Two independent pathways of regulated necrosis mediate ischemia–reperfusion injury

Regulated necrosis (RN) may result from cyclophilin (Cyp)D-mediated mitochondrial permeability transition (MPT) and receptor-interacting protein kinase (RIPK)1-mediated necroptosis, but it is currently unclear whether there is one common pathway in which CypD and RIPK1 act in or whether separate RN pathways exist. Here, we demonstrate that necroptosis in ischemia–reperfusion injury (IRI) in mice occurs as primary organ damage, independent of the immune system, and that mice deficient for RIPK3, the essential downstream partner of RIPK1 in necroptosis, are protected from IRI. Protection of RIPK3-knockout mice was significantly stronger than of CypD-deficient mice. Mechanistically, in vivo analysis of cisplatin-induced acute kidney injury and hyperacute TNF-shock models in mice suggested the distinctness of CypD-mediated MPT from RIPK1/RIPK3-mediated necroptosis. We, therefore, generated CypD-RIPK3 double-deficient mice that are viable and fertile without an overt phenotype and that survived prolonged IRI, which was lethal to each single knockout. Combined application of the RIPK1 inhibitor necrostatin-1 and the MPT inhibitor sanglifehrin A confirmed the results with mutant mice. The data demonstrate the pathophysiological coexistence and corelevance of two separate pathways of RN in IRI and suggest that combination therapy targeting distinct RN pathways can be beneficial in the treatment of ischemic injury.     

Psychosocial aspects of dental and general fears in dental phobic patients

Phobic reactions can often be a significant health problem for fearful dental patients. This is true in particular for individuals with long-time avoidance and elevated general psychological distress. The aim of this study was to investigate the expression of dental fear among 67 dental phobic individuals with a low versus high degree of general fear. Reported etiologic background factors, avoidance time, general psychological distress and psychosocial manifestations and consequences of dental phobia were studied. No significant difference in dental anxiety level between individuals with low versus high general fear was found, and both groups reported high frequencies of negative dental experiences. The low-fear group reported a longer (though not statistically significant) average avoidance time than the high-fear group. However, patients with a high level of general fear showed a significantly higher degree of psychological distress, and also reported stronger negative social consequences from their dental anxiety. These results indicate that the character of dental fear might be different between different groups of fearful patients, which makes the condition psychologically handicapping. Such aspects should be assessed in the diagnostic analysis of patients with severe dental anxiety. In particular, assessments of signs of general psychological distress are warranted.     

Parahydrogen‐induced polarization of carboxylic acids: a pilot study of valproic acid and related structures

Parahydrogen‐induced polarization (PHIP) is a promising new tool for medical applications of MR, including MRI. The PHIP technique can be used to transfer high non‐Boltzmann polarization, derived from parahydrogen, to isotopes with a low natural abundance or low gyromagnetic ratio (e.g. ¹³C), thus improving the signal‐to‐noise ratio by several orders of magnitude. A few molecules acting as metabolic sensors have already been hyperpolarized with PHIP, but the direct hyperpolarization of drugs used to treat neurological disorders has not been accomplished until now. Here, we report on the first successful hyperpolarization of valproate (valproic acid, VPA), an important and commonly used antiepileptic drug. Hyperpolarization was confirmed by detecting the corresponding signal patterns in the ¹H NMR spectrum. To identify the optimal experimental conditions for the conversion of an appropriate VPA precursor, structurally related molecules with different side chains were analyzed in different solvents using various catalytic systems. The presented results include hyperpolarized ¹³C NMR spectra and proton images of related systems, confirming their applicability for MR studies. PHIP‐based polarization enhancement may provide a new MR technique to monitor the spatial distribution of valproate in brain tissue and to analyze metabolic pathways after valproate administration. Copyright © 2014 John Wiley & Sons, Ltd.     

In vitro activity of EDTA and TOL-463 against Neisseria gonorrhoeae

Neisseria gonorrhoeae quickly develops drug resistance. Time-kill curves revealed that EDTA and TOL-463 inhibit growth similar to penicillin, ciprofloxacin, and azithromycin. Furthermore, synergistic and additive antimicrobial interactions occurred when EDTA and TOL-463 were combined with penicillin or azithromycin, respectively, suggesting that further investigations into these unconventional antimicrobials may be advantageous.     

Sleep and resting‐state functional magnetic resonance imaging connectivity in middle‐aged adults and the elderly: A population‐based study

Sleep problems increase with ageing. Increasing evidence suggests that sleep problems are not only a consequence of age‐related processes, but may independently contribute to developing vascular or neurodegenerative brain disease. Yet, it remains unclear what mechanisms underlie the impact sleep problems may have on brain health in the general middle‐aged and elderly population. Here, we studied sleep's relation to brain functioning in 621 participants (median age 62 years, 55% women) from the population‐based Rotterdam Study. We investigated cross‐sectional associations of polysomnographic and subjectively measured aspects of sleep with intrinsic neural activity measured with resting‐state functional magnetic resonance imaging on a different day. We investigated both functional connectivity between regions and brain activity (blood‐oxygen‐level‐dependent signal amplitude) within regions, hierarchically towards smaller topographical levels. We found that longer polysomnographic total sleep time is associated with lower blood‐oxygen‐level‐dependent signal amplitude in (pre)frontal regions. No objective or subjective sleep parameters were associated with functional connectivity between or within resting‐state networks. The findings may indicate a pathway through which sleep, in a ‘real‐life’ population setting, impacts brain activity or regional brain activity determines total sleep time.     

A rare presentation of cardiac amyloid deposits isolated to intramural vessels

The present case illustrates the diagnostic challenges in symptomatic patients with heart failure of unknown etiology. The patients were previously diagnosed with κ‐light chain amyloidosis without cardiac involvement. Echocardiography showed heart failure with mildly reduced ejection fraction but no signs of amyloidosis. Coronary angiogram showed normal arteries and 11C‐PIB positron emission tomography was negative for amyloid deposits. Exercise testing revealed severe heart failure and reduced coronary flow velocity reserve. Endomyocardial biopsies showed amyloid in the intramural coronary arteries without interstitial amyloid deposits. Hence, the patient was diagnosed with microvascular dysfunction‐induced heart failure due to vessel wall amyloidosis.     

Adherence to ESMO clinical recommendations for prophylaxis of chemotherapy-induced nausea and vomiting

Background  

We assessed adherence to the European Society of Medical Oncology (ESMO)/Multinational Association of Supportive Care in Cancer recommendations for prophylaxis of chemotherapy-induced nausea and vomiting (CINV) at our institution.