Aldosterone status associates with insulin resistance in patients with heart failure-data from the ALOFT study

<b>Background</b>: Aldosterone plays a key role in the pathophysiology of heart failure. In around 50% of such patients, aldosterone 'escapes' from inhibition by drugs that interrupt the renin-angiotensin axis; such patients have a worse clinical outcome. Insulin resistance is a risk factor in heart failure and cardiovascular disease. The relationship between aldosterone status and insulin sensitivity was investigated in a cohort of heart failure patients. <b>Methods</b>: 302 patients with New York Heart Association (NYHA) class II-IV heart failure on conventional therapy were randomized in ALiskiren Observation of heart Failure Treatment study (ALOFT), designed to test the safety of a directly acting renin inhibitor. Plasma aldosterone and 24-hour urinary aldosterone excretion as well as fasting insulin and Homeostasis model assessment of insulin resistance (HOMA-IR) were measured. Subjects with aldosterone escape and high urinary aldosterone were identified according to previously accepted definitions. <b>Results</b>: Twenty per-cent of subjects demonstrated aldosterone escape and 34% had high urinary aldosterone levels. At baseline, there was a positive correlation between fasting insulin and plasma(r=0.22 p<0.01) and urinary aldosterone(r=0.19 p<0.03). Aldosterone escape and high urinary aldosterone subjects both demonstrated higher levels of fasting insulin (p<0.008, p<0.03), HOMA-IR (p<0.06, p<0.03) and insulin-glucose ratios (p<0.006, p<0.06) when compared to low aldosterone counterparts. All associations remained significant when adjusted for potential confounders. <b>Conclusions</b>: This study demonstrates a novel direct relationship between aldosterone status and insulin resistance in heart failure. This observation merits further study and may identify an additional mechanism that contributes to the adverse clinical outcome associated with aldosterone escape

Resistance to the antimicrobial agent fosmidomycin and an FR900098 prodrug through mutations in the deoxyxylulose phosphate reductoisomerase gene (dxr)

There is a pressing need for new antimicrobial therapies to combat globally important drug-resistant human pathogens, including Plasmodium falciparum malarial parasites, Mycobacterium tuberculosis, and Gram-negative bacteria, including Escherichia coli. These organisms all possess the essential methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, which is not found in humans. The first dedicated enzyme of the MEP pathway, 1-deoxy-d-xylulose 5-phosphate reductoisomerase (Dxr), is inhibited by the phosphonic acid antibiotic fosmidomycin and its analogs, including the N-acetyl analog FR900098 and the phosphoryl analog fosfoxacin. In order to identify mutations in dxr that confer resistance to these drugs, a library of E. coli dxr mutants was screened at lethal fosmidomycin doses. The most resistant allele (with the S222T mutation) alters the fosmidomycin-binding site of Dxr. The expression of this resistant allele increases bacterial resistance to fosmidomycin and other fosmidomycin analogs by 10-fold. These observations confirm that the primary cellular target of fosmidomycin is Dxr. Furthermore, cell lines expressing Dxr-S222T will be a powerful tool to confirm the mechanisms of action of future fosmidomycin analogs

Control of Emi2 activity and stability through Mos-mediated recruitment of PP2A.

Before fertilization, vertebrate eggs are arrested in meiosis II by cytostatic factor (CSF), which holds the anaphase-promoting complex (APC) in an inactive state. It was recently reported that Mos, an integral component of CSF, acts in part by promoting the Rsk-mediated phosphorylation of the APC inhibitor Emi2/Erp1. We report here that Rsk phosphorylation of Emi2 promotes its interaction with the protein phosphatase PP2A. Emi2 residues adjacent to the Rsk phosphorylation site were important for PP2A binding. An Emi2 mutant that retained Rsk phosphorylation but lacked PP2A binding could not be modulated by Mos. PP2A bound to Emi2 acted on two distinct clusters of sites phosphorylated by Cdc2, one responsible for modulating its stability during CSF arrest and one that controls binding to the APC. These findings provide a molecular mechanism for Mos action in promoting CSF arrest and also define an unusual mechanism, whereby protein phosphorylation recruits a phosphatase for dephosphorylation of distinct sites phosphorylated by another kinase

Alterations in vascular function in primary aldosteronism - a cardiovascular magnetic resonance imaging study

Introduction: Excess aldosterone is associated with increased cardiovascular risk. Aldosterone has a permissive effect on vascular fibrosis. Cardiovascular magnetic resonance imaging (CMR) allows study of vascular function by measuring aortic distensibility. We compared aortic distensibility in primary aldosteronism (PA), essential hypertension (EH) and normal controls and explored the relationship between aortic distensibility and pulse wave velocity (PWV).<p></p> Methods: We studied PA (n=14) and EH (n=33) subjects and age-matched healthy controls (n=17) with CMR, including measurement of aortic distensibility, and measured PWV using applanation tonometry. At recruitment, PA and EH patients had similar blood pressure and left ventricular mass.<p></p> Results: Subjects with PA had significantly lower aortic distensibilty and higher PWV compared to EH and healthy controls. These changes were independent of other factors associated with reduced aortic distensibility, including aging. There was a significant relationship between increasing aortic stiffness and age in keeping with physical and vascular aging. As expected, aortic distensibility and PWV were closely correlated.<p></p> Conclusion: These results demonstrate that PA patients display increased arterial stiffness compared to EH, independent of vascular aging. The implication is that aldosterone invokes functional impairment of arterial function. The long-term implications of arterial stiffening in aldosterone excess require further study.<p></p&gt

Aldosterone status associates with insulin resistance in patients with heart failure-data from the ALOFT study

ABSTRACT Background: Aldosterone plays a key role in the pathophysiology of heart failure. In around 50% of such patients, aldosterone 'escapes' from inhibition by drugs that interrupt the renin-angiotensin axis; such patients have a worse clinical outcome. Insulin resistance is a risk factor in heart failure and cardiovascular disease. The relationship between aldosterone status and insulin sensitivity was investigated in a cohort of heart failure patients. Methods: 302 patients with New York Heart Association (NYHA) class II-IV heart failure on conventional therapy were randomized in ALiskiren Observation of heart Failure Treatment study (ALOFT), designed to test the safety of a directly acting renin inhibitor. Plasma aldosterone and 24-hour urinary aldosterone excretion as well as fasting insulin and Homeostasis model assessment of insulin resistance (HOMA-IR) were measured. Subjects with aldosterone escape and high urinary aldosterone were identified according to previously accepted definitions. Results: Twenty per-cent of subjects demonstrated aldosterone escape and 34% had high urinary aldosterone levels. At baseline, there was a positive correlation between fasting insulin and plasma(r=0.22 p<0.01) and urinary aldosterone(r=0.19 p<0.03). Aldosterone escape and high urinary aldosterone subjects both demonstrated higher levels of fasting insulin (p<0.008, p<0.03), HOMA-IR (p<0.06, p<0.03) and insulin-glucose ratios (p<0.006, p<0.06) when compared to low aldosterone counterparts. All associations remained significant when adjusted for potential confounders. Conclusions: This study demonstrates a novel direct relationship between aldosterone status and insulin resistance in heart failure. This observation merits further study and may identify an additional mechanism that contributes to the adverse clinical outcome associated with aldosterone escape

Mitochondrial fusion is regulated by Reaper to modulate Drosophila programmed cell death

In most multicellular organisms, the decision to undergo programmed cell death in response to cellular damage or developmental cues is typically transmitted through mitochondria. It has been suggested that an exception is the apoptotic pathway of Drosophila melanogaster, in which the role of mitochondria remains unclear. Although IAP antagonists in Drosophila such as Reaper, Hid and Grim may induce cell death without mitochondrial membrane permeabilization, it is surprising that all three localize to mitochondria. Moreover, induction of Reaper and Hid appears to result in mitochondrial fragmentation during Drosophila cell death. Most importantly, disruption of mitochondrial fission can inhibit Reaper and Hid-induced cell death, suggesting that alterations in mitochondrial dynamics can modulate cell death in fly cells. We report here that Drosophila Reaper can induce mitochondrial fragmentation by binding to and inhibiting the pro-fusion protein MFN2 and its Drosophila counterpart dMFN/Marf. Our in vitro and in vivo analyses reveal that dMFN overexpression can inhibit cell death induced by Reaper or γ-irradiation. In addition, knockdown of dMFN causes a striking loss of adult wing tissue and significant apoptosis in the developing wing discs. Our findings are consistent with a growing body of work describing a role for mitochondrial fission and fusion machinery in the decision of cells to die

Simultaneous Stretching and Contraction of Stress Fibers In Vivo

To study the dynamics of stress fiber components in cultured fibroblasts, we expressed α-actinin and the myosin II regulatory myosin light chain (MLC) as fusion proteins with green fluorescent protein. Myosin activation was stimulated by treatment with calyculin A, a serine/threonine phosphatase inhibitor that elevates MLC phosphorylation, or with LPA, another agent that ultimately stimulates phosphorylation of MLC via a RhoA-mediated pathway. The resulting contraction caused stress fiber shortening and allowed observation of changes in the spacing of stress fiber components. We have observed that stress fibers, unlike muscle myofibrils, do not contract uniformly along their lengths. Although peripheral regions shortened, more central regions stretched. We detected higher levels of MLC and phosphorylated MLC in the peripheral region of stress fibers. Fluorescence recovery after photobleaching revealed more rapid exchange of myosin and α-actinin in the middle of stress fibers, compared with the periphery. Surprisingly, the widths of the myosin and α-actinin bands in stress fibers also varied in different regions. In the periphery, the banding patterns for both proteins were shorter, whereas in central regions, where stretching occurred, the bands were wider

Outcomes of Patients with Nelson's Syndrome after Primary Treatment: A Multicenter Study from 13 UK Pituitary Centers.

CONTEXT: Long-term outcomes of patients with Nelson's syndrome (NS) have been poorly explored, especially in the modern era. OBJECTIVE: To elucidate tumor control rates, effectiveness of various treatments, and markers of prognostic relevance in patients with NS. PATIENTS, DESIGN, AND SETTING: Retrospective cohort study of 68 patients from 13 UK pituitary centers with median imaging follow-up of 13 years (range 1-45) since NS diagnosis. RESULTS: Management of Cushing's disease (CD) prior to NS diagnosis included surgery+adrenalectomy (n = 30; eight patients had 2 and one had 3 pituitary operations), surgery+radiotherapy+adrenalectomy (n = 17; two received >1 courses of irradiation, two had ≥2 pituitary surgeries), radiotherapy+adrenalectomy (n = 2), and adrenalectomy (n = 19). Primary management of NS mainly included surgery, radiotherapy, surgery+radiotherapy, and observation; 10-year tumor progression-free survival was 62% (surgery 80%, radiotherapy 52%, surgery+radiotherapy 81%, observation 51%). Sex, age at CD or NS diagnosis, size of adenoma (micro-/macroadenoma) at CD diagnosis, presence of pituitary tumor on imaging prior adrenalectomy, and mode of NS primary management were not predictors of tumor progression. Mode of management of CD before NS diagnosis was a significant factor predicting progression, with the group treated by surgery+radiotherapy+adrenalectomy for their CD showing the highest risk (hazard ratio 4.6; 95% confidence interval, 1.6-13.5). During follow-up, 3% of patients had malignant transformation with spinal metastases and 4% died of aggressively enlarging tumor. CONCLUSIONS: At 10 years follow-up, 38% of the patients diagnosed with NS showed progression of their corticotroph tumor. Complexity of treatments for the CD prior to NS diagnosis, possibly reflecting corticotroph adenoma aggressiveness, predicts long-term tumor prognosis

The Importance of Equity Finance for R&D Activity – Are There Differences Between Young and Old Companies?

This paper analyzes the importance of equity finance for the R&D activity of small and medium-sized enterprises. We use information on almost 6000 German SMEs from a company survey. Using the intensity of banking competition at the district level as instrument to control for endogeneity, we find that a higher equity ratio is conducive to more R&D for young but not for old companies. Equity may be a constraining factor for young companies which have to rely on the original equity investment of their owners since they have not yet accumulated retained earnings and can relay less on outside financing. The positive influence is found for R&D intensity but not for the decision whether to perform R&D. Equity financing is therefore especially important for the most innovative, young companies