Choice of designs and doses for early phase trials

This paper reviews state-of-art statistical designs for dose-escalation procedures in first-into-man studies. The main focus will be on studies in oncology, as most statistical procedures for phase I trials have been proposed in this context. Extensions to situations such as the observation of bivariate outcomes and healthy volunteer studies are also discussed. The number of dose levels and cohort sizes used in early phase trials are considered. Finally, this paper raises some practical issues for dose-escalation procedures.

A longitudinal study of child sleep in high and low risk families: relationship to early maternal settling strategies and child psychological functioning

Objectives To investigate whether sleep disturbances previously found to characterise high risk infants: (a) persist into childhood; (b) are influenced by early maternal settling strategies and (c) predict cognitive and emotional/behavioural functioning. Methods Mothers experiencing high and low levels of psychosocial adversity (risk) were recruited antenatally and longitudinally assessed with their children. Mothers completed measures of settling strategies and infant sleep postnatally, and at 12 and 18 months, infant age. At five years, child sleep characteristics were measured via an actigraphy and maternal report; IQ and child adjustment were also assessed. Results Sleep disturbances observed in high-risk infants persisted at five years. Maternal involvement in infant settling was greater in high risk mothers, and predicted less optimal sleep at five years. Poorer five year sleep was associated with concurrent child anxiety/depression and aggression, but there was limited evidence for an influence of early sleep problems. Associations between infant/child sleep characteristics and IQ were also limited. Conclusions Early maternal over-involvement in infant settling is associated with less optimal sleep in children, which in turn, is related to child adjustment. The findings highlight the importance of supporting parents in the early development of good settling practices, particularly in high-risk populations.

Controls on development and diversity of Early Archean stromatolites

The ≈3,450-million-year-old Strelley Pool Formation in Western Australia contains a reef-like assembly of laminated sedimentary accretion structures (stromatolites) that have macroscale characteristics suggestive of biological influence. However, direct microscale evidence of biology—namely, organic microbial remains or biosedimentary fabrics—has to date eluded discovery in the extensively-recrystallized rocks. Recently-identified outcrops with relatively good textural preservation record microscale evidence of primary sedimentary processes, including some that indicate probable microbial mat formation. Furthermore, we find relict fabrics and organic layers that covary with stromatolite morphology, linking morphologic diversity to changes in sedimentation, seafloor mineral precipitation, and inferred microbial mat development. Thus, the most direct and compelling signatures of life in the Strelley Pool Formation are those observed at the microscopic scale. By examining spatiotemporal changes in microscale characteristics it is possible not only to recognize the presence of probable microbial mats during stromatolite development, but also to infer aspects of the biological inputs to stromatolite morphogenesis. The persistence of an inferred biological signal through changing environmental circumstances and stromatolite types indicates that benthic microbial populations adapted to shifting environmental conditions in early oceans.

Long-term effectiveness of sowing high and low diversity seed mixtures to enhance plant community development on ex-arable fields

Questions: How is succession on ex-arable land affected by sowing high and low diversity mixtures of grassland species as compared to natural succession? How long do effects persist? Location: Experimental plots installed in the Czech Republic, The Netherlands, Spain, Sweden and the United Kingdom. Methods: The experiment was established on ex-arable land, with five blocks, each containing three 10 m x 10 m experiment tal plots: natural colonization, a low- (four species) and high-diversity (15 species) seed mixture. Species composition and biomass was followed for eight years. Results: The sown plants considerably affected the whole successional pathway and the effects persisted during the whole eight year period. Whilst the proportion of sown species (characterized by their cover) increased during the study period, the number of sown species started to decrease from the third season onwards. Sowing caused suppression of natural colonizing species, and the sown plots had more biomass. These effects were on average larger in the high diversity mixtures. However, the low diversity replicate sown with the mixture that produced the largest biomass or largest suppression of natural colonizers fell within the range recorded at the five replicates of the high diversity plots. The natural colonization plots usually had the highest total species richness and lowest productivity at the end of the observation period. Conclusions: The effect of sowing demonstrated dispersal limitation as a factor controlling the rate of early secondary succession. Diversity was important primarily for its 'insurance effect': the high diversity mixtures were always able to compensate for the failure of some species.

Probiotics and cancer: from in vitro to human studies

Studies in cell cultures and animal models provide evidence that probiotics can beneficially influence various stages in development of colon cancer including tumor initiation, promotion and metastasis. For example, oral administration of Lactobacillus and Bifidobacterium strains can prevent genotoxic damage to the colonic epithelium (considered to be an early stage of the carcinogenic process). Administration to rats of probiotics reduced the incidence of carcinogen-induced pre-cancerous lesions (aberrant crypt foci) in the colon. Furthermore a combination of Bifidobacterium longum and inulin (a prebiotic) was more effective than either treatment alone. In this latter study, the dietary treatments were given after exposure to the carcinogen, which suggests that the protective effects were being exerted at the promotional phase of carcinogenesis. L. acidophilus feeding has been shown to decrease the incidence of colon tumors in rats challenged with a carcinogen and B. longum reduced the incidence of carcinogeninduced colon, liver and mammary tumors. There is limited evidence from epidemiological studies for protective effects of products containing probiotics in humans, but a number of recent dietary intervention studies in healthy subjects and in polyp and cancer patients have yielded promising results on the basis of biomarkers of cancer risk and grade of colorectal tumors.

Liposomes and skin: From drug delivery to model membranes

The early eighties saw the introduction of liposomes as skin drug delivery systems, initially promoted primarily for localised effects with minimal systemic delivery. Subsequently, a novel ultradeformable vesicular system (termed "Transfersomes" by the inventors) was reported for transdermal delivery with an efficiency similar to subcutaneous injection. Further research illustrated that the mechanisms of liposome action depended on the application regime and the vesicle composition and morphology. Ethical, health and supply problems with human skin have encouraged researchers to use skin models. 'IYaditional models involved polymer membranes and animal tissue, but whilst of value for release studies, such models are not always good mimics for the complex human skin barrier, particularly with respect to the stratum corneal intercellular lipid domains. These lipids have a multiply bilayered organization, a composition and organization somewhat similar to liposomes, Consequently researchers have used vesicles as skin model membranes. Early work first employed phospholipid liposomes and tested their interactions with skin penetration enhancers, typically using thermal analysis and spectroscopic analyses. Another approach probed how incorporation of compounds into liposomes led to the loss of entrapped markers, analogous to "fluidization" of stratum corneum lipids on treatment with a penetration enhancer. Subsequently scientists employed liposomes formulated with skin lipids in these types of studies. Following a brief description of the nature of the skin barrier to transdermal drug delivery and the use of liposomes in drug delivery through skin, this article critically reviews the relevance of using different types of vesicles as a model for human skin in permeation enhancement studies, concentrating primarily on liposomes after briefly surveying older models. The validity of different types of liposome is considered and traditional skin models are compared to vesicular model membranes for their precision and accuracy as skin membrane mimics. (c) 2008 Elsevier B.V. All rights reserved.

Postprandial lipoprotein lipase, insulin and gastric inhibitory polypeptide responses to test meals of different fatty acid composition: comparison of saturated, n-6 and n-3 polyunsaturated fatty acids

OBJECTIVE: The present study was carried out to investigate effects of meals, rich in either saturated fatty acids (SFA), or n-6 or n-3 fatty acids, on postprandial plasma lipid and hormone concentrations as well as post-heparin plasma lipoprotein lipase (LPL) activity. DESIGN: The study was a randomized single-blind study comparing responses to three test meals. SETTING: The volunteers attended the Clinical Investigation Unit of the Royal Surrey County Hospital on three separate occasions in order to consume the meals. SUBJECTS: Twelve male volunteers with an average age of 22.5 +/- 1.4 years (mean +/- SD), were selected from the University of Surrey student population; one subject dropped out of the study because he found the test meal unpalatable. INTERVENTIONS: Three meals were given in the early evening and postprandial responses were followed overnight for 11h. The oils used to prepare each of the three test meals were: a mixed oil rich in saturated fatty acids (SFA) which mimicked the fatty acid composition of the current UK diet, corn oil, rich in n-6 fatty acids and a fish oil concentrate (MaxEPA) rich in n-3 fatty acids. The oil under investigation (40 g) was incorporated into the test meals which were otherwise identical [208 g carbohydrates, 35 g protein, 5.65 MJ (1350 kcal) energy]. Postprandial plasma triacylglycerol (TAG), gastric inhibitory polypeptide (GIP), and insulin responses, as well as post-heparin LPL activity (measured at 12 h postprandially only) were investigated. RESULTS: Fatty acids of the n-3 series significantly reduced plasma TAG responses compared to the mixed oil meal (P < 0.05) and increased post-heparin LPL activity 15 min after the injection of heparin (P < 0.01). A biphasic response was observed in TAG, with peak responses occurring at 1 h and between 3-7 h postprandially. GIP and insulin showed similar responses to the three test meals and no significant differences were observed. CONCLUSION: We conclude that fish oils can decrease postprandial plasma TAG levels partly through an increase in post-heparin LPL activity, which however, is not due to increased GIP or insulin concentrations.

Letterforms for handwriting and reading: print script and sanserifs in early twentieth-century England

This essay is about letterforms and typography in reading books for young children and how they were influenced by the teaching of handwriting in the early decades of the twentieth century. I examine the contributions made by infant teachers to typography and book design and draw particular attention to the print script movement and the gradual introduction of sanserif typefaces in reading books. I suggest that the use of sanserifs in reading books for young children is one of their first appearances for continuous text. Although the influence of print script on the teaching of handwriting may have had some undesirable effects, I suggest that it indirectly contributed to some innovations in book design.

Revisiting the Earth's sea-level and energy budgets from 1961 to 2008

We review the sea-level and energy budgets together from 1961, using recent and updated estimates of all terms. From 1972 to 2008, the observed sea-level rise (1.8 ± 0.2 mm yr−1 from tide gauges alone and 2.1 ± 0.2 mm yr−1 from a combination of tide gauges and altimeter observations) agrees well with the sum of contributions (1.8 ± 0.4 mm yr−1) in magnitude and with both having similar increases in the rate of rise during the period. The largest contributions come from ocean thermal expansion (0.8 mm yr−1) and the melting of glaciers and ice caps (0.7 mm yr−1), with Greenland and Antarctica contributing about 0.4 mm yr−1. The cryospheric contributions increase through the period (particularly in the 1990s) but the thermosteric contribution increases less rapidly. We include an improved estimate of aquifer depletion (0.3 mm yr−1), partially offsetting the retention of water in dams and giving a total terrestrial storage contribution of −0.1 mm yr−1. Ocean warming (90% of the total of the Earth's energy increase) continues through to the end of the record, in agreement with continued greenhouse gas forcing. The aerosol forcing, inferred as a residual in the atmospheric energy balance, is estimated as −0.8 ± 0.4 W m−2 for the 1980s and early 1990s. It increases in the late 1990s, as is required for consistency with little surface warming over the last decade. This increase is likely at least partially related to substantial increases in aerosol emissions from developing nations and moderate volcanic activity

Piety and sociability in early modern women's devotional writing

The letters of early modern women demonstrate that their experience of religion was essentially social, contrary to the impression created by much modern work on diaries or meditations. The stereotypical melancholic, pious lady is far from the ideal offered by spiritual advisors, women and men, in their correspondence. Letters demonstrate how women created networks of spiritual support within and beyond their families. Letters also testify to the agency exercised by early modern women in religious matters, particularly in their assumption of the role of religious advisor and in their engagement with ecclesiastical politics. While this is far from showing that religion empowered all early modern women, it does offer a corrective to the unduly gloomy view of the role of religion in such women's lives. Letters provide indispensable testimony to the social nature of women's responses to the changing religious culture and politics of the eighteenth century.

August Thienemann and Loch Lomond - an approach to the design of a system for monitoring the state of north-temperate standing waters

Limnologists had an early preoccupation with lake classification. It gave a necessary structure to the many chemical and biological observations that were beginning to form the basis of one of the earliest truly environmental sciences. August Thienemann was the doyen of such classifiers and his concept with Einar Naumann of oligotrophic and eutrophic lakes remains central to the world-view that limnologists still have. Classification fell into disrepute, however, as it became clear that there would always be lakes that deviated from the prescriptions that the classifiers made for them. Continua became the de rigeur concept and lakes were seen as varying along many chemical, biological and geographic axes. Modern limnologists are comfortable with this concept. That all lakes are different guarantees an indefinite future for limnological research. For those who manage lakes and the landscapes in which they are set, however, it is not very useful. There may be as many as 300000 standing water bodies in England and Wales alone and maybe as many again in Scotland. More than 80 000 are sizable (> 1 ha). Some classification scheme to cope with these numbers is needed and, as human impacts on them increase, a system of assessing and monitoring change must be built into such a scheme. Although ways of classifying and monitoring running waters are well developed in the UK, the same is not true of standing waters. Sufficient understanding of what determines the nature and functioning of lakes exists to create a system which has intellectual credibility as well as practical usefulness. This paper outlines the thinking behind a system which will be workable on a north European basis and presents some early results.

Contribution of fimbriae and flagella of Salmonella enteritidis to colonization and invasion of chicks

Isogenic mutants of Salmonella enteritidis defective for the elaboration of fimbrial types SEF14, SEF17, SEF21 and flagella were used to study the contribution these organelles made to colonization, invasion and lateral transfer in young chicks. The caecum, liver and spleen were colonized within 24 h following oral inoculation of 1-day-old chicks with 10(5) wild-type S. enteritidis strain LA5. However, for some mutants, the numbers of organisms recovered from internal organs was reduced significantly, particularly at 24 h post-inoculum, which supported the hypothesis that the organelles contribute to invasion and dissemination to internal organs. Specifically, mutations affecting SEF17, SEF21 and flagella contributed to a delay in colonization of the spleen, and those affecting SEF21 and flagella delayed colonization of the liver. Lower numbers of bacteria were recovered from the caecum with mutants deficient in elaboration of SEF21. Sentinel birds were colonized by LA5 or EAV40 (14(-), 17(-), 21(-), fla(-)) directly from the environment within 2 days, although a consistent slight delay was observed with the multiple mutant. Overall, our data suggest a collective role for SEF17, SEF21 and flagella, but not SEF14, in the early stages of colonization and invasion of young chicks by S. enteritidis, but these surface appendages appear unnecessary for colonization of birds from their immediate environment.