantly increased (pasture 18.7 ± 2.28 vs. stabled 27.2 ± 1.93% DM/day) on all days post stabling compared with measurements taken at pasture (P<0.05). Motility was significantly decreased in all regions of the large colon collectively on Day 2 post stabling (-0.76 contractions/min), and in the left colon only on Day 4 (-0.62 contractions/min; P<0.05). CONCLUSIONS: There were significant changes in large intestinal motility patterns and parameters relating to gastrointestinal water balance during a transition from pasture to stabled management, particularly during the first 5 days.

Precision shock tuning on the national ignition facility.

Ignition implosions on the National Ignition Facility [J. D. Lindl et al., Phys. Plasmas 11, 339 (2004)] are underway with the goal of compressing deuterium-tritium fuel to a sufficiently high areal density (ρR) to sustain a self-propagating burn wave required for fusion power gain greater than unity. These implosions are driven with a very carefully tailored sequence of four shock waves that must be timed to very high precision to keep the fuel entropy and adiabat low and ρR high. The first series of precision tuning experiments on the National Ignition Facility, which use optical diagnostics to directly measure the strength and timing of all four shocks inside a hohlraum-driven, cryogenic liquid-deuterium-filled capsule interior have now been performed. The results of these experiments are presented demonstrating a significant decrease in adiabat over previously untuned implosions. The impact of the improved shock timing is confirmed in related deuterium-tritium layered capsule implosions, which show the highest fuel compression (ρR~1.0 g/cm(2)) measured to date, exceeding the previous record [V. Goncharov et al., Phys. Rev. Lett. 104, 165001 (2010)] by more than a factor of 3. The experiments also clearly reveal an issue with the 4th shock velocity, which is observed to be 20% slower than predictions from numerical simulation.

Higher mode sound transmission from a point source through a rectangular aperture.

This paper considers the higher-order scattered and transmitted wave fields that result when an acoustic wave from a point source impinges at an arbitrary angle on a rectangular aperture in a rigid, thick wall. In this analysis, it is assumed that free field conditions exist on both sides of the aperture. Although the full scattered and transmitted pressure fields contain both modal sum and modal coupling effects, the modal coupling effects of the higher-order modes are ignored such that an approximate analytical solution to the uncoupled analysis can be utilized. Experiments have been undertaken to measure the sound pressure levels in the transmitted field that result when sound from a point source impinges on the opposite side of a rectangular aperture. Measurements were made with the source located at the required position to drive a particular in-aperture higher-order mode. The source was also located at positions that did not directly excite any in-aperture higher-order mode at a cut-on frequency. These results indicate that the approximate analysis developed here gives accurate solutions whether or not any mode of the aperture is driven at cut-on. Thus, the method can be used for any relative location of a source from a rectangular aperture of any dimensions.

Somatic p16(INK4a) loss accelerates melanomagenesis.

Loss of p16(INK4a)-RB and ARF-p53 tumor suppressor pathways, as well as activation of RAS-RAF signaling, is seen in a majority of human melanomas. Although heterozygous germline mutations of p16(INK4a) are associated with familial melanoma, most melanomas result from somatic genetic events: often p16(INK4a) loss and N-RAS or B-RAF mutational activation, with a minority possessing alternative genetic alterations such as activating mutations in K-RAS and/or p53 inactivation. To generate a murine model of melanoma featuring some of these somatic genetic events, we engineered a novel conditional p16(INK4a)-null allele and combined this allele with a melanocyte-specific, inducible CRE recombinase strain, a conditional p53-null allele and a loxP-stop-loxP activatable oncogenic K-Ras allele. We found potent synergy between melanocyte-specific activation of K-Ras and loss of p16(INK4a) and/or p53 in melanomagenesis. Mice harboring melanocyte-specific activated K-Ras and loss of p16(INK4a) and/or p53 developed invasive, unpigmented and nonmetastatic melanomas with short latency and high penetrance. In addition, the capacity of these somatic genetic events to rapidly induce melanomas in adult mice suggests that melanocytes remain susceptible to transformation throughout adulthood.

Do egg-laying crocodilian (Alligator mississippiensis) archosaurs form medullary bone?

It is beyond question that Mesozoic dinosaurs, like Aves and Crocodylia, are archosaurs. However, within the archosaurian clade, the origin and distribution of some major features are less clear, particularly with respect to reproductive physiology. Medullary bone, a highly mineralized, bony reproductive tissue present in the endosteal cavities of all extant egg-laying birds thus far examined, has recently been reported in Tyrannosaurus rex. Its presence or absence in extant crocodilians, therefore, may shed light on the timing of its evolutionary appearance. If medullary bone is present in all three taxa, it arose before the three lineages diverged. However, if medullary bone arose after this divergence, it may be present in both extinct dinosaurs and birds, or in birds only. If present in extinct dinosaurs and birds, but not crocodilians, it would indicate that it arose in the common ancestor of this clade, thus adding support to the closer phylogenetic relationship of dinosaurs and birds relative to crocodilians. Thus, the question of whether the crocodilian Alligator mississippiensis forms medullary bone during the production of eggs has important evolutionary significance. Our examination of long bones from several alligators (two alligators with eggs in the oviducts, one that had produced eggs in the past but was not currently in reproductive phase, an immature female and an adult male) shows no differences on the endosteal surfaces of the long bones, and no evidence of medullary bone, supporting the hypothesis that medullary bone first evolved in the dinosaur-bird line, after the divergence of crocodilians from this lineage.

The hook effect: a need for constant vigilance.

The hook effect is a well-recognized problem that can occur in assays of most tumour markers, including alpha feto-protein (AFP). We present a case of hepatoblastoma in a baby. The diagnosis was delayed as a result of unrecognized 'hooking' of a very high AFP concentration in the automated immunoassay method used. The falsely low result obtained was considered normal for the patient's age and supported the diagnosis of benign haemangioendothelioma. Liaison between clinical and laboratory staff was critical in obtaining an accurate AFP result, proceeding to liver biopsy and establishing the definitive diagnosis of hepatoblastoma. While the reasons and solutions for hook effect have been well researched and published, we believe the presence of extremely high serum AFP concentration in some hepatoblastoma patients means that the hook effect remains a problem and can generate erroneously low AFP results despite assay reformulation by manufacturers. Therefore constant vigilance by laboratory staff is still needed.

Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis.

The cyclin-dependent kinase inhibitor p16INK4a can induce senescence of human cells, and its loss by deletion, mutation or epigenetic silencing is among the most frequently observed molecular lesions in human cancer. Overlapping reading frames in the INK4A/ARF gene encode p16INK4a and a distinct tumour-suppressor protein, p19ARF (ref. 3). Here we describe the generation and characterization of a p16Ink4a-specific knockout mouse that retains normal p19Arf function. Mice lacking p16Ink4a were born with the expected mendelian distribution and exhibited normal development except for thymic hyperplasia. T cells deficient in p16Ink4a exhibited enhanced mitogenic responsiveness, consistent with the established role of p16Ink4a in constraining cellular proliferation. In contrast to mouse embryo fibroblasts (MEFs) deficient in p19Arf (ref. 4), p16Ink4a-null MEFs possessed normal growth characteristics and remained susceptible to Ras-induced senescence. Compared with wild-type MEFs, p16Ink4a-null MEFs exhibited an increased rate of immortalization, although this rate was less than that observed previously for cells null for Ink4a/Arf, p19Arf or p53 (refs 4, 5). Furthermore, p16Ink4a deficiency was associated with an increased incidence of spontaneous and carcinogen-induced cancers. These data establish that p16Ink4a, along with p19Arf, functions as a tumour suppressor in mice.

Product studies and laser flash photolysis on alkyl radicals containing two different beta-leaving groups are consonant with the formation of an olefin cation radical.

1-Bromo-2-methoxy-1-phenylpropan-2-yl (3) and 2-methoxy-1-phenyl-1-diphenylphosphatopropan-2-yl (4) were generated under continual photolysis from the respective PTOC precursors in a mixture of acetonitrile and methanol. The radicals undergo heterolytic fragmentation of the substituent in the beta-position to generate the olefin cation radical (5). Z-2-Methoxy-1-phenylpropene (15) is the major product formed in the presence of 1,4-cyclohexadiene, and is believed to result from hydrogen atom transfer to the oxygen of the olefin cation radical, followed by deprotonation. Laser flash photolysis experiments indicate that reaction between 5 and 1,4-cyclohexadiene occurs with a rate constant of approximately 6 x 10(5) M(-1) s(-1). 2,2-Dimethoxy-1-phenylpropane (18) is observed as a minor product. Laser flash photolysis experiments place an upper limit on methanol trapping of 5 at k <1 x 10(3) M(-1) s(-1) and do not provide any evidence for the formation of reactive intermediates other than 5. The use of two PTOC precursors containing different leaving groups to generate a common olefin cation radical enables one to utilize product analysis to probe for the intermediacy of other reactive intermediates. The ratio of 15:18 is dependent upon hydrogen atom donor concentration, but is independent of the PTOC precursor. These observations are consistent with the proposal that both products result from trapping of 5 that is formed via heterolysis of 3 and 4.

Dinosaurian growth rates and bird origins.

Dinosaurs, like other tetrapods, grew more quickly just after hatching than later in life. However, they did not grow like most other non-avian reptiles, which grow slowly and gradually through life. Rather, microscopic analyses of the long-bone tissues show that dinosaurs grew to their adult size relatively quickly, much as large birds and mammals do today. The first birds reduced their adult body size by shortening the phase of rapid growth common to their larger theropod dinosaur relatives. These changes in timing were primarily related not to physiological differences but to differences in growth strategy.

Genetics, experience, and host-plant preference in Eurosta solidaginis: implications for host shifts and speciation.

Host-associated mating is crucial in maintaining the partial reproductive isolation between the host races of Eurosta solidaginis (Diptera: Tephritidae), a fly that forms galls on Solidago altissima and S. gigantea. (We refer to flies reared from S. gigantea as gigantea flies and those reared from S. altissima as altissima flies.) We measured the host preference of males and females of both host races, F1 hybrids between the host races, F2, and backcrosses to both host races. Male and female altissima flies and female gigantea flies had high host fidelity, whereas male gigantea flies had low host fidelity. This result suggests that there may be gene flow between the host races due to nonassortative mating that occurs when male gigantea mate with altissima females on S. altissima. This indicates assortative-mating mechanisms in addition to host-associated mating are required to produce the partial reproductive isolation between the host races that has been observed. Nongenetic factors had no influence on host preference. Larval conditioning did not influence host preference: reciprocal F1 hybrids reared in S. altissima and S. gigantea both preferred S. gigantea. Adult experience had no impact on host preference: females preferred their natal host plant regardless of which host they encountered first as an adult. The hypothesis that maternal effects influence preferences was rejected because male and female flies did not show a consistent preference for the host plant of their mother. We also found no evidence that preference was a sex-linked trait because F1 and backcrosses to the host races with different combinations of X chromosomes from the two host races preferred S. gigantea. Our results indicate that host preference is not determined by a large number of genes because preference of hybrids did not correspond to the proportion of the genome derived from each host race. The strength of the ovipuncture preference for S. gigantea by gigantea females, the females of both reciprocal F1 hybrids, the backcross to gigantea, and F2s indicates that preference is inherited nonadditively at a limited number of loci. The F1 female hybrids, however, had a weaker host preference for S. gigantea than the pure gigantea host race, indicating that there may be incomplete dominance or modifier loci. Males had different host preference patterns than females, with individual male gigantea and male F1 hybrids usually exhibiting preference exclusively for S. gigantea or S. altissima. One hypothesis explaining the difference in host preference between males and females is that the same gene influences both female and male host preference, but it is a sex-influenced gene. Thus, males carrying the gene for S. gigantea preference have an intermediate host preference, whereas females have a strong host preference to S. gigantea. In summary, we found that the host preference that produces host-associated mating is inherited nonadditively at a relatively small number of loci on autosomal genes. This mode of inheritance meets the assumptions of models of sympatric speciation, indicating that the host races could have evolved in sympatry.

Cranial design and function in a large theropod dinosaur.

Finite element analysis (FEA) is used by industrial designers and biomechanicists to estimate the performance of engineered structures or human skeletal and soft tissues subjected to varying regimes of stress and strain. FEA is rarely applied to problems of biomechanical design in animals, despite its potential to inform structure-function analysis. Non-invasive techniques such as computed tomography scans can be used to generate accurate three-dimensional images of structures, such as skulls, which can form the basis of an accurate finite element model. Here we have applied this technique to the long skull of the large carnivorous theropod dinosaur Allosaurus fragilis. We have generated the most geometrically complete and complex FEA model of the skull of any extinct or extant organism and used this to test its mechanical properties and examine, in a quantitative way, long-held hypotheses concerning overall shape and function. The combination of a weak muscle-driven bite force, a very 'light' and 'open' skull architecture and unusually high cranial strength, suggests a very specific feeding behaviour for this animal. These results demonstrate simply the inherent potential of FEA for testing mechanical behaviour in fossils in ways that, until now, have been impossible.

Carbohydrate-loading during the follicular phase of the menstrual cycle: effects on muscle glycogen and exercise performance.

The effects of employing a high-carbohydrate diet (carbohydrate-loading) to increase glycogen storage in skeletal muscle are not well established in female athletes. On 4 occasions--2 familiarization trials and 2 experimental trials--6 well-trained female subjects completed 6 x 15-min continuous intervals of cycling (12 min at 72% VO2max, 1 min at maximal effort, and 2 min at 50% VO2max), followed by a time trial 15 min later. The women consumed their habitual diets (HD; 6-7 g carbohydrate/kg lean body mass) for 3 days after the second familiarization trial and before the first experimental trial. During the 3 days following the first experimental trial, the subjects consumed a high-carbohydrate diet (CD; 9-10 g carbohydrate/kg lean body mass) prior to the second experimental trial. Mean (+/-SEM) pre-exercise muscle glycogen concentrations were greater after CD versus HD (171.9+/-8.7 vs. 131.4+/-10.3 mmol/kg wet weight, P < 0.003). Although 4 of the 6 subjects improved their time-trial performance after CD, mean performance for the time trial was not significantly different between diets (HD: 763.9+/-35.6 s; CD: 752.9+/-30.1 s). Thus, female cyclists can increase their muscle glycogen stores after a carbohydrate-loading diet during the follicular phase of the menstrual cycle, but we found no compelling evidence of a dietary effect on performance of a cycling time trial performed after 90 min of moderate-intensity exercise.

Tetracycline-inducible system for photoreceptor-specific gene expression.

PURPOSE: To develop a system for inducible photoreceptor-specific gene expression in transgenic mice. The tetracycline regulatory system was chosen because it possesses the useful property of direct control of gene expression through use of an exogenous agent, doxycycline, a tetracycline derivative. METHODS: Transgenic mice were generated that carried the reverse tetracycline-controlled transactivator under the control of the photoreceptor-specific promoters for rhodopsin and interphotoreceptor retinoid-binding protein. These animals were crossed with transgenic mice carrying the lacZ reporter gene under control of the tetracycline operator cassette, creating doubly transgenic mice. Doxycycline was administered to induce expression of the reporter gene. Reporter assays were then performed to evaluate lacZ expression. RESULTS: Doxycycline administration led to photoreceptor-specific expression of the lacZ reporter gene in the doubly transgenic mice. X-gal staining was restricted to photoreceptor inner segments and synaptic termini. Induction could be achieved by addition of the drug to the animals' drinking water or by intravitreal injection. Induction was noted within 24 hours of doxcycline administration. Because of variability among animals, there was an approximate correlation, but not a clean dose-response curve relating drug dose to level of reporter expression. CONCLUSIONS: A transgenic system for inducible photoreceptor-specific gene expression has been developed. This system is currently being exploited to study the effects of regulated expression of genes of biological interest.

Anthropogenic emissions of carbon monoxide.

Carbon monoxide (CO) is a colorless, nonirritating, odorless and tasteless gas. Carbon monoxide combines with hemoglobin far more readily than does oxygen, leading to tissue hypoxia. Thousands of people die annually from CO poisoning, and those recovering from acute exposure commonly suffer brain damage. Chronic poisoning is of particular concern to sufferers of coronary heart disease, pregnant women, and people with certain hematological disorders. Indoor emission sources, notably fuel-burning heating appliances, cause most unintentional deaths and cases of illness and should be the main focus of concern. Motor vehicle emissions pose a chronic health risk for occupationally exposed groups. Smoking is a major source of personal exposure. Recent exposure to CO is commonly evaluated by measuring blood carboxyhemoglobin levels, which are related to the concentration of atmospheric CO. Monitoring methods are reviewed here, and monitoring is considered in relation to air quality standards and guidelines. Finally, control measures for motor vehicles and indoor heating appliances are suggested.

DNA ligase IV deficiency in mice leads to defective neurogenesis and embryonic lethality via the p53 pathway.

DNA ligase IV (LIG4) is a nonhomologous end-joining (NHEJ) protein used for V(D)J recombination and DNA repair. In mice, Lig4 deficiency causes embryonic lethality, massive neuronal apoptosis, arrested lymphogenesis, and various cellular defects. Herein, we assess potential roles in this phenotype for INK4a/ARF and p53, two proteins implicated in apoptosis and senescence. INK4a/ARF deficiency rescued proliferation/senescence defects of Lig4-deficient fibroblasts but not other phenotypic aspects. In contrast, p53 deficiency rescued embryonic lethality, neuronal apoptosis, and fibroblast proliferation/senescence defects but not lymphocyte development or radiosensitivity. Young Lig4/p53 double null mice routinely died from pro-B lymphomas. Thus, in the context of Lig4 deficiency, embryonic lethality and neuronal apoptosis likely result from a p53-dependent response to unrepaired DNA damage, and neuronal apoptosis and lymphocyte developmental defects can be mechanistically dissociated.