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Concept: Strange Case of Dr Jekyll and Mr Hyde

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Protein misfolding results in devastating degenerative diseases and cancer. Among the culprits involved in these illnesses are prions and prion-like proteins, which can propagate by converting normal proteins to the wrong conformation. For spongiform encephalopathies, a real prion can be transmitted among individuals. In other disorders, the bona fide prion characteristics are still under investigation. Besides inducing misfolding of native proteins, prions bind nucleic acids and other polyanions. Here, we discuss how nucleic-acid binding might influence protein misfolding for both disease-related and benign, functional prions and why the line between bad and good amyloids might be more subtle than previously thought.

Concepts: Proteins, Amyloid, Strange Case of Dr Jekyll and Mr Hyde, Infectious disease, Protein, Prion, Protein folding, Transmissible spongiform encephalopathy

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During the last decade, a new view into the molecular mechanisms of chronic kidney disease-mineral bone disorder (CKD-MBD) has been proposed, with fibroblast growth factor 23 (FGF23) as a novel player in the field. Enhanced serum FGF23 levels cause a reduction in serum phosphate, together with calcitriol suppression and consequent hyperparathyroidism (HPT). In contrast, reduced serum FGF23 levels are associated with hyperphosphatemia, higher calcitriol levels and parathyroid hormone (PTH) suppression. In addition, serum FGF23 levels are greatly increased and positively correlated with serum phosphate levels in CKD patients. In this population, high serum FGF23 concentration seems to predict the occurrence of refractory secondary HPT and to be associated with higher mortality risk in incident haemodialysis patients. In living-donor kidney transplant recipients, a faster normalization of FGF23 and phosphate levels with a lower prevalence of HPT, may be considered a major pathway to investigate.

Concepts: Calcitonin, Hypoparathyroidism, Parathyroid gland, Vitamin D, Parathyroid hormone, Chronic kidney disease, Hyperparathyroidism, Strange Case of Dr Jekyll and Mr Hyde

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This review summarizes the (patho)-physiological effects of ventilation with high FiO2 (0.8-1.0), with a special focus on the most recent clinical evidence on its use for the management of circulatory shock and during medical emergencies. Hyperoxia is a cornerstone of the acute management of circulatory shock, a concept which is based on compelling experimental evidence that compensating the imbalance between O2 supply and requirements (i.e., the oxygen dept) is crucial for survival, at least after trauma. On the other hand, “oxygen toxicity” due to the increased formation of reactive oxygen species limits its use, because it may cause serious deleterious side effects, especially in conditions of ischemia/reperfusion. While these effects are particularly pronounced during long-term administration, i.e., beyond 12-24 h, several retrospective studies suggest that even hyperoxemia of shorter duration is also associated with increased mortality and morbidity. In fact, albeit the clinical evidence from prospective studies is surprisingly scarce, a recent meta-analysis suggests that hyperoxia is associated with increased mortality at least in patients after cardiac arrest, stroke, and traumatic brain injury. Most of these data, however, originate from heterogenous, observational studies with inconsistent results, and therefore, there is a need for the results from the large scale, randomized, controlled clinical trials on the use of hyperoxia, which can be anticipated within the next 2-3 years. Consequently, until then, “conservative” O2 therapy, i.e., targeting an arterial hemoglobin O2 saturation of 88-95 % as suggested by the guidelines of the ARDS Network and the Surviving Sepsis Campaign, represents the treatment of choice to avoid exposure to both hypoxemia and excess hyperoxemia.

Concepts: Mechanical ventilation, Medical emergencies, Traumatic brain injury, Strange Case of Dr Jekyll and Mr Hyde, Cardiac arrest, Stroke, Intensive care medicine, Oxygen

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Abstract Objective. To explore factors and circumstances contributing to prudent antibiotic prescribing for respiratory tract infections in primary care. Design. Two focus groups representing rural and urban areas. A semi-structured interview guide with open-ended questions and an editing analysis style was used. They were examined to identify meaning units that were sorted into categories in an iterative process throughout the analysis. Setting. Primary health care in two counties in southern Sweden. Subjects. Two groups including seven and six general practitioners (GPs) respectively, men and women of different ages with different professional experiences. Main outcome measures. Exploration of categories, determination of themes, construction of models. Results. The decision to prescribe antibiotics takes place in the encounter between GP and patient, initially characterized by harmony or fight and the subsequent process by collaboration or negotiation, resulting in agreement, compromise, or disagreement. Several factors influence the meeting and contribute to enhancing the conditions for rational prescribing. These conditions are connected to the GP, the relationship, and the setting; organization as well as professional culture. The findings indicate synergies between the factors, and that one factor can sometimes compensate for lack of another. Continuity and mutual trust can make a brief consultation successful, but lack of continuity can eliminate the effects of knowledge and professional skills. Conclusions. The findings emphasize the importance of the encounter between the GP and the patient for prudent antibiotic prescribing. Furthermore, the importance of an appropriate organization of primary care, which promotes continuity and encourages professional autonomy, is demonstrated.

Concepts: Primary care, Edinburgh, Qualitative research, Strange Case of Dr Jekyll and Mr Hyde, General practitioner, Focus group

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Autophagy is a ubiquitous catabolic process, which causes cellular bulk degradation through vesicular engulfment of obsolete, damaged or harmful cytoplasmic components. While autophagy regulates cellular homeostasis during development and in youth, there is mounting evidence that autophagy becomes increasingly dysfunctional with age. Recent work in C. elegans even suggests that late-life dysfunctional autophagy exhibits detrimental effects that drive the ageing process. Other studies link elevated autophagy closely to increased health and longevity. This review aims to put these apparently opposing views into perspective and define our current understanding of the role of autophagy during ageing. This article is protected by copyright. All rights reserved.

Concepts: Senescence, Edinburgh, Strange Case of Dr Jekyll and Mr Hyde

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The four transcriptional enhancers located in the 3' regulatory region (3'RR) of the IgH locus control the late phases of B-cell maturation, namely IgH locus transcription, somatic hypermutation and class switch recombination. Doctor Jekyll by nature, the 3'RR acts as Mister Hyde in case of oncogenic translocation at the IgH locus taking under its transcriptional control the translocated oncogene. The aim of this review is to show this duality on the basis of the latest scientific advances in the structure and function of the 3'RR and to hIghlight the targeting of the 3'RR as a potential therapeutic approach in mature B-cell lymphomas.

Concepts: Protein, Adaptive immune system, Gene, Strange Case of Dr Jekyll and Mr Hyde, Antibody, B cell, Gene expression, DNA

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Currently chemotherapy dosing is determined by a patient’s weight, height and renal function. Dosing chemotherapy based on these parameters is generally effective, assuming all other physiological conditions are normal. In hypoalbuminemia patients a decrease in albumin often results in more severe side-effects, since this may lead to higher chemotherapy free drug levels. A new method to dose chemotherapy based on a patients albumin will maintain the same effective free drug levels as in patients with normal albumin. This can reduce the severity of chemotherapy side-effects and may: ensure better outcomes for patients since it allows them to complete their course of chemotherapy without interruption, decrease the cost and complications associated with severe side-effects, and will allow for enhanced treatment options. This article is protected by copyright. All rights reserved.

Concepts: Adverse effect, Nephrotic syndrome, Illness, Chemotherapy, All rights reserved, Copyright, Pharmacology, Strange Case of Dr Jekyll and Mr Hyde

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It is known that lactate accumulates in the skeletal muscle during intense anaerobic exercise but is rapidly cleared from the muscles when they resume aerobic metabolism; however, at least some lactate reaches the blood stream. It has been observed that during maximal exercise, blood lactate increases with transport of the blood to the brain. This could be interpreted as a mechanism to protect against possible “central fatigue” in times of maximal activity during the course of which the lactate would preserve the functionality of the primary cortical motor and sensory areas, even at the expense of the efficiency of the other structures. In this way, the role of lactate, both at the muscular level and in the CNS, appears to shift from being responsible for fatigue to protector from fatigue, which represents a real transition similar to that of how the image of Mr. Hyde changes to that of Dr. Jekyll.

Concepts: Muscular system, Glycogen, Metabolism, Strange Case of Dr Jekyll and Mr Hyde, Heart, Muscle, Lactic acid, Exercise physiology

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Henry and Martin (2017) and Hartwig et al. (2017) provide more insights into the non-apoptotic function of the FADD/caspase-8 duo in TRAIL signaling.

Concepts: Life, Strange Case of Dr Jekyll and Mr Hyde