NADH inhibition of SIRT1 links energy state to transcription during time-restricted feeding.

In mammals, circadian rhythms are entrained to the light cycle and drive daily oscillations in levels of NAD+, a cosubstrate of the class III histone deacetylase sirtuin 1 (SIRT1) that associates with clock transcription factors. Although NAD+ also participates in redox reactions, the extent to which NAD(H) couples nutrient state with circadian transcriptional cycles remains unknown. Here we show that nocturnal animals subjected to time-restricted feeding of a calorie-restricted diet (TRF-CR) only during night-time display reduced body temperature and elevated hepatic NADH during daytime. Genetic uncoupling of nutrient state from NADH redox state through transduction of the water-forming NADH oxidase from Lactobacillus brevis (LbNOX) increases daytime body temperature and blood and liver acyl-carnitines. LbNOX expression in TRF-CR mice induces oxidative gene networks controlled by brain and muscle Arnt-like protein 1 (BMAL1) and peroxisome proliferator-activated receptor alpha (PPARα) and suppresses amino acid catabolic pathways. Enzymatic analyses reveal that NADH inhibits SIRT1 in vitro, corresponding with reduced deacetylation of SIRT1 substrates during TRF-CR in vivo. Remarkably, Sirt1 liver nullizygous animals subjected to TRF-CR display persistent hypothermia even when NADH is oxidized by LbNOX. Our findings reveal that the hepatic NADH cycle links nutrient state to whole-body energetics through the rhythmic regulation of SIRT1.

Primum non nocere: Utility and outcomes of pediatric breast ultrasound.

PURPOSE: To assess the use and outcomes of ultrasound for the evaluation of breast signs and symptoms in pediatric females. METHODS: A retrospective database review identified all patients ≤18-years-old who underwent breast ultrasound at an academic institution over a 20-year period. Each symptomatic site was designated a case and analyses were performed on each case. Imaging findings were obtained from the radiology reports. Clinical and pathology data were obtained from the medical records. Descriptive statistics were performed. RESULTS: The final cohort comprised 124 cases in 101 patients. Mean age was 15 years (range 1-18). The most common indication for ultrasound was a palpable lump (71%). Thirty-seven cases (30%) demonstrated no sonographic correlate to the symptom; 36 (29%) had a benign correlate. The most common benign correlates were abscess/phlegmon and cyst. All cases of abscess/phlegmon had infectious symptoms. Fifty-one cases (41%) demonstrated a sonographic mass that was not characteristically benign. Of these indeterminate masses, 27 were recommended for biopsy, 13 for short-interval follow-up, and 6 had no recommendation. Of 27 biopsied masses, 63% were fibroadenomas. No symptoms were due to malignancy. Therefore, the NPV of ultrasound was 100% and the PPV 0%. CONCLUSION: In this cohort of pediatric and adolescent patients, malignancy was never the cause of breast symptoms. Imaging yielded false positives with a biopsy recommendation in 22% of cases. Ultrasound provided value in evaluating infectious symptoms. Given the extreme rarity of breast cancer in this population, surveillance may be a safe alternative for most indeterminate lesions.