Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

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Herbaspirillum seropedicae Z67 is a nitrogen-fixing bacterium able to colonize the rhizosphere and the interior of several plants. As iron is a key element for nitrogen fixation, we examined the response of this microorganism to iron deficiency under nitrogen fixing conditions. We identified a H. seropedicae exbD gene that was induced in response to iron limitation and is involved in iron homeostasis. We found that an exbD mutant grown in iron-chelated medium is unable to fix nitrogen. Moreover, we provide evidence that expression of the nifH and nifA genes is iron dependent in a H. seropedicae genetic background.

1. The aim of the present study was to assess whether protection afforded by the Na(+)/H(+) exchanger blocker dimethylamiloride (DMA) is associated with inhibition of mitochondrial permeability transition (MPT). The effects of DMA were compared with those of cyclosporine (Cs) A, an inhibitor of MPT. 2. Rat hearts were Langendorff perfused with Krebs'-bicarbonate medium containing 10 mmol/L glucose and were subjected to 25 min no-flow global ischaemia and 30 min reperfusion in the presence or absence of 10 micromol/L DMA or 0.2 micromol/L CsA. Cell viability was measured using tetrazolium stain. The MPT was determined by loading hearts with 2-deoxy-[(3)H]-glucose (2DG), which enters mitochondria only during MPT. Total heart 2DG content as an estimation of the extent of tissue damage was also measured. To assess whether DMA has any direct effect on glycolysis, a cell-free heart extract containing all the glycolytic enzymes was used. 3. Dimethylamiloride improved functional recovery (rate-pressure product) from 24 +/- 7 to 68 +/- 11% (P < 0.01) at reperfusion end, attenuated the increase in left ventricular end-diastolic pressure (from 29 +/- 7 to 6 +/- 3% 10 min after reperfusion onset; P < 0.01), improved cell viability (from 21.2 +/- 6.6 to 69.6 +/- 7.1% at reperfusion end; P < 0.05) and lessened lactate accumulation at the end of ischaemia (119 +/- 15 vs 163 +/- 14 micromol/g dry weight; P < 0.05). Dimethylamiloride limited MPT: 2DG mitochondrial entrapment, being 33.1 +/- 14.2 and 96.3 +/- 14.0 at reperfusion end in the treated and control hearts, respectively (P < 0.05), and concomitantly raised total 2DG content (51.3 +/- 4.4 vs 86.8 +/- 1.7 x 10(3) d.p.m./g wet weight in control and treated groups, respectively; P < 0.05). Cyclosporine A improved functional recovery and attenuated the amplitude of ventricular diastolic pressure in ischaemic-reperfused hearts. It also reduced mitochondrial entrapment (67.3 +/- 7.7%; P < 0.05 vs control) and increased total cell 2DG content (162.3 +/- 1.3 x 10(3) d.p.m./g wet weight; P < 0.01 vs control) at the end of reperfusion. Dimethylamiloride did not affect glucose consumption and lactate production in the cell-free heart extract. 4. In conclusion, DMA protects against the noxious effects of ischaemia-reperfusion and inhibits MPT, coinciding with present and previous findings concerning the effects of CsA. Dimethylamiloride also diminished lactate accumulation, although it did not exhibit any direct effect on glycolysis. These data suggest that blockade of Na(+)/H(+) exchange by DMA attenuates the extent of MPT in ischaemic-reperfused rat heart.

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