Glycaemic management during the inpatient enteral feeding of people with stroke and diabetes.

This paper is an abridged and modified version of guidelines produced by the Joint British Diabetes Societies for inpatient care on glycaemic management during the enteral feeding of people with stroke and diabetes. These were revised in 2017 and have been adapted specifically for Diabetic Medicine. The full version can be found at: www.diabetes.org.uk/joint-british-diabetes-society or https://abcd.care/joint-british-diabetes-societies-jbds-inpatient-care-group. Many people have both diabetes and an acute stroke, and a stanv dard approach to the management of people with stroke is the provision of adequate nutrition. Frequently, this involves a period of enteral feeding if there is impaired ability to swallow food safely. There is currently considerable variability in the management of people with diabetes fed enterally after a stroke, and the evidence base guiding diabetes management in this clinical situation is very weak, although poor glycaemic outcomes in people receiving enteral feeding after stroke may worsen recovery and cause harm. The aim of this document is to provide sensible clinical guidance in this area, written by a multidisciplinary team; this guideline had input from diabetes specialist nurses, diabetologists, dietitians, stroke physicians and pharmacists with expertise in this area, and from UK professional organizations. It is aimed at multidisciplinary teams managing people with stroke and diabetes who require enteral feeding. We recognize that there is limited clinical evidence in this area.

Review of Geant4-DNA applications for micro and nanoscale simulations.

Emerging radiotherapy treatments including targeted particle therapy, hadron therapy or radiosensitisation of cells by high-Z nanoparticles demand the theoretical determination of radiation track structure at the nanoscale. This is essential in order to evaluate radiation damage at the cellular and DNA level. Since 2007, Geant4 offers physics models to describe particle interactions in liquid water at the nanometre level through the Geant4-DNA Package. This package currently provides a complete set of models describing the event-by-event electromagnetic interactions of particles with liquid water, as well as developments for the modelling of water radiolysis. Since its release, Geant4-DNA has been adopted as an investigational tool in kV and MV external beam radiotherapy, hadron therapies using protons and heavy ions, targeted therapies and radiobiology studies. It has been benchmarked with respect to other track structure Monte Carlo codes and, where available, against reference experimental measurements. While Geant4-DNA physics models and radiolysis modelling functionalities have already been described in detail in the literature, this review paper summarises and discusses a selection of representative papers with the aim of providing an overview of a) geometrical descriptions of biological targets down to the DNA size, and b) the full spectrum of current micro- and nano-scale applications of Geant4-DNA.

GEANT4 simulation of cyclotron radioisotope production in a solid target.

The use of radioisotopes in nuclear medicine is essential for diagnosing and treating cancer. The optimization of their production is a key factor in maximizing the production yield and minimizing the associated costs. An efficient approach to this problem is the use of Monte Carlo simulations prior to experimentation. By predicting isotopes yields, one can study the isotope of interest expected activity for different energy ranges. One can also study the target contamination with other radioisotopes, especially undesired radioisotopes of the wanted chemical element which are difficult to separate from the irradiated target and might result in increasing the dose when delivering the radiopharmaceutical product to the patient. The aim of this work is to build and validate a Monte Carlo simulation platform using the GEANT4 toolkit to model the solid target system of the South Australian Health and Medical Research Institute (SAHMRI) GE Healthcare PETtrace cyclotron. It includes a GEANT4 Graphical User Interface (GUI) where the user can modify simulation parameters such as the energy, shape and current of the proton beam, the target geometry and material, the foil geometry and material and the time of irradiation. The paper describes the simulation and presents a comparison of simulated and experimental/theoretical yields for various nuclear reactions on an enriched nickel 64 target using the GEANT4 physics model QGSP_BIC_AllHP, a model recently developed to evaluate with high precision the interaction of protons with energies below 200MeV available in Geant4 version 10.1. The simulation yield of the (64)Ni(p,n)(64)Cu reaction was found to be 7.67±0.074 mCi·µA(-1) for a target energy range of 9-12MeV. Szelecsenyi et al. (1993) gives a theoretical yield of 6.71mCi·µA(-1) and an experimental yield of 6.38mCi·µA(-1). The (64)Ni(p,n)(64)Cu cross section obtained with the simulation was also verified against the yield predicted from the nuclear database TENDL and compared to experimental yield obtained from literature.

Evaluation of physician eye lens doses during permanent seed implant brachytherapy for prostate cancer.

Treatment of low grade prostate cancer with permanent implant of radioactive seeds has become one of the most common brachytherapy procedures in use today. The implant procedure is usually performed with fluoroscopy image guidance to ensure that the seeds are deployed in the planned locations. In this situation the physician performing the transperineal implant is required to be close to the fluoroscopy unit and dose to the eye lens may be of concern. In 1991 the International Commission on Radiological Protection (ICRP) provided a recommended dose limit of 150 mSv yr(-1) for occupational exposures to the lens of the eye. With more long term follow-up data, this limit was revised in 2011 to 20 mSv yr(-1). With this revised limit in mind, we have investigated the dose to the lens of the eye received by physicians during prostate brachytherapy seed implantation. By making an approximation of annual workload, we have related the dose received to the annual background dose. Through clinical and phantom measurements with thermoluminescent dosimeters, it was found that the excess dose to the physician's eye lens received for a conservative estimate of annual workload was never greater than 100% of the annual background dose.

Total variation superiorization schemes in proton computed tomography image reconstruction.

PURPOSE: Iterative projection reconstruction algorithms are currently the preferred reconstruction method in proton computed tomography (pCT). However, due to inconsistencies in the measured data arising from proton energy straggling and multiple Coulomb scattering, the noise in the reconstructed image increases with successive iterations. In the current work, the authors investigated the use of total variation superiorization (TVS) schemes that can be applied as an algorithmic add-on to perturbation-resilient iterative projection algorithms for pCT image reconstruction. METHODS: The block-iterative diagonally relaxed orthogonal projections (DROP) algorithm was used for reconstructing GEANT4 Monte Carlo simulated pCT data sets. Two TVS schemes added on to DROP were investigated; the first carried out the superiorization steps once per cycle and the second once per block. Simplifications of these schemes, involving the elimination of the computationally expensive feasibility proximity checking step of the TVS framework, were also investigated. The modulation transfer function and contrast discrimination function were used to quantify spatial and density resolution, respectively. RESULTS: With both TVS schemes, superior spatial and density resolution was achieved compared to the standard DROP algorithm. Eliminating the feasibility proximity check improved the image quality, in particular image noise, in the once-per-block superiorization, while also halving image reconstruction time. Overall, the greatest image quality was observed when carrying out the superiorization once per block and eliminating the feasibility proximity check. CONCLUSIONS: The low-contrast imaging made possible with TVS holds a promise for its incorporation into future pCT studies.

Receptor for AGEs (RAGE) blockade may exert its renoprotective effects in patients with diabetic nephropathy via induction of the angiotensin II type 2 (AT2) receptor.

AIMS/HYPOTHESIS: The receptor for AGEs (RAGE) contributes to the development and progression of diabetic nephropathy. In this study, we examined whether the protective effects of RAGE blockade are exerted via modulation of the renal angiotensin II type 2 (AT2) receptor. METHODS: Control and streptozotocin diabetic mice, wild-type or deficient in the AT2 receptor (At2 knockout [KO]) or RAGE (Rage KO), were studied for 24 weeks. Adenoviral overexpression of full-length Rage in primary rat mesangial cells was also used to determine the effects on AT2 production. RESULTS: With diabetes, Rage-deficient mice had less albuminuria, and an attenuation of hyperfiltration and glomerulosclerosis as compared with diabetic wild-type and At2 KO mice. Renal gene and protein expression of RAGE was elevated with diabetes. Diabetic Rage KO mice had a greater increase in renal AT2 receptor protein than was seen in diabetic wild-type mice. Diabetes-induced increases in renal cytosolic and mitochondrial superoxide generation were prevented in diabetic Rage KO mice, but enhanced in all At2 KO mice. Adenoviral overexpression of RAGE or AGE treatment decreased cell surface AT2 expression, in association with increasing superoxide generation; both were reversed using antioxidants N-acetylcysteine and apocynin, and soluble RAGE in primary mesangial cells. CONCLUSIONS/INTERPRETATION: RAGE appears to be a common and key modulator of AT2 receptor expression, a finding that would implicate a newly defined RAGE-AT2 axis in the development and progression of diabetic nephropathy.

A more accurate reconstruction system matrix for quantitative proton computed tomography.

An accurate system matrix is required for quantitative proton CT (pCT) image reconstruction with iterative projection algorithms. The system matrix is composed of chord lengths of individual proton path intersections with reconstruction pixels. In previous work, reconstructions were performed assuming constant intersection chord lengths, which led to systematic errors of the reconstructed proton stopping powers. The purpose of the present work was to introduce a computationally efficient variable intersection chord length in order to improve the accuracy of the system matrix. An analytical expression that takes into account the discrete stepping nature of the pCT most likely path (MLP) reconstruction procedure was created to describe an angle-dependent effective mean chord length function. A pCT dataset was simulated with GEANT4 using a parallel beam of 200 MeV protons intersecting a computerized head phantom consisting of tissue-equivalent materials with known relative stopping power. The phantom stopping powers were reconstructed with the constant chord length, exact chord length, and effective mean chord length approaches, in combination with the algebraic reconstruction technique. Relative stopping power errors were calculated for each anatomical phantom region and compared for the various methods. It was found that the error of approximately 10% in the mean reconstructed stopping power value for a given anatomical region, resulting from a system matrix with a constant chord length, could be reduced to less than 0.5% with either the effective mean chord length or exact chord length approaches. Reconstructions with the effective mean chord length were found to be approximately 20% faster than reconstructions with an exact chord length. The effective mean chord length method provides the possibility for more accurate, computationally efficient quantitative pCT reconstructions.

The influence of liberal alcohol consumption on glucose metabolism in patients with type 1 diabetes: a pilot study.

BACKGROUND: Little is known about the consequences of excessive alcohol ingestion in patients with type 1 diabetes. AIM: To examine the metabolic effects of acute ingestion of liberal amounts of alcohol in patients with type 1 diabetes. DESIGN: A pilot study using a randomized, placebo controlled, double blind design in Hospital Clinical Research Unit. METHODS: The study included 10 patients with type 1 diabetes (seven male, age 43.9 +/- 9.0 years, duration of diabetes 17.3 +/- 13.8 years, HbA(1c) 8.0 +/- 1.5%) who had a standard 600-calorie lunch on two separate occasions, together with either white wine (men eight units, women six units), or an equivalent volume of alcohol-free wine. Bloods were collected before lunch and hourly for 4 h for glucose, intermediary metabolites, counter-regulatory hormones and inflammatory markers. RESULTS: There were no significant differences between alcohol and alcohol-free days in levels of glucose, triglycerides, free fatty acids, glycerol, cortisol and growth hormone. In contrast, lactate levels rose in response to the meal but with alcohol the overall response was augmented (P = 0.014). Beta-hydroxybutyrate levels were suppressed post-prandially on the alcohol-free day but were significantly elevated with alcohol (P < 0.001). CONCLUSION: A rise in ketones following alcohol ingestion occurred despite subjects being in a strictly controlled environment with no interruption in insulin administration. Such individuals might be at risk of significant ketosis in less-controlled circumstances where insulin administration might be more erratic. Patient education material should contain information to highlight these potential problems.

A maximum likelihood proton path formalism for application in proton computed tomography.

The limited spatial resolution in proton computed tomography (pCT) in comparison to x-ray CT is related to multiple Coulomb scattering (MCS) within the imaged object. The current generation pCT design utilizes silicon detectors that measure the position and direction of individual protons prior to and post-traversing the patient to maximize the knowledge of the path of the proton within the imaged object. For efficient reconstruction with the proposed pCT system, one needs to develop compact and flexible mathematical formalisms that model the effects of MCS as the proton traverses the imaged object. In this article, a compact, matrix-based most likely path (MLP) formalism is presented employing Bayesian statistics and a Gaussian approximation of MCS. Using GEANT4 simulations in a homogeneous 20 cm water cube, the MLP expression was found to be able to predict the Monte Carlo tracks of 200 MeV protons to within 0.6 mm on average when employing 3sigma cuts on the relative exit angle and exit energy. These cuts were found to eliminate the majority of events not conforming to the Gaussian model of MCS used in the MLP derivation. M riszwana Banu

Immediate in-patient management of hyperglycaemia--confusion rather than consensus?

BACKGROUND: In-patients with high blood glucose levels have much greater mortality and morbidity rates compared to normoglycaemic individuals hospitalized with the same condition. AIM: To examine prospectively the glucose-lowering treatments used for patients admitted as acute medical emergencies with admission hyperglycaemia (11-17 mmol/l) under the care of non-diabetes specialist teams. Individuals with acute diabetes emergencies (e.g. diabetic ketoacidosis or HONK or glucose levels >17 mmol/l) were excluded. METHODS: Patients' notes were examined as they were admitted without any interventions from the diabetes team. Choice of treatment for their hyperglycaemia was noted and the average blood glucose level was calculated each day of admission for the first 5 days based on bedside fingerstick glucose measurements. RESULTS: Seventy-three in-patients [37 men, average (SD) age 74.1(12) years] with hyperglycaemia [average 13.7(1.6) mmol/l] on admission were included. Fourteen were not known to have diabetes, three had type 1 and 56 type 2 diabetes. Glycaemic control was suboptimal and achieved values were unrelated to the mode of delivery of glucose-lowering therapies. Length of stay and death rates in hospital were greatest in the group of patients who were not previously known to have diabetes. CONCLUSION: Untreated or under-treated hyperglycaemia was a common occurrence in patients admitted to hospital with an acute medical emergency. There may be a role for hospital-based specialist diabetes teams to take a lead in facilitating more acceptable glucose control to achieve standard 8 of the National Service Framework for Diabetes.

Prevalence of diabetes in care home residents.

OBJECTIVE: To determine the prevalence of known and undetected diabetes diagnosed either by an elevated fasting baseline sample or by a 2-h post-glucose load sample in a group of residents of care homes in an urban-district setting. RESEARCH DESIGN AND METHODS: We completed individual interviews with patients and caregivers in 30 care homes (both residential and nursing homes) in two metropolitan districts of Birmingham, West Midlands, U.K. All care homes were under the supervision of primary care physicians (general practitioners). We carried out 75-g oral glucose tolerance tests (OGTTs) in consenting residents without previous known diabetes. Criteria for diagnosis of diabetes were obtained from the World Health Organization (1998) and the American Diabetes Association (1997). RESULTS: Of 636 residents available for study, 76 residents (12.0%) were known to have diabetes; of the 560 remaining residents, 286 either refused to participate or were deemed too ill or unavailable to undergo testing. Complete data on 274 OGTTs were obtained (median age 83 years, range 45-101). A total of 46 subjects were diagnosed as having diabetes and 94 as having impaired glucose tolerance. Allowing for subjects who refused or were unable to participate, the calculated total prevalence (which includes known and newly detected diabetes) was 26.7% (95% CI 21.9-32.0). The calculated overall prevalence of impaired glucose tolerance was 30.2% (25.2-35.6). CONCLUSIONS: In a group of care home residents not known to have diabetes and able to undergo testing, a substantial proportion have undetected diabetes based on a 2-h postglucose load. These residents warrant further study as they may be at higher cardiovascular risk and require an intervention.

C3H apoE(-/-) mice have less atherosclerosis than C57BL apoE(-/-) mice despite having a more atherogenic serum lipid profile.

Wild-type C57BL mice are known to be susceptible to diet-induced atherosclerosis, whilst C3H mice are resistant. We investigated the effect of these background strains on the hyperlipidaemia and atherosclerosis that develops in mice deficient in apolipoprotein E (apoE(-/-)). Male and female apoE(-/-) mice on C3H/HeNHsd (C3H) and C57BL/6J (C57) backgrounds were fed atherogenic Western diet for 12 weeks. Serum cholesterol and triglyceride concentrations were measured and atherosclerosis quantified in the aortic sinus. C3H apoE(-/-) mice fed normal diet had 1.5 2 fold higher serum cholesterol levels than C57 apoE(-/-) mice and 4-5 fold higher serum triglyceride concentrations. Feeding Western diet caused a 4-5 fold increase in serum cholesterol in all mice, but levels of triglyceride were either attenuated or were unaffected in C3H apoE(-/-) and C57 apoE(-/-) mice, respectively. C3H apoE(-/-) mice had approximately 2 fold higher serum cholesterol and 4 fold higher triglyceride concentrations than the C57 apoE(-/-) mice throughout the study. Serum triglyceride concentrations were 35-108% higher in male C3H apoE(-/-) than female C3H apoE(-/-) mice. Most of the lipids were present in the very low density lipoprotein (VLDL)/chylomicron fraction in both strains of mice whether they were fed normal or Western diet. Notwithstanding the lower plasma lipid concentrations, atherosclerotic lesion areas were more than 2-fold larger in C57 apoE(-/-) than in C3H apoE(-/-) mice (males 68 +/- 11 x 10(3) vs 30 +/- 6 x 10(3) females 102 +/- 12 x 10(3) vs 41 +/- 8 x 10(3) microm2. mean +/- SEM).

Deletion of the Cul1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E.

The stability of many proteins is controlled by the ubiquitin proteolytic system, which recognizes specific substrates through the action of E3 ubiquitin ligases [1]. The SCFs are a recently described class of ubiquitin ligase that target a number of cell cycle regulators and other proteins for degradation in both yeast and mammalian cells [2] [3] [4] [5] [6]. Each SCF complex is composed of the core protein subunits Skp1, Rbx1 and Cul1 (known as Cdc53 in yeast), and substrate-specific adaptor subunits called F-box proteins [2] [3] [4]. To understand the physiological role of SCF complexes in mammalian cells, we generated mice carrying a deletion in the Cul1 gene. Cul1(-/-) embryos arrested around embryonic day 6.5 (E6.5) before the onset of gastrulation. In all cells of the mutant embryos, cyclin E protein, but not mRNA, was highly elevated. Outgrowths of Cul1(-/-) blastocysts had limited proliferative capacity in vitro and accumulated cyclin E in all cells. Within Cul1(-/-) blastocyst cultures, trophoblast giant cells continued to endocycle despite the elevated cyclin E levels. These results suggest that cyclin E abundance is controlled by SCF activity, possibly through SCF-dependent degradation of cyclin E.

MCP-1-mediated chemotaxis requires activation of non-overlapping signal transduction pathways.

Monocyte chemoattractant protein-1 (MCP-1) is a CC chemokine that attracts monocytes and T lymphocytes. Its receptor (CCR2) is a heptahelical G-protein-coupled receptor (GPCR) whose signal transduction pathways for chemotaxis have not been completely defined. Because other GPCRs stimulate the mitogen-activated protein kinase (MAPK) cascade, we examined this pathway's activity in response to MCP-1. MCP-1 induced rapid and transient activation of MAPK in human monocytes and in Chinese hamster ovary cells expressing CCR2B. This effect was largely insensitive to pertussis toxin and wortmannin, and was protein kinase C-dependent and protein tyrosine kinase-independent. PD 098059, an inhibitor of MEK activation, not only prevented MAPK activation but also inhibited MCP-1-induced chemotaxis. Because pertussis toxin and wortmannin also efficiently inhibit chemotaxis but do not completely inhibit MAPK activation, these data may define non-overlapping signal transduction pathways that all must be activated to produce chemokine-mediated chemotaxis.

Regulation of the expression of the traM gene of the F sex factor of Escherichia coli.

Conjugative F-plasmid transfer is mediated by the transfer (tra) region which encodes nearly 40 genes, 25 of which are essential for this process in Escherichia coli. TraM is required for conjugation and is encoded on a separate operon between the origin of transfer and the traJ gene. The traJ gene product is the positive regulator of transcription of the 30 kb tra operon, the first gene of which is traY. Using primer-extension assays and immunoblots on the F plasmid itself and its derivatives, we demonstrate that F TraM regulates its own expression from two promoters and that it requires TraY as well as expression of the tra operon for maximal traM transcription. traY is the first gene in the tra operon under the control of the TraJ regulator, which is in turn negatively regulated by the antisense RNA, FinP, and the FinO protein. Thus, a control circuit has been established whereby traM is negatively regulated by the FinOP fertility inhibition system through its repression of TraJ expression, which adversely affects transcription of the traY gene.

Stationary phase expression of a novel Escherichia coli outer membrane lipoprotein and its relationship with mammalian apolipoprotein D. Implications for the origin of lipocalins.

We report a novel outer membrane lipoprotein of Escherichia coli. DNA sequencing between ampC and sugE at the 94.5 min region of the E. coli chromosome revealed an open reading frame specifying 177 amino acid residues. Primer extension analysis demonstrated that the promoter is activated at the transition between exponential and stationary growth phases under control of the rpoS sigma factor gene, and this was confirmed in vivo by monitoring expression of beta-galactosidase activity from a lacZ translational fusion. The amino acid sequence exhibited 31% identity with human apolipoprotein D (apoD), which is a component of plasma high density lipoprotein and belongs to the eukaryotic family of lipocalins. The bacterial lipocalin (Blc) contained a short deletion of 7 amino acid residues corresponding to a hydrophobic surface loop that is thought to facilitate the physical interaction between apoD and high density lipoprotein. However, Blc exhibited a typical prokaryotic lipoprotein signal peptide at its amino terminus. Overexpression, membrane fractionation, and metabolic labeling with [3H]palmitate demonstrated that Blc is indeed a globomycin-sensitive outer membrane lipoprotein. Blc represents the first bacterial member of the family of lipocalins and may serve a starvation response function in E. coli.

The nature of the traK4 mutation in the F sex factor of Escherichia coli.

The sequence of traK gene of the F sex factor of Escherichia coli is presented; the traK gene product is predicted to be a protein of 25,627 Da with a signal sequence of 21 amino acids to give a mature protein of 23,307 Da. The traK4 mutation is an extremely polar mutation in the F plasmid that affects F pilus synthesis and plasmid transfer. traK genes carrying the traK4 mutation and a nonpolar mutation traK105 were cloned, sequenced, and identified as an amber nonsense and a frameshift mutation, respectively. The traK4 mutation occurred within one predicted rho-dependent transcription termination element (TTE) and immediately upstream of another, while the traK105 mutation occurred after the two potential TTEs within the traK gene. S1 nuclease protection analysis and Northern (RNA) blot analysis were used to confirm that the traK4 mutation, but not the traK105 mutation, caused premature termination of transcription. Computer analysis of the F transfer region suggested the presence of TTE motifs at regular intervals throughout the 33.4-kb sequence.