Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

Hepatitis C and kidney disease: A narrative review

Hepatitis-C (HCV) infection can induce kidney injury, mostly due to formation of immune-complexes and cryoglobulins, and possibly to a direct cytopathic effect. It may cause acute kidney injury (AKI) as a part of systemic vasculitis, and augments the risk of AKI due to other etiologies. It is responsible for mesangiocapillary or membranous glomerulonephritis, and accelerates the progression of chronic kidney disease due to other causes. HCV infection increases cardiovascular and liver-related mortality in patients on regular dialysis. HCV-infected patients are at increased risk of acute post-transplant complications. Long-term graft survival is compromised by recurrent or de novo glomerulonephritis, or chronic transplant glomerulopathy. Patient survival is challenged by increased incidence of diabetes, sepsis, post-transplant lymphoproliferative disease, and liver failure. Effective and safe directly acting antiviral agents (DAAs) are currently available for treatment at different stages of kidney disease. However, the relative shortage of DAAs in countries where HCV is highly endemic imposes a need for treatment-prioritization, for which a scoring system is proposed in this review. It is concluded that the thoughtful use of DAAs, will result in a significant change in the epidemiology and clinical profiles of kidney disease, as well as improvement of dialysis and transplant outcomes, in endemic areas

Potentiometric determination of some 1, 4-benzodiazepines in pharmaceutical preparations and biological samples

New, simple, low cost and sensitive ion selective electrodes aredescribed for the determination of some 1,4-benzodiazepines in theirpharmaceutical preparations as well as in biological fluids. Drug-tetraphenylborate and drug-phosphotungstate ion pairs have beenprepared and used as electroactive materials. Poly (vinyl chloride)(PVC), and poly(ester-urethane)s (UPCLs, UPBA, and UPDEGA)are used as the matrix. The proposed sensors give rapid nernstianresponse for 10-4-10-6 M of the above mentioned drugs in a pHrange of 3-7. The membranes developed have potential stability forup to 4 weeks and show high selectivity for the investigated drugsover many interfering ions. The electrodes are used for determiningtrace amounts of bromazepam, clonazepam and diazepam in theirpharmaceutical preparations as well as in biological fluids. Forpharmaceutical preparations, the relative standard deviation (RSD

Long-term mortality in minimally invasive compared with sternotomy coronary artery bypass surgery in the geriatric population (75 years and older patients).

OBJECTIVES: Ischaemic heart disease is the leading cause of death in the elderly population. Coronary artery bypass graft (CABG) surgery via sternotomy remains the standard of care for patients with multivessel coronary artery disease (CAD). Minimally invasive cardiac surgery (MICS)-CABG via left thoracotomy has been used as an alternative to sternotomy. The aim of our study was to assess the overall survival after MICS-CABG and sternotomy-CABG in elderly patients with CAD. METHODS: This observational study included patients who underwent coronary bypass from 2005 to 2008. Patients 75 years and older (n = 159) were included in the final analysis. Each arm was further divided into the MICS-CABG group or sternotomy-CABG group. Primary outcome and overall survival were obtained from our records and the social security death index. RESULTS: Among patients 75 years and older (159 patients), MICS-CABG had a significantly lower 5-year all-cause mortality than sternotomy-CABG (19.7 vs 47.7%, P \u3c 0.001). Similarly, Kaplan-Meier curves showed significantly higher overall survival in the MICS-CABG group compared with sternotomy-CABG (log-rank P = 0.014). After adjusting for confounders, MICS-CABG demonstrated a lower mortality than sternotomy-CABG (HR 0.51, 95% confidence interval 0.26-0.97, P = 0.04). For patients less than 75 years old, MICS and sternotomy groups had similar survival according to both uni- and multivariate analyses. CONCLUSIONS: The adjusted models demonstrated that MICS-CABG has a significantly better long-term survival than sternotomy-CABG despite slightly differing baseline characteristics. Further studies are needed to compare the short- and long-term outcomes of the two approaches among the elderly population

Ixr1 is required for the expression of the ribonucleotide reductase Rnr1 and maintenance of dNTP pools

The Saccharomyces cerevisiae Dun1 protein kinase is a downstream target of the conserved Mec1-Rad53 checkpoint pathway. Dun1 regulates dNTP pools during an unperturbed cell cycle and after DNA damage by modulating the activity of ribonucleotide reductase (RNR) by multiple mechanisms, including phosphorylation of RNR inhibitors Sml1 and Dif1. Dun1 also activates DNA-damage-inducible genes by inhibiting the Crt1 transcriptional repressor. Among the genes repressed by Crt1 are three out of four RNR genes: RNR2, RNR3, and RNR4. The fourth RNR gene, RNR1, is also DNA damage-inducible, but is not controlled by Crt1. It has been shown that the deletion of DUN1 is synthetic lethal with the deletion of IXR1, encoding an HMG-box-containing DNA binding protein, but the reason for this lethality is not known. Here we demonstrate that the dun1 ixr1 synthetic lethality is caused by an inadequate RNR activity. The deletion of IXR1 results in decreased dNTP levels due to a reduced RNR1 expression. The ixr1 single mutants compensate for the reduced Rnr1 levels by the Mec1-Rad53-Dun1-Crt1-dependent elevation of Rnr3 and Rnr4 levels and downregulation of Sml1 levels, explaining why DUN1 is indispensible in ixr1 mutants. The dun1 ixr1 synthetic lethality is rescued by an artificial elevation of the dNTP pools. We show that Ixr1 is phosphorylated at several residues and that Ser366, a residue important for the interaction of HMG boxes with DNA, is required for Ixr1 phosphorylation. Ixr1 interacts with DNA at multiple loci, including the RNR1 promoter. Ixr1 levels are decreased in Rad53-deficient cells, which are known to have excessive histone levels. A reduction of the histone gene dosage in the rad53 mutant restores Ixr1 levels. Our results demonstrate that Ixr1, but not Dun1, is required for the proper RNR1 expression both during an unperturbed cell cycle and after DNA damage