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A novel series of potent and selective αvβ3/αvβ5 dual inhibitors was designed, synthesized, and evaluated against several integrins. These compounds were synthesized through a Mitsunobu reaction between the guanidinium mimetics and the corresponding central templates. Guanidinium mimetics with enhaced rigidity (i.e., (2-pyridylamino)propoxy versus the 2-(6-methylamino-2-pyridyl)ethoxy) led to improved activity toward αvβ3. Exemplary oral bioavailability in mice was achieved using the indole central scaffold. Although, oral bioavailability was maintained when the indole molecular core was replace with the bioisosteric benzofuran or benzothiophene ring systems, it was found to not significantly impact the integrin activity or selectivity. However, the indole series displayed the best in vivo pharmacokinetic properties. Thus, the indole series was selected for further structure−activity relationships to obtain more potent αvβ3/αvβ5 dual antagonist with improved oral bioavailability.

HDM2 binds to an α-helical transactivation domain of p53, inhibiting its tumor suppressive functions. A miniaturized thermal denaturation assay was used to screen chemical libraries, resulting in the discovery of a novel series of benzodiazepinedione antagonists of the HDM2−p53 interaction. The X-ray crystal structure of improved antagonists bound to HDM2 reveals their α-helix mimetic properties. These optimized molecules increase the transcription of p53 target genes and decrease proliferation of tumor cells expressing wild-type p53.

To evaluate the influence of a low glycaemic index (GI), high GI and high fibre diet on glycaemic control and insulin requirement in Type 1 diabetic patients on intensive insulin therapy, nine well‐controlled, highly‐motivated Type 1 diabetic patients were put on a control diet for 12 days and then randomized in a consecutive manner to 12 days of each diet, in a crossover design. During each experimental diet, the study subjects adjusted their premeal insulin (soluble) dose to maintain their 1‐h postprandial capillary glucose at or below 10 mmol l−1. At the end of each experimental diet, they were submitted to a standardized breakfast of the diet under study, using the same premeal insulin dose as that required for the control diet. The control diet contained 16.0 ± 3.0 g of fibre day−1with a GI of 77.4 ± 2.7 compared to 15.3 ± 6.3 and 66.2 ± 1.2 for the low GI diet, 17.1 ± 7.2 and 92.9 ± 3.6 for the high GI diet, and 56.1 ± 3.6 (including 15 g of guar) and 73.5 ± 2.1 for the high fibre diet. Prebreakfast capillary blood glucose (6.2 ± 1.2 mmol l−1) on the low GI diet and postbreakfast capillary blood glucose (8.7 ± 1.8 mmol l−1) on the high fibre diet were significantly lower than the values obtained with the control diet (8.0 ± 1.8 and 10.6 ± 2.4, respectively; p<0.05). No change in premeal or basal insulin dose was required. During the standardized breakfasts, the incremental area under the curve was 1.6 ± 1.5 mmol l−1min−1for the control diet compared to 1.1 ± 1.8 for the low GI diet, 3.2 ± 1.4 for the high GI diet (p<0.05 versus low GI and high fibre; p= 0.08 versus control), and 1.0 ± 0.9 for the high fibre diet. These observations indicate that in well‐controlled Type 1 diabetic subjects on intensive insulin therapy, major alterations in the GI and fibre content of meals induce small but significant changes in glucose profile. In everyday life, however, these differences are blunted, and plasma glucose remains within the target range for optimal metabolic control. © 1998 John Wiley & Sons, Ltd.

Facial consummatory responses reflecting ingestive and aversive perceptions were studied and quantified in rats chronically implanted with gastric and oral catheters. A gustatory stimulus of 50 μl of 0.6 mol·1−1sucrose was injected into the mouth every 5 min during 90 min. At time zero, one of seven loads was injected into the stomach. These consisted of, 5 ml of water, or 5 ml solution containing 1 g glucose, 3 g glucose, 1 g casein hydrolyzate, 3 g casein hydrolyzate, or of oil 0.6 ml, or 1.4 ml. The typical ingestive facial consummatory responses in response to sweet stimuli were observed prior to all gastric loads, and also after the water load. On the other hand, the consummatory responses to sweet stimuli turned aversive after all three high-calorie gastric loads. The magnitude of this decrease in palatability (negative alliesthesia) was similar after glucose, casein hydrolyzate, and oil. The reversal of the consummatory responses from ingestive to aversive did not reach the threshold of statistical significance after the three low-calorie gastric loads. These results would tend to show that the intestinal signal for alimentary alliesthesia is nonspecific.

We describe and analyze the complexity of verifying the notion of infinite-step opacity in systems that are modeled as non-deterministic finite automata with partial observation on their transitions. Specifically, a system is infinite-step opaque if the entrance of the system state, at any particular instant, to a set of secret states remains opaque (uncertain), for the length of the system operation, to an intruder who observes system activity through some projection map. Infinite-step opacity can be used to characterize the security requirements in many applications, including encryption using pseudo-random generators, coverage properties in sensor networks, and anonymity requirements in protocols for web transactions. We show that infinite-step opacity can be verified via the construction of a set of appropriate initial state estimators and provide illustrative examples. We also establish that the verification of infinite-step opacity is a PSPACE-hard problem. [ABSTRACT FROM PUBLISHER]

In this technical note, we consider adaptive learning control problem for a class of nonlinear systems with periodic bounded disturbances. The bounds of the disturbance are unknown, and the minimum period T^\ast of the disturbance can be written as T^\ast=l^\ast\tau, with \tau being a known constant and l^\ast being an unknown integer. Our proposed adaptive controller consists of a learning law and two kinds of parameter tuning mechanisms: one is the conventional parameter update law, and the other is a logic-based switching mechanism which tunes in a switching manner the saturation level and the period in the learning law. It has been proved that under our proposed control all closed-loop states are bounded and asymptotic regulation is achieved. [ABSTRACT FROM PUBLISHER]

OBJECTIVE--Although carbohydrate counting is routine practice in type 1 diabetes, hyperglycemic episodes are common. A food insulin index (FII) has been developed and validated for predicting the normal insulin demand [...]

Diabetes has long been viewed as a disorder of carbohydrate metabolism due to its hallmark feature of hyperglycemia. Indeed, hyperglycemia is the cause of the acute symptoms associated with diabetes [...]

Recently, the Food and Nutrition Board of the National Academies, Institute of Medicine, released acceptable ranges of intake of energy sources--fat, carbohydrate, and protein. Previously, the American Heart Association (AHA), [...]

OBJECTIVE--The use of diets with low glycemic index (GI) in the management of diabetes is controversial, with contrasting recommendations around the world. We performed a meta-analysis of randomized controlled trials [...]

Research supports the importance of medical nutrition therapy in achieving diabetes treatment goals. For persons requiring insulin therapy, the first priority is to integrate an insulin regimen into the patient's [...]

OBSERVATIONS Association Between Vitamin D Receptor Genotype and Age of Onset in Juvenile Japanese Patients With Type 1 Diabetes 1,25-dihydroxyvitamin [D.sub.3][1,25[(OH).sub.2][D.sub.3]] not only regulates calcium metabolism but also modulates the [...]

OBJECTIVE -- To evaluate whether a 5-week low-glycemic index (LGI) diet versus a high-glycemic index (HGI) diet can modify glucose and lipid metabolism as well as total fat mass in [...]

Marion J. Franz (1) John P. Bantle (2) Christine A. Beebe (3) John D. Brunzell (4) Jean-Louis Chiasson (5) Abhimanyu Garg (6) Lea Ann Holzmeister (7) Byron Hoogwerf (8) Elizabeth [...]

It is essential that clinicians be aware of expected outcomes from possible nutrition therapy interventions so that they can assist people with diabetes using the best approaches to achieve metabolic [...]

OBJECTIVE -- To evaluate and validate appropriate premeal insulin dose reductions for postprandial exercises of different intensities and durations to minimize the risk of exercise-induced hypoglycemia in type 1 diabetic [...]

A 21-year old white woman (BMI 21.2 kg/[m.sub.2]) was admitted for management of uncontrolled diabetes with cutaneous allergies to insulin. Past medical history was marked by several allergies, including coconuts [...]