Grafting functional antioxidants on highly crosslinked polyethylene

The problem of interference of antioxidants, such as hindered phenols, with peroxide-initiated crosslinking of polyethylene was addressed through the use of functional (reactive) graftable antioxidants (g-AO). Reactive derivatives of hindered phenol and hindered amine antioxidants were synthesised, characterised and used to investigate their grafting reactions in high density polyethylene; both non-crosslinked (PE) and highly peroxide-crosslinked (PEXa). Assessment of the extent of in-situ grafting of the antioxidants, their retention after exhaustive solvent extraction in PE and PEXa, and the stabilising performance of the grafted antioxidants (g-AO) in the polymer were examined and benchmarked against conventionally stabilised crosslinked & non-crosslinked polyethylene. It was shown that the functional antioxidants graft to a high extent in PEXa, and that the level of interference of the g-AOs with the polymer crosslinking process was minimal compared to that of conventional antioxidants which bear the same antioxidant function. The much higher level of retention of the g-AOs in PEXa after exhaustive solvent extraction, compared to that of the corresponding conventional antioxidants, accounts for their superior long-term thermal stabilising performance under severe extractive conditions.

18-Fluorodeoxyglucose positron emission tomography/computed tomography in the management of aggressive non-Hodgkin's B-cell lymphoma

18-Fluorodeoxyglucose (FDG-PET/CT) is an established imaging modality that has been proven to be of benefit in the management of aggressive B-cell non-Hodgkin's lymphoma, such as diffuse large B-cell lymphoma and advanced stage follicular lymphoma. The combination of anatomic and functional imaging afforded by FDG-PET/CT has led to superior sensitivity and specificity in the primary staging, restaging, and assessment of response to treatment of hematological malignancies when compared to FDG-PET and CT alone. The use of FDG-PET/CT for post treatment surveillance imaging remains controversial, and further study is needed to ascertain whether this modality is cost effective and appropriate for use in this setting.

Functional Evaluation of Causal Mutations Identified in Human Genetic Studies

Human genetics has been experiencing a wave of genetic discoveries thanks to the development of several technologies, such as genome-wide association studies (GWAS), whole-exome sequencing, and whole genome sequencing. Despite the massive genetic discoveries of new variants associated with human diseases, several key challenges emerge following the genetic discovery. GWAS is known to be good at identifying the locus associated with the patient phenotype. However, the actually causal variants responsible for the phenotype are often elusive. Another challenge in human genetics is that even the causal mutations are already known, the underlying biological effect might remain largely ambiguous. Functional evaluation plays a key role to solve these key challenges in human genetics both to identify causal variants responsible for the phenotype, and to further develop the biological insights from the disease-causing mutations.

We adopted various methods to characterize the effects of variants identified in human genetic studies, including patient genetic and phenotypic data, RNA chemistry, molecular biology, virology, and multi-electrode array and primary neuronal culture systems. Chapter 1 is a broader introduction for the motivation and challenges for functional evaluation in human genetic studies, and the background of several genetics discoveries, such as hepatitis C treatment response, in which we performed functional characterization.

Chapter 2 focuses on the characterization of causal variants following the GWAS study for hepatitis C treatment response. We characterized a non-coding SNP (rs4803217) of IL28B (IFNL3) in high linkage disequilibrium (LD) with the discovery SNP identified in the GWAS. In this chapter, we used inter-disciplinary approaches to characterize rs4803217 on RNA structure, disease association, and protein translation.

Chapter 3 describes another avenue of functional characterization following GWAS focusing on the novel transcripts and proteins identified near the IL28B (IFNL3) locus. It has been recently speculated that this novel protein, which was named IFNL4, may affect the HCV treatment response and clearance. In this chapter, we used molecular biology, virology, and patient genetic and phenotypic data to further characterize and understand the biology of IFNL4. The efforts in chapter 2 and 3 provided new insights to the candidate causal variant(s) responsible for the GWAS for HCV treatment response, however, more evidence is still required to make claims for the exact causal roles of these variants for the GWAS association.

Chapter 4 aims to characterize a mutation already known to cause a disease (seizure) in a mouse model. We demonstrate the potential use of multi-electrode array (MEA) system for the functional characterization and drug testing on mutations found in neurological diseases, such as seizure. Functional characterization in neurological diseases is relatively challenging and available systematic tools are relatively limited. This chapter shows an exploratory research and example to establish a system for the broader use for functional characterization and translational opportunities for mutations found in neurological diseases.

Overall, this dissertation spans a range of challenges of functional evaluations in human genetics. It is expected that the functional characterization to understand human mutations will become more central in human genetics, because there are still many biological questions remaining to be answered after the explosion of human genetic discoveries. The recent advance in several technologies, including genome editing and pluripotent stem cells, is also expected to make new tools available for functional studies in human diseases.

Engineering Highly-functional, Self-regenerative Skeletal Muscle Tissues with Enhanced Vascularization and Survival in Vivo

Tissue engineering of biomimetic skeletal muscle may lead to development of new therapies for myogenic repair and generation of improved in vitro models for studies of muscle function, regeneration, and disease. For the optimal therapeutic and in vitro results, engineered muscle should recreate the force-generating and regenerative capacities of native muscle, enabled respectively by its two main cellular constituents, the mature myofibers and satellite cells (SCs). Still, after 20 years of research, engineered muscle tissues fall short of mimicking contractile function and self-repair capacity of native skeletal muscle. To overcome this limitation, we set the thesis goals to: 1) generate a highly functional, self-regenerative engineered skeletal muscle and 2) explore mechanisms governing its formation and regeneration in vitro and survival and vascularization in vivo.

By studying myogenic progenitors isolated from neonatal rats, we first discovered advantages of using an adherent cell fraction for engineering of skeletal muscles with robust structure and function and the formation of a SC pool. Specifically, when synergized with dynamic culture conditions, the use of adherent cells yielded muscle constructs capable of replicating the contractile output of native neonatal muscle, generating >40 mN/mm2 of specific force. Moreover, tissue structure and cellular heterogeneity of engineered muscle constructs closely resembled those of native muscle, consisting of aligned, striated myofibers embedded in a matrix of basal lamina proteins and SCs that resided in native-like niches. Importantly, we identified rapid formation of myofibers early during engineered muscle culture as a critical condition leading to SC homing and conversion to a quiescent, non-proliferative state. The SCs retained natural regenerative capacity and activated, proliferated, and differentiated to rebuild damaged myofibers and recover contractile function within 10 days after the muscle was injured by cardiotoxin (CTX). The resulting regenerative response was directly dependent on the abundance of SCs in the engineered muscle that we varied by expanding starting cell population under different levels of basic fibroblast growth factor (bFGF), an inhibitor of myogenic differentiation. Using a dorsal skinfold window chamber model in nude mice, we further demonstrated that within 2 weeks after implantation, initially avascular engineered muscle underwent robust vascularization and perfusion and exhibited improved structure and contractile function beyond what was achievable in vitro.

To enhance translational value of our approach, we transitioned to use of adult rat myogenic cells, but found that despite similar function to that of neonatal constructs, adult-derived muscle lacked regenerative capacity. Using a novel platform for live monitoring of calcium transients during construct culture, we rapidly screened for potential enhancers of regeneration to establish that many known pro-regenerative soluble factors were ineffective in stimulating in vitro engineered muscle recovery from CTX injury. This led us to introduce bone marrow-derived macrophages (BMDMs), an established non-myogenic contributor to muscle repair, to the adult-derived constructs and to demonstrate remarkable recovery of force generation (>80%) and muscle mass (>70%) following CTX injury. Mechanistically, while similar patterns of early SC activation and proliferation upon injury were observed in engineered muscles with and without BMDMs, a significant decrease in injury-induced apoptosis occurred only in the presence of BMDMs. The importance of preventing apoptosis was further demonstrated by showing that application of caspase inhibitor (Q-VD-OPh) yielded myofiber regrowth and functional recovery post-injury. Gene expression analysis suggested muscle-secreted tumor necrosis factor-α (TNFα) as a potential inducer of apoptosis as common for muscle degeneration in diseases and aging in vivo. Finally, we showed that BMDM incorporation in engineered muscle enhanced its growth, angiogenesis, and function following implantation in the dorsal window chambers in nude mice.

In summary, this thesis describes novel strategies to engineer highly contractile and regenerative skeletal muscle tissues starting from neonatal or adult rat myogenic cells. We find that age-dependent differences of myogenic cells distinctly affect the self-repair capacity but not contractile function of engineered muscle. Adult, but not neonatal, myogenic progenitors appear to require co-culture with other cells, such as bone marrow-derived macrophages, to allow robust muscle regeneration in vitro and rapid vascularization in vivo. Regarding the established roles of immune system cells in the repair of various muscle and non-muscle tissues, we expect that our work will stimulate the future applications of immune cells as pro-regenerative or anti-inflammatory constituents of engineered tissue grafts. Furthermore, we expect that rodent studies in this thesis will inspire successful engineering of biomimetic human muscle tissues for use in regenerative therapy and drug discovery applications.

Structural and functional vulnerability to elevated pCO2 in marine benthic communities

The effect of elevated pCO2/low pH on marine invertebrate benthic biodiversity, community structure and selected functional responses which underpin ecosystem services (such as community production and calcification) was tested in a medium-term (30 days) mesocosm experiment in June 2010. Standardised intertidal macrobenthic communities, collected (50.3567°N, 4.1277°W) using artificial substrate units (ASUs), were exposed to one of seven pH treatments (8.05, 7.8. 7.6, 7.4, 7.2, 6.8 and 6.0). Community net calcification/dissolution rates, as well as changes in biomass, community structure and diversity, were measured at the end of the experimental period. Communities showed significant changes in structure and reduced diversity in response to reduced pH: shifting from a community dominated by calcareous organisms to one dominated by non-calcareous organisms around either pH 7.2 (number of individuals and species) or pH 7.8 (biomass). These results were supported by a reduced total weight of CaCO3 structures in all major taxa at lowered pH and a switch from net calcification to net dissolution around pH 7.4 (Omega calc = 0.78, Omega ara = 0.5). Overall community soft tissue biomass did not change with pH and high mortality was observed only at pH 6.0, although molluscs and arthropods showed significant decreases in soft tissue. This study supports and refines previous findings on how elevated pCO2 can induce changes in marine biodiversity, underlined by differential vulnerability of different phyla. In addition, it shows significant elevated pCO2-/low pH-dependent changes in fundamental community functional responses underpinning changes in ecosystem services.

Global distributions of diazotrophs abundance, biomass and nitrogen fixation rates - Gridded data product (NetCDF) - Contribution to the MAREDAT World Ocean Atlas of Plankton Functional Types

The MAREDAT atlas covers 11 types of plankton, ranging in size from bacteria to jellyfish. Together, these plankton groups determine the health and productivity of the global ocean and play a vital role in the global carbon cycle. Working within a uniform and consistent spatial and depth grid (map) of the global ocean, the researchers compiled thousands and tens of thousands of data points to identify regions of plankton abundance and scarcity as well as areas of data abundance and scarcity. At many of the grid points, the MAREDAT team accomplished the difficult conversion from abundance (numbers of organisms) to biomass (carbon mass of organisms). The MAREDAT atlas provides an unprecedented global data set for ecological and biochemical analysis and modeling as well as a clear mandate for compiling additional existing data and for focusing future data gathering efforts on key groups in key areas of the ocean. This is a gridded data product about diazotrophic organisms . There are 6 variables. Each variable is gridded on a dimension of 360 (longitude) * 180 (latitude) * 33 (depth) * 12 (month). The first group of 3 variables are: (1) number of biomass observations, (2) biomass, and (3) special nifH-gene-based biomass. The second group of 3 variables is same as the first group except that it only grids non-zero data. We have constructed a database on diazotrophic organisms in the global pelagic upper ocean by compiling more than 11,000 direct field measurements including 3 sub-databases: (1) nitrogen fixation rates, (2) cyanobacterial diazotroph abundances from cell counts and (3) cyanobacterial diazotroph abundances from qPCR assays targeting nifH genes. Biomass conversion factors are estimated based on cell sizes to convert abundance data to diazotrophic biomass. Data are assigned to 3 groups including Trichodesmium, unicellular diazotrophic cyanobacteria (group A, B and C when applicable) and heterocystous cyanobacteria (Richelia and Calothrix). Total nitrogen fixation rates and diazotrophic biomass are calculated by summing the values from all the groups. Some of nitrogen fixation rates are whole seawater measurements and are used as total nitrogen fixation rates. Both volumetric and depth-integrated values were reported. Depth-integrated values are also calculated for those vertical profiles with values at 3 or more depths.

STRUCTURAL AND FUNCTIONAL CORRELATES OF EXERCISE VENTILATORY INEFFICIENCY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS WITH MILD-TO-MODERATE SPIROMETRIC ABNORMALITIES

Background: Individuals with chronic obstructive pulmonary disease (COPD) have higher than normal ventilatory equivalents for carbon dioxide (VE/VCO2) during exercise. There is growing evidence that emphysema on thoracic computed tomography (CT) scans is associated with poor exercise capacity in COPD patients with only mild-to-moderate airflow obstruction. We hypothesized that emphysema is an underlying cause of microvascular dysfunction and ventilatory inefficiency, which in turn contributes to reduced exercise capacity. We expected ventilatory inefficiency to be associated with a) the extent of emphysema; b) lower diffusing capacity for carbon monoxide; c) a reduced pulmonary blood flow response to exercise; and d) reduced exercise capacity. Methods: In a cross-sectional study, 19 subjects with mild-to-moderate COPD (mean ± SD FEV1= 82 ± 13% predicted, 12 GOLD grade 1) and 26 age-, sex-, and activity-matched controls underwent a ramp-incremental symptom-limited exercise test on a cycle ergometer. Ventilatory inefficiency was assessed by the minimum VE/VCO2 value (nadir). A subset of subjects also completed repeated constant work rate exercise bouts with non-invasive measurements of pulmonary blood flow. Emphysema was quantified as the percentage of attenuation areas below -950 Housefield Units on CT scans. An electronic scoresheet was used to keep track of emphysema sub-types. Results: COPD subjects typically had centrilobular emphysema (76.8 ± 10.1% of total emphysema) in the upper lobes (upper/lower lobe ratio= 0.82 ± 0.04). They had lower peak oxygen uptake (VO2), higher VE/VCO2 nadir and greater dyspnea scores than controls (p<0.05). Lower peak O2 and worse dyspnea were found in COPD subjects with VE/VCO2 nadirs ≥ 30. COPD subjects had blunted increases in pulmonary blood flow from rest to iso-VO2 exercise (p<0.05). Higher VE/VCO2 nadir in COPD subjects correlated with emphysema severity (r= 0.63), which in turn correlated with reduced lung diffusing capacity (r= -0.72) and blunted changes in pulmonary blood flow from rest to exercise (r= -0.69) (p<0.01). Conclusions: Ventilation “wasted” in emphysematous areas is associated with reduced exercise ventilatory efficiency in mild-to-moderate COPD. Exercise ventilatory inefficiency links structure (emphysema) and function (gas transfer) to a key clinical outcome (reduced exercise capacity) in COPD patients with modest spirometric abnormalities.

Structural and Functional Characterization of the Human Tribbles Homologue 2 Pseudokinase

The Tribbles Homologues are a family of three eukaryotic pseudokinases (Trb1, Trb2, Trb3) that act as allosteric inhibitors and regulatory scaffold sites in pathways governing adipogenesis, cell proliferation and insulin signaling. The Tribbles Homologues have the same overall tertiary structure of the eukaryotic protein kinase domain, but lack multiple residues necessary to catalysis in the nucleotide-binding P-loop and the Mg2+-coordinating DFG motif. Trb1 has been shown conclusively to be incapable of binding ATP, whereas a recent study presents evidence that Trb2 autophosphorylates independently of Mg2+ in vitro. This finding is surprising given the high degree of sequence similarity between the two proteins (71%), and suggests unique nucleotide binding and phosphotransfer mechanisms. The goal of this project was to investigate whether Trb2 possesses kinase activity or not and determine its structural basis. A method for the high-yield recombinant expression and purification of stable Trb2 was developed. Trb2 nucleotide binding and autophosphorylation could not be detected across multiple experimental approaches, including thermal shift assays, MANT-ATP fluorescence, radiolabeled phosphate incorporation, and nonspecific ATPase activity assays. Further characterization also revealed that Trb2 forms homomultimers with possible functional consequences, and extensive crystallization screening has yielded multiple promising conditions that could produce diffraction-quality crystals with further optimization. This project explores the difficulties in functionally characterizing putatively active pseudokinases, and proposes a structural basis for the conserved pseudokinase features of the Tribbles homologues.

Who is in charge? An L2 Discourse Intonation Study on Four Prosodic Parameters to Exert the Pragmatic Function of Dominance and Control in the Context of L2 Non-specialist Public Speaking

This paper reports the findings from a study of the learning of English intonation by Spanish speakers within the discourse mode of L2 oral presentation. The purpose of this experiment is, firstly, to compare four prosodic parameters before and after an L2 discourse intonation training programme and, secondly, to confirm whether subjects, after the aforementioned L2 discourse intonation training, are able to match the form of these four prosodic parameters to the discourse-pragmatic function of dominance and control. The study designed the instructions and tasks to create the oral and written corpora and Brazil’s Pronunciation for Advanced Learners of English was adapted for the pedagogical aims of the present study. The learners’ pre- and post-tasks were acoustically analysed and a pre / post- questionnaire design was applied to interpret the acoustic analysis. Results indicate most of the subjects acquired a wider choice of the four prosodic parameters partly due to the prosodically-annotated transcripts that were developed throughout the L2 discourse intonation course. Conversely, qualitative and quantitative data reveal most subjects failed to match the forms to their appropriate pragmatic functions to express dominance and control in an L2 oral presentation.

Structural and Functional Lung Impairment in Adult Survivors of Bronchopulmonary Dysplasia

RATIONALE: As more preterm infants recover from severe bronchopulmonary dysplasia (BPD), it is critical to understand the clinical consequences of this condition on the lung health of adult survivors.

OBJECTIVES: To assess structural and functional lung parameters in young adult BPD survivors and preterm and term controls Methods: Young adult survivors of BPD (mean age 24) underwent spirometry, lung volumes, transfer factor, lung clearance index and fractional exhaled nitric oxide measurements together with high-resolution chest tomographic (CT) imaging and cardiopulmonary exercise testing.

MEASUREMENTS AND MAIN RESULTS: 25 adult BPD survivors, (mean ± SD gestational age 26.8 ± 2.3 weeks; birth weight 866 ± 255 g), 24 adult prematurely born non-BPD controls (gestational age 30.6 ± 1.9 weeks; birth weight 1234 ± 207 g) and 25 adult term birth control subjects (gestational age 38.5 ± 0.9 weeks; and birth weight 3569 ± 2979 g) were studied. BPD subjects were more likely to be wakened by cough (OR 9.7, 95% CI: 1.8 to 52.6), p<0.01), wheeze and breathlessness (OR 12.2, 95%CI: 1.3 to 112), p<0.05) than term controls after adjusting for sex and current smoking. Preterm subjects had greater airways obstruction than term subjects. BPD subjects had significantly lower values for FEV1 and FEF25-75 (% predicted and z scores) than term controls (both p<0.001). Although non-BPD subjects also had lower spirometric values than term controls, none of the differences reached statistical significance. More BPD subjects (25%) had fixed airflow obstruction than non-BPD (12.5%) and term (0%) subjects (p=0.004). Both BPD and non-BPD subjects had significantly greater impairment in gas transfer (KCO % predicted) than term subjects (both p<0.05). Eighteen (37%) preterm participants were classified as small for gestational age (birth weight < 10th percentile for gestational age). These subjects had significantly greater impairment in FEV1 (% predicted and z scores) than those born appropriate for gestational age. BPD survivors had significantly more severe radiographic structural lung impairment than non-BPD subjects. Both preterm groups had impaired exercise capacity compared to term controls. There was a trend for greater limitation and leg discomfort in BPD survivors.

CONCLUSIONS: Adult preterm birth survivors, especially those who developed BPD, continue to experience respiratory symptoms and exhibit clinically important levels of pulmonary impairment.

Expression of high amounts of the CD117 molecule in a case of B-cell non-Hodgkin's lymphoma carrying the t(14:18) translocation.

The c-kit proto-oncogen (CD117) has been described to be present in normal and neoplastic hemopoietic cells including both myeloid and lymphoid lineages. Among the normal lymphoid cells CD117 expression would be restricted to a small subset of NK-cells, and to early T-cell precursors and it is not expressed by normal B-cells. Regarding chronic lymphoproliferative disorders the only data provided up to now suggests that CD117 expression is restricted to cases of Hodgkin's disease and anaplastic large-cell lymphoma. In the present paper we describe a case of a B-cell chronic lymphoproliferative disorder carrying the t(14:18) translocation as demonstrated by molecular studies, in which the flow cytometric immunophenotypic analysis of both peripheral blood and bone marrow samples revealed the expression of high amounts of the CD117 antigen in the surface of the clonal B-cell population. Further studies are necessary to explore both the functional role of c-kit expression in the neoplastic B-cells from this patient and its potential utility for the diagnosis and follow-up of patients with B-cell non-Hodgkin's lymphoma.

Functional management of ankle sprains: what volume and intensity of walking is undertaken in the first week

BACKGROUND:
Acute ankle sprains are usually managed functionally, with advice to undertake progressive weight-bearing and walking. Mechanical loading is an important modular of tissue repair; therefore, the clinical effectiveness of walking after ankle sprain may be dose dependent. The intensity, magnitude and duration of load associated with current functional treatments for ankle sprain are unclear.
AIM:
To describe physical activity (PA) in the first week after ankle sprain and to compare results with a healthy control group.
METHODS:
Participants (16-65 years) with an acute ankle sprain were randomised into two groups (standard or exercise). Both groups were advised to apply ice and compression, and walk within the limits of pain. The exercise group undertook additional therapeutic exercises. PA was measured using an activPAL accelerometer, worn for 7 days after injury. Comparisons were made with a non-injured control group.
RESULTS:
The standard group were significantly less active (1.2 ± 0.4 h activity/day; 5621 ± 2294 steps/day) than the exercise (1.7 ± 0 .7 h/day, p=0.04; 7886 ± 3075 steps/day, p=0.03) and non-injured control groups (1.7 ± 0.4 h/day, p=0.02; 8844 ± 2185 steps/day, p=0.002). Also, compared with the non-injured control group, the standard and exercise groups spent less time in moderate (38.3 ± 12.7 min/day vs 14.5 ± 11.4 min/day, p=0.001 and 22.5 ± 15.9 min/day, p=0.003) and high-intensity activity (4.1 ± 6.9 min/day vs 0.1 ± 0.1 min/day, p=0.001 and 0.62 ± 1.0 min/day p=0.005).
CONCLUSION:
PA patterns are reduced in the first week after ankle sprain, which is partly ameliorated with addition of therapeutic exercises. This study represents the first step towards developing evidence-based walking prescription after acute ankle sprain.

Non-pharmacological interventions for cognitive impairment due to systemic cancer treatment (Review)

Background

It is estimated that up to 75% of cancer survivors may experience cognitive impairment as a result of cancer treatment and given the increasing size of the cancer survivor population, the number of affected people is set to rise considerably in coming years. There is a need, therefore, to identify effective, non-pharmacological interventions for maintaining cognitive function or ameliorating cognitive impairment among people with a previous cancer diagnosis.
Objectives

To evaluate the cognitive effects, non-cognitive effects, duration and safety of non-pharmacological interventions among cancer patients targeted at maintaining cognitive function or ameliorating cognitive impairment as a result of cancer or receipt of systemic cancer treatment (i.e. chemotherapy or hormonal therapies in isolation or combination with other treatments).
Search methods

We searched the Cochrane Centre Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PUBMED, Cumulative Index of Nursing and Allied Health Literature (CINAHL) and PsycINFO databases. We also searched registries of ongoing trials and grey literature including theses, dissertations and conference proceedings. Searches were conducted for articles published from 1980 to 29 September 2015.
Selection criteria

Randomised controlled trials (RCTs) of non-pharmacological interventions to improve cognitive impairment or to maintain cognitive functioning among survivors of adult-onset cancers who have completed systemic cancer therapy (in isolation or combination with other treatments) were eligible. Studies among individuals continuing to receive hormonal therapy were included. We excluded interventions targeted at cancer survivors with central nervous system (CNS) tumours or metastases, non-melanoma skin cancer or those who had received cranial radiation or, were from nursing or care home settings. Language restrictions were not applied.
Data collection and analysis

Author pairs independently screened, selected, extracted data and rated the risk of bias of studies. We were unable to conduct planned meta-analyses due to heterogeneity in the type of interventions and outcomes, with the exception of compensatory strategy training interventions for which we pooled data for mental and physical well-being outcomes. We report a narrative synthesis of intervention effectiveness for other outcomes.
Main results

Five RCTs describing six interventions (comprising a total of 235 participants) met the eligibility criteria for the review. Two trials of computer-assisted cognitive training interventions (n = 100), two of compensatory strategy training interventions (n = 95), one of meditation (n = 47) and one of physical activity intervention (n = 19) were identified. Each study focused on breast cancer survivors. All five studies were rated as having a high risk of bias. Data for our primary outcome of interest, cognitive function were not amenable to being pooled statistically. Cognitive training demonstrated beneficial effects on objectively assessed cognitive function (including processing speed, executive functions, cognitive flexibility, language, delayed- and immediate- memory), subjectively reported cognitive function and mental well-being. Compensatory strategy training demonstrated improvements on objectively assessed delayed-, immediate- and verbal-memory, self-reported cognitive function and spiritual quality of life (QoL). The meta-analyses of two RCTs (95 participants) did not show a beneficial effect from compensatory strategy training on physical well-being immediately (standardised mean difference (SMD) 0.12, 95% confidence interval (CI) -0.59 to 0.83; I2= 67%) or two months post-intervention (SMD - 0.21, 95% CI -0.89 to 0.47; I2 = 63%) or on mental well-being two months post-intervention (SMD -0.38, 95% CI -1.10 to 0.34; I2 = 67%). Lower mental well-being immediately post-intervention appeared to be observed in patients who received compensatory strategy training compared to wait-list controls (SMD -0.57, 95% CI -0.98 to -0.16; I2 = 0%). We assessed the assembled studies using GRADE for physical and mental health outcomes and this evidence was rated to be low quality and, therefore findings should be interpreted with caution. Evidence for physical activity and meditation interventions on cognitive outcomes is unclear.
Authors' conclusions

Overall, the, albeit low-quality evidence may be interpreted to suggest that non-pharmacological interventions may have the potential to reduce the risk of, or ameliorate, cognitive impairment following systemic cancer treatment. Larger, multi-site studies including an appropriate, active attentional control group, as well as consideration of functional outcomes (e.g. activities of daily living) are required in order to come to firmer conclusions about the benefits or otherwise of this intervention approach. There is also a need to conduct research into cognitive impairment among cancer patient groups other than women with breast cancer.

Introduction: dispersed minorities and non-territorial autonomy

The concept of non-territorial autonomy gives rise to at least two important questions: the range of functional areas over which autonomy extends, and the extent to which this autonomy is indeed non-territorial. A widely used early description significantly labelled this ‘national cultural autonomy’, implying that its focus is mainly on cultural matters, such as language, religion, education and family law. In many of the cases that are commonly cited, ‘autonomy’ may not even extend this far: its most visible expression is the existence of separate electoral registers or quotas for the various groups. Part of the dilemma lies in the difficulty of devolving substantial power on a non-territorial basis: to the extent that devolved institutions are state-like, they ideally require a defined territory. Ethnic groups, however, vary in the extent to which they are territorially concentrated, and therefore in the degree to which any autonomous arrangements for them are territorial or non-territorial. This article explores the dilemma generated by this tension between ethnic geography (pattern of ethnic settlement) and political autonomy (degree of selfrule), and introduces a set of case studies where the relationship between these two features is discussed further: the Ottoman empire and its successor states, the Habsburg monarchy, the Jewish minorities of Europe, interwar Estonia, contemporary Belgium, and two indigenous peoples, the Sa´mi in Norway and the Maori in New Zealand.

Molecular and Functional Characterization of Antimicrobial Peptides in Crustaceans

Most living organisms are constantly exposed to potentially harmful pathogens. It is the immune system of the organism that enables it to survive in an environment loaded with dangerous pathogenic microorganisms. The innate immunity provides organisms with a rapid and non-specific first line of defense against pathogens. It includes physical barriers such as skin and mucous membranes and chemical barriers including the high acidity of gastric juice, and specialized soluble molecules that possess antimicrobial activity. One of the well-known innate immune defense mechanisms is the production of antimicrobial substances by specific cells or tissues of the organisms. Antimicrobial peptides (AMPs) are such natural substances that