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The observed partitioning of poleward heat transport between atmospheric and oceanic heat transports (AHT and OHT) is compared to that in coupled climate models. Model ensemble mean poleward OHT is biased low in both hemispheres, with the largest biases in the Southern Hemisphere extratropics. Poleward AHT is biased high in the Northern Hemisphere, especially in the vicinity of the peak AHT near 40°N. The significant model biases are persistent across three model generations (CMIP3, CMIP5, CMIP6) and are insensitive to the satellite radiation and atmospheric reanalyzes products used to derive observational estimates of AHT and OHT. Model biases in heat transport partitioning are consistent with biases in the spatial structure of energy input to the ocean and atmosphere. Specifically, larger than observed model evaporation in the tropics adds excess energy to the atmosphere that drives enhanced poleward AHT at the expense of weaker OHT. Plain Language Summary: The equator‐to‐pole contrast of solar radiation entering the climate system drives the large‐scale oceanic and atmospheric circulations that, in turn, move heat from the equator to the poles to moderate latitudinal temperature contrasts. The ocean moves the majority of heat in the tropics whereas the atmosphere moves the vast majority of heat in the mid‐ and polar‐latitudes. We demonstrate that, on average, state‐of‐the‐art climate models representing both oceanic and atmospheric circulations simulate too little oceanic heat transport and too much atmospheric heat transport relative to observational estimates. These model biases in the atmosphere‐ocean partitioning of poleward heat transport are persistent across three generations of climate model ensembles spanning 20 years of progress in climate modeling and are insensitive to the choice of datasets used to calculate observed heat transports. The model biases are consistent with stronger than observed surface evaporation in the tropics which enhances atmospheric heat transport at the expense of oceanic heat transport. Key Points: Climate models simulate too little poleward oceanic heat transport and too much poleward atmospheric heat transport in the extratropicsModel biases in heat transport partitioning are persistent across model generation and are insensitive to the observational data sets usedStronger than observed evaporation in models enhances atmospheric heat transport at the expense of oceanic heat transport [ABSTRACT FROM AUTHOR]

We report an assessment for determining the contribution by diatoms to community productivity and respiration within a coastal benthic ecosystem with multiple autotrophs. During summer, cores of open sediment and seagrass habitat were collected from a lagoon within the Northern Gulf of Mexico. Cores were maintained in an outdoor mesocosm. Germanic acid, an inhibitor of diatom cell division, was added to half the cores and quantification of production and respiration was done. Inhibition of diatoms reduced benthic productivity within the seagrass habitat. 71–83% production was attributable to diatoms and this contribution moved the benthic system into net autotrophy. Diatom contribution to production in other habitat‐community components was more variable (varied from 0% to 86%). Findings underscore the ecological importance of diatoms as producers in seagrass beds, the role of seagrasses in maintaining productivity, and infer that diatoms may have similar contributions in other aquatic vegetated habitats. [ABSTRACT FROM AUTHOR]

SUMMARY: Some introduced species compete directly with native species for resources and their spread can alter communities, while others do not proliferate and remain benign. This study compares community structure and diversity in adjacent areas dominated by the introduced alga Avrainvillea sp. or native algal species on a hard substrate reef. The biomass and species composition of 15 paired plots (30 in total, plot type based on dominance of Avrainvillea sp. or native species) were quantified. Plots dominated by Avrainvillea sp. had a significantly different assemblage of species characterized by lower algal diversity, mostly Dictyota spp. and Laurencia sp., and a higher abundance and diversity of invertebrates, such as small arthropods, polychaetes, and brittlestars. These results suggest that as Avrainvillea sp. becomes more abundant on hard substrate reefs, it will engineer a different community composed of algal epiphytes and an invertebrate assemblage more typically associated with algae in soft sediments. [ABSTRACT FROM AUTHOR]

Much research examining primary caregivers of children with cancer has focused on their distress levels and coping strategies. Drawing on qualitative data from semi‐structured interviews with 38 Australian primary caregivers, this article examines their experiences through their child's cancer diagnosis and early treatment period. However, it does so retrospectively with their child in remission (a minimum of 5 years post diagnosis). This methodology gave caregivers the time to evaluate and reflect on their experiences through their child's cancer. Interviews with caregivers were recorded, transcribed verbatim and analysed using a grounded constant comparison approach. The concept of neo‐normal was developed to represent caregivers’ responses to having a child with cancer – characterised by the existential threat of cancer, the shattering of notions of control and certainty in their capacity to protect their child's well‐being and reliance on medical intervention. Paradoxically, conceding to this disempowered position facilitated new ways to be a caregiver of a child with cancer. The findings illustrate the social processes and cultural context in which caregivers construct new normalising strategies as they transition through their child's illness. The study also gives recognition to the vital care, advocacy and pseudo‐nursing contributions that caregivers bring to the paediatric oncology setting. [ABSTRACT FROM AUTHOR]

There is a growing body of evidence on the importance of work following a diagnosis of cancer and the need to provide better information, advice and related support to patients on work engagement. The aim of this study was to better understand the nature of those needs and to identify better ways to meet these for those with a urological cancer. The focus was on the issues that were common to three key stakeholder groups. Semi-structured interviews were conducted with stakeholders in North East Scotland: 12 individuals with kidney, bladder or prostate cancer, 10 healthcare providers and 10 managers from large organisations. Five key themes emerged from the Framework Analysis: perceived importance of work engagement; decision-making: treatment, work and cancer; roles and responsibilities; education and training; information, advice and support resources. The data confirmed that work engagement is important to those with urological cancer. It also made clear that the current provision of information and advice could be improved. Any such interventions should involve all three key stakeholder groups with greater clarity on their respective roles and responsibilities. Finally, any new system would be best integrated with existing care provision and supported by adequate education and training of those involved. [ABSTRACT FROM AUTHOR]

We present data from sediment cores collected from IODP Site C0012 in the Shikoku Basin. Our site lies at the Nankai Trough, just prior to subduction of the 19 Ma Philippine Sea plate. Our data indicate that the sedimentary package is undergoing multiple routes of electron transport and that these differing pathways for oxidant supply generate a complex array of metabolic routes and microbial communities involved in carbon cycling. Numerical simulations matched to pore water data document that Ca2+ and Cl1- are largely supplied via diffusion from a high-salinity (44.5 psu) basement fluid, which supports the presence of halophile Archean communities within the deep sedimentary package that are not observed in shallow sediments. Sulfate supply from basement supports anaerobic oxidation of methane ( AOM) at a rate of ~0.2 pmol cm−3 day−1 at ~400 mbsf. We also note the disappearance of δ -Proteobacteria at 434 mbsf, coincident with the maximum in methane concentration, and their reappearance at 463 mbsf, coinciding with the observed deeper increase in sulfate concentration toward the basement. We did not, however, find ANME representatives in any of the samples analyzed (from 340 to 463 mbsf). The lack of ANME may be due to an overshadowing effect from the more dominant archaeal phylotypes or may indicate involvement of unknown groups of archaea in AOM (i.e., unclassified Euryarchaeota). In addition to the supply of sulfate from a basement aquifer, the deep biosphere at this site is also influenced by an elevated supply of reactive iron (up to 143 μmol g−1) and manganese (up to 20 μmol g−1). The effect of these metal oxides on the sulfur cycle is inferred from an accompanying sulfur isotope fractionation much smaller than expected from traditional sulfate-reducing pathways. The detection of the manganese- and iron-reducer γ -Proteobacteria Alteromonas at 367 mbsf is consistent with these geochemical inferences. [ABSTRACT FROM AUTHOR]

Biological interactions can alter predictions that are based on single-species physiological response. It is known that leaf segments of the seagrass Posidonia oceanica will increase photosynthesis with lowered pH, but it is not clear whether the outcome will be altered when the whole plant and its epiphyte community, with different respiratory and photosynthetic demands, are included. In addition, the effects on the Posidonia epiphyte community have rarely been tested under controlled conditions, at near-future pH levels., In order to better evaluate the effects of pH levels as projected for the upcoming decades on seagrass meadows, shoots of P. oceanica with their associated epiphytes were exposed in the laboratory to three pH levels (ambient: 8.1, 7.7 and 7.3, on the total scale) for 4 weeks. Net productivity, respiration, net calcification and leaf fluorescence were measured on several occasions. At the end of the study, epiphyte community abundance and composition, calcareous mass and crustose coralline algae growth were determined. Finally, photosynthesis vs. irradiance curves ( PE) was produced from segments of secondary leaves cleaned of epiphytes and pigments extracted., Posidonia leaf fluorescence and chlorophyll concentrations did not differ between pH treatments. Net productivity of entire shoots and epiphyte-free secondary leaves increased significantly at the lowest pH level yet limited or no stimulation in productivity was observed at the intermediate pH treatment. Under both pH treatments, significant decreases in epiphytic cover were observed, mostly due to the reduction of crustose coralline algae. The loss of the dominant epiphyte producer yet similar photosynthetic response for epiphyte-free secondary leaves and shoots suggests a minimal contribution of epiphytes to shoot productivity under experimental conditions., Synthesis. Observed responses indicate that under future ocean acidification conditions foreseen in the next century an increase in Posidonia productivity is not likely despite the partial loss of epiphytic coralline algae which are competitors for light. A decline in epiphytic cover could, however, reduce the feeding capacity of the meadow for invertebrates. In situ long-term experiments that consider both acidification and warming scenarios are needed to improve ecosystem-level predictions. [ABSTRACT FROM AUTHOR]

Objective To assess whether human laser epilation technology can permanently prevent wool growth in sheep. Design An observational study. Methods Two commercial human epilation lasers ( Sharplan alexandrite 755 nm laser, and Lumenis Light Sheer® 800 nm diode laser) were tested at energies between 10 and 100 J/cm2 and pulse widths from 2 to 400 ms. Wool was clipped from flank, breech, pizzle and around the eyes of superfine Merino sheep with Oster clippers. After initial laser removal of residual wool to reveal bare skin, individual skin sites were treated with up to 15 cycles of laser irradiation. Behavioural responses during treatment, skin temperature immediately after treatment and skin and wool responses for 3 months after treatment were monitored. Results A clear transudate was evident on the skin surface within minutes. A dry superficial scab developed by 24 h and remained adherent for at least 6 weeks. When scabs were shed, there was evidence of scarring at sites receiving multiple treatment cycles and normal wool growth in unscarred skin. There was no evidence of laser energy level or pulse width affecting the response of skin and wool to treatment and no evidence of permanent inhibition of wool growth by laser treatment. Laser treatment was well tolerated by the sheep. Conclusions Treatment of woolled skin with laser parameters that induce epilation by selective photothermolysis in humans failed to induce permanent inhibition of wool growth in sheep. Absence of melanin in wool may have contributed to the result. [ABSTRACT FROM AUTHOR]

High density mineralised protrusions (HDMP) from the tidemark mineralising front into hyaline articular cartilage (HAC) were first described in Thoroughbred racehorse fetlock joints and later in Icelandic horse hock joints. We now report them in human material. Whole femoral heads removed at operation for joint replacement or from dissection room cadavers were imaged using magnetic resonance imaging (MRI) dual echo steady state at 0.23 mm resolution, then 26-lm resolution high contrast X-ray microtomography, sectioned and embedded in polymethylmethacrylate, blocks cut and polished and re-imaged with 6-lm resolution X-ray microtomography. Tissue mineralisation density was imaged using backscattered electron SEM (BSE SEM) at 20 kV with uncoated samples. HAC histology was studied by BSE SEM after staining block faces with ammonium triiodide solution. HDMP arise via the extrusion of an unknown mineralisable matrix into clefts in HAC, a process of acellular dystrophic calcification. Their formation may be an extension of a crack self-healing mechanism found in bone and articular calcified cartilage. Mineral concentration exceeds that of articular calcified cartilage and is not uniform. It is probable that they have not been reported previously because they are removed by decalcification with standard protocols. Mineral phase morphology frequently shows the agglomeration of many fine particles into larger concretions. HDMP are surrounded by HAC, are brittle, and show fault lines within them. Dense fragments found within damaged HAC could make a significant contribution to joint destruction. At least larger HDMP can be detected with the best MRI imaging ex vivo. [ABSTRACT FROM AUTHOR]

Aim UK cancer guidelines recommend patients with colonic obstruction due to suspected malignancy be considered for stenting with a self-expanding metal stent ( SEMS). Considerable variation in practice exists due to a lack of expertise, technical difficulties and other, as yet ill-defined features. This retrospective multi-centre study aims to determine the outcome following colonic stenting for large bowel obstruction and identify factors associated with successful intervention. Method A regional programme of colonic stenting for large bowel obstruction, in five UK centres from 2005 to 2010 was evaluated for outcome including technical and clinical success, survival, complications and reoperation. Results A SEMS was inserted in 334 patients, including 264 (79.0%) for palliation and 52 (15.6%) as a bridge to surgery. Technical success was achieved in 292 (87.4%) patients, with 46 (13.8%) experiencing a complication or technical failure. Reoperation was required in 39 (14.8%) patients stented for palliation of colorectal cancer of whom 16 (6.1%) subsequently required a colostomy. A one-stage primary anastomosis was achieved in 35 (67.3%) of the 52 patients undergoing stenting as a bridge to resection. Technical success did not vary by indication or site of obstruction ( P = 0.60) but was higher for operators who had performed more than 10 procedures ( OR 3.34, P = 0.001). ASA grade ≥3 predicted a worse clinical outcome ( OR 0.43, P = 0.04). The through-the-scope ( TTS) endoscopy technique was more successful than radiological placement alone (90.3% vs 74.8%, P < 0.001). Conclusion Experienced operators using a TTS technique achieved a better outcome for the emergency management of large bowel obstruction. Older, sicker patients and those with extracolonic and benign strictures fared less well. [ABSTRACT FROM AUTHOR]

The success of enzymatic replacement in Gaucher disease has stimulated development of targeted protein replacement for other lysosomal disorders, including Anderson-Fabry disease, which causes fatal cardiac, cerebrovascular and renal injury: deficiency of lysosomal α-Galactosidase A induces accumulation of glycosphingolipids. Endothelial cell storage was the primary endpoint in a clinical trial that led to market authorization. Two α-Galactosidase A preparations are licensed worldwide, but fatal outcomes persist, with storage remaining in many tissues. We compare mechanisms of uptake of α -Galactosidase A into cells relevant to Fabry disease, in order to investigate if the enzyme is targeted to the lysosomes in a mannose-6-phosphate receptor dependent fashion, as generally believed. α -Galactosidase A uptake was examined in fibroblasts, four different endothelial cell models, and hepatic cells in vitro. Uptake of europium-labeled human α -Galactosidase A was measured by time-resolved fluorescence. Ligand-specific uptake was quantified in inhibitor studies. Targeting to the lysosome was determined by precipitation and by confocal microscopy. The quantity and location of cation-independent mannose-6-phosphate receptors in the different cell models were investigated using confocal microscopy. Uptake and delivery of α -Galactosidase A to lysosomes in fibroblasts is mediated by the canonical mannose-6-phosphate receptor pathway, but in endothelial cells in vitro this mechanism does not operate. Moreover, this observation is supported by a striking paucity of expression of cation independent mannose-6-phosphate receptors on the plasma membrane of the four endothelial cell models and by little delivery of enzyme to lysosomes, when compared with fibroblasts. If these observations are confirmed in vivo, alternative mechanisms will be needed to explain the ready clearance of storage from endothelial cells in patients undergoing enzyme replacement therapy. [ABSTRACT FROM AUTHOR]

The article presents a study on actions made in a citizen action program that assure data quality and show the validity of citizen-generated data. The study involved data collected by secondary school students, as part of a program that quantitatively sampled benthic rocky intertidal communities in Maui, Molokai and Oahu in Hawaii from 2004 to 2007. The results showed that nonexpert students accurately collect community-level data in the range of the variation that occurs between researchers.

Prior to 1996 and the Congolese wars, exploitative land policies pushed farmers in the eastern highlands of the Democratic Republic of the Congo (DRC) into a vulnerable position, with cattle manure sustaining intensive cultivation. This exposed households to a complete breakdown in mixed farming as cattle became targets of war. This study of villages in South Kivu offers an inside understanding of continuity and change in farming practices in a region where there are no easy solutions, and it assesses how the province lost its present and where farmers look when they glance to the future. For farmers, who hold a broad view of soil fertility, the casualties of war were not only people and cattle but also the land itself, which has enduring scars. Perceiving a rupture in tradition, South Kivu farmers are searching desperately for new livelihoods that are built on education instead of livestock, setting aside old ethnic signifiers to seek a future beyond protracted conflict. [ABSTRACT FROM AUTHOR]

Abstract: Weight loss and gastrointestinal disturbances are often seen during miglustat therapy for lysosomal storage diseases. A retrospective analysis of data from a mixed group of patients treated with miglustat at two UK centres was performed to evaluate the effect of two different dietary interventions on body weight and gastrointestinal tolerability during the initial 6 months of miglustat therapy. Neurological outcomes in these patients are not discussed herein. Data were analysed from a total of 29 patients with varied neurolipidoses (21 children/adolescents; 8 adults). Negative mean changes in body weight were seen in children/adolescents on an unmodified diet (−8.1%), and in adults (−4.1%) and children/adolescents (−5.2%) on a low‐lactose diet. Patients on the low‐disaccharide diet showed a positive mean change in body weight (+2.0%), although there was high variability in this group. Non‐parametric sub‐analysis of median body‐weight change in children/adolescents also showed high variability both within and between diet groups, with no statistically significant difference between the effects of different diets on body weight (p = 0.062). The low‐lactose diet reduced gastrointestinal disturbances; single small doses of loperamide were required in some patients. Patients on the low‐disaccharide diet showed the lowest frequency of gastrointestinal effects. In conclusion, simple dietary modifications allowed the maintenance of body‐weight gain in line with normal growth potential during miglustat therapy in young patients with lysosomal storage diseases, and reduced gastrointestinal disturbances. [ABSTRACT FROM AUTHOR]

Aim: This study examines the overlap between children with bulbar cerebral palsy (Worster-Drought syndrome [WDS]) and perisylvian polymicrogyria. Method: A total of 121 children (81 males, 40 females; mean age 5y 5mo, SD 3y 6mo; age range 1mo-15y 4mo) were studied using retrospective clinical data and magnetic resonance imaging. In all, 70 children had WDS with normal perisylvian imaging, 31 had congenital bilateral perisylvian polymicrogyria (CBPP), and 20 had congenital unilateral perisylvian polymicrogyria (CUPP). Results: All groups shared aetiological markers (male sex, congenital contractures, low familial incidence, excess antenatal events). There was a common phenotype of pseudobulbar palsy with mild limb pyramidal signs in all children with WDS, 90% of those with CBPP, and one-third of those with CUPP, often also associated with learning disability*, epilepsy, and behavioural difficulties. A further 15% of children with CUPP acquired this phenotype through an epileptic encephalopathy. Pseudobulbar palsy rather than polymicrogyria was more predictive of additional impairments other than epilepsy. Interpretation: We propose that congenital perisylvian dysfunction is a spectrum encompassing the WDS phenotype and perisylvian polymicrogyria imaging abnormalities. As with other prenatal brain abnormalities, there is not necessarily concordance between imaging and clinical findings, although the phenotype is often more severe to manifest imaging abnormality. Clinical phenotype is the best indicator of prognosis. Epileptic encephalopathy can cause an acquired form of perisylvian dysfunction where there is. [ABSTRACT FROM AUTHOR]

Acoustic signals from the bird wrasse Gomphosus varius and saddle wrasse Thalassoma duperrey were recorded on coral reefs in Hawaii. Terminal phase males in both species emit two types of pulse trains (type I and type II). Type I pulses were produced during spawning and courtship, while type II pulses were associated only with courtship behaviours. Gomphosus varius type I pulses were of lower frequency than T. duperrey type I pulses (271 v. 840 Hz) and were of narrower band. Discriminant function analyses revealed interspecific differences between type I pulse trains and individual pulses of both types. This study is the first documentation of courtship and spawning sounds in sympatric labrids and shows divergence in acoustic signals. [ABSTRACT FROM AUTHOR]

Information about the topics discussed at the U.S. Environmental Protection Agency (USEPA) workshop which was held on February 13-14, 2007 in Denver, Colorado is presented. Topics include the modeling of metals in high-altitude streams, rivers and watershed, state of the art for knowledge gaps and future directions in metals modeling. The workshop was participated by several experts from government, academia, and consulting.

Enzyme replacement was introduced as treatment for non-neuronopathic Gaucher disease more than 15 years ago. To ensure the best use of this costly ultra-orphan agent, a systematic disease management approach has been proposed by an international panel; this includes the development, by consensus, of achievable treatment goals. Here we critically review these goals and monitoring guidelines and incorporate emerging experience of the disease in the therapeutic era, as well as contemporary clinical research. This review makes recommendations related specifically to the management of pregnancy; the appropriate use of splenectomy and bisphosphonate treatment; the relevance of biochemical markers to disease monitoring; and the use of semi-quantitative methods for assessing bone marrow infiltration. In addition, we identify key areas for development, including the requirement for a validated index of disease severity; the need to correlate widely used biomarkers with long-term disease outcomes, and the desirability of establishing agreed standards for monitoring of bone disease particularly in infants and children with Gaucher disease. [ABSTRACT FROM AUTHOR]

Fishers, scientists, and resource managers have made substantial progress in reducing bycatch of sea turtles, seabirds, and marine mammals through physical modifications to fishing gear. Many bycatch-avoidance measures have been developed and tested successfully in controlled experiments, which have led to regulated implementation of modified or new fishing gear. Nevertheless, successful bycatch experiments may not translate to effective mitigation in commercial fisheries because experimental conditions are relaxed in commercial fishing operations. Such a difference between experimental results and real-world results with fishing fleets may have serious consequences for management and conservation of protected species taken as bycatch. We evaluated preimplementation experimental measures and postimplementation efficacy from primary and gray literature for three case studies: acoustic pingers that warn marine mammals of the presence of gill nets, turtle excluder devices that reduce bycatch of turtles in trawls, and various measures to reduce seabird bycatch in longlines. Three common themes to successful implementation of bycatch reduction measures are long-standing collaborations among the fishing industry, scientists, and resource managers; pre- and postimplementation monitoring; and compliance via enforcement and incentives. [ABSTRACT FROM AUTHOR]

We report a case of a 7-month-old male with primary intracranial haemorrhage 2 months after infection with varicella zoster virus (VZV). His initial clinical course was complicated by seizures and right hemiparesis; when last seen at 22 months the only positive finding was of left hand preference. Although the literature has recently established the association of arterial ischaemic stroke and VZV infection, primary intracranial haemorrhage has been reported only in one case. The child reported here had anterior interhemispheric haemorrhage due to a focal arteritis of the left anterior cerebral artery. The vascular abnormality was transient and had radiological features compatible with either a focal arteritis or vasospasm as a direct result of blood surrounding the vessels. We postulate that direct invasion of VZV caused extensive inflammation of the vessel wall and aggressive tissue penetration resulting in necrotizing angiitis and intracranial haemorrhage. We suggest that VZV infection should be considered a potential risk factor for intracranial haemorrhage in children. [ABSTRACT FROM AUTHOR]

The treatment of disordered lipoprotein metabolism with the statin class of drugs is one of the most striking successes in the field of applied medical science: here the use of selective inhibitors of the first committed step of cholesterol biosynthesis, in a complex and highly regulated pathway, leads to improved outcome from a common lipid storage disease that is a blight on whole populations - atherosclerosis. By the same token, substrate reduction is an emerging therapeutic strategy' for the arcane field of the lysosomal storage diseases (LSDs). Reduced biosynthesis of glucosylceramide is postulated to allow correction of the imbalance between formation and breakdown of glycosphingolipids; the therapeutic effect of substrate reduction depends upon the presence of residual hydrolytic activity towards those accumulated glycosphingolipid substrates derived from glucosylceramide. First pioneered in the laboratory by Norman Radin, this approach has now been introduced into the clinic: based on the ability to inhibit uridine diphosphate glucosylceramide transferase, the semi-selective iminosugar, N-butyldeoxynojirimycin, is licensed for the treatment of type 1 Gaucher disease. Conclusion: Inhibition of substrate formation has wide application in the treatment of LSDs. Decreased glucosylceramide biosynthesis has therapeutic potential in glycosphingolipidoses other than Gaucher disease, and offers promise in several neurodegenerative storage disorders that are currently beyond the reach of other procedures. The results of ongoing clinical trials of miglustat in type 3 Gaucher disease, Niemann-Pick disease type C and GM2 gangliosidosis are eagerly awaited. [ABSTRACT FROM AUTHOR]

Novel or candidate biomarkers require thorough evaluation to establish their utility in a clinical setting. This paper describes an evaluation of' several established enzyme markers of Gaucher disease and a newly-described chemokine, pulmonary and activation-regulated chemokine (PARC). The ability of the biomarkers to rank patients with Gaucher disease in order of disease severity and organ bulk, and to reflect changes in key clinical parameters in response to enzyme replacement therapy were evaluated. PARC concentrations were found to be reliably correlated with visceral disease and with key clinical responses to enzyme replacement in an unbiased manner. Unlike chitotriosidase and serum angiotensin-converting enzyme activity, genetic variation in serum PARC did not appear to influence its utility as a biomarker. Conclusion: For each new candidate biomarker of lysosomal storage diseases, a similar clinical evaluation will be required, though the approach will need to he modified according to the clinical features and natural history of each disorder. [ABSTRACT FROM AUTHOR]

A biomarker is generally an analyte that indicates the presence or extent of a biological process, which is itself directly linked to the clinical manifestations and outcome of a particular disease. An ideal biomarker provides indirect but ongoing and specific determinations of disease activity. These characteristics emphasize the value of surrogate biomarkers for non-invasive and detailed monitoring to demonstrate the efficacy of orphan drugs in clinical trials. The emergence of novel laboratory methods has facilitated the search for biomarkers in lysosomal storage diseases (LSDs), by allowing the systematic identification of molecules whose expression is altered as a result of the primary storage pathology. In Gaucher disease, for example, a chemokine, CCLI 8, has been identified as a biomarker for clinical development that reflects disease severity and response to treatment. Conclusion: New methods for the identification of novel biomarkers have the potential to provide mechanistic insights into the molecular pathogenesis of LSDs, including Fabry disease and Gaucher disease. [ABSTRACT FROM AUTHOR]

Anderson-Fabry disease (referred to as Fabry disease) is an X-linked disorder characterized by a deficiency of the lysosomal enzyme α-galactosidase A and the subsequent accumulation in various tissues of globotriaosylceramide (Gb3), the main substrate of the defective enzyme. Enzyme replacement therapy (ERT) offers a specific treatment for patients with Fabry disease, though monitoring of treatment is hampered by a lack of surrogate markers of response. In this study, the efficacy of long-term ERT in six Fabry hemizygotes and two symptomatic heterozygotes has been evaluated. Patients were administered recombinant α-galactosidase A every 2 weeks for up to a year. The efficacy of ERT was assessed by monitoring symptomatology and renal function. Urinary glycolipid concentration was estimated by a novel tandem mass spectrometric method. Urine glycolipid (Gb3) was elevated at baseline and fell impressively on ERT where patients were hemizygotes and in the absence of renal transplantation. In heterozygotes and in a recipient of a renal allograft, elevations and changes in urine glycolipids were less pronounced. In one patient, after several months of ERT, there was a transient increase in Gb3 concentrations to baseline (pre-ERT) levels, associated with the presence of antibodies to the recombinant α-galactosidase A. The marked decline in urine Gb3 on ERT, and its subsequent increase in association with an inhibitory antibody response, suggest that this analyte deserves further investigation as a potential marker of disease severity and response to treatment. [ABSTRACT FROM AUTHOR]

Summary: It has been shown that treatment with miglustat (Zavesca, N-butyldeoxynojirimycin, OGT 918) improves key clinical features of type I Gaucher disease after 1 year of treatment. This study reports longer-term efficacy and safety data. Patients who had completed 12 months of treatment with open-label miglustat (100-300 mg three times daily) were enrolled to continue with therapy in an extension study. Data are presented up to month 36. Liver and spleen volumes measured by CT or MRI were scheduled every 6 months. Biochemical and haematological parameters, including chitotriosidase activity (a sensitive marker of Gaucher disease activity) were monitored every 3 months. Safety data were also collected every 3 months. Eighteen of 22 eligible patients at four centres entered the extension phase and 14 of these completed 36 months of treatment with miglustat. After 36 months, there were statistically significant improvements in all major efficacy endpoints. Liver and spleen organ volumes were reduced by 18% and 30%, respectively. In patients whose haemoglobin value had been below 11.5 g/dl at baseline, mean haemoglobin increased progressively from baseline by 0.55 g/dl at month 12 (NS), 1.28 g/dl at month 24 ( p=0.007), and 1.30 g/dl at month 36 ( p=0.013). The mean platelet count at month 36 increased from baseline by 22×109/L. No new cases of peripheral neuropathy occurred since previously reported. Diarrhoea and weight loss, which were frequently reported during the initial 12-month study, decreased in magnitude and prevalence during the second and third years. Patients treated with miglustat for 3 years show significant improvements in organ volumes and haematological parameters. In conclusion, miglustat was increasingly effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years. [ABSTRACT FROM AUTHOR]

Cox TC. Taking it to the max: The genetic and developmental mechanisms coordinating midfacial morphogenesis and dysmorphology. The rapid proliferative expansion and complex morphogenetic events that coordinate the development of the face underpin the sensitivity of this structure to genetic and environmental insult and provide an explanation for the high incidence of midfacial malformation. Most notable of these malformations is cleft lip with or without cleft palate (CLP) that, with an incidence of between one in 600 and one in 1000 live births, is the fourth most common congenital disorder in humans. Despite the obvious global impact of the disorder and some recent progress in identifying causative genes for some prominent syndromal forms, our knowledge of the key genetic factors contributing to the more common isolated cases of CLP is still remarkably patchy. The current understanding of the molecular and cellular processes that orchestrate morphogenesis of the midface, with emphasis on events leading to fusion of the lip and primary palate, is detailed in this review. The roles of crucial factors identified from relevant animal model systems, including BMP4 and SHH, and the likely events perturbed by key genes pinpointed in human studies [such as PVRL1, IRF6 p63, MID1, MSX1, and PTCH1] are discussed in this light. New candidates for human CLP genes are also proposed. [ABSTRACT FROM AUTHOR]

N-Butyldeoxynojirimycin (NB-DNJ, miglustat 'Zavesca') is an orallyactive iminosugar which inhibits the biosynthesis of macromolecular substrates that accumulate pathologically in glycosphingolipidoses. Clinical trials of NB-DNJ in patients with Gaucher's disease demonstrate the therapeutic potential of such substrate inhibitors in the glycolipid storage disorders. However, macrophage-targetted enzyme replacement using intravenous mannose-terminated human glucocerebrosidase (imiglucerase, Cerezyme) is highly effective in ameliorating many of the manifestations of Gaucher's disease and is a treatment in widespread use. Given that imiglucerase and miglustat are now both licensed for the treatment of Gaucher's disease, there is a need to review their therapeutic status. Here the treatment of type 1 (non-neuronopathic) Gaucher disease is evaluated with particular reference to the emerging role of oral N-butyldeoxynojirimycin (miglustat) as a substrate-reducing agent. This position statement represents the consensus viewpoint of an independent international advisory council to the European Working Group on Gaucher Disease. [ABSTRACT FROM AUTHOR]

Gaucher disease is a typical lysosomal storage disease, resulting from an inborn deficiency of glucocerebrosidase. This leads to the accumulation of glycolipidsin macrophages, particularly those in the liver, bone marrow, spleen and lung. In addition, disease of the nervous system can arise as a result of the accumulation of endogenous glycosphingolipid metabolites in brain tissue. About 150 mutations of the glucocerebrosidase gene have been identified in patients with Gaucher disease, some of which are predictive of phenotype. However, even patients and siblings with the same mutation, including monozygotic twins, may exhibit marked variability in disease expression and severity, illustrating our lack of understanding of thephenotype–genotype relationship in the sphingolipidoses. Massive organomegaly, particularly of the spleen, is a frequent feature of the disease. Although the liver and spleen may increase greatly in size, the amount of pathological lipid stored in the affected macrophages (Gaucher cells) accounts for less than 2% of the additional tissue mass. It is therefore clear that an inflammatory response occurs in affected individuals and that the clinical phenotype is due to an effect of macrophage storage beyond the physical presence of the Gaucher cells. Factors released by Gaucher cells, including pro-inflammatory cytokines and perhaps cathepsins, provide a mechanistic link between lysosomal storage and the diverse clinical manifestations of Gaucher disease. Emerging proteomic technology and gene expression profiling should not only improve our understanding of pathogenesis but also offer the prospect of identifying novel biomarkers that can be used as surrogate measures of disease activity and responses to treatment. [ABSTRACT FROM AUTHOR]

The glycosphingolipid (GSL) lysosomal storage diseases are caused by mutations in the genes encoding the glycohydrolases that catabolize GSLs within lysosomes. In these diseases the substrate for the defective enzyme accumulates in the lysosome and the stored GSL leads to cellular dysfunction and disease. The diseases frequently have a progressive neurodegenerative course. The therapeutic options for treating these diseases are relatively limited, and for the majority there are no effective therapies. The problem is further compounded by difficulties in delivering therapeutic agents to the brain. Most research effort to date has focused on strategies for augmenting enzyme levels to compensate for the underlying defect. These include bone marrow transplantation (BMT), enzyme replacement and gene therapy. An alternative strategy that we have been exploring is substrate deprivation. This approach aims to balance the rate of GSL synthesis with the impaired rate of GSL breakdown. The imino sugar N-butyldeoxynojirimycin (NB-DNJ) inhibits the first step in GSL biosynthesis and has been used to evaluate this approach. Studies in an asymptomatic mouse model of Tay–Sachs disease have shown that substrate deprivation prevents GSL storage in the CNS. In a severe neurodegenerative mouse model of Sandhoff disease, substrate deprivation delayed the onset of symptoms and disease progression and significantly increased life expectancy. Combining NB-DNJ and BMT was found to be synergistic in the Sandhoff mouse model. A clinical trial in type I Gaucher disease has been undertaken and has shown beneficial effects. Efficacy was demonstrated on the basis of significant decreases in liver and spleen volumes, gradual but significant improvement in haematological parameters and disease activity markers, together with diminished GSL biosynthesis and storage as determined by independent biochemical assays. Further trials in type I Gaucher disease are in progress; studies are planned in patients with GSL storage in the CNS. [ABSTRACT FROM AUTHOR]

Summary Tartrate-resistant acid phosphatase (TRAP) is a lysosomal di-iron protein of mononuclear phagocytes and osteoclasts. Hitherto, no role for the enzyme in immunity has been identified; however, knockout mice lacking TRAP have a skeletal phenotype caused by an intrinsic osteoclast defect. To investigate a putative function for TRAP in macrophages (Mφ), we investigated proinflammatory responses and systemic microbial clearance in knockout mice compared with age- and gender-matched congenic wild-type mice. Phorbol 12-myristate 13-acetate (PMA)-stimulated and interferon-γ (IFN-γ)-induced superoxide formation was enhanced in peritoneal Mφ lacking TRAP; nitrite production in response to stimulation with lipopolysaccharide (LPS) and IFN-γ was also increased. In addition, secretion of the proinflammatory cytokines, tumour necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-12, was significantly greater in TRAP-deficient Mφ when stimulated with LPS, with or without addition of either TNF-α or IFN-γ. The activity of tartrate-sensitive (lysosomal) acid phosphatase was increased in Mφ from the knockout mice but activities of the lysosomal hydrolases N-acetyl β-glucosaminidase and acid β-glucuronidase were unchanged, indicating selective activation of compensatory acid phosphatase activity. Evidence of impaired Mφ function in vivo was obtained in TRAP knockout mice, which showed delayed clearance of the microbial pathogen, Staphylococcus aureus, after sublethal intraperitoneal inoculation. After microbial challenge, peritoneal exudates obtained from TRAP knockout mice had a reduced population of Mφ. As peritoneal Mφ and neutrophils lacking TRAP were able to phagocytose and kill S. aureus normally in vitro, TRAP may directly or indirectly influence recruitment of Mφ to sites of microbial invasion. Our study shows that TRAP participates in the inflammatory response of the Mφ... [ABSTRACT FROM AUTHOR]

Physiological and psychological instruments were used in the measurement of stress in an occupational training situation. The physiological instrument, the measurement of capilliary blood glucose levels, showed a progressive increase throughout the period of the exercise being observed. The psychological instrument, a stress and arousal adjective checklist (SACL), showed no significant changes in arousal but did show a significant drop in the level of reported stress across the task period. Correlational analysis permits the construction of a model which describes the relationship between the measures and also the results obtained. Changes in the training course are suggested which may alleviate some of the stressfulness perceived by the trainees. [ABSTRACT FROM AUTHOR]

The bottleneck restricting introgression of useful genes directly from diploid into hexaploid wheats is the low number of BC1F1 seeds obtained. In crosses between hexaploid wheat (Triticum aestivum L.; AABBDD) and Aegilops squarrosa L. (DD) or T. urartu Thum. (AA), this bottleneck may be over- come simply by pollinating a sufficient number of F1 spikes. However, hybrids between hexaploid wheat cultivars (T. aestivuin) and T. monococcum L. (AA) generally are highly female-sterile, often having no pistils. One T. monococcum accession, PT 355520, when crossed with T. aestivum, produced hybrids with female fertility in the same range as that of T. aestivum/A. squarrosa or T. aestivum./urartu hybrids, ca. 0.5 to 1.0 backcross seed per spike. We found that female fertility was controlled by two duplicate genes in PI 355520, and that this accession can be used as a bridging parent to introgress genes from other T. monococcum accessions into hexaploid wheat. Pairing of homologous chromosomes was less frequent and weaker in such crosses than in T. aestivutm/A. squarrosa crosses, but homoeologous bivalents occurred at a rate of almost 0.5 II per ceil. Restitution division was detected in crosses involving all three diploid species and was confirmed cytologically in crosses with PT 355520. Chromosome numbers of BC1F1 plants ranged from 35 to 67; plants with 49 or more chromosomes occurred at frequencies of 0.09 to 0.21 among progeny of A. squarrosa and T. urartu and 0.29 in progeny of A. squarrosa/T. urartu crosses involving PI 355520. These results are consistent with those of previous studies, demonstrating the potential of direct hexaploid/diploid crosses for rapidly introgressing useful genes into hexaploid wheat with minimum disturbance of the background genotype. [ABSTRACT FROM AUTHOR]

Patterns of seedling emergence of ten weed species from soil cultivated at intervals of approximately one month are described. All species examined showed clearly defined emergence patterns. Polygonum persicaria L. seedlings emerged in spring and early summer. Seedlings of Chenopodium album agg., Portulaca oleracea L. and Solanum nigrum L. emerged in late spring, summer and early autumn. Plantago major L., Rumex spp. (mostly R. obtusifolius L.) and Trifolium spp. (mostly T. repens L.) emerged mostly in spring and early summer. Coronopus didymus (L.) Sm. and Juncus bufonius L. tended to emerge in both autumn and spring. Veronica persica Poir, emerged in spring, summer and autumn. Close similarity between emergence patterns in New Zealand and northern Europe, despite differences in rainfall and temperature, suggests that annual dormancy: nondormancy cycles of seeds buried in the soil are largely responsible for seedling emergence patterns. In New Zealand, seedling emergence tended to be more spread out than in Europe, although seasonal patterns were still distinct. Further work on dormancy cycles in these species would be useful, as would a comparison of the factors inducing and breaking dormancy of comparable seed populations in northern and southern Europe and New Zealand. When seeds were left buried for several years before being encouraged to germinate, seedling emergence patterns tended to be of smaller amplitude, although the overall patterns were still very similar. [ABSTRACT FROM AUTHOR]

The long-term effect of different depths of soil cultivation on weed seedling emergence from naturally occurring populations of weed seeds in the soil was examined in four experiments on land previously in pasture, raspberry canes or intensive vegetable production. At approximately monthly intervals, weed seedlings were counted and then killed with contact herbicides, after which plots were cultivated to 250 or 10 mm, or were left undisturbed. The treatments were continued for 7 years. One experiment was then discontinued whilst the previously uncultivated plots on the other three were cultivated to 150 mm at approximately monthly intervals for a further 4 years in one experiment, and for 8 years in the other two. After the first year, very few seedlings emerged in the uncultivated and shallow cultivated plots, and seedling numbers declined slowly in the deep-cultivated plots. Under repeated deep cultivation, seedling emergence of almost all species declined exponentially. Different species declined at different rates, with Rubus idaeus L., Plantago lanceolata L., Veronica arvensis L. and Ranunculus spp. being the most rapidly declining group. Rates of decline for individual species were similar to those observed in Europe. Juncus bufonius L. behaved differently from the other species, and showed no decline in seedling numbers. In the initial 7-year period, 28 000 weed seedlings per m-² emerged from the deep-cultivated plots on soil previously cropped with vegetables. Over the same period, less than 11 000 seedlings emerged in shallow-cultivated plots, and just over 4000 in uncultivated plots. In the second phase of the experiments, fewer seedlings of most species emerged than in the first phase, and the decline in numbers of Coronpous didymus (L.) Sm. seedlings was slower. [ABSTRACT FROM AUTHOR]

Partial deficiency of the last enzyme of haem biosynthesis, ferrochelatase, leads to a distinct syndrome of photosensitivity caused by overproduction of protoporphyrin by erythropoietic tissue. Erythropoietic protoporphyria has an indeterminate pattern of inheritance and may be complicated by fulminating liver disease. The recent development of simple assays for ferrochelatase activity and cloning of the human ferrochelatase gene promises to shed light on the transmission of this disorder and may allow clinical expression of disease to be predicted. This review surveys the pathological features, genetics and treatment of porphyria. [ABSTRACT FROM AUTHOR]

The wild tetraploid wheat species Triticum timopheevii (Zhuk.) Zhuk. var. araraticum is a source of pest resistance genes for Triticum aestivum L. Our objectives were to describe the breeding bebhaviour of T. araraticum when backcrossed to common wheat, and to transfer resistant to leaf rust (caused by Puccinia recondite f.sp. tritici) and powdery mildew (caused by Blumeria graminis f.sp. tritici) to wheat. Crosses were made between five wheat gentoypes and 12 T. araraticum accessions. Fertility and chromosome numbers of BC1F1, BC2F1, and BC3F1 plants were determined. Resistance to leaf rust was transferred to BC2-derived families from 10 different T. araraticum accessions. Leaf rust resistance genes in nine T. araraticum accessions can be assigned to at least four loci. Leaf rust resistance transferred from three accessions was inherited in the hexaploid derivatives as a single, dominant gene in each case. Resistance to powdery mildew was also detected in the T. araraticum backcross derivatives. Fertile hexaploid derivatives expressing T. araraticum-derived resistance genes can be recovered after two backcrosses to wheat cultivars. [ABSTRACT FROM AUTHOR]

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Copyright of Weed Research is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)