Age-related immune reconstitution during highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children.

OBJECTIVES: To evaluate the immune reconstitution in HIV-1-infected children in whom highly active antiretroviral therapy (HAART) controlled viral replication and to assess the existence of a relation between the magnitude of this restoration and age. METHODS: All HIV-1-infected children in whom a new HAART decreased plasma viral load below 400 copies/ml after 3 months of therapy were prospectively enrolled in a study of their immune reconstitution. Viral load, lymphocyte phenotyping, determination of CD4+ and CD8+ T cell receptor repertoires and proliferative responses to mitogens and recall antigens were assessed every 3 months during 1 year. RESULTS: Nineteen children were evaluated. Naive and memory CD4+ percentages were already significantly increased after 3 months of HAART. In contrast to memory CD4+ percentages, naive CD4+ percentages continued to rise until 12 months. Age at baseline was inversely correlated with the magnitude of the rise in naive CD4+ cells after 3, 6 and 9 months of therapy but not after 12 months. Although memory and activated CD8+ cells were already decreasing after 3 months, abnormalities of the CD8 T cell receptor repertoire and activation of CD8+ cells persisted at 1 year. HAART increased the response to mitogens as early as 3 months after starting therapy. CONCLUSIONS: In children the recovery of naive CD4+ cells occurs more rapidly if treatment is started at a younger age, but after 1 year of viral replication control, patients of all ages have achieved the same level of restoration. Markers of chronic activation in CD8+ cells persist after 1 year of HAART.

IGF-1 or insulin, and the TSH cyclic AMP cascade separately control dog and human thyroid cell growth and DNA synthesis, and complement each other in inducing mitogenesis.

The regular doubling of cell mass, and therefore of cell protein content, is required for repetitive cell divisions. Preliminary observations have shown that in dog thyrocytes insulin induces protein accumulation but not DNA synthesis, while TSH does not increase protein accumulation but triggers DNA synthesis in the presence of insulin. We show here that EGF and phorbol myristate ester complement insulin action in the same way. HGF is the only factor activating both protein accumulation and DNA synthesis. The effects of insulin on protein accumulation and in permitting the TSH effect are reproduced by IGF-1 and are mediated, at least in part by the IGF-1 receptor. The concentration effect curves are similar for both effects. Similar results are obtained in human thyrocytes. They reflect true cell growth, as shown by increases in RNA content and cell size. Carbachol and fetal calf serum also stimulate protein synthesis and accumulation without triggering DNA synthesis, but they are not permissive for the mitogenic effects of TSH or of the general adenylate cyclase activator, forskolin. Moreover the mitogenic effect of TSH greatly decreased in cells deprived of insulin for 2 days although these cells remain hypertrophic. Hypertrophy may therefore be necessary for cell division, but it is not sufficient to permit it. Three different mechanisms can therefore be distinguished in the mitogenic action of TSH: (1) the increase of cell mass (hypertrophy) induced by insulin or IGF-1; (2) the permissive effect of insulin or IGF-1 on the mitogenic effect of TSH which may involve both the increase of cell mass and the induction of specific proteins such as cyclin D3 and (3) the mitogenic effect of the TSH cyclic AMP cascade proper.

Operator non-availability periods

In the scheduling literature, the notion of machine non availability periods is well known, for instance for maintenance. In our case of planning chemical experiments, we have special periods (the week-ends, holidays, vacations) where the chemists are not available. However, human intervention by the chemists is required to handle the starting and termination of the experiments. This gives rise to a new type of scheduling problems, namely problems of finding schedules that respect the operator non availability periods. These problems are analyzed on a single machine with the makespan as criterion. Properties are described and performance ratios are given for list scheduling and other polynomial-time algorithms.

Counter-terrorism, anti-extremism, armed conflict and human rights: using a Russian case study

This paper critically examines Russia’s compliance with human rights obligations and the rule of law in its ‘war on terror’. It seeks to draw wider parallels with respect for human rights in the framework of the fight against ‘new global terrorism’. Threats to due process, the discriminatory application of the forces of law and order specifically against perceived “non-traditional” Muslim communities, and a ratcheting up of fear of an Islamist threat can be traced following the war in Chechnya and the handling of the Dubrovka Theatre and Beslan school sieges. To what extent are there commonalities with UK complicity in the practice of extraordinary rendition, with atrocities perpetrated in Iraq and Afghanistan, and abuses in Abu Ghraib and Guantanamo? Are the impact of these reflected in domestic security policy and British minority ethnic community relations? [From the Author]

Epidemiological and nutrition transition in developing countries: impact on human health and development

Whereas common infectious and parasitic diseases such as malaria and the HIV/AIDS pandemic remain major unresolved health problems in many developing countries, emerging non-communicable diseases relating to diet and lifestyle have been increasing over the last two decades, thus creating a double burden of disease and impacting negatively on already over-stretched health services in these countries. Prevalence rates for type 2 diabetes mellitus and CVD in sub-Saharan Africa have seen a 10-fold increase in the last 20 years. In the Arab Gulf current prevalence rates are between 25 and 35% for the adult population, whilst evidence of the metabolic syndrome is emerging in children and adolescents. The present review focuses on the concept of the epidemiological and nutritional transition. It looks at historical trends in socio-economic status and lifestyle and trends in nutrition-related non-communicable diseases over the last two decades, particularly in developing countries with rising income levels, as well as the other extreme of poverty, chronic hunger and coping strategies and metabolic adaptations in fetal life that predispose to non-communicable disease risk in later life. The role of preventable environmental risk factors for obesity and the metabolic syndrome in developing countries is emphasized and also these challenges are related to meeting the millennium development goals. The possible implications of these changing trends for human and economic development in poorly-resourced healthcare settings and the implications for nutrition training are also discussed.

Impact of human activities on benthic biotopes and species

Executive Summary 1. The Marine Life Information Network (MarLIN) has been developed since 1998. Defra funding has supported a core part of its work, the Biology and Sensitivity Key Information Sub-programme. This report relates to Biology and Sensitivity work for the period 2001-2004. 2. MarLIN Biology and Sensitivity research takes information on the biology of species to identify the likely effects of changing environmental conditions linked to human activities on those species. In turn, species that are key functional, key structural, dominant, or characteristic in a biotope (the habitat and its associated species) are used to identify biotope sensitivity. Results are displayed over the World Wide Web and can be accessed via a range of search tools that make the information of relevance to environmental management. 3. The first Defra contract enabled the development of criteria and methods of research, database storage methods and the research of a wide range of species. A contract from English Nature and Scottish Natural Heritage enabled biotopes relevant to marine SACs to be researched. 4. Defra funding in 2001-2004 has especially enabled recent developments to be targeted for research. Those developments included the identification of threatened and declining species by the OSPAR Biodiversity Committee, the development of a new approach to defining sensitivity (part of the Review of Marine Nature Conservation), and the opportunity to use Geographical Information Systems (GIS) more effectively to link survey data to MarLIN assessments of sensitivity. 5. The MarLIN database has been developed to provide a resource to 'pick-and-mix' information depending on the questions being asked. Using GIS, survey data that provides locations for species and biotopes has been linked to information researched by MarLIN to map the likely sensitivity of an area to a specified factor. Projects undertaken for the Irish Sea pilot (marine landscapes), in collaboration with CEFAS (fishing impacts) and with the Countryside Council for Wales (oil spill response) have demonstrated the application of MarLIN information linked to survey data in answering, through maps, questions about likely impacts of human activities on seabed ecosystems. 6. GIS applications that use MarLIN sensitivity information give meaningful results when linked to localized and detailed survey information (lists of species and biotopes as point source or mapped extents). However, broad landscape units require further interpretation. 7. A new mapping tool (SEABED map) has been developed to display data on species distributions and survey data according to search terms that might be used by an environmental manager. 8. MarLIN outputs are best viewed on the Web site where the most up-to-date information from live databases is available. The MarLIN Web site receives about 1600 visits a day. 9. The MarLIN approach to assessing sensitivity and its application to environmental management were presented in papers at three international conferences during the current contract and a 'touchstone' paper is to be published in the peer-reviewed journal Hydrobiologia. The utility of MarLIN information for environmental managers, amongst other sorts of information, has been described in an article in Marine Pollution Bulletin. 10. MarLIN information is being used to inform the identification of potential indicator species for implementation of the Water Framework Directive including initiatives by ICES. 11. Non-Defra funding streams are supporting the updating of reviews and increasing the amount of peer review undertaken; both of which are important to the maintenance of the resource. However, whilst MarLIN information is sufficiently wide ranging to be used in an 'operational' way for marine environmental protection and management, new initiatives and the new biotopes classification have introduced additional species and biotopes that will need to be researched in the future. 12. By the end of the contract, the Biology and Sensitivity Key Information database contained full Key Information reviews on 152 priority species and 117 priority biotopes, together with basic information on 412 species; a total of 564 marine benthic species.

Oceans and Human Health: A Rising Tide of Challenges and Opportunities for Europe

The European Marine Board recently published a position paper on linking oceans and human health as a strategic research priority for Europe. With this position paper as a reference, the March 2014 Cornwall Oceans and Human Health Workshop brought together key scientists, policy makers, funders, business, and non governmental organisations from Europe and the US to review the recent interdisciplinary and cutting edge research in oceans and human health specifically the growing evidence of the impacts of oceans and seas on human health and wellbeing (and the effects of humans on the oceans). These impacts are a complex mixture of negative influences (e.g. from climate change and extreme weather to harmful algal blooms and chemical pollution) and beneficial factors (e.g. from natural products including seafood to marine renewable energy and wellbeing from interactions with coastal environments). Integrated approaches across disciplines, institutions, and nations in science and policy are needed to protect both the oceans and human health and wellbeing now and in the future.

Assessing the sensitivity of blue mussel beds to pressures associated with human activities.

The Joint Nature Conservation Committee (JNCC) commissioned this project to generate an improved understanding of the sensitivities of blue mussel (Mytilus edulis) beds, found in UK waters, to pressures associated with human activities in the marine environment. The work will provide an evidence base that will facilitate and support management advice for Marine Protected Areas, development of UK marine monitoring and assessment, and conservation advice to offshore marine industries. Blue mussel beds are identified as a Habitat of Principle Importance (HPI) under the Natural Environment and Rural Communities (NERC) Act 2006, as a Priority Marine Feature (PMF) under the Marine (Scotland) Act 2010, and included on the OSPAR (Annex V) list of threatened and declining species and habitats. The purpose of this project was to produce sensitivity assessments for the blue mussel biotopes included within the HPI, PMF and OSPAR habitat definitions, and clearly document the supporting evidence behind the assessments and any differences between them. A total of 20 pressures falling in five categories - biological, hydrological, physical damage, physical loss, and pollution and other chemical changes - were assessed in this report. The review examined seven blue mussel bed biotopes found on littoral sediment and sublittoral rock and sediment. The assessments were based on the sensitivity of M. edulis rather than associated species, as M. edulis was considered the most important characteristic species in blue mussel beds. To develop each sensitivity assessment, the resistance and resilience of the key elements are assessed against the pressure benchmark using the available evidence gathered in this review. The benchmarks were designed to provide a ‘standard’ level of pressure against which to assess sensitivity. Blue mussel beds were highly sensitive to a few human activities: • introduction or spread of non-indigenous species (NIS); • habitat structure changes - removal of substratum (extraction); and • physical loss (to land or freshwater habitat). Physical loss of habitat and removal of substratum are particularly damaging pressures, while the sensitivity of blue mussel beds to non-indigenous species depended on the species assessed. Crepidula fornicata and Crassostrea gigas both had the potential to outcompete and replace mussel beds, so resulted in a high sensitivity assessment. Mytilus spp. populations are considered to have a strong ability to recover from environmental disturbance. A good annual recruitment may allow a bed to recovery rapidly, though this cannot always be expected due to the sporadic nature of M. edulis recruitment. Therefore, blue mussel beds were considered to have a 'Medium' resilience (recovery within 2-10 years). As a result, even where the removal or loss of proportion of a mussel bed was expected due to a pressure, a sensitivity of 'Medium' was reported. Hence, most of the sensitivities reported were 'Medium'. It was noted, however, that the recovery rates of blue mussel beds were reported to be anywhere between two years to several decades. In addition, M. edulis is considered very tolerant of a range of physical and chemical conditions. As a result, blue mussel beds were considered to be 'Not sensitive' to changes in temperature, salinity, de-oxygenation, nutrient and organic enrichment, and substratum type, at the benchmark level of pressure. The report found that no distinct differences in overall sensitivity exist between the HPI, PMF and OSPAR definitions. Individual biotopes do however have different sensitivities to pressures, and the OSPAR definition only includes blue mussel beds on sediment. These differences were determined by the position of the habitat on the shore and the sediment type. For example, the infralittoral rock biotope (A3.361) was unlikely to be exposed to pressures that affect sediments. However in the case of increased water flow, mixed sediment biotopes were considered more stable and ‘Not sensitive’ (at the benchmark level) while the remaining biotopes were likely to be affected.

Using a clearly documented, evidence-based approach to create sensitivity assessments allows the assessment basis and any subsequent decision making or management plans to be readily communicated, transparent and justifiable. The assessments can be replicated and updated where new evidence becomes available ensuring the longevity of the sensitivity assessment tool. For every pressure where sensitivity was previously assessed as a range of scores in MB0102, the assessments made by the evidence review have supported one of the MB0102 assessments. The evidence review has reduced the uncertainty around assessments previously undertaken in the MB0102 project (Tillin et al., 2010) by assigning a single sensitivity score to the pressures as opposed to a range. Finally, as blue mussel bed habitats also contribute to ecosystem function and the delivery of ecosystem services, understanding the sensitivity of these biotopes may also support assessment and management in regard to these. Whatever objective measures are applied to data to assess sensitivity, the final sensitivity assessment is indicative. The evidence, the benchmarks, the confidence in the assessments and the limitations of the process, require a sense-check by experienced marine ecologists before the outcome is used in management decisions.

Oceans and Human Health: A rising tide of challenges and opportunities for Europe

The European Marine Board recently published a position paper on linking oceans and human health as a strategic research priority for Europe. With this position paper as a reference, the March 2014 Cornwall Oceans and Human Health Workshop brought together key scientists, policy makers, funders, business, and non governmental organisations from Europe and the US to review the recent interdisciplinary and cutting edge research in oceans and human health specifically the growing evidence of the impacts of oceans and seas on human health and wellbeing (and the effects of humans on the oceans). These impacts are a complex mixture of negative influences (e.g. from climate change and extreme weather to harmful algal blooms and chemical pollution) and beneficial factors (e.g. from natural products including seafood to marine renewable energy and wellbeing from interactions with coastal environments). Integrated approaches across disciplines, institutions, and nations in science and policy are needed to protect both the oceans and human health and wellbeing now and in the future.

Extraction and radioimmunoassay quantitation of neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP) from human dental pulp tissue

The measurement of neuropeptides in complex biological tissue samples requires efficient and appropriate extraction methods so that immunoreactivity is retained for subsequent radioimmunoassay detection. Since neuropeptides differ in their molecular mass, charge and hydrophobicity, no single method will suffice for the optimal extraction of various neuropeptides. In this study, dental pulp tissue was obtained from 30 human non-carious teeth. Of the three different neuropeptide extraction methods employed, boiling in acetic acid in the presence of protease inhibitors yielded the highest levels of neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP). High pressure liquid chromatography (HPLC) analysis of dental pulp tissue verified the authenticity of the neuropeptides extracted. © 2003 Elsevier Science Ltd. All rights reserved.

Identification of the region of non-A beta component (NAC) of alzheimer's disease amyloid responsible for its aggregation and toxicity

The non-beta-amyloid (Aß) component of Alzheimer's disease amyloid (NAC) and its precursor a-synuclein have been linked to amyloidogenesis in several neurodegenerative diseases. NAC and a-synuclein both form ß-sheet structures upon ageing, aggregate to form fibrils, and are neurotoxic. We recently established that a peptide comprising residues 3±18 of NAC retains these properties. To pinpoint the exact region responsible we have carried out assays of toxicity and physicochemical properties on smaller fragments of NAC. Toxicity was measured by the ability of fresh and aged peptides to inhibit the reduction of the redox dye 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) by rat pheochromocytoma PC12 cells and human neuroblastoma SHSY-5Y cells. On immediate dissolution, or after ageing, the fragments NAC(8±18) and NAC(8±16) are toxic, whereas NAC(12±18), NAC(9±16) and NAC(8±15) are not. Circular dichroism indicates that none of the peptides displays ß-sheet structure; rather all remain random coil throughout 24 h. However, in acetonitrile, an organic solvent known to induce ß sheet, fragments NAC(8±18) and NAC(8±16) both form ß-sheet structure. Only NAC(8±18) aggregates, as indicated by concentration of peptide remaining in solution after 3 days, and forms fibrils, as determined by electron microscopy. These findings indicate that residues 8±16 of NAC, equivalent to residues 68±76 in a-synuclein, comprise the region crucial for toxicity.

Vasoactive intestinal polypeptide (VIP) and VPAC1 receptor in adult human dental pulp in relation to caries

Objective: To quantitatively measure VIP levels and to qualitatively study the distribution of VIP fibres and demonstrate the presence of the VPAC1 receptor in human dental pulp from carious and non-carious adult human teeth. Design: Dental pulp samples were collected from non-carious, moderately carious and grossly carious adult human teeth. VIP levels were determined using radioimmunoassay. The distribution of VIP fibres was studied using immunohistochemistry. The VPAC1 receptor protein expression was determined by Western blotting. Results: VIP levels were found to be significantly elevated in the dental pulp of moderately carious compared with non-carious (p = 0.0032) or grossly carious teeth (p = 0.0029). The distribution of VIP fibres was similar in non-carious and carious teeth, except that nerve bundles appeared thicker in the pulp samples from carious compared with non-carious teeth. Western blotting indicated that the VPAC1 receptor proteins were detected in similar levels in pooled dental pulp samples from both carious and non-carious teeth. Conclusion: It is concluded that quantitative changes in the levels of VIP in human dental pulp during the caries process and the expression of VPAC1 receptor proteins in membrane extracts from carious and non-carious teeth suggests a role for VIP in modulating pulpal health and disease. © 2006 Elsevier Ltd. All rights reserved.

Identification and bisection of temporal durations and tone frequencies: Common models for temporal and non-temporal stimuli.

Two experiments examined identification and bisection of tones varying in temporal duration (Experiment 1) or frequency (Experiment 2). Absolute identification of both durations and frequencies was influenced by prior stimuli and by stimulus distribution. Stimulus distribution influenced bisection for both stimulus types consistently, with more positively skewed distributions producing lower bisection points. The effect of distribution was greater when the ratio of the largest to smallest stimulus magnitude was greater. A simple mathematical model, temporal range frequency theory, was applied. It is concluded that (a) similar principles describe identification of temporal durations and other stimulus dimensions and (b) temporal bisection point shifts can be understood in terms of psychophysical principles independently developed in nontemporal domains, such as A. Parducci's (1965) range frequency theory.

Genomic organization, complex splicing pattern and expression of a human septin gene on chromosome 17q25.3

The Ov/Br septin gene, which is also a fusion partner of MLL in acute myeloid leukaemia, is a member of a family of novel GTP binding proteins that have been implicated in cytokinesis and exocytosis. In this study, we describe the genomic and transcriptional organization of this gene, detailing seventeen exons distributed over 240 kb of sequence. Extensive database analyses identified orthologous rodent cDNAs that corresponded to new, unidentified 5' splice variants of the Ov/Br septin gene, increasing the total number of such variants to six. We report that splicing events, occurring at non-canonical sites within the body of the 3' terminal exon, remove either 1801 bp or 1849 bp of non-coding sequence and facilitate access to a secondary open reading frame of 44 amino acids maintained near the end of the 3' UTR. These events constitute a novel coding arrangement and represent the first report of such a design being implemented by a eukaryotic gene. The various Ov/Br proteins either differ minimally at their amino and carboxy termini or are equivalent to truncated versions of larger isoforms. Northern analysis with an Ov/Br septin 3' UTR probe reveals three transcripts of 4.4, 4 and 3 kb, the latter being restricted to a sub-set of the tissues tested. Investigation of the identified Ov/Br septin isoforms by RT-PCR confirms a complex transcriptional pattern, with several isoforms showing tissue-specific distribution. To date, none of the other human septins have demonstrated such transcriptional complexity.