Cardiac lipid levels show diurnal changes and long-term variations in healthy human subjects

(1) H-MRS is regularly applied to determine lipid content in ectopic tissue - mostly skeletal muscle and liver - to investigate physiological and/or pathologic conditions, e.g. insulin resistance. Technical developments also allow non-invasive in vivo assessment of cardiac lipids; however, basic data about methodological reliability (repeatability) and physiological variations are scarce. The aim of the presented work was to determine potential diurnal changes of cardiac lipid stores in humans, and to put the results in relation to methodological repeatability and normal physiological day-to-day variations. Optimized cardiac- and respiratory-gated (1) H-MRS was used for non-invasive quantification of intracardiomyocellular lipids (ICCL), creatine, trimethyl-ammonium compounds (TMA), and taurine in nine healthy young men at three time points per day on two days separated by one week. This design allowed determination of (a) diurnal changes, (b) physiological variation over one week and (c) methodological repeatability of the ICCL levels. Comparison of fasted morning to post-absorptive evening measurements revealed a significant 37 ± 19% decrease of ICCL during the day (p = 0.0001). There was a significant linear correlation between ICCL levels in the morning and their decrease during the day (p = 0.015). Methodological repeatability for the ICCL/creatine ratio was excellent, with a coefficient of variance of ~5%, whereas physiological variation was found to be considerably higher (22%) in spite of a standardized physiological preparation protocol. In contrast, TMA levels remained stable over this time period. The proposed (1) H-MRS technique provides a robust way to investigate relevant physiological changes in cardiac metabolites, in particular ICCL. The present results suggest that ICCL reveal a diurnal course, with higher levels in the morning as compared to evening. In addition, a considerable long-term variation of ICCL levels, in both the morning and evening, was documented. Given the high methodological repeatability, these effects should be taken into account in studies investigating the metabolic role of ICCL.

Influence of muscle fiber orientation on water and metabolite relaxation times, magnetization transfer, and visibility in human skeletal muscle

PURPOSE To gain a deeper understanding of the influence of skeletal muscle fiber orientation on metabolite visibility, magnetization transfer from water, and water proton relaxation rates in (1) H MR spectra. METHODS Non-water-suppressed MR spectroscopy was performed in tibialis anterior muscle (TA) of 10 healthy adults, with the TA oriented either parallel or at the magic angle to the 3T field. Spectra were acquired with metabolite-cycled PRESS, and water inversion from 50 to 2510 ms before excitation. Water proton T2 relaxation was sampled with STEAM with echo times from 12 to 272 ms. RESULTS Apparent concentrations of total creatine (tCr), taurine, and trimethylammonium compounds were reduced by 29% to 67% when TA was parallel to B0 . Both tCr peak areas were strongly correlated to the methylene peak splitting. Magnetization transfer rates from water to tCr CH3 were not significantly different between orientations. Water T1 s were similar between orientations, but T2 s were statistically significantly shorter by 1 ms in the parallel orientation (P = 0.002). CONCLUSION Muscle metabolite visibilities in MR spectroscopy and water T2 times depend substantially on muscle fiber orientation relative to B0 . In contrast, magnetization transfer rates appear to depend on muscle composition, rather than fiber orientation. Magn Reson Med, 2015. © 2015 Wiley Periodicals, Inc.

Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs

Although platinum-based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume-regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E. Cell swelling strongly enhanced LRRC8-dependent cisplatin uptake, bolstering the notion that cisplatin enters cells through VRAC. LRRC8A disruption also suppressed drug-induced apoptosis independently from drug uptake, possibly by impairing VRAC-dependent apoptotic cell volume decrease. Hence, by mediating cisplatin uptake and facilitating apoptosis, VRAC plays a dual role in the cellular drug response. Incorporation of the LRRC8D subunit into VRAC substantially increased its permeability for cisplatin and the cellular osmolyte taurine, indicating that LRRC8 proteins form the channel pore. Our work suggests that LRRC8D-containing VRACs are crucial for cell volume regulation by an important organic osmolyte and may influence cisplatin/carboplatin responsiveness of tumors.

Health significance of chlorination byproducts in drinking water: The Houston experience: A continuation study

Background. Houston, Texas, once obtained all its drinking water from underground sources. However, in 1853, the city began supplementing its water from the surface source Lake Houston. This created differences in the exposure to disinfection byproducts (DBPs) in different parts of Houston. Trihalomethanes (THMs) are the most common DBP and are useful indicators of DBPs in treated drinking water. This study examines the relationship between THMs in chlorinated drinking water and the incidence of bladder cancer in Houston. ^ Methods. Individual bladder cancer deaths, from 1975 to 2004, were assigned to four surface water exposure areas in Houston utilizing census tracts—area A used groundwater the longest, area B used treated lake water the longest, area C used treated lake water the second longest, and area D used a combination of groundwater and treated lake water. Within each surface water exposure area mortality rates were calculated in 5 year intervals by four race-gender categories. Linear regression models were fitted to the bladder cancer mortality rates over the entire period of available data (1990–2004). ^ Results. A decrease in bladder cancer mortality was observed amongst white males in area B (p = 0.030), white females in area A (p = 0.008), non-white males in area D (p = 0.003), and non-white females in areas A and B (p = 0.002 & 0.001). Bladder cancer mortality differed by race-gender and time (p ≤ 0.001 & p ≤ 0.001), but not by surface water exposure area (p = 0.876). ^ Conclusion. The relationship between bladder cancer mortality and the four surface water exposure areas (signifying THM exposure) was insignificant. This result could be attributable to Houston controlling for THMs starting in the early 1980’s by using chloramine as a secondary disinfectant in the drinking water purification process.^

Organic compounds in sediments and pore waters of ODP Sites 117-723 and 117-724

Total organic carbon, amino compounds, and carbohydrates were measured in pore waters and sediments of Pliocene to Pleistocene age from Sites 723 and 724 (ODP Leg 117) to evaluate (1) relationships between organic matter in the sediment and in the pore water, (2) the imprint of lithological variations on the abundance and contribution of organic substances, (3) degradation of amino compounds and carbohydrates with time and/or depth, and (4) the dependence of the ammonia concentration in the pore water on the degradation of amino compounds in the sediment. Total organic carbon concentrations (TOC) of the investigated sediment samples range from 0.9% to 8.7%, and total nitrogen concentrations (TN) from 0.1% to 0.5%. Up to 4.9% of the TOC is contributed by hydrolyzable amino acids (THAA) which are present in amounts between 1.1 and 21.3 µmol/g dry sediment and decrease strongly downhole. Hydrolyzable carbohydrates (THCHO) were found in concentrations from 1.3 to 6.6 ?mol/g sediment constituting between 0.1% and 2.0% of the TOC. Differences between the distribution patterns of monomers in Sites 723 and 724 indicate higher terrigenous influence for Site 724 and, furthermore, enhanced input of organic matter that is relatively resistant to microbial degradation. Lithologically distinct facies close to the Pliocene/Pleistocene boundary yield different organic matter compositions. Laminated horizons seem to correspond with enhanced amounts of biogenic siliceous material and minor microbiological degradation. Total amounts of dissolved organic carbon (DOC) in pore waters vary between 11 and 131 mg/L. Concentrations of DOC as well as of dissolved amino compounds and carbohydrates appear to be related to microbial activity and/or associated redox zones and not so much to the abundance of organic matter in the sediments. Distributions of amino acids and monosaccharides in pore waters show a general enrichment in relatively stable components in comparison to those of the sediments. Nevertheless, the same trend appears between amino acids present in the sediments from Sites 723 and 724 as well as between amino acids in pore waters from these two sites, indicating a direct relation between the dissolved and the sedimentary organic fractions. Different ammonia concentrations in the pore waters of Sites 723 and 724 seem to be related to enhanced release of ammonia from degradation of amino compounds in Site 723.

Amino acids in interstitial waters from ODP Sites 126-790 and 126-791

Sites 790 and 791 lie in the eastern half graben of the Sumisu Rift, a backarc graben west of the active Izu-Bonin arc volcanoes Sumisu Jima and Tori Shima, at 30°54.96'N, 139°50.66'E, in 2223 m water depth and 30°54.97'N, 139°52.20'E, in 2268 m water depth, respectively. A small decrease in the sulfate concentration in the interstitial waters from these sites suggests fairly low microbial activity by sulfate-reducing bacteria. The values of the dissolved free amino acids (DFAA) in the interstitial waters from both sites range from 1.26 to 6.82 µmol/L, with an average of 3.81 µmol/L. The acidic, basic, neutral, aromatic, and sulfur-containing amino acids have average values of 0.32, 0.50, 2.71, 0.15, and 0.09 µmol/L, respectively. The relative abundances of the acidic, basic, neutral, aromatic, and sulfur-containing amino acids average 8, 13,72, 4, and 1 mol%, respectively. Glycine, serine, alanine, ornithine, and aspartic acid are major constituent amino acids. The dissolved combined amino acids (DCAA) values range between 1.25 and 44.35 µmol/L, with an average of 10.36 µmol/L. The mean concentrations and relative abundances of the acidic, basic, neutral, aromatic, and sulfur-containing amino acids are 2.29 (22 mol%), 0.60 (6 mol%), 6.70 (65 mol%), 0.09 (1 mol%), and 0.00 µmol/L (0 mol%), respectively. Glycine is the most abundant amino acid residue, followed by glutamic acid, serine, and alanine. The predominance of DCAA over DFAA present in the interstitial waters from Sites 790 and 791 is consistent with previous results from interstitial-water and seawater analyses. The most plausible source for the DCAA is biogenic calcareous debris. A much greater depletion of aspartic acid and the basic fraction, except for ornithine, is found in the DCAA. The decomposition of the basic amino acid fraction or its incorporation to clay minerals would result in a decrease in its relative abundance, whereas ornithine is produced during early diagenesis. The characteristics of the amino acids in the interstitial waters are (1) a greater depletion of the acidic amino acid fraction in the DFAA than in the DCAA and (2) the enrichment of glycine and serine in both. The adsorption or reaction of the amino acids in interstitial waters with biogenic carbonates would be responsible for the lower relative abundance of the acidic fraction of the DFAA. The production of glycine during early diagenesis and its stability in solution would raise its relative abundance in the interstitial waters.

Amino acid concentrations in interstitial waters from ODP Sites 113-689 and 113-690

Biogenic calcareous and siliceous sediments were drilled at ODP Sites 689 and 690 on the Maud Rise, Antarctic Ocean. We analyzed dissolved combined amino acids (DCAA) and dissolved free amino acids (DFAA) in interstitial waters in order to characterize the amino acids in dissolved organic matter. The DFAA was predominant over the DCAA in interstitial waters at Sites 689 and 690, which contradicted the previous results from interstitial water and seawater studies. The DCAA in the interstitial waters probably originated from calcareous biogenic debris with less amounts of siliceous debris. Although glutamic acid constituted 41% of the total concentration of DCAA, it accounted for only 1% of the total concentration of DFAA due to the adsorption and/or reaction with biogenic carbonate. Ornithine, a nonprotein amino acid, is a decomposed product of arginine and made up 17 mol% of the total DFAA and. The total hydrolyzable amino acids (=DCAA + DFAA) accounted for 5 to 28% of the dissolved organic carbon (DOC) concentration, which implied that high molecular weight organic matter was a major contributor for the DOM (dissolved organic matter) in interstitial waters. Fairly positive correlation between the dissolved manganese and the total DCAA values suggested that the redox condition plays a significant role in controlling the total DCAA content. A small decrease in the sulfate concentration in the interstitial waters from both sites suggested fairly low microbial activity by sulfate-reducing bacteria.

Amino acids from ODP Holes 117-722B and 177-724C

Sedimentary d15N records are valuable archives of ocean history but they are often modified during early diagenesis. Here we quantify the effect of early diagenetic enrichment on sedimentary N-isotope composition in order to obtain the pristine signal of reactive N assimilated in the euphotic zone. This is possible by using paired data of d15N and amino acid composition of sediment samples, which can be applied to estimate the degree of organic matter degradation. We determined d15N and amino acid composition in coeval sediments from Ocean Drilling Program (ODP) Hole 772 B in the central Arabian Sea and from Hole 724 C situated on the Oman Margin in the western Arabian Sea coastal upwelling area. The records span the last 130 kyr and include two glacial-interglacial cycles. These new data are used in conjunction with data available for surface sediments that cover a wide range of organic matter degradation states, and with other cores from the northern and eastern Arabian Sea to explore spatial variations in the isotopic signal. In order to reconstruct pristine N values we apply the relationship between organic matter degradation and 15N enrichment in surface sediments to correct the core records for early diagenetic enrichment. Reconstructed d15N values suggest a significant role of N2-fixation during glacial stages. An evaluation of two preservation indices based on amino acid composition (Reactivity Index, RI; Jennerjahn and Ittekkot, 1997; and the Degradation Index, DI; Dauwe et al., 1999) in both recent sediments and core samples suggests that the RI is more suitable than the DI in correcting Arabian Sea d15N records for early diagenetic enrichment.

Amino acids in the interstitial waters from ODP Hole 113-695A

Site 695 lies on the southeast margin of the South Orkney microcontinent on the northern margin of the Weddell Sea, at 62°23.48'S, 43°27.10'W in 1305 m water depth. The inorganic properties of interstitial waters at this site, including sulfate reduction, biogenic methane production, and high concentrations of ammonia and phosphate, imply high microbial activity. However, no clear relationship between amino acid composition and concentration and the type of microbial activity (e.g., sulfate reduction or methane production) can be identified. The THAA (total hydrolyzable amino acids) values range between 2.45 and 17.31 µmol/L, averaging 7.14 µmol/L. The mean concentrations and relative abundance values of acidic, basic, neutral, aromatic, and sulfur-containing amino acids are 1.34 (18%), 1.09 (15%), 3.93 (54%), 0.50 (8%), and 0.02 (0%) µmol/L, respectively. Glycine is the most abundant amino acid residue, with serine, glutamic acid, and ornithine next. The DFAA (dissolved free amino acids) values range from 0.10 to 12.73 µmol/L, averaging 4.07 µmol/L. The acidic, basic, neutral, aromatic, and sulfurcontaining amino acids are on average 0.21, 0.79, 2.56, 0.41, and 0.01 µmol/L, respectively. The relative abundances of acidic, basic, neutral, and aromatic amino acids average 4%, 18%, 58%, and 15%, respectively. Predominance of DFAA over DCAA (dissolved combined amino acids) in interstitial waters of Lithologic Units I and II is contrary to the predominance of DCAA over DFAA in other interstitial waters and seawater. The comparison of amino acid compositions between DCAA and siliceous plankton suggests that the DCAA in interstitial waters originally comes from amino acids derived from siliceous plankton. However, other sources which are much enriched in glutamic acid contribute to the DCAA composition.