The impact of salsalate treatment on serum levels of advanced glycation end products in type 2 diabetes.

OBJECTIVE Salsalate is a nonacetylated salicylate that lowers glucose levels in people with type 2 diabetes (T2D). Here we examined whether salsalate also lowered serum-protein-bound levels of early and advanced glycation end products (AGEs) that have been implicated in diabetic vascular complications. RESEARCH DESIGN AND METHODS Participants were from the Targeting Inflammation Using Salsalate for Type 2 Diabetes (TINSAL-T2D) study, which examined the impact of salsalate treatment on hemoglobin A1c (HbA1c) and a wide variety of other parameters. One hundred eighteen participants received salsalate, 3.5 g/day for 48 weeks, and 109 received placebo. Early glycation product levels (HbA1c and fructoselysine [measured as furosine]) and AGE levels (glyoxal and methylglyoxal hydroimidazolones [G-(1)H, MG-(1)H], carboxymethyllysine [CML], carboxyethyllysine [CEL], pentosidine) were measured in patient serum samples. RESULTS Forty-eight weeks of salsalate treatment lowered levels of HbA1c and serum furosine (P \u3c 0.001) and CML compared with placebo. The AGEs CEL and G-(1)H and MG-(1)H levels were unchanged, whereas pentosidine levels increased more than twofold (P \u3c 0.001). Among salsalate users, increases in adiponectin levels were associated with lower HbA1c levels during follow-up (P \u3c 0.001). Changes in renal and inflammation factor levels were not associated with changes in levels of early or late glycation factors. Pentosidine level changes were unrelated to changes in levels of renal function, inflammation, or cytokines. CONCLUSIONS Salsalate therapy was associated with a reduction in early but not late glycation end products. There was a paradoxical increase in serum pentosidine levels suggestive of an increase in oxidative stress or decreased clearance of pentosidine precursor

Probabilistic approaches for modeling text structure and their application to text-to-text generation

Since the early days of generation research, it has been acknowledged that modeling the global structure of a document is crucial for producing coherent, readable output. However, traditional knowledge-intensive approaches have been of limited utility in addressing this problem since they cannot be effectively scaled to operate in domain-independent, large-scale applications. Due to this difficulty, existing text-to-text generation systems rarely rely on such structural information when producing an output text. Consequently, texts generated by these methods do not match the quality of those written by humans – they are often fraught with severe coherence violations and disfluencies. In this chapter, I will present probabilistic models of document structure that can be effectively learned from raw document collections. This feature distinguishes these new models from traditional knowledge intensive approaches used in symbolic concept-to-text generation. Our results demonstrate that these probabilistic models can be directly applied to content organization, and suggest that these models can prove useful in an even broader range of text-to-text applications than we have considered here.National Science Foundation (U.S.) (CAREER grant IIS- 0448168)Microsoft Research. New Faculty Fellowshi

Unsupervised Paraphrasing via Deep Reinforcement Learning

Paraphrasing is expressing the meaning of an input sentence in different wording while maintaining fluency (i.e., grammatical and syntactical correctness). Most existing work on paraphrasing use supervised models that are limited to specific domains (e.g., image captions). Such models can neither be straightforwardly transferred to other domains nor generalize well, and creating labeled training data for new domains is expensive and laborious. The need for paraphrasing across different domains and the scarcity of labeled training data in many such domains call for exploring unsupervised paraphrase generation methods. We propose Progressive Unsupervised Paraphrasing (PUP): a novel unsupervised paraphrase generation method based on deep reinforcement learning (DRL). PUP uses a variational autoencoder (trained using a non-parallel corpus) to generate a seed paraphrase that warm-starts the DRL model. Then, PUP progressively tunes the seed paraphrase guided by our novel reward function which combines semantic adequacy, language fluency, and expression diversity measures to quantify the quality of the generated paraphrases in each iteration without needing parallel sentences. Our extensive experimental evaluation shows that PUP outperforms unsupervised state-of-the-art paraphrasing techniques in terms of both automatic metrics and user studies on four real datasets. We also show that PUP outperforms domain-adapted supervised algorithms on several datasets. Our evaluation also shows that PUP achieves a great trade-off between semantic similarity and diversity of expression

Neutron-Rich Freeze-Out in Viscously Spreading Accretion Disks Formed from Compact Object Mergers

Accretion disks with masses ~0.001-0.1 Msun form during the merger of neutron star (NS)-NS and black hole-NS binaries. Initially, such hyper-accreting disks cool efficiently by neutrino emission and their composition is driven neutron-rich by pair captures under degenerate conditions. However, as the disk viscously spreads and its temperature drops, cooling becomes inefficient and the disk becomes advective. Analytic arguments and numerical simulations suggest that once this occurs, powerful winds likely drive away most of the disk's remaining mass. We calculate the thermal evolution and nuclear composition of viscously spreading accretion disks formed from compact object mergers using one-dimensional height-integrated simulations. We show that freeze-out from weak equilibrium necessarily accompanies the disk's late-time transition to an advective state. As a result, hyper-accreting disks generically freeze out neutron-rich (with electron fraction Ye ~ 0.2-0.4), and their late-time outflows robustly synthesize rare neutron-rich isotopes. Using the measured abundances of these isotopes in our solar system, we constrain the compact object merger rate in the Milky Way to be < 1e-5 (M_d,0/0.1 Msun)^(-1) per year, where M_d,0 is the average initial mass of the accretion disk. Thus, either the NS-NS merger rate is at the low end of current estimates or the average disk mass produced during a typical merger is << 0.1 Msun. We also show that if most short duration gamma-ray bursts (GRBs) are produced by compact object mergers, their beaming fraction must exceed f_b ~ 0.13(M_d,0/0.1 Msun), corresponding to a jet half-opening angle > 30(M_d,0/0.1 Msun)^(1/2) degrees. This is consistent with other evidence that short duration GRB outflows are less collimated than those produced in long duration GRBs.Comment: 12 pages, 9 figures, 1 table; accepted to MNRAS; minor changes to text and figure

Hemoglobin A1c and Arterial and Ventricular Stiffness in Older Adults

Objective: Arterial and ventricular stiffening are characteristics of diabetes and aging which confer significant morbidity and mortality; advanced glycation endproducts (AGE) are implicated in this stiffening pathophysiology. We examined the association between HbA1c, an AGE, with arterial and ventricular stiffness measures in older individuals without diabetes. Research Design & Methods: Baseline HbA1c was measured in 830 participants free of diabetes defined by fasting glucose or medication use in the Cardiovascular Health Study, a population-based cohort study of adults aged ≥65 years. We performed cross-sectional analyses using baseline exam data including echocardiography, ankle and brachial blood pressure measurement, and carotid ultrasonography. We examined the adjusted associations between HbA1c and multiple arterial and ventricular stiffness measures by linear regression models and compared these results to the association of fasting glucose (FG) with like measures. Results: HbA1c was correlated with fasting and 2-hour postload glucose levels (r = 0.21; p<0.001 for both) and positively associated with greater body-mass index and black race. In adjusted models, HbA1c was not associated with any measure of arterial or ventricular stiffness, including pulse pressure (PP), carotid intima-media thickness, ankle-brachial index, end-arterial elastance, or left ventricular mass (LVM). FG levels were positively associated with systolic, diastolic and PP and LVM. Conclusions: In this sample of older adults without diabetes, HbA1c was not associated with arterial or ventricular stiffness measures, whereas FG levels were. The role of AGE in arterial and ventricular stiffness in older adults may be better assessed using alternate AGE markers

Inverse association between insulin resistance and gait speed in nondiabetic older men: results from the U.S. National Health and Nutrition Examination Survey (NHANES) 1999-2002

<p>Abstract</p> <p>Background</p> <p>Recent studies have revealed the associations between insulin resistance (IR) and geriatric conditions such as frailty and cognitive impairment. However, little is known about the relation of IR to physical impairment and limitation in the aging process, eg. slow gait speed and poor muscle strength. The aim of this study is to determine the effect of IR in performance-based physical function, specifically gait speed and leg strength, among nondiabetic older adults.</p> <p>Methods</p> <p>Cross-sectional data were from the population-based National Health and Nutrition Examination Survey (1999-2002). A total of 1168 nondiabetic adults (≥ 50 years) with nonmissing values in fasting measures of insulin and glucose, habitual gait speed (HGS), and leg strength were analyzed. IR was assessed by homeostasis model assessment (HOMA-IR), whereas HGS and peak leg strength by the 20-foot timed walk test and an isokinetic dynamometer, respectively. We used multiple linear regression to examine the association between IR and performance-based physical function.</p> <p>Results</p> <p>IR was inversely associated with gait speed among the men. After adjusting demographics, body mass index, alcohol consumption, smoking status, chronic co-morbidities, and markers of nutrition and cardiovascular risk, each increment of 1 standard deviation in the HOMA-IR level was associated with a 0.04 m/sec decrease (p = 0.003) in the HGS in men. We did not find such association among the women. The IR-HGS association was not changed after further adjustment of leg strength. Last, HOMA-IR was not demonstrated in association with peak leg strength.</p> <p>Conclusion</p> <p>IR is inversely associated with HGS among older men without diabetes. The results suggest that IR, an important indicator of gait function among men, could be further investigated as an intervenable target to prevent walking limitation.</p

Maternal but Not Paternal Association of Ambulatory Blood Pressure With Albumin Excretion in Young Offspring With Type 1 Diabetes

OBJECTIVE: Familial predisposition to hypertension has been associated with the development of diabetic nephropathy in adults, but there are limited data in adolescents. Our aim was to assess whether parental ambulatory blood pressure (ABP) was associated with ABP and albumin excretion in young offspring with type 1 diabetes. RESEARCH DESIGN AND METHODS: Twenty-four-hour ABP monitoring was performed in 509 young offspring (mean +/- SD age 15.8 +/- 2.3 years) with type 1 diabetes, 311 fathers, and 444 mothers. Systolic (SBP) and diastolic blood pressure (DBP) measurements during 24 h, daytime, and nighttime were calculated. Three early morning urinary albumin-to-creatinine ratios (ACRs), A1C, and anthropometric parameters were available for the offspring. RESULTS: All paternal ABP parameters, except for nighttime SBP, were independently related to the offspring's ABP (24-h SBP beta = 0.18, 24-h DBP beta = 0.22, daytime SBP beta = 0.25, daytime DBP beta = 0.23, and nighttime DBP beta = 0.18; all P < 0.01). Maternal 24-h DBP (beta = 0.19, P = 0.004), daytime DBP (beta = 0.09, P = 0.04), and nighttime SBP (beta = 0.24 P = 0.001) were related to the corresponding ABP parameter in the offspring. Significant associations were found between the offspring's logACR and maternal ABP. The association with 24-h DBP (beta = 0.16, P = 0.02), daytime DBP (beta = 0.16 P = 0.02), and nighttime DBP (beta = 0.15 P = 0.03) persisted even after adjustment for the offspring's ABP. Mothers of offspring with microalbuminuria had higher ABP than mothers of offspring without microalbuminuria (all P < 0.05). CONCLUSIONS: In this cohort, parental ABP significantly influenced offspring blood pressure, therefore confirming familial influences on this trait. In addition, maternal ABP, particularly DBP, was closely related to ACR in the offspring, suggesting a dominant effect of maternal genes or an effect of the intrauterine environment on microalbuminuria risk