Aquatic contaminants in Solomon Islands and Vanuatu: Evidence from passive samplers and Microtox toxicity assessment.

Water Quality issues in many Pacific countries are rising, with the increase in coastal populations and associated urban runoff but management requires contamination issues in the aquatic environment to be identified and prioritised. In Vanuatu and Solomon Islands there are few laboratories and resources to assess for the presence or impact of complex chemical contaminants. The extent and impact of chemical contamination of the marine and coastal environment is poorly described. Passive chemical samplers were used to measure a range of aquatic pollutants around the capital cities, Honiara (Solomon Islands) and Port Vila (Vanuatu). We detected a range of chemicals indicative of agricultural and industrial contamination and a few sites had concerning concentrations of specific hydrocarbons and pesticides. The rapid ecotoxicology test, Microtox, indicated toxic impacts in rivers, coastal sites and urban drains This work provides new data on chemical contamination and possible impacts of that contamination for both countries. The techniques could be applied widely across the region to generate critical data for environmental management, guide monitoring efforts and measure the impact of policy or land-use changes.

Quasi-Isotropic and Pseudo-Ductile Highly Aligned Discontinuous Fibre Composites Manufactured with the HiPerDiF (High Performance Discontinuous Fibre) Technology.

Conventional composite materials reinforced with continuous fibres display high specific strength but have a number of drawbacks including: the elastic-brittle behaviour, difficulties in producing defect-free components of complex shape with high-volume automated manufacturing processes, and inherent lack of recyclability. Highly aligned, discontinuous fibre-reinforced composites (ADFRCs) are truly beneficial for mass production applications, with the potential to offer better formability and comparable mechanical properties with continuous fibre-reinforced composites. In previous publications, the High Performance Discontinuous Fibre (HiPerDiF) technology has been shown to offer the possibility to intimately hybridise different types of fibres, to achieve pseudo-ductile tensile behaviour, and remanufacture reclaimed fibres into high-performance recycled composites. However, to date, the work has been conducted with unidirectional (UD) laminates, which is of limited interest in engineering applications with mechanical stresses acting across many directions; this paper reports, for the first time, the mechanical behaviour of quasi-isotropic (QI) ADFRCs. When compared with randomly-oriented discontinuous fibre composites (RODFRCs), QI ADFRCs offer enhanced stiffness (+26%) and strength (+77%) with higher consistency, i.e., a reduction of the coefficient of variance from the 25% of RODFRCs to the 6% of ADFRCs. Furthermore, hybrid QI ADFRCs retain the pseudo-ductility tensile behaviour previously observed in unidirectional (UD) lay-up.

The convergence of regenerative medicine and rehabilitation: federal perspectives.

Regenerative rehabilitation is the synergistic integration of principles and approaches from the regenerative medicine and rehabilitation fields, with the goal of optimizing form and function as well as patient independence. Regenerative medicine approaches for repairing or replacing damaged tissue or whole organs vary from utilizing cells (e.g., stem cells), to biologics (e.g., growth factors), to approaches using biomaterials and scaffolds, to any combination of these. While regenerative medicine offers tremendous clinical promise, regenerative rehabilitation offers the opportunity to positively influence regenerative medicine by inclusion of principles from rehabilitation sciences. Regenerative medicine by itself may not be sufficient to ensure successful translation into improving the function of those in the most need. Conversely, with a better understanding of regenerative medicine principals, rehabilitation researchers can better tailor rehabilitation efforts to accommodate and maximize the potential of regenerative approaches. Regenerative rehabilitative strategies can include activity-mediated plasticity, exercise dosing, electrical stimulation, and nutritional enhancers. Critical barriers in translating regenerative medicine techniques into humans may be difficult to overcome if preclinical studies do not consider outcomes that typically fall in the rehabilitation research domain, such as function, range of motion, sensation, and pain. The authors believe that encouraging clinicians and researchers from multiple disciplines to work collaboratively and synergistically will maximize restoration of function and quality of life for disabled and/or injured patients, including U.S. Veterans and Military Service Members (MSMs). Federal Government agencies have been investing in research and clinical care efforts focused on regenerative medicine (NIH, NSF, VA, and DoD), rehabilitation sciences (VA, NIH, NSF, DoD) and, more recently, regenerative rehabilitation (NIH and VA). As science advances and technology matures, researchers need to consider the integrative approach of regenerative rehabilitation to maximize the outcome to fully restore the function of patients.

Metastatic endometrial cancer of the paranasal sinuses.

Endometrial carcinoma is the fourth most common cancer affecting women in the UK. Its most frequent sites of spread are to the pelvic and para-aortic lymph nodes, vagina and peritoneum. We report a case of a 63-year-old woman with known endometrial cancer who presented with left facial swelling and eye displacement. Investigations revealed an expansile soft-tissue density mass arising within the bone, centred on the left zygoma, with exophytic extension into the left maxillary antrum, infratemporal fossa and inferiorly into the orbit. Endoscopic biopsies were taken and histology confirmed metastatic deposits of endometrial cancer. Clinicians should be aware that distant spread of endometrial cancer is linked with advanced disseminated disease and palliative treatments should be considered.

THE EFFECTS OF THE ALKALOID SCOPOLAMINE ON THE PERFORMANCE AND BEHAVIOR OF TWO CATERPILLAR SPECIES.

Plants have evolved many defenses against insect herbivores, including numerous chemicals that can reduce herbivore growth, performance, and fitness. One group of chemicals, the tropane alkaloids, is commonly found in the nightshade family (Solanaceae) and has been thought to reduce performance and fitness in insects. We examined the effects of the tropane alkaloid scopolamine, the alkaloid constituent of Datura wrightii, which is the most frequent host plant for the abundant and widespread insect herbivore Manduca sexta in the southwestern United States. We exposed caterpillars of two different species to scopolamine: M. sexta, which has a shared evolutionary history with Datura and other solanceous plants, and Galleria mellonella, which does not. We showed that the addition of ecologically-realistic levels of scopolamine to both the diet and the hemolymph of these two caterpillar species (M. sexta and G. mellonella) had no effect on the growth of either species. We also showed that M. sexta has no behavioral preference for or against scopolamine incorporated into an artificial diet. These results are contrary to other work showing marked differences in performance for other insect species when exposed to scopolamine, and provide evidence that scopolamine might not provide the broad-spectrum herbivore resistance typically attributed to it. It also helps to clarify the coevolutionary relationship between M. sexta and one of its main host plants, as well as the physiological mechanism of resistance against scopolamine.

Medication appropriateness tool for co-morbid health conditions in dementia: consensus recommendations from a multidisciplinary expert panel.

BACKGROUND: Medication management for people living with dementia is a complex task as it is unclear what constitutes optimal medication management in this population due to the shifting focus of health priorities and the balance between the benefits and harms of medications. AIM: This study sought expert opinion to create a consensus list to define appropriate medication management of co-morbidities for people with dementia. METHODS: This study used the Delphi technique. We invited multidisciplinary experts in geriatric therapeutics including pharmacists, doctors, nurse practitioners, a patient advocate and a psychologist to participate. Participants were asked to engage into three or more rounds of questioning. Round 1 was a questionnaire comprised of one question defining dementia and seven open-ended questions about appropriate management of co-morbidities in people with dementia. Two investigators qualitatively analysed the responses to questions from Round 1 using thematic analysis. The results of this analysis were provided to participants as statements in the Round 2 survey. The participants were asked to rate their agreement with each statement on a 5-point Likert scale. The median and interquartile range (IQR) were calculated for the responses to each statement. Consensus was pre-specified as an IQR less than or equal to 1. Statements where consensus was not achieved were presented to participants in Round 3. The Round 2 median and IQR values were provided and participants were again asked to rate their agreement with each statement on a 5-point Likert scale. The statements where participants agreed or strongly agreed were included in the Medication Appropriateness Tool for Co-morbid Health conditions in Dementia criteria. RESULTS: Fifty-seven experts agreed to participate in the study, of whom 58% were pharmacists and 36% were medical practitioners. Fifty-five participants completed the Round 1 (95% response rate). A total of 128 statements was included in the Round 2 survey. Consensus was reached on 93 statements in Round 2 (n = 48 responders, 84% response rate) and on 18 statements in Round 3 (n = 43 responders, 75% response rate). The participants reached consensus on 111 of 128 statements. Of these statements, 67 statements were included in the Medication Appropriateness Tool for Co-morbid Health conditions in Dementia criteria. The statements were in the broad themes of preventative medication, symptom management, disease progression, psychoactive medication, treatment goals, principles of medication use, side-effects and medication reviews. DISCUSSION: This research provides consensus-based guidance for clinicians who manage co-morbid health conditions in people with dementia.

Efficient heterocyclisation by (di)terpene synthases.

While cyclic ether forming terpene synthases are known, the basis for such heterocyclisation is unclear. Here it is reported that numerous (di)terpene synthases, particularly including the ancestral ent-kaurene synthase, efficiently produce isomers of manoyl oxide from the stereochemically appropriate substrate. Accordingly, such heterocyclisation is easily accomplished by terpene synthases. Indeed, the use of single residue changes to induce production of the appropriate substrate in the upstream active site leads to efficient bifunctional enzymes producing isomers of manoyl oxide, representing novel enzymatic activity.

Amyloid formation in human islets is enhanced by heparin and inhibited by heparinase.

Islet transplantation is a promising therapy for patients with diabetes, but its long-term success is limited by many factors, including the formation of islet amyloid deposits. Heparin is employed in clinical islet transplantation to reduce clotting but also promotes fibrillization of amyloidogenic proteins. We hypothesized that heparin treatment of islets during pre-transplant culture may enhance amyloid formation leading to beta cell loss and graft dysfunction. Heparin promoted the fibrillization of human islet amyloid polypeptide (IAPP) and enhanced its toxicity to INS-1 beta cells. Heparin increased amyloid deposition in cultured human islets, but surprisingly decreased islet cell apoptosis. Treatment of human islets with heparin prior to transplantation increased the likelihood of graft failure. Removal of islet heparan sulfate glycosaminoglycans, which localize with islet amyloid deposits in type 2 diabetes, by heparinase treatment decreased amyloid deposition and protected against islet cell death. These findings raise the possibility that pretransplant treatment of human islets with heparin could potentiate IAPP aggregation and amyloid formation and may be detrimental to subsequent graft function.

Bighorn sheep × domestic sheep hybrids survive Mannheimia haemolytica challenge in the absence of vaccination.

Bighorn sheep (BHS, Ovis canadensis) are much more susceptible than domestic sheep (DS, Ovis aries) to pneumonia caused by leukotoxin (Lkt)-producing members of the Family Pasteurellaceae, particularly Mannheimia haemolytica and Bibersteinia trehalosi. Leukotoxin is widely accepted as the critical virulence factor of these bacteria since Lkt-negative mutants do not cause death of BHS. Typically, DS carry Lkt-positive M. haemolytica and/or B. trehalosi as commensal bacteria in their nasopharynx. In contrast, most BHS do not carry Lkt-positive M. haemolytica or B. trehalosi, or carry Lkt-negative strains in their nasopharynx. In previous studies, we demonstrated that unimmunized DS resist M. haemolytica challenge while BHS succumb to it. We hypothesized that Lkt-neutralizing antibodies, induced by Lkt-positive M. haemolytica and/or B. trehalosi innately carried by DS in their nasopharynx, render them less susceptible to infection by these bacteria. In this study we developed BHS×DS F1 hybrids by artificial insemination of domestic ewes with BHS semen. F1 hybrids were fertile, and produced F2 hybrids and back-crosses. The F1, F2, and back-crosses were raised together with domestic ewes. All these animals acquired Lkt-positive M. haemolytica and/or B. trehalosi, and developed high titers of Lkt-neutralizing antibodies in the absence of vaccination. Furthermore, all of these animals resisted challenge with lethal dose of M. haemolytica. These results suggest that lack of previous exposure to Lkt is at least partially responsible for fatal pneumonia in BHS when they acquire Lkt-positive M. haemolytica and/or B. trehalosi from DS when the two species commingle.

A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma.

Dysregulated expression of factors that control protein synthesis is associated with poor prognosis of many cancers, but the underlying mechanisms are not well defined. Analysis of the diffuse large B-cell lymphoma (DLBCL) translatome revealed selective upregulation of mRNAs encoding anti-apoptotic and DNA repair proteins. We show that enhanced synthesis of these proteins in DLBCL is mediated by the relief of repression that is normally imposed by structure in the 5'-untranslated regions of their corresponding mRNAs. This process is driven by signaling through mammalian target of rapamycin, resulting in increased synthesis of eukaryotic initiation factor (eIF) 4B complex (eIF4B), a known activator of the RNA helicase eIF4A. Reducing eIF4B expression alone is sufficient to decrease synthesis of proteins associated with enhanced tumor cell survival, namely DAXX, BCL2 and ERCC5. Importantly, eIF4B-driven expression of these key survival proteins is directly correlated with patient outcome, and eIF4B, DAXX and ERCC5 are identified as novel prognostic markers for poor survival in DLBCL. Our work provides new insights into the mechanisms by which the cancer-promoting translational machinery drives lymphomagenesis.

The c.7409G>A (p.Cys2470Tyr) Variant of FBN1: Phenotypic Variability across Three Generations.

Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin gene FBN1, which encodes an extracellular matrix glycoprotein. Major features of Marfan syndrome occur in the ocular, cardiovascular, and skeletal systems as well as in the dura mater. Approximately 60% of known disease-causing mutations are missense mutations of single amino acid residues. Effects on the cardiovascular system are classically associated with mutations in exons 24-32 of the 65 FBN1 exons and many, though not all, reports associate missense mutations in exons 59-65 with a mild cardiovascular phenotype. Here we present 5 related individuals among whom a c.7409G>A (p.Cys2470Tyr) missense variant in exon 59 of FBN1 is associated with significant cardiovascular features. The index case also had an apparently de novo 46,XX,del(5)(q33.1q33.3) deletion on chromosome 5. This family demonstrates skeletal, dermatological and neurological features consistent with Marfan syndrome but lacks significant ophthalmological findings to date. These findings suggest that FBN1 C-terminal missense mutations may not confer the ophthalmological features of Marfan syndrome, but they also confer a more significant risk for cardiovascular pathology than that suggested by previous studies. Furthermore, clinical data from this family supports the previously reported association of dural ectasia with C-terminal mutations.

Metabolic stress, IAPP and islet amyloid.

Amyloid forms within pancreatic islets in type 2 diabetes from aggregates of the ß-cell peptide islet amyloid polypeptide (IAPP). These aggregates are toxic to ß-cells, inducing ß-cell death and dysfunction, as well as inciting islet inflammation. The ß-cell is subject to a number of other stressors, including insulin resistance and hyperglycaemia, that may contribute to amyloid formation by increasing IAPP production by the ß-cell. ß-Cell dysfunction, evident as impaired glucose-stimulated insulin secretion and defective prohormone processing and exacerbated by metabolic stress, is also a likely prerequisite for islet amyloid formation to occur in type 2 diabetes. Islet transplants in patients with type 1 diabetes face similar stressors, and are subject to rapid amyloid formation and impaired proinsulin processing associated with progressive loss of ß-cell function and mass. Declining ß-cell mass is predicted to increase metabolic demand on remaining ß-cells, promoting a feed-forward cycle of ß-cell decline.

Reverse engineering an amyloid aggregation pathway with dimensional analysis and scaling.

Human islet amyloid polypeptide (hIAPP) is a cytotoxic protein that aggregates into oligomers and fibrils that kill pancreatic ß-cells. Here we analyze hIAPP aggregation in vitro, measured via thioflavin-T fluorescence. We use mass-action kinetics and scaling analysis to reconstruct the aggregation pathway, and find that the initiation step requires four hIAPP monomers. After this step, monomers join the nucleus in pairs, until the first stable nucleus (of size approximately 20 monomers) is formed. This nucleus then elongates by successive addition of single monomers. We find that the best-fit of our data is achieved when we include a secondary fibril-dependent nucleation pathway in the reaction scheme. We predict how interventions that change rates of fibril elongation or nucleation rates affect the accumulation of potentially cytotoxic oligomer species. Our results demonstrate the power of scaling analysis in reverse engineering biochemical aggregation pathways.

Immunoglobulin sequence analysis and prognostication in CLL: guidelines from the ERIC review board for reliable interpretation of problematic cases.

Immunoglobulin gene sequence analysis is widely utilized for prognostication in chronic lymphocytic leukemia (CLL) and the definition of standardized procedures has allowed reliable and reproducible results. Occasionally, a straightforward interpretation of the sequences is not possible because of the so-called 'problematic sequences' that do not fit the 'classic' interpretation and pose scientific questions at the cross-road between hematology and immunology. Thanks to a dedicated effort within the European Research Initiative on CLL (ERIC), we have now the possibility to present such cases, offer a scientific explanation and propose recommendations in terms of prognostication.

Spina bifida with associated malformations of the central nervous system in Dorper-cross sheep.

CASE HISTORY: In 2008, six lambs within a flock of Dorper-cross sheep were born with musculoskeletal and neurological disease. Clinical signs included hindlimb weakness, and urinary incontinence. CLINICAL FINDINGS: All lambs had focal, inverted areas of alopecic skin over the caudal sacrum, and short, often kinked tails. Four affected lambs were subject to euthanasia, and necropsied. On gross examination, the arches of sacral vertebrae were absent, and spinal nerves and meninges were adherent to the overlying subcutis. Other gross lesions included narrow, elongated skulls, herniation of the occipital lobes into the caudal fossas, hydrocephalus, and syringomyelia. One lamb had coning of the cerebellar vermis, but cerebellar herniation through the foramen magnum was not identified. DIAGNOSIS: Spina bifida, with associated malformations of the central nervous system. CLINICAL RELEVANCE: Examination of breeding records suggested either an autosomal recessive or partially penetrant autosomal dominant pattern of inheritance. Because of the associated tail lesions it is proposed that the pathogenesis of this syndrome involves a defect in development of the tail bud (secondary neurulation), that tethering of the spinal cord resulted in the clinical signs, and abnormal pressure of the cerebral spinal fluid resulted in the defects in the skull and brain.

The continued development of the Spallation Neutron Source external antenna H- ion source.

The U.S. Spallation Neutron Source (SNS) is an accelerator-based, pulsed neutron-scattering facility, currently in the process of ramping up neutron production. In order to ensure that the SNS will meet its operational commitments as well as provide for future facility upgrades with high reliability, we are developing a rf-driven, H(-) ion source based on a water-cooled, ceramic aluminum nitride (AlN) plasma chamber. To date, early versions of this source have delivered up to 42 mA to the SNS front end and unanalyzed beam currents up to approximately 100 mA (60 Hz, 1 ms) to the ion source test stand. This source was operated on the SNS accelerator from February to April 2009 and produced approximately 35 mA (beam current required by the ramp up plan) with availability of approximately 97%. During this run several ion source failures identified reliability issues, which must be addressed before the source re-enters production: plasma ignition, antenna lifetime, magnet cooling, and cooling jacket integrity. This report discusses these issues, details proposed engineering solutions, and notes progress to date.

Toxic oligomers and islet beta cell death: guilty by association or convicted by circumstantial evidence?

Type 2 diabetes is a progressive disease characterised by islet amyloid deposits in the majority of patients. Amyloid formation is considered a significant factor in deterioration of islet function and reduction in beta cell mass, and involves aggregation of monomers of the normally soluble beta cell peptide, human islet amyloid polypeptide (hIAPP) into oligomers, fibrils and, ultimately, mature amyloid deposits. Despite extensive in vitro studies, the process of hIAPP aggregation in vivo is poorly understood, though it is widely reported to promote cytotoxicity. Recently, studies have suggested that only the early stages of fibril assembly, and in particular small hIAPP oligomers, are responsible for beta cell cytotoxicity. This challenges the prior concept that newly formed fibrils and/or mature fibrillar amyloid are cytotoxic. Herein, evidence both for and against the toxic hIAPP oligomer hypothesis is presented; from this, it is apparent that what exactly causes beta cell death when hIAPP aggregates remains debatable. Moreover, substantially more work with more specific reagents and techniques than are currently available will be required to identify conclusively the toxic species resulting from hIAPP aggregation. Keeping an open mind on the nature of the cytotoxic insult has implications for therapeutic developments and clinical care in type 2 diabetes.

Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts.

Islet transplantation is a promising treatment for diabetes but long-term success is limited by progressive graft loss. Aggregates of the beta cell peptide islet amyloid polypeptide (IAPP) promote beta cell apoptosis and rapid amyloid formation occurs in transplanted islets. Porcine islets are an attractive alternative islet source as they demonstrate long-term graft survival. We compared the capacity of transplanted human and porcine islets to form amyloid as an explanation for differences in graft survival. Human islets were transplanted into streptozotocin-diabetic immune-deficient mice. Amyloid deposition was detectable at 4 weeks posttransplantation and was associated with islet graft failure. More extensive amyloid deposition was observed after 8 weeks. By contrast, no amyloid was detected in transplanted neonatal or adult porcine islets that had maintained normoglycemia for up to 195 days. To determine whether differences in IAPP sequence between humans and pigs could explain differences in amyloid formation and transplant viability, we sequenced porcine IAPP. Porcine IAPP differs from the human sequence at 10 positions and includes substitutions predicted to reduce its amyloidogenicity. Synthetic porcine IAPP was considerably less amyloidogenic than human IAPP as determined by transmission electron microscopy, circular dichroism, and thioflavin T binding. Viability assays indicated that porcine IAPP is significantly less toxic to INS-1 beta cells than human IAPP. Our findings demonstrate that species differences in IAPP sequence can explain the lack of amyloid formation and improved survival of transplanted porcine islets. These data highlight the potential of porcine islet transplantation as a therapeutic approach for human diabetes.

Simultaneous magnetically directed drug convection and MR imaging.

Superparamagnetic iron oxide nanoparticles (IO NPs) are of interest for their usefulness in biomedical applications. In this work, we have synthesized iron oxide nanocomposites surface-modified with different biocompatible polymers. Bovine serum albumin (BSA) was physisorbed onto these IO NPs along with an excipient during freeze-drying. The mass transport of the protein attached to the iron oxide core-shell nanoparticles (IO cs-NPs) under a gradient magnetic field of an MRI instrument was observed in vitro and in an egg as a model system for a biological fluid. From the in vitro experiments in agarose gels, it was observed that the protein gets separated from the core during mass transport for some cs-IO, but co-migration was observed for PEG-modified IO cs-NPs. These experiments demonstrated proof-of-concept for the use of IO cs-NPs in magnetically directed drug convection.

Intrinsic electronic transitions of the absorption spectrum of (OPy)2Ti(TAP)2: implications toward photostructural modifications.

Theoretical calculations based on time-dependent density functional theory are used to characterize the electronic absorption spectrum of a heteroleptic Ti-alkoxide molecule, (OPy)(2)Ti(TAP)(2) [OPy = pyridine carbinoxide, TAP = 2,4,6 tris(dimethylamino)phenoxide] under investigation as a photosensitive precursor for use in optically initiated solution synthesis of the metal oxide. Computational results support the assignment of UV absorption features observed in solid-state precursor films to key intrinsic ground-state transitions that involve ligand-to-metal charge transfer and pi-pi* transitions within the cyclic ligand moieties present. The nature of electron density redistribution associated with these transitions provides early insight into the excitation wavelength dependence of photostructural modification previously observed in this precursor system.