Multi-Tracer Studies of Brain Oxygen and Glucose Metabolism Using a Time-of-Flight Positron Emission Tomography - Computed Tomography Scanner.

The authors have developed a paradigm using positron emission tomography (PET) with multiple radiopharmaceutical tracers that combines measurements of cerebral metabolic rate of glucose (CMRGlc), cerebral metabolic rate of oxygen (CMRO2), cerebral blood flow (CBF), and cerebral blood volume (CBV), culminating in estimates of brain aerobic glycolysis (AG). These in vivo estimates of oxidative and non-oxidative glucose metabolism are pertinent to the study of the human brain in health and disease. The latest positron emission tomography-computed tomography (PET-CT) scanners provide time-of-flight (TOF) imaging and critical improvements in spatial resolution and reduction of artifacts. This has led to significantly improved imaging with lower radiotracer doses. Optimized methods for the latest PET-CT scanners involve administering a sequence of inhaled 15O-labeled carbon monoxide (CO) and oxygen (O2), intravenous 15O-labeled water (H2O), and 18F-deoxyglucose (FDG)-all within 2-h or 3-h scan sessions that yield high-resolution, quantitative measurements of CMRGlc, CMRO2, CBF, CBV, and AG. This methods paper describes practical aspects of scanning designed for quantifying brain metabolism with tracer kinetic models and arterial blood samples and provides examples of imaging measurements of human brain metabolism.

Comparison of the Ekblom-Bak Submaximal Test to a Maximal Test in a Cohort of Healthy Younger and Older Adults in the United States.

Cardiorespiratory fitness (CRF) is routinely investigated in diverse populations, including in older adults of varying physical activity levels. Commonly performed maximal exercise testing protocols might be contraindicated and/or inadequate for older individuals who have physical or cognitive impairment. Moreover, early termination of an attempted maximal exercise test could result in underestimation of CRF in this population. The goal of the current study was to compare CRF estimates using the Ekblom-Bak (EB) submaximal exercise test - previously validated in a cohort of Scandinavian adults - versus a subsequent maximal exercise test in a diverse, Midwestern United States cohort. Fifteen generally healthy individuals were included in this study who were either "Young" (25-34 years old) or "Older" (55-75 years old) as well as either sedentary or highly active. Participants completed the EB submaximal exercise test, followed immediately by a maximal exercise test. We found that all 15 individuals were able to successfully perform the EB submaximal testing method. Across the wide range of volumes of maximal oxygen consumption (VO2max; 12-52 ml/kg/min), the EB submaximal estimates of VO2max correlated highly with the maximal test based values (Pearson's r = 0.98), but with a small bias (6 ml/kg/min, 95% limits of agreement -1.06 and -11.29). Our results suggest that the EB submaximal testing method may be useful in identifying wide differences in CRF among a diverse cohort of older adults in the United States, but larger studies will be needed to determine the degree of its accuracy and precision in identifying smaller differences.

The State of the Science of Preterm Birth: Assessing Contemporary Screening and Preventive Strategies.

Preterm birth remains a leading cause of morbidity and mortality during the perinatal and neonatal periods. Now affecting approximately 1 in 10 births in the United States, preterm birth often occurs spontaneously and without a clear etiology. Careful assessment of risk factors, however, identifies vulnerable women allowing targeted interventions such as progestogen therapy and cerclage. This article is intended to highlight preterm birth risk factors and current predictive and preventive strategies for midwives, nurse practitioners, clinical nurse specialists, and perinatal nurses.

Acetylation of the Entamoeba histone H4 N-terminal domain is influenced by short-chain fatty acids that enter trophozoites in a pH-dependent manner.

Treatment of higher eukaryotic cells with short-chain fatty acids (SCFA) such as butyrate causes decreased levels of histone deacetylase (HDAC) activity and hyperacetylation of histones, and thereby affects gene expression, cell growth and differentiation. Entamoeba parasites encounter high levels of SCFA in the host colon, and in vitro these compounds allow trophozoite stage parasites to multiply but prevent their differentiation into infectious cysts. The Entamoeba invadens IP-1 histone H4 protein has an unusual number of lysines in its N-terminus, and these become hyperacetylated in trophozoites exposed to the HDAC inhibitors trichostatin A (TSA) or HC-toxin, but not in trophozoites exposed to butyrate. We have now found that several other commonly studied isolates of Entamoeba parasites also have an extended set of histone H4 acetylation sites that become hyperacetylated in response to TSA, but hypoacetylated in response to butyrate, suggesting an unusual sensitivity of this parasite's histone modifying enzymes to SCFA. Butyrate was found to enter trophozoites in a pH-dependent manner consistent with diffusive entry of the un-ionised form of the fatty acid into the amoebae. Transit of the Entamoeba organism through areas of the host intestine with distinct pH and SCFA concentrations would therefore result in very different levels of SCFA within the parasite. Entamoeba appears to have acquired unique alterations of its histone acetylation mechanism that may allow for its growth in the presence of varying amounts of the bacterial fermentation products.

Entamoeba invadens: restriction of ploidy by colonic short chain fatty acids.

The DNA content of Entamoeba parasites appears to be regulated by an unusual mechanism. This conclusion, however, was based on experiments that examined parasites grown in media that did not contain short chain fatty acids (SCFAs) normally found in the colonic lumen. Since one of these SCFAs, butyrate, is known to affect DNA replication in eukaryotic cells, we examined the effect of SCFAs on Entamoeba trophozoite DNA content. Similar to reports from others, we found that Entamoeba invadens trophozoite cultures grown in conventional medium (TYI-S-33) contained cells with 2N, 4N, 8N, and 16N amounts of DNA. In contrast, cultures grown in TYI medium containing colonic SCFAs added in place of glucose contained a minor population with 2N, a major population with 4N, and very few cells with higher amounts of DNA. SCFAs also prevented the normal increase in the number of nuclei per cell in trophozoites that were induced to encyst. These results suggest that E. invadens trophozoite stage parasites growing in the intestine in the presence of high amounts of SCFAs have a ploidy range restricted to 2N/4N. Axenic growth of trophozoites in the absence of SCFAs, however, appears to allow trophozoites to increase the amount of DNA per cell, which they must do during the normal encystment process.

Colonic short-chain fatty acids inhibit encystation of Entamoeba invadens.

Entamoeba parasites multiply as trophozoites in the layer of mucus that overlies the colonic epithelium. In response to stimuli that are not understood, trophozoites stop multiplying and differentiate into cysts that are released to infect another host. In the colon, Entamoeba trophozoites are exposed to the large variety of biochemicals that are carried into or are produced within this organ. The normal bacterial population of the colon releases large amounts of short-chain fatty acids (SCFAs). These compounds have effects on the growth, differentiation and repair of the colonic epithelium that correlate with de-creased activity of a Class I/II histone deacetylase (HDAC). We found that the formation of cysts, but not the growth of trophozoite-stage Entamoeba invadens parasites, was inhibited by physiologic concentrations of SCFAs. Variable levels of cyst formation did occur if SCFA concentrations were lowered. Specific inhibitors of Class I/II-type HDACs also prevented encystation, and trophozoites exposed to these compounds had increased levels of acetylation of histone H4 and other nuclear proteins. These results suggest that production of the infectious cyst stage of Entamoeba parasites is regulated in part by the levels of SCFAs made by the bacterial population of the colon.