Catastrophic NAD+ Depletion in Activated T Lymphocytes through Nampt Inhibition Reduces Demyelination and Disability in EAE

Nicotinamide phosphoribosyltransferase (Nampt) inhibitors such as FK866 are potent inhibitors of NAD+ synthesis that show promise for the treatment of different forms of cancer. Based on Nampt upregulation in activated T lymphocytes and on preliminary reports of lymphopenia in FK866 treated patients, we have investigated FK866 for its capacity to interfere with T lymphocyte function and survival. Intracellular pyridine nucleotides, ATP, mitochondrial function, viability, proliferation, activation markers and cytokine secretion were assessed in resting and in activated human T lymphocytes. In addition, we used experimental autoimmune encephalomyelitis (EAE) as a model of T-cell mediated autoimmune disease to assess FK866 efficacy in vivo. We show that activated, but not resting, T lymphocytes undergo massive NAD+ depletion upon FK866-mediated Nampt inhibition. As a consequence, impaired proliferation, reduced IFN-γ and TNF-α production, and finally autophagic cell demise result. We demonstrate that upregulation of the NAD+-degrading enzyme poly-(ADP-ribose)-polymerase (PARP) by activated T cells enhances their susceptibility to NAD+ depletion. In addition, we relate defective IFN-γ and TNF-α production in response to FK866 to impaired Sirt6 activity. Finally, we show that FK866 strikingly reduces the neurological damage and the clinical manifestations of EAE. In conclusion, Nampt inhibitors (and possibly Sirt6 inhibitors) could be used to modulate T cell-mediated immune responses and thereby be beneficial in immune-mediated disorders

Acute physical exercise can influence the accuracy of metacognitive judgments

Acute exercise generally benefits memory but little research has examined how exercise affects metacognition (knowledge of memory performance). We show that a single bout of exercise can influence metacognition in paired-associate learning. Participants completed 30- min of moderate-intensity exercise before or after studying a series of word pairs (cloudivory), and completed cued-recall (cloud-?; Experiments 1 & 2) and recognition memory tests (cloud-? spoon; ivory; drill; choir; Experiment 2). Participants made judgments of learning prior to cued-recall tests (JOLs; predicted likelihood of recalling the second word of each pair when shown the first) and feeling-of-knowing judgments prior to recognition tests (FOK; predicted likelihood of recognizing the second word from four alternatives). Compared to noexercise control conditions, exercise before encoding enhanced cued-recall in Experiment 1 but not Experiment 2 and did not affect recognition. Exercise after encoding did not influence memory. In conditions where exercise did not benefit memory, it increased JOLs and FOK judgments relative to accuracy (Experiments 1 & 2) and impaired the relative accuracy of JOLs (ability to distinguish remembered from non-remembered items; Experiment 2). Acute exercise seems to signal likely remembering; this has implications for understanding the effects of exercise on metacognition, and for incorporating exercise into study routines

Costs and cost-effectiveness of tuberculosis cultures using solid and liquid media in a developing country.

SETTING: The expansion of culture has been proposed to aid tuberculosis (TB) control in developing countries. OBJECTIVES: To examine the cost and cost-effectiveness at the Zambian National TB Reference Laboratory of homemade and commercially produced Löwenstein-Jensen culture (HLJ and CLJ) as well as automated and manually read liquid culture (AMGIT and MMGIT). DESIGN: Costs were estimated from the provider's perspective and based on the average monthly throughput. Cost-effectiveness estimates were based on yield during the study period. RESULTS: All techniques show comparable costs per culture (between US$28 and$32). Costs per Mycobacterium tuberculosis specimen detected were respectively US$197,$202, $312 and$340 for MMGIT, AMGIT, CLJ and HLJ. When modelled for the maximum throughput, costs were above US$95 per M. tuberculosis specimen detected for all techniques. When only performed among smear-negative specimens, costs per additionally identified M. tuberculosis would be US$487 for MMGIT and higher for other methods. CONCLUSION: Based on cost-effectiveness grounds, liquid media compare well with conventional solid media, especially where yield of MGIT is substantially higher than that of LJ media. The results indicate high overall costs per culture; the expansion of culture to decentralised levels with lower throughputs may result in even higher costs