Higher Performance of QuantiFERON TB Compared to Tuberculin Skin Test in Latent Tuberculosis Infection Prospective Diagnosis

Background: The Tuberculin skin test (TST) has been used for years in the latent tuberculosis infection (LTBI) diagnosis, but it has, well-documented, low sensitivity and specificity. Interferon-ϒ release assays (IGRA) has been reported to be more sensitive and specific than TST. Therefore, this study aimed to evaluate the performance of a commercial IGRA, QuantiFERON®-TB Gold In-Tube (QFT-GIT), comparatively to TST in LTBI diagnosis. Patients and Methods: This study included 238 patients who were candidate for an anti-TNF therapy. The screening for LTBI was performed by both TST and QFT-GIT test for all patients. In order to evaluate the strength of associations, the odds ratios (OR) together with 95% confidence intervals (CI) were calculated. The correlation between QFT-GIT and TST was evaluated using κ statistics. Results: Sixty-three (26.4%) sera were positive for QFT-GIT with a mean level of IFN-ϒ of about 1.18 IU/ml, while 81 (34%) patients were positive for TST. Agreement between QFT-GIT and TST was poor (37 QFT-GIT+/TST- and 55 QFT-GIT-/TST+), κ=0.09 (SD=0.065). The positivity of QFT-GIT was not influenced by BCG vaccination or by immunosuppression. Nevertheless, it was significantly associated to both history of an earlier tuberculosis disease (HETD) and its radiological sequel (RS), p=6E-7 and p=1E-8, respectively. Inversely, the TST results were not correlated to either HETD or RS, but the TST positivity was less frequent in immunosuppressed patients (45.5% vs. 73.9%), p=1E-5, OR (95% CI) = 0.29 [0.17-0.52]. Moreover, the extent of both the immunosuppression period and the time elapsed from the last BCG injection was significantly correlated to a lesser TST positivity, p=3E-12 and p=5E-7, respectively. Among the QFT-GIT-/TST+ patients (n=55) whom received an anti-TNF agent without any prophylactic treatment of LTBI, no tuberculosis was detected with a median follow-up of 78 weeks [56-109]. Conclusion: Our study suggests that the QFT-GIT has a higher performance comparatively to TST in the LTBI screening that is unaffected by either BCG vaccination or immunosuppression. Therefore, IGRAs has to replace TST especially in patients who are under consideration for an anti-TNF therapy

A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism

Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, are repressed during diet-induced obesity (DIO) and refeeding, whilst nutrient deprivation induced lncRNAs in mouse liver. Similarly, lncRNAs are lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirm that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in mouse hepatocytes and obese mice elicits a fasting-like gene expression profile, improves glucose metabolism, de-represses lncRNAs and impairs mammalian target of rapamycin (mTOR) activation. We find that obesity-repressed LincIRS2 is controlled by MAFG and observe that genetic and RNAi-mediated LincIRS2 loss causes elevated blood glucose, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease

A MAFG-lncRNA axis links systemic nutrient abundance to hepatic glucose metabolism

Obesity and type 2 diabetes mellitus are global emergencies and long noncoding RNAs (lncRNAs) are regulatory transcripts with elusive functions in metabolism. Here we show that a high fraction of lncRNAs, but not protein-coding mRNAs, are repressed during diet-induced obesity (DIO) and refeeding, whilst nutrient deprivation induced lncRNAs in mouse liver. Similarly, lncRNAs are lost in diabetic humans. LncRNA promoter analyses, global cistrome and gain-of-function analyses confirm that increased MAFG signaling during DIO curbs lncRNA expression. Silencing Mafg in mouse hepatocytes and obese mice elicits a fasting-like gene expression profile, improves glucose metabolism, de-represses lncRNAs and impairs mammalian target of rapamycin (mTOR) activation. We find that obesity-repressed LincIRS2 is controlled by MAFG and observe that genetic and RNAi-mediated LincIRS2 loss causes elevated blood glucose, insulin resistance and aberrant glucose output in lean mice. Taken together, we identify a MAFG-lncRNA axis controlling hepatic glucose metabolism in health and metabolic disease

LincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat

Brown adipose tissue (BAT) thermogenesis counteracts obesity and promotes metabolic health. The role of long non-coding RNAs (lncRNAs) in the regulation of this process is not well understood. Here the authors identify a maternally expressed lncRNA, H19, that increases BAT oxidative metabolism and energy expenditure

LincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat

Increasing brown adipose tissue (BAT) thermogenesis in mice and humans improves metabolic health and understanding BAT function is of interest for novel approaches to counteract obesity. The role of long noncoding RNAs (lncRNAs) in these processes remains elusive. We observed maternally expressed, imprinted lncRNA H19 increased upon cold-activation and decreased in obesity in BAT. Inverse correlations of H19 with BMI were also observed in humans. H19 overexpression promoted, while silencing of H19 impaired adipogenesis, oxidative metabolism and mitochondrial respiration in brown but not white adipocytes. In vivo, H19 overexpression protected against DIO, improved insulin sensitivity and mitochondrial biogenesis, whereas fat H19 loss sensitized towards HFD weight gains. Strikingly, paternally expressed genes (PEG) were largely absent from BAT and we demonstrated that H19 recruits PEG-inactivating H19-MBD1 complexes and acts as BAT-selective PEG gatekeeper. This has implications for our understanding how monoallelic gene expression affects metabolism in rodents and, potentially, humans.(VLID)460224