The response of the adaptive immune system is usually less intense in premature neonates than term neonates. The primary objective of this study was to determine whether immunological parameters vary between preterm (PT) neonates (≥32 weeks of gestational age) and very preterm (VPT) neonates (<32 weeks of gestational age). A cross-sectional study was designed to prospectively follow PT and VPT neonates at risk of developing sepsis. Plasma concentrations of IFN-γ, TNF-α, IL-6, IL-4, and IL-10 were detected using flow cytometry. C-reactive protein (C-RP) and the complex SC5b-9 were detected in the plasma using commercial kits. A total of 83 patients were included. The laboratory results and clinical histories showed that 26 patients had sepsis; 14 were VPT, and 12 were PT. The levels of C-RP, SC5b-9 (innate immune response mediators), and IL-10 or IL-4 (anti-inflammatory cytokines) were elevated during sepsis in both groups. IFN-γ, TNF-α, and IL-6 (proinflammatory cytokines) were differentially elevated only in PT neonates. The VPT neonates with sepsis presented increases in C-RP, SC5b-9, and anti-inflammatory cytokines but not in proinflammatory cytokines, whereas PT neonates showed increases in all studied mediators of inflammation.

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SummaryObjectiveOur review analyses the studies that have specifically compared the association iDPP4/metformin with glimepiride/metformin, both in second line pharmacotherapy of type 2 diabetes mellitus (DM2).MethodsSystematic literature review with a meta‐analysis of clinical trials comparing glimepiride with any iDPP4, both used together with metformin as a second line treatment of DM2. The effectiveness variables used were as follows: %HbA1c variation, fasting plasma glucose variation, patients achieving the therapeutic objective of HbA1c <7%, treatment dropouts due to lack of effectiveness and rescue treatments needed. The safety variables included were as follows: weight variation at the end of treatment; presentation of any type of adverse event; presentation of serious adverse events; patients who experienced any type of hypoglycaemia; patients who experienced severe hypoglycaemia; treatments suspended due to adverse effects; and deaths for any reason.ResultsFour studies met the inclusion criteria. The group treated with glimepiride showed better results in all effectiveness variables. Regarding safety variables, the main differences observed were in the greater number of cases with hypoglycaemia in the group treated with glimepiride, and the serious adverse events or treatment discontinuations due to these which occurred in slightly over 2% more cases in this group compared to the iDPP4 group. The remaining adverse events, including mortality, did not show any differences between both groups. The variation in the weight difference between groups (2.1 kg) is not considered clinically relevant.ConclusionsA greater effectiveness is seen in the glimepiride/metformin association, which should not be diminished by slight differences in adverse effects, with absence of severe hypoglycaemia in over 98% of patients under treatment. The association of glimepiride/metformin, both due to cost as well as effectiveness and safety, may be the preferential treatment for most DM2 patients, and it offers a potential advantage in refractory hyperglycemic populations, tolerant to treatment.

Californiconus californicus, previously named Conus californicus, has always been considered a unique species within cone snails, because of its molecular, toxicological and morphological singularities; including the wide range of its diet, since it is capable of preying indifferently on fish, snails, octopus, shrimps, and worms. We report here a new cysteine pattern conotoxin assigned to the O1-superfamily capable of inhibiting the growth of Mycobacterium tuberculosis (Mtb). The conotoxin was tested on a pathogen reference strain (H37Rv) and multidrug-resistant strains, having an inhibition effect on growth with a minimal inhibitory concentration (MIC) range of 3.52–0.22 μM, similar concentrations to drugs used in clinics. The peptide was purified from the venom using reverse phase high-performance liquid chromatography (RP-HPLC), a partial sequence was constructed by Edman degradation, completed by RACE and confirmed with venom gland transcriptome. The 32-mer peptide containing eight cysteine residues was named O1_cal29b, according to the current nomenclature for this type of molecule. Moreover, transcriptomic analysis of O-superfamily toxins present in the venom gland of the snail allowed us to assign several signal peptides to O2 and O3 superfamilies not described before in C. californicus, with new conotoxins frameworks.

The liver is a main target tissue of the biguanide metformin which activates AMP-activated protein kinase (AMPK). We have previously reported that administration of metformin glycinate showed a greater decrease in glycated hemoglobin A1c than placebo in patients with type 2 diabetes mellitus (T2DM). Herein, we have compared the effects of metformin hydrochloride, the oral antidiabetic drug of first choice, with those of metformin glycinate in hepatocytes from non-diabetic, diabetic mice and humans. Both formulations were equally potent in the reduction of basal and glucagon-induced glucose production and mRNA levels of gluconeogenic enzymes (Pck1 and G6pc) in hepatocytes from C57/Bl6 mice and humans. In contrast, phosphorylation of AMPK and its substrate acetyl CoA carboxylase (ACC) was more rapid in hepatocytes treated with metformin glycinate. Likewise, in hepatocytes from obese/diabetic db/db mice we found stronger reduction of glucagon-induced glucose output and more sustained AMPK phosphorylation by the treatment with metformin glycinate. Importantly, insulin sensitization regarding phosphorylation of AKT (Ser473) was enhanced in hepatocytes from db/db mice or humans pretreated with metformin glycinate. Altogether, our data point out preclinical mechanistic evidences in hepatocytes suggesting that metformin glycinate might represent a superior alternative therapy against insulin resistance during obesity and/or T2DM. Response to Reviewers: Point-by-point response to the Reviewer´s comments. Reviewer #1: This manuscript compares the effects of metformin hydrochloride and metformin glycinate in reducing basal and induced glucose production as well as the regulation of gluconeogenesis. The authors use hepatocytes from mice, db/db mice as well as from humans for their study. The experimental data reported by the authors suggests that metformin glycinate can effect some facets of glucose regulation at a INSTITUTO DE INVESTIGACIONES BIOMÉDICAS "ALBERTO SOLS", IIBM http://www.iib.uam.es C/Arturo Duperier, nº 4 28029 MADRID ESPAÑA PHO: (34) 91 585 4400 FAX: (34) 91 585 4401 Dear Editor: Find enclosed the electronic submission of the revised manuscript referenced as FCT-D-18-01715 entitled "Differential effects of metformin glycinate and hydrochloride in glucose production, AMPK phosphorylation and insulin sensitivity in hepatocytes from non-diabetic and diabetic mice" to be considered for publication in Food and Chemical Toxicology. In this revised manuscript we have addressed all the minor issues raised by the Reviewers (highlighted in red font). We also provide a detailed point-by-point response letter to the Reviewer´s comments.

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Administration of metformin glycinate during a 2-month period showed a greater decrease in A1C concentrations than placebo in a selected group of drug-naive adult patients with T2DM.