Loss of LEUCINE CARBOXYL METHYLTRANSFERASE 1 interferes with metal homeostasis in Arabidopsis and enhances susceptibility to environmental stresses.

The biochemical function of LEUCINE CARBOXYL METHYLTRANSFERASE 1 (LCMT1) is to transfer a methyl group from the methyl donor S-adenosylmethionine (SAM) to the catalytic subunits of PROTEIN PHOSPHATASE 2A (PP2Ac), PP4 and PP6. This post-translational modification by LCMT1 is found throughout eukaryotes from yeast to animals and plants, indicating that its function is essential. However, Arabidopsis with knocked out LCMT1 still grows and develops almost normally, at least under optimal growth conditions. We therefore proposed that the presence of LCMT1 would be important under non-optimal growth conditions and favoured plant survival during evolution. To shed light on the physiological functions of plant LCMT1, phenotypes of the lcmt1 mutant and wild type Arabidopsis were compared under various conditions including exposure to heavy metals, variable chelator concentrations, and increased temperature. The lcmt1 mutant was found to be more susceptible to these environmental changes than wild type and resulted in poor growth of seedlings and rosette stage plants. Element analysis of rosette stage plants mainly showed a difference between the lcmt1 mutant and wild type regarding concentrations of sodium and boron, two-fold up or halved, respectively. In both lcmt1 and wild type, lack of EDTA in the growth medium resulted in enhanced concentration of copper, manganese, zinc and sulphur, and especially lcmt1 growth was hampered by these conditions. The altered phenotype in response to stress, the element and mRNA transcript analysis substantiate that LCMT1 has an important role in metal homeostasis and show that functional LCMT1 is necessary to prevent damages from heat, heavy metals or lack of chelator.

"Triple therapy" of heart failure with angiotensin-converting enzyme inhibitor, beta-blocker, and aldosterone antagonist may triple survival time: shouldn't we tell patients?

Prescription and adherence to medical therapy for heart failure are disappointing despite convincing randomized controlled trial (RCT) evidence for angiotensin-converting enzyme inhibition, beta-blockade, and aldosterone antagonism. In this study, we report an imbalanced approach amongst clinicians, who describe focusing during patient consultations on perceived risks of therapy rather than survival benefits. Only one-half of clinicians mention increased lifespan, and very few suggest to the patient how large this gain might be. We calculate from the available RCT data that, for patients whose lifespan is limited by heart failure, triple therapy triples lifespan.

Serum albumin changes and multivariate dynamic risk modelling in chronic heart failure.

BACKGROUND: We examined the prognostic utility of rate of change in serum albumin over time in chronic heart failure (CHF), as well as the utility of multivariate dynamic risk modelling. METHODS AND RESULTS: The survival implication of ∆albumin was analysed in 232 systolic CHF patients and validated in 212 patients. A multivariate dynamic risk score predicated on the rate of change in 6 simple indices including albumin was calculated and related to mortality. In derivation patients, 50 (22%) deaths occurred over 13 months. Greater rates of decline in albumin related to higher mortality (HR 0.55, 95% CI 0.41-0.73, P<0.0001) independently, incrementally and more accurately than other covariates including baseline albumin. A rate of attenuation >0.4 g/dL/month optimally forecasted death and was associated with a 5-fold escalated risk of mortality (HR 5.13, 95% CI 2.92-9.00, P<0.0001). Similar results were seen in the validation cohort. On multivariate dynamic risk modelling, survival at 1-year worsened with higher scores-a score ≥ 3 was associated with a 12-fold greater risk of death than a score of 0, a 6-fold higher risk of death than a score of 1, and a 4-fold enhanced risk of mortality than a score of 2. CONCLUSION: Attenuations in serum albumin over time relate to increased mortality in CHF, and a risk model predicated on the rate of change in 6 simple indices can identify patients at a 12-fold enhanced risk of death over the coming year.

Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information.

BACKGROUND: Patients trying life-preserving agents such as beta-blockers may be discouraged by listings of harmful effects provided in good faith by doctors, drug information sheets, and media. We systematically review the world experience of side-effect information in blinded, placebo-controlled beta-blockade in heart failure. We present information for a physician advising a patient experiencing an unwanted symptom and suspecting the drug. METHODS: We searched Medline for double-blinded randomized trials of beta-blocker versus placebo in heart failure reporting side-effects. We calculated, per 100 patients reporting the symptom on beta-blockade, how many would have experienced it on placebo: the "proportion of symptoms non-pharmacological". RESULTS: 28 of the 33 classically-described side-effects are not significantly more common on beta-blockers than placebo. Of the 100 patients developing dizziness on beta-blockers, 81 (95% CI 73-89) would have developed it on placebo. For diarrhoea this proportion is 82/100 (70-95), and hyperglycaemia 83/100 (68-98). For only two side-effects is this under half (i.e. predominantly due to beta-blocker): bradycardia (33/100, CI 21-44) and intermittent claudication (41/100, 2-81). At least 6 so-called side-effects are less common on beta-blocker than placebo, including depression (reduced by 35%, p<0.01) and insomnia (by 27%, p=0.01). CONCLUSIONS: Clinicians might reconsider whether it is scientifically and ethically correct to warn a patient that a drug might cause them a certain side-effect, when randomized controlled trials show no significant increase, or indeed a significant reduction. A better informed consultation could, in patients taking beta-blockers, alleviate suffering. In patients who might otherwise not take the drug, it might prevent deaths.

Recurrent acute pancreatitis as the first and sole presentation of undiagnosed primary hyperparathyroidism.

INTRODUCTION: We highlight the pitfalls in delaying the diagnosis of primary hyperparathyroidism (pHPT) in patients with acute pancreatitis as the sole clinical presentation. Primary hyperparathyroidism is a recognised, but rare, cause of acute pancreatitis. Hypercalcaemia caused by undiagnosed pHPT may be the only causative factor of recurrent acute pancreatitis. PATIENTS AND METHODS: Three patients with multiple admissions for acute pancreatitis were diagnosed having pHPT during the work-up to identify possible causative factors. None of the patients had any other common predisposing factor for acute pancreatitis as revealed by clinical examination, blood tests and imaging. In retrospect, all had abnormally elevated calcium during previous admissions which was not further assessed. RESULTS: After diagnosis of pPTH, patients underwent bilateral neck exploration and parathyroidectomy. Histology confirmed parathyroid adenomas. The blood calcium level returned to normal and the patients remain well and asymptomatic after operation. CONCLUSIONS: The role of pHPT as a causative factor is underestimated when managing patients with acute pancreatitis, and frequently the underlying disease remains undiagnosed for a long time. Proper early diagnosis and management prevent unnecessary morbidity.