Distal Limb Ischaemia in Association With Takotsubo Cardiomyopathy.

Raynaud's phenomenon (RP) is a common clinical condition associated with digital ischaemia. A 73-year-old woman with a history of RP presented with bilateral distal lower limb ischaemia. Although no chest pain was reported, her serum troponin was greater than 25,000 ng/ml with lateral lead ST-segment elevation on ECG. Her coronary angiogram was normal, but echocardiography revealed a hypokinetic apical region consistent with Takotsubo cardiomyopathy. She was treated with iloprost, but her toes became necrotic, mummified and auto-amputated over six months. It is hypothesised that a surge in serum catecholamines may link the two processes.

'Attorneys of the poor': Training physicians to tackle health inequalities.

The stellar gains in life expectancy and health over the past century have been accompanied by an increase in societal and health inequalities. This health gap between the most and least fortunate in our society is widening, driven by complex social determinants of health, as well as healthcare systems themselves. Physicians are not just well-qualified and well-placed to act as advocates for change, but have a moral duty to do so: to stand by silently is to be complicit. Following a workshop on health inequalities and medical training at the Royal College of Physicians Trainees Committee, we sought to examine how health inequalities could be addressed through changes to the medical education system. We discuss the arguments for reform in recruitment to medicine, and changes to undergraduate, postgraduate and continuing medical education in order to equip the profession to deliver meaningful improvements in health inequalities. We propose a population health credential as a mechanism by which specialists can gain additional skills to take on leadership roles addressing health inequalities, allowing them to support colleagues in public health and bring in specialty-specific knowledge and experience.

Artery of Percheron infarct: hiding in plain sight.

A 54-year-old woman presented to the emergency department with fluctuating consciousness without localising signs and non-specific neurology. Urgent computed tomography (CT) was unremarkable and differentials of opioid overdose or post-ictal state were considered. Magnetic resonance imaging of the brain demonstrated an artery of Percheron (AOP) infarct; resulting from occlusion of an uncommon anatomical variant in the thalamic and midbrain circulation. This should be considered in patients presenting with fluctuating consciousness and normal CT.

Ascorbate and ferritin interactions: Consequences for iron release in vitro and in vivo and implications for inflammation.

This review discusses the chemical mechanisms of ascorbate-dependent reduction and solubilization of ferritin's ferric iron core and subsequent release of ferrous iron. The process is accelerated by low concentrations of Fe(II) that increase ferritin's intrinsic ascorbate oxidase activity, hence increasing the rate of ascorbate radical formation. These increased rates of ascorbate oxidation provide reducing equivalents (electrons) to ferritin's core and speed the core reduction rates with subsequent solubilization and release of Fe(II). Ascorbate-dependent solubilization of ferritin's iron core has consequences relating to the interpretation of 59Fe uptake sourced from 59Fe-lebelled holotransferrin into ferritin. Ascorbate-dependent reduction of the ferritin core iron solubility increases the size of ferritin's iron exchangeable pool and hence the rate and amount of exchange uptake of 59Fe into ferritin, whilst simultaneously increasing net iron release rate from ferritin. This may rationalize the inconsistency that ascorbate apparently stabilizes 59Fe ferritin and retards lysosomal ferritinolysis and whole cell 59Fe release, whilst paradoxically increasing the rate of net iron release from ferritin. This capacity of ascorbate and iron to synergise ferritin iron release has pathological significance, as it lowers the concentration at which ascorbate activates ferritin's iron release to within the physiological range (50-250 µM). These effects have relevance to inflammatory pathology and to the pro-oxidant effects of ascorbate in cancer therapy and cell death by ferroptosis.

The therapeutic role of ivabradine in heart failure.

Heart failure represents a major global cause of morbidity and mortality. Ivabradine is a selective funny current (If) inhibitor, which acts on the sinoatrial node, resulting in a reduction in heart rate. Ivabradine is currently licensed for use in patients with symptomatic heart failure with reduced ejection fraction and a heart rate persistently at least 70 beats per minute in spite of otherwise optimal prognostic heart failure pharmacotherapy. In this review article, we examine the mechanism of action of ivabradine, evaluate the clinical trials underpinning its application in heart failure and discuss its current recommended clinical use in this capacity.

Labile iron potentiates ascorbate-dependent reduction and mobilization of ferritin iron.

Ascorbate mobilizes iron from equine spleen ferritin by two separate processes. Ascorbate alone mobilizes ferritin iron with an apparent Km (ascorbate) ≈1.5mM. Labile iron >2µM, complexed with citrate (10mM), synergises ascorbate-dependent iron mobilization by decreasing the apparent Km (ascorbate) to ≈270µM and raising maximal mobilization rate by ≈5-fold. Catalase reduces the apparent Km(ascorbate) for both ascorbate and ascorbate+iron dependent mobilization by ≈80%. Iron mobilization by ascorbate alone has a higher activation energy (Ea=45.0±5.5kJ/mole) than when mediated by ascorbate with labile iron (10µM) (Ea=13.7±2.2kJ/mole); also mobilization by iron-ascorbate has a three-fold higher pH sensitivity (pH range 6.0-8.0) than with ascorbate alone. Hydrogen peroxide inhibits ascorbate's iron mobilizing action. EPR and autochemiluminescence studies show that ascorbate and labile iron within ferritin enhances radical formation, whereas ascorbate alone produces negligible radicals. These findings suggest that iron catalysed single electron transfer reactions from ascorbate, involving ascorbate or superoxide and possibly ferroxidase tyrosine radicals, accelerate iron mobilization from the ferroxidase centre more than EPR silent, bi-dentate two-electron transfers. These differing modes of electron transference from ascorbate mirror the known mono and bidentate oxidation reactions of dioxygen and hydrogen peroxide with di-ferrous iron at the ferroxidase centre. This study implies that labile iron, at physiological pH, complexed with citrate, synergises iron mobilization from ferritin by ascorbate (50-4000µM). This autocatalytic process can exacerbate oxidative stress in ferritin-containing inflamed tissue.