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OBJECTIVETo assess the efficacy/safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, compared with glimepiride over 104 weeks in patients with type 2 diabetes inadequately controlled with metformin. RESEARCH DESIGN AND METHODSIn this randomized, double-blind study, patients (N = 1,450) received canagliflozin 100 or 300 mg or glimepiride (titrated up to 6 or 8 mg/day) during a 52-week core period followed by a 52-week extension. RESULTSAt week 104, reductions from baseline in A1C were 20.65%, 20.74%, and 20.55% (27.1, 28.1, and 26.0 mmol/mol) with canagliflozin 100 and 300 mg and glimepiride, respectively. Durability analyses showed sustained A1C lowering with both canagliflozin doses versus glimepiride. Reductions in body weight (24.1%, 24.2%, and 0.9%, respectively) and systolic blood pressure (22.0, 23.1, and 1.7 mmHg, respectively) were seen with canagliflozin 100 and 300 mg compared with glimepiride at week 104. The overall adverse event (AE) incidence was 73.3%, 77.9%, and 78.4% with canagliflozin 100 and 300 mg and glimepiride; the incidence of AE-related discontinuations was low across groups (6.2%, 9.5%, and 7.3%, respectively). Incidences of genital mycotic infections, urinary tract infections, and osmotic diuresis-related AEs were higher with canagliflozin than glimepiride; these were generally mild to moderate in intensity and led to few discontinuations. Fewer patients had hypoglycemia episodes with canagliflozin 100 and 300 mg than glimepiride (6.8%, 8.2%, and 40.9%). Mild decreases in estimated glomerular filtration rate occurred initially with canagliflozin; these attenuated over 104 weeks. CONCLUSIONSCanagliflozin provided durable glycemic improvements compared with glimepiride and was generally well tolerated in patients with type 2 diabetes receiving background treatment with metformin over 104 weeks.

Non-local methods for image denoising and inpainting have gained considerable attention in recent years. This is in part due to their superior performance in textured images, a known weakness of purely local methods. Local methods on the other hand have demonstrated to be very appropriate for the recovering of geometric structures such as image edges. The synthesis of both types of methods is a trend in current research. Variational analysis in particular is an appropriate tool for a unified treatment of local and non-local methods. In this work we propose a general variational framework non-local image inpainting, from which important and representative previous inpainting schemes can be derived, in addition to leading to novel ones. We explicitly study some of these, relating them to previous work and showing results on synthetic and real images.

The introduction of farming had far-reaching impacts on health, social structure and demography. Although the spread of domesticated plants and animals has been extensively tracked, it is unclear how these nascent economies developed within different environmental and cultural settings. Using molecular and isotopic analysis of lipids from pottery, here we investigate the foods prepared by the earliest farming communities of the European Atlantic seaboard. Surprisingly, we find an absence of aquatic foods, including in ceramics from coastal sites, except in the Western Baltic where this tradition continued from indigenous ceramic using hunter-gatherer-fishers. The frequency of dairy products in pottery increased as farming was progressively introduced along a northerly latitudinal gradient. This finding implies that early farming communities needed time to adapt their economic practices before expanding into more northerly areas. Latitudinal differences in the scale of dairy production might also have influenced the evolution of adult lactase persistence across Europe.

Increased levels of TSH are associated to a decrease in HL activity, explaining our findings of an LDL particle rich in TG. This qualitative lipoprotein alteration suggests a pro-atherogenic pattern in sH. Treatment with L-T(4), however, did not correct the basal lipid derangement.

This chapter presents the available information on the late Mesolithic and the early Neolithic in north-west Iberia, and discusses its significance when attempting to understand the processes of transition from foraging to peasant societies. The north-west of the Iberian Peninsula provides, in a restricted area, a huge variety of Neolithization processes, probably interrelated, on an unequal background of Mesolithic populations, with great contrast between densely populated areas, such as the Cantabrian coast or the Upper Ebro, and others with lower densities. It is precisely in one of these densely populated areas that the first contacts appear to have happened. The evidence from Mendandia suggests that, about 5500 cal bc, not much later than the time when the first Neolithic groups were established on the Mediterranean coast, the first pottery could have reached the Upper Ebro. The earliest pots were probably no more than attractive prestige goods, which reached this area through exchange networks whose existence is proved by the presence of Mediterranean shells in the local Mesolithic.

We investigated the effect of ovariectomy (OVX) and subsequent estradiol benzoate (EB) treatment upon the N-methyl-D-aspartate (NMDA)-induced LH secretion in adult female rats. Furthermore, the release of LHRH, norepinephrine (NE), dopamine (DA), 5-hydroxyindoleacetic acid (5-HIAA) and γ-aminobutyric acid (GABA) from superfused hypothalamic fragments ex-planted from OVX and OVX-EB rats was determined. Two weeks after OVX, animals received EB (100 mg/kg) s.c, or oil vehicle (OVX-EB or OVX groups, respectively). Two days thereafter, at 09.00 h, NMDA (15 or 30 mg/ kg) was given as an i.v. bolus; blood samples were drawn before and 10 min after drug administration. In OVX rats, NMDA had no significant effect on LH levels, whereas it stimulated LH release in OVX-EB animals at both doses tested (315 and 362% from basal values, p < 0.001). For hypothalamic super-fusion studies OVX and OVX-EB animals were decapitated at 09.00 h, and the mediobasal hypothalami (MBH) dissected on ice. NMDA (10-4 M) was added to the superfusion medium for a 10 min period. Basal LHRH release (OVX: 1.41 ± 0.18; OVX-EB: 1.59 ± 0.28 pg/10 min/MBH) was significantly (p < 0.05) enhanced by NMDA (OVX: 2.97 ± 0.95; OVX-EB: 2.80 ± 0.61 pg/10 min/MBH). EB treatment had no significant effect on basal or NMDA-induced LHRH output. NMDA significantly (p < 0.05) decreased NE (OVX: 30.8 ± 6.7%; OVX-EB: 47.5 ± 9.7% from basal values), DA (OVX: 63.8 ± 10.7%; OVX-EB: 39.7 ± 14.6% from basal values), and 5-HIAA(OVX: 52.6 ± 7.7%; OVX-EB: 57.5 ± 9.7% from basal values) release, and increased GABA output (OVX: 155.6 ± 16.7%; OVX-EB: 183.1 ± 19.2% from basal values). The observation that OVX-EB rats show a massive LH release after NMDA, and that EB treatment does not alter NMDA-induced LHRH secretion, indicates that the predominant site of action of estradiol is exerted within the pituitary. The physiological implications of the NMDA-induced changes in neurotransmitter release remain to be studied.

We investigated the genetic composition of six Canis remains from western Iberia, directly radiocarbon dated to 7,903-7,570 years (cal BP). They were identified as dogs via their archaeological and depositional context, osteometry, and a high percentage of aquatic diet shared with humans. For comparison, genetic data were obtained from an additional 37 Iberian dog remains from the Neolithic to Late Antiquity, as well as two Palaeolithic and a Chalcolithic Canis identified as wolves. Previous data indicated that dog mtDNA haplogroup A (HgA) is prevalent in extant European dogs (>50%), in the Near East and Asia, but rare or absent (<10%) in European Canis older than 3,000 years (cal BP). We found a high frequency (83%) of dog HgA in Mesolithic Iberian dog remains. This is the first report of a high frequency of dog HgA in pre-Neolithic Europe. We show that, contrary to the current view, Canis with HgA did not necessarily arrive in Europe from East-Asia. This phylogeographical difference in HgA frequency demonstrates that genetic differentiation was high prior to, or as a consequence of, domestication which may be linked with pre-Neolithic local processes for Iberian wolf domestication. Our results emphasize that knowledge of both ancient wolves' and early dogs' genetic profiles from the European periphery should improve our understanding of the evolution of the European dog.