Order versus Disorder: in vivo bone formation within osteoconductive scaffolds

In modern biomaterial design the generation of an environment mimicking some of the extracellular matrix features is envisaged to support molecular cross-talk between cells and scaffolds during tissue formation/remodeling. In bone substitutes chemical biomimesis has been particularly exploited; conversely, the relevance of pre-determined scaffold architecture for regenerated bone outputs is still unclear. Thus we aimed to demonstrate that a different organization of collagen fibers within newly formed bone under unloading conditions can be generated by differently architectured scaffolds. An ordered and confined geometry of hydroxyapatite foams concentrated collagen fibers within the pores, and triggered their self-assembly in a cholesteric-banded pattern, resulting in compact lamellar bone. Conversely, when progenitor cells were loaded onto nanofibrous collagen-based sponges, new collagen fibers were distributed in a nematic phase, resulting mostly in woven isotropic bone. Thus specific biomaterial design relevantly contributes to properly drive collagen fibers assembly to target bone regeneration

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure < 100 mmHg (n = 1127), estimated glomerular filtration rate < 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Migraine in young females with irritable bowel syndrome: still a challenge

Doina Georgescu,1 Daniela Reisz,2 Camelia Vidita Gurban,3 Liviu Andrei Georgescu,4 Ioana Ionita,5 Oana Elena Ancusa,1 Daniel Lighezan1 1Department of Internal Medicine, “Victor Babes” University of Medicine and Pharmacy, Timisoara, 2Department of Neurology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, 3Department of Biochemistry and Pharmacology“Victor Babes” University of Medicine and Pharmacy, Timisoara, 4Department of Urology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, 5Department of Hematology, “Victor Babes” University of Medicine and Pharmacy, Timisoara, RomaniaAbstract: Migraine without aura is frequently reported in female patients with irritable bowel syndrome (IBS), but knowledge about the relationship between these two conditions is still lacking. This study was aimed to explore the particularities of migraine without aura in young female patients with IBS in order to establish a possible link between them. From a cohort of young female patients hospitalized with IBS in the Internal Medicine Department, 30 joined this pilot study, and they were assigned into two groups on the basis of presence or absence of migraine. In this sample, 15 patients have mild to moderate migraine without aura, with a recently taken normal brain scan, and 15 were without migraine. Diseases and conditions not related to migraine and other possible specific female comorbidities were ruled out. Patients undertook a thorough clinical examination in order to assess fibromyalgia (FM) and chronic pelvic pain (CPP), Questionnaires for migraine disability assessment (MIDAS) and generalized anxiety disorder (GAD) were performed. Laboratory testing of blood, urine, and stool were also performed. Optimized lymphocyte proliferation test for food allergy (FA) and a fecal microbiota (microbiological semiquantitative method) for dysbiosis (DB) assessment were performed. Based on the results, migraine-positive group displayed more severe comorbidities: FM (p=0.0002), FA (p=0.0006), CPP (p=0.026), higher scores of anxiety (GAD, p=0.0008), and more severe DB (p=0.0009). We noticed a strong positive correlation between MIDAS and GAD (r=0.83), a good positive correlation between MIDAS and DB (r=0.56), and a moderate positive correlation between MIDAS, FM, and FA (r=0.46 and 0.41). In conclusion, young female patients with IBS and migraine without aura displayed more severe associated issues – anxiety, intestinal DB, FM, FA, and CPP. The severity of migraine correlated well with anxiety range and DB magnitude and moderately with FM and FA. Keywords: migraine without aura, IBS, young female

Standardization of the assessment protocol of mitochondrial respiration in human platelets

OBJECTIVES AND BACKGROUND The purpose of this study was to standardize the methodology for platelet isolation and measurement of oxygen consumption using high-resolution respirometry. MATERIALS AND METHODS The platelet isolation protocol consisted of two consecutive centrifugations of 12 mL blood probes collected from healthy adult females (n = 10) yielding a platelet-rich plasma sample. Respiration was measured at 370C using the Oxygraph-2k, according to a substrateuncoupler-inhibitor-titration protocol. Platelets permeabilized with digitonin were allowed to respire in the presence of complex I (glutamate and malate) and II (succinate) substrates. RESULTS We obtained a respiratory control ratio of 2.77 ± 3.65 that indicates a good oxidative phosphorylation coupling efficiency. CONCLUSIONS In vitro measurement of platelet respiration is a reliable method that can be used to evaluate the human bioenergetic profile. The standardized technique will be used to assess the occurrence of mitochondrial dysfunction in the peripheral blood in the setting of noncommunicable diseases. REFERENCES 1. Ferguson MA, Sutton RM, Karlsson M, Sjovall F, Becker LB, Berg RA, Margulies SS, Kilbaugh TJ. Increased platelet mitochondrial respiration after cardiac arrest and resuscitation as a potential peripheral biosignature of cerebral bioenergetic dysfunction. J Bioenerg Biomembr. 2016;48:269- 279. 2. Tyrell DJ, Bharadwaj MS, Van Horn CG, Marsh AP, Nicklas BJ, Molina AJ. Blood-cell bioenergetics are associated with physical function and inflammation in overweight/obese older adults. Exp Gerontol. 2015;70:84-91. 3. Siewiera K, Kassassir H, Talar M, Wieteska L, Watala C. Higher mitochondrial potential and elevated mitochondrial respiration are associated with excessive activation of blood platelets in diabetic rats. Life Sci. 2016;148:293-30

Pleiotropic Effects of Eugenol: The Good, the Bad, and the Unknown

Phytocompounds and medicinal herbs were used in traditional ancient medicine and are nowadays increasingly screened in both experimental and clinical settings due to their beneficial effects in several major pathologies. Similar to the drug industry, phytotherapy is interested in using nanobased delivery systems to view the identification and characterization of the cellular and molecular therapeutic targets of plant components. Eugenol, the major phenolic constituent of clove essential oil, is a particularly versatile phytochemical with a vast range of therapeutic properties, among which the anti-inflammatory, antioxidant, and anticarcinogenic effects have been systematically addressed. In the past decade, with the emerging understanding of the role of mitochondria as critical organelles in the pathophysiology of noncommunicable diseases, research regarding the role of phytochemicals as modulators of bioenergetics and metabolism is on a rise. Here, we present a brief overview of the major pharmacological properties of eugenol, with special emphasis on its applications in dental medicine, and provide preliminary data regarding its effects, alone, and included in polyurethane nanostructures, on mitochondrial bioenergetics, and glycolysis in human HaCaT keratinocytes

Assessment of Mitochondrial Dysfunction and Monoamine Oxidase Contribution to Oxidative Stress in Human Diabetic Hearts

Mitochondria-related oxidative stress is a pathomechanism causally linked to coronary heart disease (CHD) and diabetes mellitus (DM). Recently, mitochondrial monoamine oxidases (MAOs) have emerged as novel sources of oxidative stress in the cardiovascular system and experimental diabetes. The present study was purported to assess the mitochondrial impairment and the contribution of MAOs-related oxidative stress to the cardiovascular dysfunction in coronary patients with/without DM. Right atrial appendages were obtained from 75 patients randomized into 3 groups: (1) Control (CTRL), valvular patients without CHD; (2) CHD, patients with confirmed CHD; and (3) CHD-DM, patients with CHD and DM. Mitochondrial respiration was measured by high-resolution respirometry and MAOs expression was evaluated by RT-PCR and immunohistochemistry. Hydrogen peroxide (H2O2) emission was assessed by confocal microscopy and spectrophotometrically. The impairment of mitochondrial respiration was substrate-independent in CHD-DM group. MAOs expression was comparable among the groups, with the predominance of MAO-B isoform but no significant differences regarding oxidative stress were detected by either method. Incubation of atrial samples with MAOs inhibitors significantly reduced the H2O2 in all groups. In conclusion, abnormal mitochondrial respiration occurs in CHD and is more severe in DM and MAOs contribute to oxidative stress in human diseased hearts with/without DM

Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel

Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are musclerelated. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term ‘statin intolerance’. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10–15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented.Maciej Banach ... Stephen J. Nicholls ... et al

Statin intolerance - An attempt at a unified definition. Position paper from an International Lipid Expert Panel

Statins are one of the most commonly prescribed drugs in clinical practice. They are usually well tolerated and effectively prevent cardiovascular events. Most adverse effects associated with statin therapy are musclerelated. The recent statement of the European Atherosclerosis Society (EAS) has focused on statin associated muscle symptoms (SAMS), and avoided the use of the term 'statin intolerance'. Although muscle syndromes are the most common adverse effects observed after statin therapy, excluding other side effects might underestimate the number of patients with statin intolerance, which might be observed in 10-15% of patients. In clinical practice, statin intolerance limits effective treatment of patients at risk of, or with, cardiovascular disease. Knowledge of the most common adverse effects of statin therapy that might cause statin intolerance and the clear definition of this phenomenon is crucial to effectively treat patients with lipid disorders. Therefore, the aim of this position paper was to suggest a unified definition of statin intolerance, and to complement the recent EAS statement on SAMS, where the pathophysiology, diagnosis and the management were comprehensively presented