A new gender-specific model for skin autofluorescence risk stratification

Advanced glycation endproducts (AGEs) are believed to play a significant role in the pathophysiology of a variety of diseases including diabetes and cardiovascular diseases. Non-invasive skin autofluorescence (SAF) measurement serves as a proxy for tissue accumulation of AGEs. We assessed reference SAF and skin reflectance (SR) values in a Saudi population (n = 1,999) and evaluated the existing risk stratification scale. The mean SAF of the study cohort was 2.06 (SD = 0.57) arbitrary units (AU), which is considerably higher than the values reported for other populations. We show a previously unreported and significant difference in SAF values between men and women, with median (range) values of 1.77 AU (0.79–4.84 AU) and 2.20 AU (0.75–4.59 AU) respectively (p-value « 0.01). Age, presence of diabetes and BMI were the most influential variables in determining SAF values in men, whilst in female participants, SR was also highly correlated with SAF. Diabetes, hypertension and obesity all showed strong association with SAF, particularly when gender differences were taken into account. We propose an adjusted, gender-specific disease risk stratification scheme for Middle Eastern populations. SAF is a potentially valuable clinical screening tool for cardiovascular risk assessment but risk scores should take gender and ethnicity into consideration for accurate diagnosis

Antimicrobial resistance in human populations: challenges and opportunities.

Antimicrobial resistance (AMR) is a global public health threat. Emergence of AMR occurs naturally, but can also be selected for by antimicrobial exposure in clinical and veterinary medicine. Despite growing worldwide attention to AMR, there are substantial limitations in our understanding of the burden, distribution and determinants of AMR at the population level. We highlight the importance of population-based approaches to assess the association between antimicrobial use and AMR in humans and animals. Such approaches are needed to improve our understanding of the development and spread of AMR in order to inform strategies for the prevention, detection and management of AMR, and to support the sustainable use of antimicrobials in healthcare

RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells

Regulator of calcineurin 1 (RCAN1) is an endogenous inhibitor of the calcineurin pathway in cells. It is expressed as two isoforms in vertebrates: RCAN1.1 is constitutively expressed in most tissues, whereas transcription of RCAN1.4 is induced by several stimuli that activate the calcineurin-NFAT pathway. RCAN1.4 is highly upregulated in response to VEGF in human endothelial cells in contrast to RCAN1.1 and is essential for efficient endothelial cell migration and tubular morphogenesis. Here, we show that RCAN1.4 has a role in the regulation of agonist-stimulated VEGFR-2 internalisation and establishment of endothelial cell polarity. siRNA-mediated gene silencing revealed that RCAN1 plays a vital role in regulating VEGF-mediated cytoskeletal reorganisation and directed cell migration and sprouting angiogenesis. Adenoviral-mediated overexpression of RCAN1.4 resulted in increased endothelial cell migration. Antisense-mediated morpholino silencing of the zebrafish RCAN1.4 orthologue revealed a disrupted vascular development further confirming a role for the RCAN1.4 isoform in regulating vascular endothelial cell physiology. Our data suggest that RCAN1.4 plays a novel role in regulating endothelial cell migration by establishing endothelial cell polarity in response to VEGF

Macrocyclic colibactin induces DNA double-strand breaks via copper-mediated oxidative cleavage.

Colibactin is an assumed human gut bacterial genotoxin, whose biosynthesis is linked to the clb genomic island that has a widespread distribution in pathogenic and commensal human enterobacteria. Colibactin-producing gut microbes promote colon tumour formation and enhance the progression of colorectal cancer via cellular senescence and death induced by DNA double-strand breaks (DSBs); however, the chemical basis that contributes to the pathogenesis at the molecular level has not been fully characterized. Here, we report the discovery of colibactin-645, a macrocyclic colibactin metabolite that recapitulates the previously assumed genotoxicity and cytotoxicity. Colibactin-645 shows strong DNA DSB activity in vitro and in human cell cultures via a unique copper-mediated oxidative mechanism. We also delineate a complete biosynthetic model for colibactin-645, which highlights a unique fate of the aminomalonate-building monomer in forming the C-terminal 5-hydroxy-4-oxazolecarboxylic acid moiety through the activities of both the polyketide synthase ClbO and the amidase ClbL. This work thus provides a molecular basis for colibactin's DNA DSB activity and facilitates further mechanistic study of colibactin-related colorectal cancer incidence and prevention

Amblyopia and quality of life: a systematic review

Background/Aims Amblyopia is a common condition which can affect up to 5% of the general population. The health-related quality of life (HRQoL) implications of amblyopia and/or its treatment have been explored in the literature. Methods A systematic literature search was undertaken (16th-30th January 2007) to identify the HRQoL implications of amblyopia and/or its treatment. Results A total of 25 papers were included in the literature review. The HRQoL implications of amblyopia related specifically to amblyopia treatment, rather than the condition itself. These included the impact upon family life; social interactions; difficulties undertaking daily activities; and feelings and behaviour. The identified studies adopted a number of methodologies. The study populations included; children with the condition; parents of children with amblyopia; and adults who had undertaken amblyopia treatment as a child. Some studies developed their own measures of HRQoL, and others determined HRQoL through proxy measures. Conclusions The reported findings of the HRQoL implications are of importance when considering the management of cases of amblyopia. Further research is required to assess the immediate and long-term effects of amblyopia and/or its treatment upon HRQoL using a more standardised approach

Star Architecture as Socio-Material Assemblage

Taking inspiration from new materialism and assemblage, the chapter deals with star architects and iconic buildings as socio-material network effects that do not pre-exist action, but are enacted in practice, in the materiality of design crafting and city building. Star architects are here conceptualized as part of broader assemblages of actors and practices ‘making star architecture’ a reality, and the buildings they design are considered not just as unique and iconic objects, but dis-articulated as complex crafts mobilizing skills, technologies, materials, and forms of knowledge not necessarily ascribable to architecture. Overcoming narrow criticism focusing on the symbolic order of icons as unique creations and alienated repetitions of capitalist development, the chapter’s main aim is to widen the scope of critique by bridging culture and economy, symbolism and practicality, making star architecture available to a broad, fragmented arena of (potential) critics, unevenly equipped with critical tools and differentiated experiences

Erratum: Antimicrobial resistance in human populations: challenges and opportunities - ERRATUM.

[This corrects the article DOI: 10.1017/gheg.2017.4.]

XM02 is superior to placebo and equivalent to Neupogen™ in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy

Abstract Background Recombinant granulocyte colony-stimulating factors (G-CSFs) such as Filgrastim are used to treat chemotherapy-induced neutropenia. We investigated a new G-CSF, XM02, and compared it to Neupogen™ after myelotoxic chemotherapy in breast cancer (BC) patients. Methods A total of 348 patients with BC receiving docetaxel/doxorubicin chemotherapy were randomised to treatment with daily injections (subcutaneous 5 μg/kg/day) for at least 5 days and a maximum of 14 days in each cycle of XM02 (n = 140), Neupogen™ (n = 136) or placebo (n = 72). The primary endpoint was the duration of severe neutropenia (DSN) in cycle 1. Results The mean DSN in cycle 1 was 1.1, 1.1, and 3.9 days in the XM02, Neupogen™, and placebo group, respectively. Superiority of XM02 over placebo and equivalence of XM02 with Neupogen™ could be demonstrated. Toxicities were similar between XM02 and Neupogen™. Conclusion XM02 was superior to placebo and equivalent to Neupogen™ in reducing DSN after myelotoxic chemotherapy. Trial Registration Current Controlled Trials ISRCTN02270769</p