The serum bile acid profile, the hepatic gene expression pattern and the gut microbiome composition consistently support an elevated bile acid production in NAFLD. The increased proportion of FXR antagonistic bile acid explains, at least in part, the suppression of hepatic FXR-mediated and FGFR4-mediated signalling. Our study suggests that future NAFLD intervention may target the components of FXR signalling, including the bile acid converting gut microbiome.

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We propose the use of the information-theoretical entrophy, S = -sigman pi log2 pi, as a measure of variability at a given position in a set of aligned sequences. pi stands for the fraction of times the i-th type appears at a position. For protein sequences, the sum has up to 20 terms, for nucleotide sequences, up to 4 terms, and for codon sequences, up to 61 terms. We compare S and Vs, a related measure, in detail with Vk, the traditional measure of immunoglobulin sequence variability, both in the abstract and as applied to the immunoglobulins. We conclude that S has desirable mathematical properties that Vk lacks and has intuitive and statistical meanings that accord well with the notion of variability. We find that Vk and the S-based measures are highly correlated for the immunoglobulins. We show by analysis of sequence data and by means of a mathematical model that this correlation is due to a strong tendency for the frequency of occurrence of amino acid types at a given position to be log-linear. It is not known whether the immunoglobulins are typical or atypical of protein families in this regard, nor is the origin of the observed rank-frequency distribution obvious, although we discuss several possible etiologies.

OBJECTIVETo gather preliminary data on the feasibility and efficacy of etanercept therapy to prolong endogenous insulin production in pediatric patients with newly diagnosed type 1 diabetes.RESEARCH DESIGN AND METHODSThis was a 24-week double-blind, randomized, placebo-controlled study conducted at the Diabetes Center, Women and Children's Hospital of Buffalo. Eighteen subjects (11 male and 7 female, aged 7.8–18.2 years) were randomly assigned to receive either placebo or etanercept. Inclusion criteria included age 3–18 years, GAD-65 and/or islet cell antibody positivity, A1C >6%, three insulin injections per day, white blood cell count 3,000–10,000, platelets >100,000, and normal liver and renal function. Intention-to-treat analysis was used.RESULTSA1C at week 24 was lower in the etanercept group (5.91 ± 0.5%) compared with that in the placebo group (6.98 ± 1.2%; P < 0.05) with a higher percent decrease from baseline than in the placebo group (etanercept 0.41 ± 0.1 vs. placebo 0.18 ± 0.21; P < 0.01). The percent change in C-peptide area under the curve from baseline to week 24 showed a 39% increase in the etanercept group and a 20% decrease in the placebo group (P < 0.05). From baseline to week 24 insulin dose decreased 18% in the etanercept group compared with a 23% increase in the placebo group (P < 0.05). Seventeen patients completed the study, and none withdrew because of adverse events.CONCLUSIONSIn this small pilot study, treatment of pediatric patients newly diagnosed with type 1 diabetes with etanercept resulted in lower A1C and increased endogenous insulin production, suggesting preservation of β-cell function. A larger study is needed to further explore safety and efficacy.