Environmental Nanoparticle-Induced Toughening and Pinning of a Growing Crack in a Biopolymer Hydrogel.

We study the interplay between a crack tip slowly propagating through a hydrogel and nanoparticles suspended in its liquid environment. Using a proteinic gel enables us to tune the electrostatic interaction between the network and silica colloids. Thereby, we unveil two distinct, local toughening mechanisms. The primary one is charge independent and involves the convective building of a thin particulate clog, hindering polymer hydration in the crack process zone. When particles and network bear opposite charges, transient adhesive bonding superimposes, permitting the remarkable pinning of a crack by a liquid drop.

Preferential hydration fully controls the renaturation dynamics of collagen in water-glycerol solvents.

Glycerol is one of the additives which stabilize collagen, as well as globular proteins, against thermally induced denaturation --an effect explained by preferential hydration, i.e. by the formation, in water/glycerol solvents, of a hydration layer whose entropic cost favors the more compact triple-helix native structure against the denatured one, gelatin. Quenching gelatin solutions promotes renaturation which, however, remains incomplete, as the formation of a gel network gives rise to growing topological constraints. So, gelatin gels exhibit glass-like dynamical features such as slow aging of their shear modulus and stretched exponential stress relaxation, the study of which gives us access to the re(de)naturation dynamics of collagen. We show that this dynamics is independent of the bulk solvent viscosity and controlled by a single parameter, the undercooling [Formula: see text] below the glycerol-concentration-dependent denaturation temperature. This provides direct proof of i) the presence of a nanometer thick, glycerol-free hydration layer, ii) the high locality of the kinetically limiting process governing renaturation.

Exenatide decreases liver fat content and epicardial adipose tissue in patients with obesity and type 2 diabetes: a prospective randomized clinical trial using magnetic resonance imaging and spectroscopy.

AIM: To conduct a prospective randomized trial to investigate the effect of glucagon-like peptide-1 (GLP-1) analogues on ectopic fat stores. METHODS: A total of 44 obese subjects with type 2 diabetes uncontrolled on oral antidiabetic drugs were randomly assigned to receive exenatide or reference treatment according to French guidelines. Epicardial adipose tissue (EAT), myocardial triglyceride content (MTGC), hepatic triglyceride content (HTGC) and pancreatic triglyceride content (PTGC) were assessed 45 min after a standardized meal with 3T magnetic resonance imaging and proton magnetic resonance spectroscopy before and after 26 weeks of treatment. RESULTS: The study population had a mean glycated haemoglobin (HbA1c) level of 7.5 ± 0.2% and a mean body mass index of 36.1 ± 1.1 kg/m(2) . Ninety five percent had hepatic steatosis at baseline (HTGC ≥ 5.6%). Exenatide and reference treatment led to a similar improvement in HbA1c (-0.7 ± 0.3% vs. -0.7 ± 0.4%; p = 0.29), whereas significant weight loss was observed only in the exenatide group (-5.5 ± 1.2 kg vs. -0.2 ± 0.8 kg; p = 0.001 for the difference between groups). Exenatide induced a significant reduction in EAT (-8.8 ± 2.1%) and HTGC (-23.8 ± 9.5%), compared with the reference treatment (EAT: -1.2 ± 1.6%, p = 0.003; HTGC: +12.5 ± 9.6%, p = 0.007). No significant difference was observed in other ectopic fat stores, PTGC or MTGC. In the group treated with exenatide, reductions in liver fat and EAT were not associated with homeostatic model assessment of insulin resistance index, adiponectin, HbA1c or fructosamin change, but were significantly related to weight loss (r = 0.47, p = 0.03, and r = 0.50, p = 0.018, respectively). CONCLUSION: Our data indicate that exenatide is an effective treatment to reduce liver fat content and epicardial fat in obese patients with type 2 diabetes, and these effects are mainly weight loss dependent.

Glass-like dynamics of the strain-induced coil/helix transition on a permanent polymer network.

We study the stress response to a step strain of covalently bonded gelatin gels in the temperature range where triple helix reversible crosslink formation is prohibited. We observe slow stress relaxation towards a T-dependent finite asymptotic level. We show that this is assignable to the strain-induced coil → helix transition, previously evidenced by Courty et al. [Proc. Natl. Acad. Sci. U. S. A. 102, 13457 (2005)], of a fraction of the polymer strands. Relaxation proceeds, in a first stage, according to a stretched exponential dynamics, then crosses over to a terminal simple exponential decay. The respective characteristic times τK and τf exhibit an Arrhenius-like T-dependence with an associated energy E incompatibly larger than the activation barrier height for the isomerisation process which sets the clock for an elementary coil → helix transformation event. We tentatively assign this glass-like slowing down of the dynamics to the long-range couplings due to the mechanical noise generated by the local elementary events in this random elastic medium.

Two-step build-up of a thermoreversible polymer network: From early local to late collective dynamics.

We probe the mechanisms at work in the build-up of thermoreversible gel networks, with the help of hybrid gelatin gels containing a controlled density of irreversible, covalent crosslinks (CLs), which we quench below the physical gelation temperature. The detailed analysis of the dependence on covalent crosslink density of both the shear modulus and optical activity evolutions with time after quench enables us to identify two stages of the physical gelation process, separated by a temperature-dependent crossover modulus: (i) an early nucleation regime during which rearrangements of the triple-helix CLs play a negligible role, and (ii) a late, logarithmic aging one, which is preserved, though slowed down, in the presence of irreversible CLs. We show that aging is fully controlled by rearrangements and discuss the implication of our results in terms of the switch from an early, local dynamics to a late, cooperative long-range one.

Ectopic fat storage in the pancreas using 1H-MRS: importance of diabetic status and modulation with bariatric surgery-induced weight loss.

OBJECTIVES: Recent literature suggests that ectopic fat deposition in the pancreas may contribute to endocrine and exocrine organ dysfunction, such as type 2 diabetes (T2D), pancreatitis or pancreatic cancer. The aim of this study was to determine factors associated with pancreatic triglyceride content (PTGC), and to investigate the impact of bariatric surgery on ectopic fat pads, pancreatic fat (PTGC) and hepatic fat (HTGC). SUBJECTS: In all, 45 subjects (13 lean, 13 obese nondiabetics and 19 T2D, matched for age and gender) underwent 1H-magnetic resonance spectroscopy, computed tomography of the visceral abdominal fat, metabolic and lipidomic analysis, including insulin-resistance homeostasis model assessment (HOMA-IR), insulin-secretion homeostasis model assessment (HOMA-B) and plasma fatty-acid composition. Twenty obese subjects were reassessed 6 months after the bariatric surgery. RESULTS: PTGC was significantly higher in type 2 diabetic subjects (23.8±3.2%) compared with obese (14.0±3.3; P=0.03) and lean subjects (7.5±0.9%; P=0.0002). PTGC remained significantly associated with T2D after adjusting for age and sex (ß=0.47; P=0.004) or even after adjusting for waist circumference, triglycerides and HOMA-IR (ß=0.32; P=0.04). T2D, C18:1n-9 (oleic acid), uric acid, triglycerides and plasminogen activator inhibitor-1 were the five more important parameters involved in PTGC prediction (explained 80% of PTGC variance). Bariatric surgery induced a huge reduction of both HTGC (-51.2±7.9%) and PTGC (-43.8±7.0%) reaching lean levels, whereas body mass index remained greatly elevated. An improvement of insulin resistance HOMA-IR and no change in HOMA-B were observed after bariatric surgery. The PTGC or HTGC losses were not correlated, suggesting tissue-specific mobilization of these ectopic fat stores. CONCLUSION: Pancreatic fat increased with T2D and drastically decreased after the bariatric surgery. This suggests that decreased PTGC may contribute to improved beta cell function seen after the bariatric surgery. Further, long-term interventional studies are warranted to examine this hypothesis and to determine the degree to which ectopic fat mobilization may mediate the improvement in endocrine and exocrine pancreatic functions.

Telemedicine and type 1 diabetes: is technology per se sufficient to improve glycaemic control?

AIM: In the TELEDIAB-1 study, the Diabeo system (a smartphone coupled to a website) improved HbA1c by 0.9% vs controls in patients with chronic, poorly controlled type 1 diabetes. The system provided two main functions: automated advice on the insulin doses required; and remote monitoring by teleconsultation. The question is: how much did each function contribute to the improvement in HbA1c? METHODS: Each patient received a smartphone with an insulin dose advisor (IDA) and with (G3 group) or without (G2 group) the telemonitoring/teleconsultation function. Patients were classified as "high users" if the proportion of "informed" meals using the IDA exceeded 67% (median) and as "low users" if not. Also analyzed was the respective impact of the IDA function and teleconsultations on the final HbA1c levels. RESULTS: Among the high users, the proportion of informed meals remained stable from baseline to the end of the study 6months later (from 78.1±21.5% to 73.8±25.1%; P=0.107), but decreased in the low users (from 36.6±29.4% to 26.7±28.4%; P=0.005). As expected, HbA1c improved in high users from 8.7% [range: 8.3-9.2%] to 8.2% [range: 7.8-8.7%] in patients with (n=26) vs without (n=30) the benefit of telemonitoring/teleconsultation (-0.49±0.60% vs -0.52±0.73%, respectively; P=0.879). However, although HbA1c also improved in low users from 9.0% [8.5-10.1] to 8.5% [7.9-9.6], those receiving support via teleconsultation tended to show greater improvement than the others (-0.93±0.97 vs -0.46±1.05, respectively; P=0.084). CONCLUSION: The Diabeo system improved glycaemic control in both high and low users who avidly used the IDA function, while the greatest improvement was seen in the low users who had the motivational support of teleconsultations.

Microstructuration stages during gelation of gelatin under shear.

We study gelation under shear of aqueous gelatin by measuring the evolution of the apparent viscosity, thus extending the previous study by de Carvalho and Djabourov (W. de Carvalho, M. Djabourov, Rheol. Acta 36, 591 (1997)). From a set of experiments under constant stress, we deduce that the microstructure evolves through the following succession of regimes: i) nucleation and growth until crowding of a microgel suspension; ii) coalescence into strata parallel to the flow; iii) gradual thickening of these strata via transverse cross-linking until the flow finally localizes into two interfacial sliding bands which close sequentially. The transition between these regimes occurs at characteristic viscosity values. This scenario is fully confirmed by experiments performed at constant shear rates. We expect it to be relevant for all materials forming thermoreversible gels.

Ramadan fasting with diabetes: an interview study of inpatients' and general practitioners' attitudes in the South of France.

AIM: The aim of this study was to evaluate attitudes in hospital inpatients and physicians towards Ramadan fasting and diabetes in Marseille. METHODOLOGY: This cross-sectional study was conducted during the three months prior to the month of Ramadan. A total of 101 patients (age: 57±17 years) and 101 general practitioners (GPs) were recruited into the study. RESULTS: The patients had low levels of education (52% illiteracy). Of the 101 patients, 52 continued to fast during Ramadan, and only 65 patients had discussed the matter with their GP. Of these, 36 were told that fasting was forbidden, but more than half (n=19) fasted despite the medical advice. Six patients thus experienced daily hypoglycaemia because they had continued to take their hypoglycaemic agent or insulin analogue at noon. Both inadequate education and religious attitudes were found to endanger patients during the fast: 15 patients skipped the meal scheduled before dawn, five of whom persisted in taking their sulphonylurea. Also, 27% of patients refused, in spite of daytime hypoglycaemia, to ingest anything orally to avoid breaking their fast. Among the GP population, medical knowledge of Ramadan fasting with diabetes was low, leading to medically unjustified negative advice for fasting and a lack of patient education on adjusting treatments. This particular situation weakened the patient-physician relationship. CONCLUSION: This study confirms the importance of Ramadan fasting for Muslim patients, and reveals a wide cross-cultural gap between GPs and their patients. Systematic advice on treatment adjustment needs to be given. For this reason, we encourage more sensitive care of these patients and more medical training for physicians.

Cooperative effect of stress and ion displacement on the dynamics of cross-link unzipping and rupture of alginate gels.

We study the effect of nonbinding Na(+) ions on the kinetics of rupture of alginate gels cross-linked by Ca(2+). Wetting a crack tip with a saline solution at physiological concentrations is found to be able to induce a quasi-instantaneous, 10-fold velocity jump. This effect is analyzed with a phenomenological model for the rate-dependent fracture energy in physical gels, extended here to account for the role of ions on the rate of cross-link "unzipping". Ionic interaction is found to act cooperatively with mechanical tension, leading to an enhanced rate of rupture. The kinetics turns out to be second order in counterion concentration. The definition of the reference state requires to take into account counterion condensation due to long-range interactions in the polyelectrolyte gel. Surprisingly, the contribution of the Na(+) ions to the free energy of the activated state is essentially entropic, suggesting that the displacement of Ca(2+) is primarily a steric process, electrostatic interactions being reduced to the constraint of charge conservation. This phenomenon may have important consequences on the rate of degradation of alginate based scaffolds for in vivo tissue regeneration.

A convective instability mechanism for quasistatic crack branching in a hydrogel.

Experiments on quasistatic crack propagation in gelatin hydrogels reveal a new branching instability triggered by wetting the tip opening with a drop of aqueous solvent less viscous than the bulk one. We show that the emergence of unstable branches results from a balance between the rate of secondary crack growth and the rate of advection away from a non-linear elastic region of size G/E , where G is the fracture energy and E the small strain Young modulus. We build a minimal, predictive model that combines mechanical characteristics of this mesoscopic region and physical features of the process zone. It accounts for the details of the stability diagram and lends support to the idea that non-linear elasticity plays a critical role in crack front instabilities.

Interplay between shear loading and structural aging in a physical gelatin gel.

We show that the aging of the mechanical relaxation of a gelatin gel exhibits the same scaling phenomenology as polymer and colloidal glasses. In addition, gelatin is known to exhibit logarithmic structural aging (stiffening). We find that stress accelerates this process. However, this effect is definitely irreducible to a mere age shift with respect to natural aging. We suggest that it is interpretable in terms of elastically aided elementary (coil --> helix) local events whose dynamics gradually slows down as aging increases geometric frustration.

From thermally activated to viscosity controlled fracture of biopolymer hydrogels.

We report on rate-dependent fracture energy measurements over three decades of steady crack velocities in alginate and gelatin hydrogels. We evidence that irrespective of gel thermoreversibility, thermally activated "unzipping" of the noncovalent cross-link zones results in slow crack propagation, prevailing against the toughening effect of viscous solvent drag during chain pull-out, which becomes efficient above a few mm s(-1). We extend a previous model [T. Baumberger et al., Nat. Mater. 5, 552 (2006)] to account for both mechanisms and estimate the microscopic unzipping rates.

Magic angles and cross-hatching instability in hydrogel fracture.

The full 2D analysis of roughness profiles of fracture surfaces resulting from quasistatic crack propagation in gelatin gels reveals an original behavior characterized by (i) strong anisotropy with maximum roughness at V-independent symmetry-preserving angles and (ii) a subcritical instability leading, below a critical velocity, to a cross-hatched regime due to straight macrosteps drifting at the same magic angles and nucleated on crack-pinning network inhomogeneities. Step height values are determined by the width of the strain-hardened zone, governed by the elastic crack blunting characteristic of soft solids with breaking stresses much larger than low strain moduli.

Factors related to CSII compliance.

Many studies have demonstrated the metabolic efficacy of continuous subcutaneous insulin infusion (CSII) and particularly a reduction of glycaemic fluctuations in type 1 diabetic patients. Despite this benefit, many patients decide to discontinue the use of CSII. To determine the factors related to discontinuation of CSII we analyzed clinical data from a group of 70 patients who had been consecutively started on this treatment from April 2000 to April 2002. Patients were followed for up to 2 years. Eighteen (25.7%) patients decided to terminate CSII during the study after an average of 235 days (range 21-293). The reasons for stopping CSII were decision of the patients (10), end of pregnancy (4), needle site infections (3) and lack of compliance (1). No significant difference was found between patients who had continued and those who had discontinued CSII for age, duration of diabetes, reasons for starting CSII, marital status, prepump concentration of HbA1c and prepump frequency of hypoglycaemia. There tend to be more discontinuations for pregnant women, patients attending hospital visits versus liberal practitioner and patients with lower educational level (below or over baccalaureat) although none of these differences was statistically significant. In conclusion we could not identify any predictive factor of CSII discontinuation.

Self-healing slip pulses and the friction of gelatin gels.

We present an extensive experimental study and scaling analysis of friction of gelatin gels on glass. At low driving velocities, sliding occurs via propagation of periodic self-healing slip pulses whose velocity is limited by collective diffusion of the gel network. Healing can be attributed to a frictional instability occurring at the slip velocity V=Vc. For V>Vc, sliding is homogeneous and friction is ruled by the shear-thinning rheology of an interfacial layer of thickness of order the (nanometric) mesh size, containing a solution of polymer chain ends hanging from the network. In spite of its high degree of confinement, the rheology of this system does not differ qualitatively from known bulk ones. The observed ageing of the static friction threshold reveals the slow increase of adhesive bonding between chain ends and glass. Such structural ageing is compatible with the existence of a velocity-weakening regime at velocities smaller than Vc, hence with the existence of the healing instability.

Molecular positional order in langmuir-blodgett films by atomic force microscopy.

Langmuir-Blodgett films of barium arachidate have been studied on both macroscopic and microscopic scales by atomic force microscopy. As prepared, the films exhibit a disordered hexagonal structure; molecularly resolved images in direct space establish a connection between the extent of the positional order and the presence of defects such as dislocations. Upon heating, the films reorganize into a more condensed state with a centered rectangular crystallographic arrangement; in this new state the films exhibit long-range positional order and unusual structural features, such as a height modulation of the arachidic acid molecules.