Diabetes downregulates large-conductance Ca2+-activated potassium beta 1 channel subunit in retinal arteriolar smooth muscle

Retinal vasoconstriction and reduced retinal blood flow precede the onset of diabetic retinopathy. The pathophysiological mechanisms that underlie increased retinal arteriolar tone during diabetes remain unclear. Normally, local Ca(2+) release events (Ca(2+)-sparks), trigger the activation of large-conductance Ca(2+)-activated K(+)(BK)-channels which hyperpolarize and relax vascular smooth muscle cells, thereby causing vasodilatation. In the present study, we examined BK channel function in retinal vascular smooth muscle cells from streptozotocin-induced diabetic rats. The BK channel inhibitor, Penitrem A, constricted nondiabetic retinal arterioles (pressurized to 70mmHg) by 28%. The BK current evoked by caffeine was dramatically reduced in retinal arterioles from diabetic animals even though caffeine-evoked [Ca(2+)](i) release was unaffected. Spontaneous BK currents were smaller in diabetic cells, but the amplitude of Ca(2+)-sparks was larger. The amplitudes of BK currents elicited by depolarizing voltage steps were similar in control and diabetic arterioles and mRNA expression of the pore-forming BKalpha subunit was unchanged. The Ca(2+)-sensitivity of single BK channels from diabetic retinal vascular smooth muscle cells was markedly reduced. The BKbeta1 subunit confers Ca(2+)-sensitivity to BK channel complexes and both transcript and protein levels for BKbeta1 were appreciably lower in diabetic retinal arterioles. The mean open times and the sensitivity of BK channels to tamoxifen were decreased in diabetic cells, consistent with a downregulation of BKbeta1 subunits. The potency of blockade by Pen A was lower for BK channels from diabetic animals. Thus, changes in the molecular composition of BK channels could account for retinal hypoperfusion in early diabetes, an idea having wider implications for the pathogenesis of diabetic hypertension.

Vegetarian diets, low-meat diets and health:a review

OBJECTIVE: To review the epidemiological evidence for vegetarian diets, low-meat dietary patterns and their association with health status in adults. DESIGN: Published literature review focusing primarily on prospective studies and meta-analyses examining the association between vegetarian diets and health outcomes. RESULTS: Both vegetarian diets and prudent diets allowing small amounts of red meat are associated with reduced risk of diseases, particularly CHD and type 2 diabetes. There is limited evidence of an association between vegetarian diets and cancer prevention. Evidence linking red meat intake, particularly processed meat, and increased risk of CHD, cancer and type 2 diabetes is convincing and provides indirect support for consumption of a plant-based diet. CONCLUSIONS: The health benefits of vegetarian diets are not unique. Prudent plant-based dietary patterns which also allow small intakes of red meat, fish and dairy products have demonstrated significant improvements in health status as well. At this time an optimal dietary intake for health status is unknown. Plant-based diets contain a host of food and nutrients known to have independent health benefits. While vegetarian diets have not shown any adverse effects on health, restrictive and monotonous vegetarian diets may result in nutrient deficiencies with deleterious effects on health. For this reason, appropriate advice is important to ensure a vegetarian diet is nutritionally adequate especially for vulnerable groups.

An orientation free adaptive step detection algorithm using a smart phone in physical activity monitoring

In this paper we present an Orientation Free Adaptive Step Detection (OFASD) algorithm for deployment in a smart phone for the purposes of physical activity monitoring. The OFASD algorithm detects individual steps and measures a user’s step counts using the smart phone’s in-built accelerometer. The algorithm considers both the variance of an individual’s walking pattern and the orientation of the smart phone. Experimental validation of the algorithm involved the collection of data from 10 participants using five phones (worn at five different body positions) whilst walking on a treadmill at a controlled speed for periods of 5 min. Results indicated that, for steps detected by the OFASD algorithm, there were no significant differences between where the phones were placed on the body (p > 0.05). The mean step detection accuracies ranged from 93.4 % to 96.4 %. Compared to measurements acquired using existing dedicated commercial devices, the results demonstrated that using a smart phone for monitoring physical activity is promising, as it adds value to an accepted everyday accessory, whilst imposing minimum interaction from the user. The algorithm can be used as the underlying component within an application deployed within a smart phone designed to promote self-management of chronic disease where activity measurement is a significant factor, as it provides a practical solution, with minimal requirements for user intervention and less constraints than current solutions.

The Role of Variation at AβPP, PSEN1, PSEN2, and MAPT in Late Onset Alzheimer's Disease

Rare mutations in AßPP, PSEN1, and PSEN2 cause uncommon early onset forms of Alzheimer's disease (AD), and common variants in MAPT are associated with risk of other neurodegenerative disorders. We sought to establish whether common genetic variation in these genes confer risk to the common form of AD which occurs later in life (>65 years). We therefore tested single-nucleotide polymorphisms at these loci for association with late-onset AD (LOAD) in a large case-control sample consisting of 3,940 cases and 13,373 controls. Single-marker analysis did not identify any variants that reached genome-wide significance, a result which is supported by other recent genome-wide association studies. However, we did observe a significant association at the MAPT locus using a gene-wide approach (p = 0.009). We also observed suggestive association between AD and the marker rs9468, which defines the H1 haplotype, an extended haplotype that spans the MAPT gene and has previously been implicated in other neurodegenerative disorders including Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. In summary common variants at AßPP, PSEN1, and PSEN2 and MAPT are unlikely to make strong contributions to susceptibility for LOAD. However, the gene-wide effect observed at MAPT indicates a possible contribution to disease risk which requires further study.

A simultaneous voltammetric temperature and humidity sensor

We report the simultaneous measurement of temperature and humidity by analysing square wave voltammetric responses of two ferrocene derivatives, decamethylferrocene (DmFc) and 1,2-diferrocenylethylene (bisferrocene, BisFc) in 1-(2-methoxyethyl)-1-methyl-pyrrolidinium tris(pentafluoroethyl) trifluorophosphate ([Moepyrr][FAP]). These two molecules produce three peaks in square wave voltammetry. Through study of the peak potentials of BisFc/BisFc(+) (vs. DmFc/DmFc(+)) and BisFc(+)/BisFc(2+) (vs. DmFc/DmFc(+)) over a temperature range of 298 K to 318 K and humidity range of 1% to 50% using square wave voltammetry, the temperature and humidity dependences of the relative peak potentials were investigated. A reliable method to calculate the humidity and temperature based on the voltammetric experiment is characterised and demonstrated.

Tuning solute redox potentials by varying the anion component of room temperature ionic liquids

The electrode potentials for the two one electron oxidations of 1,2-diferrocenylethylene (bisferrocene, BF) were studied relative to that of the one electrode oxidation of decamethylferrocene in a variety of RTILs. The difference in these potentials was found to be very sensitive to the anion component of the ionic liquid showing the scope of these solutes as 'designer media' to tune the thermodynamic properties of solutes dissolved in them.

BRCA1 Immunohistochemical Staining as a Prognostic Indicator in Uterine Serous Carcinoma

OBJECTIVES: The objective of this study was to investigate the relationship between BRCA1 protein expression, as determined by immunohistochemistry, and clinical outcome in uterine serous carcinoma (USC). METHODS: A tissue microarray containing duplicate cores of 73 cases of USC was immunohistochemically stained with mouse anti-BRCA1 (Ab-1) mouse monoclonal (MS110) antibody. The cores were scored in a semiquantitative manner evaluating both the distribution and intensity of nuclear staining. BRCA1 protein expression was correlated with progression-free survival. RESULTS: Seventy-two of 73 cases were assessable, and there was a statistically significant decreased progression-free survival for those cases exhibiting tumor cell nuclei staining of 76% or greater (P = 0.0023). CONCLUSIONS: Our study illustrates that a low level of BRCA1 protein expression is a favorable prognostic indicator in USC, similar to what is observed in high-grade serous ovarian carcinoma. Further studies should focus on the BRCA1 status of USCs at a molecular level and also investigate whether BRCA1 protein expression is associated with response to chemotherapy in USC.

The Palisades is a key reference site for the middle Pleistocene of eastern Beringia: New evidence from paleomagnetics and regional tephrostratigraphy

The Palisades, in central Alaska, is one of the most prominent exposures of Quaternary sediments on the Yukon River. Perennially-frozen silt and sand at the Palisades are presently thought to preserve paleoenvironmental records from the Holocene to ~Marine Isotope Stage (MIS) 8 and, beneath a major unconformity, the earliest Pleistocene (~2 Ma). We present new paleomagnetic and tephrochronologic constraints that substantially revise the age of the sediments at the Palisades. We describe 15 new tephra beds, including five beds below the prominent PAL tephra that correlate to known tephra with independent age control from other sites in eastern Beringia. These five known tephra include Chester Bluff tephra, which is present in east-central Alaska and the Yukon, and the newly named Alyeska Pipeline and Taylor Highway tephra from central Alaska; all are constrained to the middle Pleistocene. Paleomagnetic transects from the base of the bluff to the MIS 5e forest bed yield normal polarity, with the exception of a brief reversal event between Old Crow tephra (124 ± 10 ka) and the MIS 5e forest bed that is likely the first documentation of the Blake paleomagnetic event in Alaskan loess. The detailed tephrostratigraphy and paleomagnetic data collectively suggest that most of the sedimentary record at the Palisades is middle Pleistocene in age. The Palisades thus preserves a rare record of late to middle Pleistocene paleoenvironments with multiple regionally distributed tephra beds. © 2013 Elsevier Ltd.

Controlled chemistry of Moisture Sensitive Reagents in Ionic Liquids

Many reactions involving phosphorus reagents require highly anhydrous and inert conditions for their successful implementation. In particular, the use of PCl3 and its derivatives for synthesis is often hampered by the inherent sensitivity of the materials themselves. Ionic liquids are emerging as green alternative solvents for a range of processes, and in particular have proven to be excellent media for highly sensitive phosphorus reagents without the need for anhydrous or inert conditions. Herein, we report the use of ionic liquids as both storage and reaction media which allows difficult and sensitive chemistry to be achieved in a more accessible manner.

Current treatments in diabetic macular oedema:systematic review and meta-analysis

The aim of this systematic review is to appraise the evidence for the use of anti-VEGF drugs and steroids in diabetic macular oedema (DMO) as assessed by change in best corrected visual acuity (BCVA), central macular thickness and adverse events

Changed reactivity of the 1-bromo-4-nitrobenzene radical anion in a room temperature ionic liquid

Radical anions of 1-bromo-4-nitrobenzene (p-BrC6H4NO2) are shown to be reactive in the room temperature ionic liquid N-butyl-N-methylpyrrolidinium bis(trifluoromethylsulfonyl)imide, ([C(4)mPyrr][NTf2]), by means of voltammetric measurements. In particular, they are shown to react via a DISP type mechanism such that the electrolysis of p-BrC6H4NO2 occurs consuming between one and two electrons per reactant molecule, leading to the formation of the nitrobenzene radical anion and bromide ions. This behaviour is a stark contrast to that in conventional non-aqueous solvents such as acetonitrile, dimethyl sulfoxide or N,N-dimethylformamide, which suggests that the ionic solvent promotes the reactivity of the radical anion, probably via stabilisation of the charged products.

Pinning down the solid-state polymorphism of the ionic liquid [bmim][PF6]

The solid-state polymorphism of the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate, [bmim][PF6], has been investigated via low-temperature and high-pressure crystallisation experiments. The samples have been characterised by single-crystal X-ray diffraction, optical microscopy and Raman spectroscopy. The solid-state phase behaviour of the compound is confirmed and clarified with respect to previous phase diagrams. The structures of the previously reported gamma-form, which essentially exhibits a G'T cation conformation, as well as those of the elusive beta- and alpha-forms, are reported. Crystals of the beta-phase are twinned and the structure is heavily disordered; the cation conformation in this form is predominantly TT, though significant contributions from other less frequently encountered conformers are also observed at low temperature and high pressure. The cation conformation in the alpha-form is GT; the presence of the G'T conformer at 193 K in this phase can be eliminated on cooling to 100 K. Whilst X-ray structural data are overall in good agreement with previous interpretations based on Raman and NMR studies, they also reveal a more subtle interplay of intermolecular interactions, which give rise to a wider range of conformers than previously considered.