Tissue-specific regulation of 1,25-dihydroxyvitamin D action in the target tissues of rats

Tissue response to 1,25(OH)[subscript]2D[subscript]3 action was evaluated by examining vitamin D-dependent VDR, 24-OHase, and CaBP mRNA expressions, 24-OHase activities, and VDR concentrations in kidney and intestine. Of 4 groups of rats, 2 groups were fed an adequate vitamin D (300-600 IU/wk), 1.0-1.2% calcium (Ca) diet, designated NC, and 2 groups were fed an adequate vitamin D, 0.02% Ca diet, designated LC. One group from each diet was treated with excess vitamin D[subscript]3 (75,000 IU/wk). These groups were designated NCT and LCT, respectively;Plasma 1,25(OH)[subscript]2D[subscript]3 concentrations were quantified and used to calculate metabolic clearance rates (MCR) and production rates (PR) of 1,25(OH)[subscript]2D[subscript]3. Plasma 1,25(OH)[subscript]2D[subscript]3 concentration in NCT rats was low to normal compared with that of NC rats. An increase in plasma 1,25(OH)[subscript]2D[subscript]3 concentration was measured in LC rats (5- to 6-fold) over that of NC rats. Plasma 1,25(OH)[subscript]2D[subscript]3 concentration in LCT rats was not significantly increased. Increases in 1,25(OH)[subscript]2D[subscript]3 PR in hypercalcemic NCT rats by 3 fold and in 1,25(OH)[subscript]2D[subscript]3 MCR in hypocalcemic LCT rats by 3.8-fold, indicated induction of extrarenal 1[alpha]-hydroxylase and 24-hydroxylase, respectively;Plasma PTH concentrations were low (~45 pg/ml) in both NC and NCT rats. Dietary Ca restriction of both LC and LCT groups, however, caused a significant (P \u3c 0.01) and proportional increases in PTH concentration. In the kidney, VDR concentration and 24-OHase activity in NCT rats were increased, but these responses were decreased in LC and LCT rats. In similar fashion, the expression of renal VDR, 24-OHase, and CaBP mRNAs were increased in NCT rats and decreased in LC and LCT rats. In the intestine, VDR concentration was increased by NCT treatment, however, 24-OHase activity appeared suppressed. Thyroparathyroidectomy of NCT rats resulted in a 2-fold increase in intestinal 24-OHase activity over that of intact NCT rats, which suggested a potential role of calcitonin in the suppression of intestinal 24-OHase. Furthermore, calcitonin administration to LCT rats resulted in a significant (P \u3c 0.001) decrease in intestinal 24-OHase mRNA expression. The same calcitonin effect was not attributable to kidney;These results demonstrate tissue-specific regulation of 1,25(OH)[subscript]2D[subscript]3 action in rat kidney and intestine. The data also are suggestive of a novel role for calcitonin as a negative modulator of intestinal 24-OHase activity that would potentially block an important inactivation pathway of 1,25(OH)[subscript]2D[subscript]3

Examining the generalizability of research findings from archival data

This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability—for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples

Effects of size and density selective consumption of zooplankton communities by Notropis cornutus.

Field observations show that there is generally a greater abundance of larger zooplankton in aquatic environments that lack fish than those with fish present. One possible explanation of this phenomenon is the top down model of community organization which suggests that the composition of lower trophic level communities are influenced by higher trophic level predators. This study attempted to test this theory by performing experiments to determine if fish selectively feed on large rather than small zooplankton and if density of prey effects fish predation. The results indicate that fish do feed selectively on larger zooplankton. No significant difference in rate of predation was found for differing prey densities.http://deepblue.lib.umich.edu/bitstream/2027.42/54624/1/3064.pdfDescription of 3064.pdf : Access restricted to on-site users at the U-M Biological Station

A community‐wide quality improvement initiative to improve hypertension control and reduce disparities

Initiatives to improve hypertension control within academic medical centers and closed health systems have been extensively studied, but large community‐wide quality improvement (QI) initiatives have been both less common and less successful in the United States. The authors examined a community‐wide QI initiative across 226 843 patients from 198 practices in nine counties across upstate New York to improve hypertension control and reduce disparities. The QI initiative focused on (a) providing population and practice‐level comparative data, (b) community engagement, especially in underserved communities, and (c) practice‐level quality improvement assistance, but was not designed to examine causality of specific components. Across the nine counties, hypertension control rates improved from 61.9% in 2011 to 69.5% in 2016. Improvements were greatest among whites (73.7%‐81.5%) and more modest among black patients (58.8%‐64.7%). The authors noted a considerable improvement in BP within the group of patients with the highest risk (defined as a BP ≥ 160/100) and a decrease in disparities within this group. The quality collaborative identified five key lessons to help guide future community initiatives: (a) anticipate a plateauing of response; (b) distinguish the needs of disparate populations and create subpopulation‐specific strategies to address and reduce disparities; (c) recognize the variation across low SES practices; (d) remain open to the refinement of outcome measures; and (e) continually seek best practices and barriers to success. Overall, a large community‐wide QI initiative, involving multiple different stakeholders, was associated with improvements in BP control and modest reductions in some targeted disparities

The cytotoxicity of nitroxyl: possible implications for the pathophysiological role of NO

In addition to the broad repertoire of regulatory functions nitric oxide (NO) serves in mammalian physiology, the L-arginine:NO pathway is also involved in numerous pathophysiological mechanisms. While NO itself may actually protect cells from the toxicity of reactive oxygen radicals in some cases, it has been suggested that reactive nitrogen oxide species formed from nitric oxide synthase (NOS) can be cytotoxic. In addition to NO, the one electron reduction product NO- has been proposed to be formed from NOS. We investigated the potential cytotoxic role of nitroxyl (NO-), using the nitroxyl donor Angelis's salt, (AS; sodium trioxodinitrate, Na2N2O3) as the source of NO-. As was found to be cytotoxic to Chinese hamster V79 lung fibroblast cells over a concentration range of 2-4 mM. The presence of equimolar ferricyanide (Fe(III)-(CN6)3-), which converts NO- to NO, afforded dramatic protection against AS-mediated cytotoxicity. Treatment of V79 cells with L-buthionine sulfoximine to reduce intracellular glutathione markedly enhanced AS cytotoxicity, which suggests that GSH is critical for cellular protection against the toxicity of NO-. Further experiments showed that low molecular weight transition metal complexes associated with the formation of reactive oxygen species are not involved in AS-mediated cytotoxicity since metal chelators had no effect. However, under aerobic conditions, AS was more toxic than under hypoxic conditions, suggesting that oxygen dramatically enhanced AS-mediated cytotoxicity. At a molecular level, AS exposure resulted in DNA double strand breaks in whole cells, and this effect was completely prevented by coincubation of cells with ferricyanide or Tempol. The data in this study suggest that nitroxyl may contribute to the cytotoxicity associated with an enhanced expression of the L-arginine:NO pathway under different biological conditions