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Numerous classifications are used to discern metabolically healthy obese (MHO) from metabolically abnormal obese (MAO) individuals. The goal of this study was to compare a single phenotype approach, adiposopathy (i.e., the plasma adiponectin/leptin ratio), with four commonly used classifications (International Diabetes Federation (IDF), Karelis, Lynch, Wildman), all based on obesity with other risk factors), for their ability to discern phenotypic differences between MAO and MHO postmenopausal women. Anthropometry, body composition, blood pressure, cardiorespiratory fitness (CRF), lipid-lipoprotein, hepatic, inflammatory, and adipokine profiles, as well as glucose-insulin homeostasis, were assessed in 79 obese sedentary postmenopausal women (60 ± 5 years; body mass index, BMI, 34.0 ± 3.7 kg/m 2 ). Abdominal subcutaneous adipose tissue (SCAT) expression of selected genes involved in fatty acid metabolism and inflammation was used as markers of tissue state (n = 48). Beyond their intrinsic criteria, adiposopathy was almost as effective as the Karelis definition in discerning differences in MHO for adiposity (reduced body weight, BMI, waist circumference, and fat mass), lipid-lipoprotein (lower triacylglycerol and higher HDL-cholesterol levels, reduced atherogenic ratios) and adipokine (higher adiponectin and lower leptin levels) profiles, and glucose-insulin homeostasis (lower insulin resistance) as well as for some SCAT gene expression related to lipolysis and lipogenesis, but was the only one able to distinguish these subjects for greater CRF. The other classifications revealed fewer differences between MAO and MHO women. These data suggest that considering a marker of AT dysfunction such as adiposopathy either alone or in addition to other criteria could be potentially interesting in discerning the MHO phenotype.

Aims/hypothesis: For individuals living with type 1 diabetes, closed-loop insulin delivery improves glycaemic control. Nonetheless, maintenance of glycaemic control during exercise while a prandial insulin bolus remains active is a challenge even to closed-loop systems. We investigated the effect of exercise announcement on the efficacy of a closed-loop system, to reduce hypoglycaemia during postprandial exercise., Methods: A single-blind randomised, crossover open-label trial was carried out to compare three strategies applied to a closed-loop system at mealtime in preparation for exercise taken 90 min after eating at a research testing centre: (1) announced exercise to the closed-loop system (increases target glucose levels) in addition to a 33% reduction in meal bolus (A-RB); (2) announced exercise to the closed-loop system and a full meal bolus (A-FB); (3) unannounced exercise and a full meal bolus (U-FB). Participants performed 60 min of exercise at 60% [Formula: see text] 90 min after eating breakfast. The investigators were not blinded to the interventions. However, the participants were blinded to the sensor glucose readings and to the insulin infusion rates throughout the intervention visits., Results: The trial was completed by 37 adults with type 1 diabetes, all using insulin pumps: mean±SD, 40.0 ± 15.0 years of age, HbA 1c 57.1 ± 10.8 mmol/mol (7.3 ± 1.0%). Reported results were based on plasma glucose values. During exercise and the following 1 h recovery period, time spent in hypoglycaemia (<3.9 mmol/l; primary outcome) was reduced with A-RB (mean ± SD; 2.0 ± 6.2%) and A-FB (7.0 ± 12.6%) vs U-FB (13.0 ± 19.0%; p < 0.0001 and p = 0.005, respectively). During exercise, A-RB had the least drop in plasma glucose levels: A-RB -0.3 ± 2.8 mmol/l, A-FB -2.6 ± 2.9 mmol/l vs U-FB -2.4 ± 2.7 mmol/l (p < 0.0001 and p = 0.5, respectively). Comparison of A-RB vs U-FB revealed a decrease in the time spent in target (3.9-10 mmol/l) by 12.7% (p = 0.05) and an increase in the time spent in hyperglycaemia (>10 mmol/l) by 21% (p = 0.001). No side effects were reported during the applied strategies., Conclusions/interpretation: Combining postprandial exercise announcement, which increases closed-loop system glucose target levels, with a 33% meal bolus reduction significantly reduced time spent in hypoglycaemia compared with the other two strategies, yet at the expense of more time spent in hyperglycaemia., Trial Registration: ClinicalTrials.gov NCT0285530 FUNDING: JDRF (2-SRA-2016-210-A-N), the Canadian Institutes of Health Research (354024) and the Fondation J.-A. DeSève chair held by RR-L.

In this study, an eco-friendly fast simple method was developed for simultaneous determination of norfloxacin and tinidazole based on thin-layer chromatography and image-processing analysis. The binary mixture was separated using reversed phase - thin layer chromatography plates and 30% trifluoroacetic acid only as mobile phase. Mobile phase composition was optimized using Taguchi orthogonal array and Derringer's desirability function. The plates were viewed under UV lamp and photographed by iPhone camera followed by image processing with Fiji software using integrated density as the measured response. As decreasing illumination increases the sensitivity of the method, this method was applied on two different ranges for each drug. The first one was 0.6-6.0 and 0.9-9.0 µg/spot for norfloxacin and tinidazole, respectively measured on the original image with normal illumination. The second one was measured after decreasing the illumination of the captured images at 0.06-0.60 and 0.09-0.90 µg/spot for norfloxacin and tinidazole, respectively. The proposed method was successfully applied for the determination of both drugs in tablets dosage form without interference from the commonly encountered excipients. Analytical Eco-Scale was used to evaluate the greenness profile of the proposed method and it was found to be excellent green analytical method., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Physical activity is important for patients living with type 1 diabetes (T1D) but limited by the challenges associated with physical activity induced glucose variability. Optimizing glycemic control without increasing the risk of hypoglycemia is still a hurdle despite many advances in insulin formulations, delivery methods, and continuous glucose monitoring systems. In this respect, the artificial pancreas (AP) system is a promising therapeutic option for a safer practice of physical activity in the context of T1D. It is important that healthcare professionals as well as patients acquire the necessary knowledge about how the AP system works, its limits, and how glucose control is regulated during physical activity. This review aims to examine the current state of knowledge on exercise-related glucose variations especially hypoglycemic risk in T1D and to discuss their effects on the use and development of AP systems. Though effective and highly promising, these systems warrant further research for an optimized use around exercise.

IN BRIEF Artificial pancreas systems are rapidly developing and constitute the most promising technology for insulin-requiring diabetes management. Single-hormone systems (SH-AP) that deliver only insulin and have a hybrid design that necessitates patients' interventions around meals and exercise are the first to appear on the market. Trials with SH-AP have demonstrated improvement in time spent with blood glucose levels within target ranges, with a concomitant decrease in hypoglycemia. Longer and larger trials involving different patient populations are ongoing to further advance this important technology.

Continuous glucose monitoring (CGM) systems help diabetes management in patients with type 1 diabetes (T1D) but could have lower accuracy during exercise. We aim to evaluate the dynamics of CGM accuracy during exercise in patients with T1D. Secondary analysis of data was carried out on 22 patients with T1D (glycated hemoglobin [HbA 1c ]: 7.3% ± 1.0%, diabetes duration: 23 ± 13 years), who did three exercise sessions (45 min at 60% VO 2max on an ergocycle, 3 h postmeal) with paired Dexcom G4 Platinum, and capillary glucose values that were collected every 5 min. Dexcom accuracy was evaluated using sensor bias (SB) and absolute relative difference (ARD). For dynamics of SB analysis, data pairs following hypoglycemia correction were excluded. The analyzed data included 792 pairs (594 during 66 exercise sessions, 198 at rest before exercise). Median ARD was 8.44 (5.35-12.13)% at rest and increased to 16.77 (10.75-26.72)% during exercise ( P < 0.001). During exercise, mean SB values evolved from T0 minutes = 5.95 ± 16.04 mg/dL (exercise start); T5 = 9.55 ± 16.40; T10 = 13.51 ± 18.02; T15 = 15.32 ± 20.36; T20 = 17.30 ± 18.92; T25 = 19.46 ± 17.48; T30 = 21.08 ± 19.64; T35 = 19.10 ± 20.36; T40 = 19.82 ± 20.18; and T45 = 18.02 ± 20.90 (exercise end). CGM overestimated capillary at a mean SB of 14.23 ± 16.76 mg/dL over the whole exercise session. CGM accuracy decreased during moderate aerobic exercise as previously described. However, the trend to overestimate capillary glucose was maintained at relatively stable values within 15 min of exercise initiation, which could help patients in their clinical decisions. Similar analyses would be needed for other types of exercise.

Physical activity is highly recommended for patients living with type 1 diabetes (T1D) due to its varied health benefits. Nevertheless, glucose management, during and in the hours following exercise, represents a great challenge for these patients who most often end up leading a sedentary life style. Important technological advances in insulin delivery devices and glucose monitoring are now available and continue to progress. These technologies could be used to alleviate glucose management related to physical activity in T1D. Continuous glucose monitoring (CGM) helps patients observe the trends of glycemic fluctuations when exercising and in the following night to deal pre-emptively with hypoglycemic risks and treat hypoglycemic episodes in a timely manner. Insulin pumps offer the flexibility of adjusting insulin basal rates and boluses according to patient's specific needs around exercise. The artificial pancreas links CGM to pump through an intelligent hormone dosing algorithm to close the loop of glucose control and has thus the potential to ease the burden of exercise in T1D. This review will examine and discuss the literature related to physical activity practice using each of these technologies. The aim is to discuss their benefits as well as their limitations and finally the additional research needed in the future to optimize their use in T1D.

Aims: To assess perceptions of patients using subcutaneous insulin infusion (CSII) about metabolic control, pump malfunctions, technical and insertion site adverse events (AEs) related to infusion sets/catheters as well as patients' practices., Methods: Online survey (from June 2016 to January 2017) using an actualized 39-item questionnaire directed to adults with type 1 diabetes (T1D) using CSII therapy and living in the province of Quebec, Canada., Results: Participants with T1D (n = 115, 72% females, 39.7 ± 14.0 years, diabetes duration: 20.9 ± 12.2 years, CSII use: 6.2 ± 4.1 years) adequately completed the survey. Infusion sets were changed every 3.3 ± 0.9 day. Improved glucose control and decreased number/severity of hypoglycemic episodes were reported by 80% and 68%/50% of subjects, respectively. Over the past year of CSII use, participants perceived no increase in anxiety/worry (84%), no negative impact on life (89%) or on time off from work/school (82%). Conversely, many experienced at least one clinical AEs at insertion site [pain (84%), adhesion (76%), irritation (69%), lipodystrophy (45%)] and technical issues [blockage (52%), cannula kinking (50%), pump stop (55%), air bubbles (46%)]. No significant association was observed between catheter wear-time and AEs. All participants had one or more problems related to CSII use, although only 37% reported addressing these issues with health professionals., Conclusion: Our study suggests that patients positively perceived CSII use although they experienced a high frequency of clinical and technical AEs. This warrants further attention by health professionals, investigators and manufacturers to optimize CSII therapy., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Increasing proportions of patients with diabetes use continuous subcutaneous insulin infusion (CSII) therapy mostly due to its clinical efficacy and flexibility for insulin dosing and adjustments. Some challenges are nevertheless associated with this technology. A key and underlooked component of CSII technical difficulties is the subcutaneous catheter used to infuse insulin. Several adverse events (AEs) have been experienced by patients in relation to catheters, such as blockage, kinking, and insertion site reactions, including irritation, infections, lipohypertrophies etc., all of which could compromise the metabolic control. With the objective of minimizing these AEs, recommendations for changing catheters every 2-3 days have historically been provided by manufacturers based on reports derived from small studies and anecdotal data. The aim of this review was to provide an updated analysis of current recommendations and patients' practices in relation to frequency of catheter change. Our main findings are: (1) adequately designed and powered studies investigating optimal catheter wearing time are still lacking; (2) increasing catheter wearing time is generally associated with increased frequency of catheter AEs; (3) however, interpatient variability is large, with some individuals needing to change their catheters every 2-3 days, whereas others probably being able to keep them in place for longer periods without problems. Further research is thus warranted to provide more solid and evidence-based recommendations while exploring personalized approaches at the same time. Increasing catheter wear life without significant side effects is an important goal to simplify CSII therapy and reduce its associated costs and burdens.

The current state of consumer-grade electronics means that researchers, clinicians, students, and members of the general public across the globe can create high-quality auditory stimuli using tablet computers, built-in sound hardware, and calibrated consumer-grade headphones. Our laboratories have created a free application that supports this work: PART (Portable Automated Rapid Testing). PART has implemented a range of psychoacoustical tasks including: spatial release from speech-on-speech masking, binaural sensitivity, gap discrimination, temporal modulation, spectral modulation, and spectrotemporal modulation (STM). Here, data from the spatial release and STM tasks are presented. Data were collected across the globe on tablet computers using applications available for free download, built-in sound hardware, and calibrated consumer-grade headphones. Spatial release results were as good or better than those obtained with standard laboratory methods. Spectrotemporal modulation thresholds were obtained rapidly and, for younger normal hearing listeners, were also as good or better than those in the literature. For older hearing impaired listeners, rapid testing resulted in similar thresholds to those reported in the literature. Listeners at five different testing sites produced very similar STM thresholds, despite a variety of testing conditions and calibration routines. Download Spatial Release, PART, and Listen: An Auditory Training Experience for free at https://bgc.ucr.edu/games/.

For patients with type 1 diabetes, closed-loop delivery systems (CLS) combining an insulin pump, a glucose sensor and a dosing algorithm allowing a dynamic hormonal infusion have been shown to improve glucose control when compared with conventional therapy. Yet, reducing glucose excursion and simplification of prandial insulin doses remain a challenge. The objective of this literature review is to examine current meal-time strategies in the context of automated delivery systems in adults and children with type 1 diabetes. Current challenges and considerations for post-meal glucose control will also be discussed. Despite promising results with meal detection, the fully automated CLS has yet failed to provide comparable glucose control to CLS with carbohydrate-matched bolus in the post-meal period. The latter strategy has been efficient in controlling post-meal glucose using different algorithms and in various settings, but at the cost of a meal carbohydrate counting burden for patients. Further improvements in meal detection algorithms or simplified meal-priming boluses may represent interesting avenues. The greatest challenges remain in regards to the pharmacokinetic and dynamic profiles of available rapid insulins as well as sensor accuracy and lag-time. New and upcoming faster acting insulins could provide important benefits. Multi-hormone CLS (eg, dual-hormone combining insulin with glucagon or pramlintide) and adjunctive therapy (eg, GLP-1 and SGLT2 inhibitors) also represent promising options. Meal glucose control with the artificial pancreas remains an important challenge for which the optimal strategy is still to be determined., (© 2017 John Wiley & Sons Ltd.)

Background: Available glucagon formulations are approved for immediate use after reconstitution for severe hypoglycemia emergency treatment. However, they are used in dual-hormone artificial pancreas (insulin and glucagon) studies through subcutaneous infusion pumps over 24 h. Chemical and physical stability of such glucagon use have not been reported in a comprehensive manner., Materials and Methods: Recombinant Glucagon DNA (Eli Lilly) was used. Compatibility and sterility of glucagon delivery through subcutaneous pump systems were verified. Glucagon degradation through liquid chromatography with tandem mass spectrometry (LC-MS/MS), fibrillation using intrinsic tryptophan fluorescence shift, and bioactivity through a cell-protein kinase A-based fluorescent bioassay were assessed over a range of different physical conditions (temperature, movement, and air bubbles)., Results: Subcutaneous infusion pump systems administered glucagon in sterile conditions and with comparable accuracy to insulin delivery; mean absolute relative difference of actual versus expected weights were 1.2% ± 1.1% for glucagon and 1.1% ± 0.5% for insulin (P = 0.9). In comparison to freshly reconstituted samples, glucagon analyzed through LC-MS/MS was intact at 93.0% ± 7.0% after 24 h (P = 0.42) and 83.04% ± 6.0% after 48 h (P = 0.02) of incubation in pumps at 32°C. Peak wavelengths for Trp fluorescence did not differ from samples exposed to air bubbles or movement whether incubated (in infusion sets for 24 h at 32°) immediately or 24- and 48-h poststorage at 4°C (P = 0.10, 0.70 and 0.80, respectively) and no significant differences in bioactivity (shifts in EC 50 ) were found for the same conditions (P = 0.13, 0.83, and 0.63)., Conclusion: Available glucagon formulations are chemically and physically stable, as well as compatible with delivery through subcutaneous infusion pumps over 24 h and can be used in long-term clinical trials.

Pan-genotypic nucleoside HCV inhibitors display a high genetic barrier to drug resistance and are the preferred direct-acting agents to achieve complete sustained virologic response in humans. Herein, we report, the discovery of a β-d-2'-Cl,2'-F-uridine phosphoramidate nucleotide 16, as a nontoxic pan-genotypic anti-HCV agent. Phosphoramidate 16 in its 5'-triphosphate form specifically inhibited HCV NS5B polymerase with no marked inhibition of human polymerases and cellular mitochondrial RNA polymerase. Studies on the intracellular half-life of phosphoramidate 16-TP in live cells demonstrated favorable half-life of 11.6 h, suggesting once-a-day dosing. Stability in human blood and favorable metabolism in human intestinal microsomes and liver microsomes make phosphoramidate 16 a prospective candidate for further studies to establish its potential value as a new anti-HCV agent.

Objectives: The relative contribution of muscle and liver insulin resistance (IR) in the development of dysglycemia and metabolic abnormalities is difficult to establish. The present study aimed to investigate the relative contribution of muscle IR vs. liver IR to dysglycemia in non-diabetic overweight or obese postmenopausal women and to determine differences in body composition and cardiometabolic indicators associated with hepatic or muscle IR., Material and Methods: Secondary analysis of 156 non-diabetic overweight or obese postmenopausal women. Glucose tolerance was measured using an oral glucose tolerance test. Whole-body insulin sensitivity (IS) was determined as glucose disposal rate during a euglycemic-hyperinsulinemic clamp. Muscle and liver IR have been calculated using Abdul-Ghani et al. OGTT-derived formulas. Participant's body compositions as well as cardiometabolic risk indicators were also determined., Results: Overall, 57 (36.5%) of patients had dysglycemia, among them 25 (16.0%); 21 (13.5%); 11 (7.1%) had impaired fasting glycemia, impaired glucose tolerance and combined glucose intolerance respectively. Fifty-three (34.0%) participants were classified as combined IS while on the opposite 51 participants (32.7%) were classified as combined IR and 26 (16.7%) participants had either muscle IR or liver IR. For similar body mass index and total fat mass, participants with liver IR were more likely to have lower whole-body IS, dysglycemia and higher visceral fat, liver fat index, triglycerides and alanine aminotransferase than participants with muscle IR., Conclusion: In the present study, the presence of liver IR is associated with a higher prevalence of dysglycemia, ectopic fat accumulation and metabolic abnormalities than muscle IR., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

The role of glucagon in the pathophysiology of diabetes has long been recognized, although its approved clinical use has so far been limited to the emergency treatment of severe hypoglycaemia. A novel use of glucagon as intermittent mini-boluses is proposed in the dual-hormone version (insulin and glucagon) of the external artificial pancreas. Short-term studies suggest that the incorporation of glucagon into artificial pancreas systems has the potential to further decrease hypoglycaemic risk and improve overall glucose control; however, the potential long-term safety and benefits also need to be investigated given the recognized systemic effects of glucagon. In the present report, we review the available animal and human data on the physiological functions of glucagon, as well as its pharmacological use, according to dosing and duration (acute and chronic). Along with its main role in hepatic glucose metabolism, glucagon affects the cardiovascular, renal, pulmonary and gastrointestinal systems. It has a potential role in weight reduction through its central satiety function and its role in increasing energy expenditure. Most of the pharmacological studies investigating the effects of glucagon have used doses exceeding 1 mg, in contrast to the mini-boluses used in the artificial pancreas. The available data are reassuring but comprehensive human studies using small but chronic glucagon doses that are close to the physiological ranges are lacking. We propose a list of variables that could be monitored during long-term trials of the artificial pancreas. Such trials should address the questions about the risk-benefit ratio of chronic glucagon use., (© 2016 John Wiley & Sons Ltd.)

Aims/hypothesis: The aim of this study was to assess whether the dual-hormone (insulin and glucagon) artificial pancreas reduces hypoglycaemia compared with the single-hormone (insulin alone) artificial pancreas during two types of exercise., Methods: An open-label randomised crossover study comparing both systems in 17 adults with type 1 diabetes (age, 37.2 ± 13.6 years; HbA 1c, 8.0 ± 1.0% [63.9 ± 10.2 mmol/mol]) during two exercise types on an ergocycle and matched for energy expenditure: continuous (60% [Formula: see text] for 60 min) and interval (2 min alternating periods at 85% and 50% [Formula: see text] for 40 min, with two 10 min periods at 45% [Formula: see text] at the start and end of the session). Blocked randomisation (size of four) with a 1:1:1:1 allocation ratio was computer generated. The artificial pancreas was applied from 15:30 hours until 19:30 hours; exercise was started at 18:00 hours and announced 20 min earlier to the systems. The study was conducted at the Institut de recherches cliniques de Montréal., Results: During single-hormone control compared with dual-hormone control, exercise-induced hypoglycaemia (plasma glucose <3.3 mmol/l with symptoms or <3.0 mmol/l regardless of symptoms) was observed in four (23.5%) vs two (11.8%) interventions (p = 0.5) for continuous exercise and in six (40%) vs one (6.25%) intervention (p = 0.07) for interval exercise. For the pooled analysis (single vs dual hormone), the median (interquartile range) percentage time spent at glucose levels below 4.0 mmol/l was 11% (0.0-46.7%) vs 0% (0-0%; p = 0.0001) and at glucose levels between 4.0 and 10.0 mmol/l was 71.4% (53.2-100%) vs 100% (100-100%; p = 0.003). Higher doses of glucagon were needed during continuous (0.126 ± 0.057 mg) than during interval exercise (0.093 ± 0.068 mg) (p = 0.03), with no reported side-effects in all interventions., Conclusions/interpretation: The dual-hormone artificial pancreas outperformed the single-hormone artificial pancreas in regulating glucose levels during announced exercise in adults with type 1 diabetes., Trial Registration: ClinicalTrials.gov NCT01930110 FUNDING: : Société Francophone du Diabète and Diabète Québec.

Background: Despite technological advances, the accuracy of continuous glucose monitoring (CGM) systems may not always be satisfactory with rapidly changing glucose levels, as is notable during exercise. We compare the performance of two current and widely used CGM systems, Dexcom G4 Platinum (Dexcom) and Medtronic Paradigm Veo Enlite system (Enlite), during both rest and exercise in adults with type 1 diabetes (T1D)., Research Design and Methods: Paired sensor and plasma glucose (PG) values (total of 431 data pairs for Dexcom and 425 for Enlite) were collected from 17 adults (37.3 ± 13.6 years) with T1D. To evaluate and compare the accuracy of sensor readings, criteria involving sensor bias (sensor minus PG levels), absolute relative difference (ARD), and percentage of readings meeting International Organization for Standardization (ISO) criteria were considered., Results: Both Dexcom and Enlite performed equally well during the rest period, with respective mean/median biases of -0.12/-0.02 mmol/L versus -0.18/-0.40 (P = 0.78, P = 0.66) mmol/L and ARDs of 13.77/13.34% versus 12.38/11.95% (P = 0.53, P = 0.70). During exercise, sensor bias means/medians were -0.40/-0.21 mmol versus -0.26/-0.24 mmol/L (P = 0.67, P = 0.62) and ARDs were 22.53/15.13% versus 20.44/14.11% (P = 0.58, P = 0.68) for Dexcom and Enlite, respectively. Both sensors demonstrated significantly lower performance during exercise; median ARD comparison at rest versus exercise for both Dexcom and Enlite showed a P = 0.02. More data pairs met the ISO criteria for Dexcom and Enlite at rest, 73.6% and 76.9% compared with exercise 48.2% and 53.9%., Conclusion: Dexcom and Enlite demonstrated comparable overall performances during rest and physical activity. However, a lower accuracy was observed during exercise for both sensors, necessitating a fine-tuning of their performance with physical activity.

The prevention and management of exercise-induced hypoglycaemia remains a challenge for patients with type 1 diabetes. Strategies involving changes to insulin dosing and/or carbohydrate consumption in anticipation of or during different types of exercise have proved to be helpful but not sufficient to fully prevent the hypoglycaemic risk. Meanwhile, the defect in glucagon secretion in response to hypoglycaemia in diabetes and the contributory role of somatostatin to this dysregulation constitute an important therapeutic target. In this issue of Diabetologia (DOI 10.1007/s00125-016-3953-0 ), Leclair et al show that selective somatostatin receptor 2 antagonists can enhance glucagon secretion in rats with streptozotocin-induced diabetes during exercise. The implications of their interesting findings are discussed, as well as limitations and potential for clinical applications, together with other glucagon-based options for tackling exercise-induced hypoglycaemia in diabetes.

The tiling of surfaces has long attracted the attention of scientists, not only because it is intriguing intrinsically, but also as a way to control the properties of surfaces. However, although random tiling networks are studied increasingly, their degree of randomness (or partial order) has remained notoriously difficult to control, in common with other supramolecular systems. Here we show that the random organization of a two-dimensional supramolecular array of isophthalate tetracarboxylic acids varies with subtle chemical changes in the system. We quantify this variation using an order parameter and reveal a phase behaviour that is consistent with long-standing theoretical studies on random tiling. The balance between order and randomness is driven by small differences in intermolecular interaction energies, which can be related by numerical simulations to the experimentally measured order parameter. Significant variations occur with very small energy differences, which highlights the delicate balance between entropic and energetic effects in complex self-assembly processes.

RFX6 has recently been found to be essential for the development of the endocrine pancreas through studies in both humans and mice. Interestingly, this gene maintains a specific expression in the postnatal hormone producing cells of the pancreas. Moreover in humans, different types of diabetes mellitus affect obligate carriers of RFX6 mutations. Therefore, RFX6 appears to have a pivotal role in the maintenance of the phenotype of the β-cells in addition to their development. Extensive research is needed to specify this role and explore its significance in the efforts to treat diabetes with medications, or more importantly, through β-cell replacement.

The synthesis, structural and magnetic characterisation of trinuclear manganese cluster, [Mn(3)O(O(2)C-anth)(6)(HOCH(3))(3)] 1 (where O(2)C-anth = 9-anthracenecarboxylate), with crystallographic three-fold (C(3)) symmetry, are described. The cluster was prepared by a carboxylate exchange reaction between HO(2)C-anth and [Mn(12)O(12)(O(2)CMe)(16)(H(2)O)(4)] with concomitant fragmentation of the dodecanuclear Mn core of the starting material to form a trinuclear Mn(3)(μ(3)-O) cluster capped by six carboxylate ligands. Bond valence sum calculations and SQUID magnetometric measurements establish the oxidation states of the metal ions as Mn(II)·2 Mn(III) which are antiferromagnetically coupled.

Single molecule magnets based on the dodecamanganese (III, IV) cluster with two different types of ligand (acetate and benzoate) have been studied on the Au(111) surface. Due to the non-volatile and fragile nature of the molecules, we have used ultra-high vacuum electrospray deposition to produce a series of surface coverages from a fraction of a monolayer to multilayer films in both cases. Synchrotron radiation based electron spectroscopy has been used to study the adsorption of the molecules on the Au(111) surface and the effect that this has on the oxidation states of the manganese atoms in the core. In both cases, reduction of the core is observed due to the interaction with the surface, to essentially the same extent despite substantial differences in the size and nature of the ligand shell.

Self-assembly of planar molecules on a surface can result in the formation of a wide variety of close-packed or porous structures. Two-dimensional porous arrays provide host sites for trapping guest species of suitable size. Here we show that a non-planar guest species (C(60)) can play a more complex role by promoting the growth of a second layer of host molecules (p-terphenyl-3,5,3″,5″-tetracarboxylic acid) above and parallel to the surface so that self-assembly is extended into the third dimension. The addition of guest molecules and the formation of the second layer are co-dependent. Adding a planar guest (coronene) can displace the C(60) and cause reversion to a monolayer arrangement. The system provides an example of a reversible transformation between a planar and a non-planar supramolecular network, an important step towards the controlled self-assembly of functional, three-dimensional, surface-based supramolecular architectures.

Patients with type 1 diabetes (a TH1 disease) have been reported to be at a lower risk of developing asthma (a TH2 disease). Both diseases are affected by environmental and genetic factors. Our objective is to examine this relationship in Lebanon, a Middle-Eastern country, where no previous similar studies are available. This is a cross-sectional observational study conducted at the Chronic Care Center, a referral medical center for type 1 diabetics. Patients with type 1 diabetes aged 6-39 years old, their unaffected siblings and age-matched control completed the International Primary Care Airways Group asthma screening questionnaire. The prevalence of asthma symptoms was compared among the three groups and separately within a subgroup of diabetics in relation to their carrier state of previously collected genetic data. Among 305 diabetics, 776 siblings and 187 controls, diabetics were at lower risk of having any asthma symptoms than controls; OR 0.48 (95% CI 0.32-0.72, p < 0.001) and siblings were at lower risk than diabetics and controls; OR 0.64 (95% CI 0.45-0.91, p = 0.01) and 0.28 (95% CI 0.19-0.42, p < 0.001), respectively. Among 66 diabetics, carriers of the HLA-DQB1*0201 allele were at lower risk of having any asthma symptoms than non-carriers (25.5 vs. 53.3%, p = 0.04). Only a statistically non-significant trend of higher risk was observed in carriers of HLA-DQB1*0301 and G allele at the 49 (A/G) nucleotide of CTLA-4 gene. The TH1-TH2 paradigm might partially explain these findings, since siblings were the least to report asthma symptoms. Future research is needed with diagnostic tests for asthma and extensive genetic testing.

The spontaneous ordering of molecules into two-dimensional self-assembled arrays is commonly stabilized by directional intermolecular interactions that may be promoted by the addition of specific chemical side groups to a molecule. In this paper, we show that self-assembly may also be driven by anisotropic interactions that arise from the three-dimensional shape of a complex molecule. We study the molecule Mn(12)O(12)(O(2)CCH(3))(16)(H(2)O)(4) (Mn(12)(acetate)(16)), which is transferred from solution onto a Au(111) substrate held in ultrahigh vacuum using electrospray deposition (UHV-ESD). The deposited Mn(12)(acetate)(16) molecules form filamentary aggregates because of the anisotropic nature of the molecule-molecule and molecule-substrate interactions, as confirmed by molecular dynamics calculations. The fragile Mn(12)O(12) core of the Mn(12)(acetate)(16) molecule is compatible with the UHV-ESD process, which we demonstrate using near-edge X-ray adsorption fine-structure spectroscopy. UHV-ESD of Mn(12)(acetate)(16) onto a surface that has been prepatterned with a hydrogen-bonded supramolecular network provides additional control of lateral organization.

Insulin from the beta-cells of the pancreatic islets of Langerhans controls energy homeostasis in vertebrates, and its deficiency causes diabetes mellitus. During embryonic development, the transcription factor neurogenin 3 (Neurog3) initiates the differentiation of the beta-cells and other islet cell types from pancreatic endoderm, but the genetic program that subsequently completes this differentiation remains incompletely understood. Here we show that the transcription factor Rfx6 directs islet cell differentiation downstream of Neurog3. Mice lacking Rfx6 failed to generate any of the normal islet cell types except for pancreatic-polypeptide-producing cells. In human infants with a similar autosomal recessive syndrome of neonatal diabetes, genetic mapping and subsequent sequencing identified mutations in the human RFX6 gene. These studies demonstrate a unique position for Rfx6 in the hierarchy of factors that coordinate pancreatic islet development in both mice and humans. Rfx6 could prove useful in efforts to generate beta-cells for patients with diabetes.

Image registration is a fundamental task used in image processing to match two or more images taken at different times, from different sensors or from different viewpoints. The objective is to find in a huge search space of geometric transformations, an acceptable accurate solution in a reasonable time to provide better registered images. Exhaustive search is computationally expensive and the computational cost increases exponentially with the number of transformation parameters and the size of the data set. In this work, we present an efficient image registration algorithm that uses genetic algorithms within a multi-resolution framework based on the Non-Subsampled Contourlet Transform (NSCT). An adaptable genetic algorithm for registration is adopted in order to minimize the search space. This approach is used within a hybrid scheme applying the two techniques fitness sharing and elitism. Two NSCT based methods are proposed for registration. A comparative study is established between these methods and a wavelet based one. Because the NSCT is a shift-invariant multidirectional transform, the second method is adopted for its search speeding up property. Simulation results clearly show that both proposed techniques are really promising methods for image registration compared to the wavelet approach, while the second technique has led to the best performance results of all. Moreover, to demonstrate the effectiveness of these methods, these registration techniques have been successfully applied to register SPOT, IKONOS and Synthetic Aperture Radar (SAR) images. The algorithm has been shown to work perfectly well for multi-temporal satellite images as well, even in the presence of noise.

SUMMARY Suppression subtractive hybridization was used to isolate the genes which are specifically up-regulated in the biotrophic phase of the incompatible interaction between a potato genotype, 1512 c(16), containing the resistance gene R2, and a Phytophthora infestans isolate containing the avirulence gene Avr2. Eight cDNAs were up-regulated in the biotrophic phase of the incompatible interaction. Seven of these were also up-regulated in the compatible interaction, but not until late in the necrotrophic phase. Amongst the sequences to be isolated were genes encoding the cysteine protease cathepsin B, StCathB, and an oxysterol binding protein, StOBP1; equivalent genes are involved in programmed cell death (PCD) processes in animals, but have yet to be implicated in such processes in plants. Whereas StOBP1 was up-regulated early in potato plants containing either R gene-mediated or moderate to high levels of field resistance, the highest levels of up-regulation of StCathB were observed early in R gene-mediated resistance but gradually increased from the early to late stages of field resistance, revealing these genes to be components of independent defence pathways and providing a means of distinguishing between these forms of resistance. StOBP1 was up-regulated by oligogalacturonides (plant cell wall breakdown products generated by pectinase activities), indicating that it is also a component of a general, non-specific defence pathway and is unlikely to play a role in PCD. In contrast, the expression of StCathB was unaffected by oligogalacturonide treatment, further associating its up-regulation specifically with the gene-for-gene interaction.

Chiral stationary phases obtained by immobilization of human serum albumin (HSA) on various polymer-coated silicas were tested to resolve DL-tryptophan, DL-NBP, RS-oxazepam and RS-warfarin racemic mixtures. HSA immobilized on anion exchangers [quaternized poly(vinylimidazole)-coated silica] was highly selective. Stable and selective chiral stationary phases were also prepared by covalent binding of HSA to silica particles via reactive-polymers. Poly(acryloyl chloride), poly(methacryloyl chloride) and poly(vinyl chloroformate) derivatives were compared. Parameters that govern the selectivity of resulting chiral supports were evaluated, especially the orientation of HSA after immobilization, the mobility of polymer chains and the number of covalent linkages between the protein and the polymer.

The gastrointestinal tuberculosis is a rare disease and it can mimic a large variety of gastrointestinal diseases. The most common site of gastrointestinal tuberculosis is the ileocoecal region followed by the ascending colon and jejunum. Complications are an absolute indication for surgical intervention. Perforation is an extremely uncommon complication of mycobacterium tuberculosis infection.

It is classical to separate gastro-intestinal non Hodgkin lymphomas into two epidemiological profiles: an "occidental" type frequently encountered in West countries (Europe and USA) and an "occidental" type which is dominant in the Middle East regions and is distinguished from the occidental type by the following features: the younger age of patients, the rarity of gastric involvement compared to the small intestinal involvement, the prevalence of Immuno Proliferative Small Intestinal Disease within the small intestinal non Hodgkin lymphomas. An epidemiological study was done on 100 cases of digestive non Hodgkin lymphomas seen in Lebanon between 1965 and 1991 in hospitals affiliated with Saint-Joseph University. The statistical analysis of our study leads to several conclusions: the ISPID is disappearing in Lebanon during the last twenty-five years; the site of gastrointestinal involvement is changing with time, the small intestinal involvement becoming more rare and the gastric involvement more frequent. So during this twenty-five years period, there was an occidentalization of the epidemiological profile. This varying pattern with time in the epidemiology of gastrointestinal non Hodgkin lymphomas could be due to changing in the environmental factors like the intestinal bacterial and parasitological infestation.

It is classical to separate gastro-intestinal non Hodgkin Lymphomas into two epidemiological profiles: 1--an "occidental" type frequently encountered in West countries (Europe and USA); 2--an "occidental" type which is dominant in the Middle East regions and is distinguished from the occidental type by the following features: the younger age of patients; the rarity of gastric involvement compared to the small intestinal involvement; the prevalence of Immuno Proliferative Small Intestinal Disease within the small intestinal non Hodgkin lymphomas. An epidemiological study was done on 100 cases of digestive non Hodgkin lymphomas seen in Lebanon between 1965 and 1991 in hospitals affiliated with Saint-Joseph University. The statistical analysis of our study leads to several conclusions: 1--the ISPID is disappearing in Lebanon during the last twenty-five years; 2--the site of gastrointestinal involvement is changing with time, the small intestinal involvement becoming more rare and the gastric involvement more frequent. So during this twenty-five years period, there was an occidentalization of the epidemiological profile. This varying pattern with time in the epidemiology of gastrointestinal non Hodgkin lymphomas could be due to changing in the environmental factors like the intestinal bacterial and parasitological infestation.

A total of 59 febrile neutropenic episodes were retrospectively recorded at Hôtel-Dieu de France Hospital between August 1st 1991 and December 31st 1992. These episodes were recorded in 51 cancer patients. Median neutropenia was less than one week in 50% of the cases. The etiology of these fever was documented in 27 episodes (46%) and in 70% of the cases gram (-) rods were documented. B-Lactam and Aminoglycoside antibiotics were used in 34 episodes at the initial treatment of these patients. Success rate at this initial treatment or with a modification of the antibiotic therapy was recorded in 85% of the patients. Only 15% of the patients failed to this antibiotherapy, 2/3 of them had their disease in progression. The systemic use of Amphotericine E in those patients with prolonged febrile neutropenia and the concommitent use of growth factors in a sub-group of patients at high risk could lead to a higher success rate in these patients.

Ischemic spinal lesions following graft replacement of an infrarenal aortic aneurysm are rare complications. Even more rare is the development of this complication in case of aortoiliac occlusive disease. We report one further case who developed transient paraplegia following sigma resection six years after implantation of an aortobifemoral bifurcation graft because of aortoiliac occlusive disease. The abdominal vessel and the collateral situation of this site of the caudal aorta is discussed and the possibility of late ischemic spinal lesions is pointed out.

The treatment of Wilms' tumor has shown a great success in the pediatric oncology. Our study, which includes 12 cases of nephroblastoma, between 1979 and 1987, has confirmed this results. This tumor that shows no sex prevalence, occurs in a mean age of 2.5 years. The volume of the mass is the most presenting sign in 75% of the cases, I.V.P. confirm the diagnosis in 90% of the cases. Remission occurred in 5 infants who have been in stage I, the other cases who are in stage II to V have bad prognosis. In the future, we hope more advancement in the cure of Wilms tumor, and all the remaining questions will find their answer.

We have studied 20 cases of haematosarcomas belonging to lymphosarcomas (T or B-cell markers, absence of the reticulosarcoma characters in sections, on smears, with conventional and scanning electron microscopy). Their cells which appear as large pyroninophilic cells on sections, as large very basophilic cells with blastic nuclei and often cytoplasmic vacuoles on smears, as having many polyribosomes and usually no ergastoplasm with conventional electron microscopy, and as large cells of the lymphocytic series with scanning electron microscopy resemble the cells which we described in adenitis in 1955 (9) and in the graft-versus-host-reaction in 1961 (6), which Gowans (15) showed resulted from lymphocyte transformation, and which Dameshek (10) called immunoblasts. Many of these cases of immunoblastic lymphosarcoma (ILS) identified on their cytohistological characteristics [also recognized by Lukes et al. (24, 25) and Lennert et al. (21, 22)], present aetiological, clinical and pronostic characters which let us suppose that it may be not only a cytological entity but also a cytoclinical entity : a) it affects males in 85% or the subjects; eight patients came from mediterranean countries outside France; two patients had a history of chronic rheumatoid manifestations; b) the disease was at stage IV at the first presentation in 10 patients out of 20; it was revealed by profound (mediastinal or abdominal) localizations in 60% of cases (12 out of 20); it presented a hypoglobulinaemia in eight out of 13 patients; in six out of the 15 patients treated before leukaemic conversion, the chemotherapy usually efficient in lymphosarcoma (LS) failed to induce remission. This type of LS has a poorer prognosis than other types of LS (median for all stages : eight months). It led to the death either after its conversion to leukaemia (nine out of 20 cases), or by vital organ (as brain or kidney) infiltrations.