Charles McCurdy (blousesingle82)

It also differed from that of reading age-matched controls when accounting for individual reading performance. Furthermore, the CA group displayed an implicit serial order facilitation for item memory, whereas this implicit recruitment of serial order abilities was completely absent in children with DD. Our results suggest that the domain-general cognitive ability to maintain the serial order of information interacts with the development of reading competency, especially during a middle training phase of word reading, and this particular relationship is markedly impaired in children with DD. On the basis of epidemiological studies it has been proposed that cannabis use plays a causal role in the abuse of highly addictive drugs (Gateway Hypothesis). However, epidemiological studies are intrinsically unable to provide evidence of causality. Experimental studies can provide this evidence but they are feasible only in animal models and to date such evidence is lacking. In view of the importance of genetic factors in drug abuse, we investigated the influence of adolescent cannabis exposure on adult heroin reinforcement in two inbred rat strains differentially vulnerable to drugs of abuse, addiction prone Lewis (LEW) and addiction resistant Fischer 344 (F344) strains. Male LEW and F344 rats aged six weeks were exposed to increasing Δ9-tetrahydrocannabinol (THC) doses, twice a day for 3 days (2, 4, 8 mg/kg, i.p.). At adulthood they were allowed to self-administer heroin (0.025 mg/kg) under both Fixed- (FR) and Progressive- (PR) ratio schedules of responding. Following extinction, responding was reinstated by drug-cues and/or by heroin priming. THC pre-exposure increased responding for heroin and heroin intake under FR-3 and FR-5 as well as PR protocols and increased breaking point in PR schedules in LEW but not F344 rats. Drug cues and heroin priming reinstated responding in LEW and F344, but THC pre-exposure increased reinstatement by priming in LEW rats and by cues in F344 rats. These observations show that in genetically predisposed individuals, adolescent cannabis exposure increases heroin reinforcing properties, thus providing a mechanism for a causal role of adolescent cannabis use in heroin abuse. AIMS This study compared the reduction of glycated haemoglobin (HbA1c) with sodium-glucose cotransporter type-2 inhibitors (SGLT2is) vs. dipeptidyl peptidase-4 inhibitors (DPP-4is) as add-ons to metformin in patients with type 2 diabetes mellitus (T2DM), with a specific focus on HbA1c changes according to baseline HbA1c. MATERIALS AND METHODS Electronic databases were scrutinized for randomized controlled trials (RCTs) evaluating the reduction of HbA1c from baseline (Δ HbA1c) with an SGLT2i or DPP-4i in patients with T2DM not well controlled by metformin monotherapy. The endpoint was Δ HbA1c using both indirect and direct comparisons. RESULTS Overall, Δ HbA1c was slightly greater with SGLT2is (-0.80±0.20% from 8.03±0.35%; 44 analyses, 29 RCTs, 15 with two doses, n=9321) than with DPP-4is (-0.71±0.23% from 8.05±0.43%; 61 analyses, 59 RCTs, n=17,914; P=0.0354). When the mean baseline HbA1c was less then 8% ([64mmol/mol] 7.79±0.15% vs. 7.71±0.23%), Δ HbA1c averaged -0.735±0.17% vs. -0.62±0.16% (P=0.0117) with SGLT2is vs. DPP-4is, respectively. However, this difference vanished when the mean baseline HbA1c was≥8% (-0.87±0.22% from 8.27±0.32% with SGLT2is vs. -0.80±0.24% from 8.35±0.33% with DPP-4is; P=0.2756). The relationship between Δ HbA1c and baseline HbA1c was only slightly stronger with SGLT2is (slope -0.39, r2=-0.43; P less then 0.0001) than with DPP-4is (slope -0.26, r2=-0.25; P less then 0.0001). CONCLUSION Because of the small difference in Δ HbA1c whatever the baseline HbA1c level with SGLT2is vs. DPP-4is as add-ons to metformin, choosing between these glucose-lowering agents in clinical practice should be based on other efficacy criteria (such as weight and blood pressure changes, cardiovascular and renal protecti