Hydrogen sulfide and sulfaceutic or sulfanutraceutic agents: Classification, differences and relevance in preclinical and clinical studies.

Hydrogen sulfide (H2S) has been extensively studied as a signal molecule in the body for the past 30 years. Researchers have conducted studies using both natural and synthetic sources of H2S, known as H2S donors, which have different characteristics in terms of how they release H2S. These donors can be inorganic salts or have various organic structures. In recent years, certain types of sulfur compounds found naturally in foods have been characterized as H2S donors and explored for their potential health benefits. These compounds are referred to as "sulfanutraceuticals," a term that combines "nutrition" and "pharmaceutical". It is used to describe products derived from food sources that offer additional health advantages. By introducing the terms "sulfaceuticals" and "sulfanutraceuticals," we categorize sulfur-containing substances based on their origin and their use in both preclinical and clinical research, as well as in dietary supplements.

[Computerized oculomotor training in dyslexia: A randomized, crossover clinical trial in pediatric population]. / Rééducation oculomotrice informatisée dans la dyslexie : essai clinique randomisé en crossover en population pédiatrique.

OBJECTIVE: Several studies have reported abnormal oculomotor capacities leading to reading/writing difficulties among dyslexic children. However, no randomized clinical trial has been conducted to determine whether oculomotor training improves reading/writing skills of these children. The present study aims to evaluate the efficacy of computer-based oculomotor training among dyslexic children. METHOD: Crossover randomized trial with enrollment from January 12, 2015 to July 24, 2015, and follow-up to February 4, 2016. Eleven children (aged 7 to 12 years old) with dyslexia were included in a French psychiatric unit. The computer-based oculomotor training consisted of exercises focused on control of saccadic movements (reflexes and voluntary saccades), vergences and visual attention and memory. At baseline, 3 and 6 months, participants were assessed on reading and writing skills as well as phonological skills, visuo-attentional skills and verbal memory using the French batterie analytique du langage écrit (BALE). Saccadic and antisaccadic ocular movements (latencies and gains) were recorded using a specific device. Several Anova models were performed to test whether oculomotor training improves reading, writing and phonological, verbal memory and visuo-attentional skills. Our analyses were considered exploratory (alpha at 5%). RESULTS: No effect of oculomotor training was found on reading skills. However, oculomotor training was associated with a short-term effect (after 3 months of training) on several tests measuring phonological skills (syllabic suppression; P-value=0.022), visuo-attentional skills (search of anarchic verbal cues; P-value=0.035) and verbal memory (digit span backward; P-value=0.022) and with a long-term effect (3 months after the end of the 3 months of training) on a measure of writing skills (regular words; P-value=0.019). Finally, training was associated with an increase of saccadic latencies indicating an increase of visuo-attentional skills (P-value=0.026). CONCLUSIONS: Our results suggested that computer-based oculomotor training might be effective on writing skills and several cognitive skills among dyslexic children, but future clinical trials are needed to confirm our results.

Lp(a) and cardiovascular risk: Investigating the hidden side of the moon.

AIMS: This article reports current evidence on the association between Lp(a) and cardiovascular (CV) disease and on pathophysiological mechanisms. The available information on therapy for reduction of lipoprotein(a) is also discussed. DATA SYNTHESIS: Although some evidence is conflicting, Lp(a) seems to increase CV risk through stimulation of platelet aggregation, inhibition of tissue factor pathway inhibitor, alteration of fibrin clot structure and promotion of endothelial dysfunction and phospholipid oxidation. Lp(a) 3.5-fold higher than normal increases the risk of coronary heart disease and general CV events, particularly in those with LDL cholesterol ≥ 130 mg/dl. High Lp(a) values represent also an independent risk factor for ischemic stroke (more relevant in young stroke patients), peripheral artery disease (PAD) and aortic and mitral stenosis. Furthermore, high Lp(a) levels seem to be associated with increased risk of cardiovascular events in patients with chronic kidney disease, particularly in those undergoing percutaneous coronary intervention. CONCLUSIONS: Lipoprotein (a) (Lp[a]) seems to significantly influence the risk of cardiovascular events. The effects of statins and fibrates on Lp(a) are limited and extremely variable. Nicotinic acid was shown effective in reducing Lp(a) but, due to its side effects and serious adverse events during clinical trials, it is no longer considered a possible option for treatment. To date, the treatment of choice for high levels of Lp(a) in high CV risk patients is represented by LDL-Apheresis. Thanks to innovative technologies, new selectively inhibiting LPA drugs are being developed and tested.

Identification of microRNAs 758 and 33b as potential modulators of ABCA1 expression in human atherosclerotic plaques.

BACKGROUND AND AIM: Adenosine triphosphate (ATP)-binding cassette (ABC) transporters A1 and G1 are the main transporters involved in macrophage cholesterol efflux. The understanding of the molecular mechanism(s) of their regulation in atherosclerosis is crucial for potential therapeutic approaches. Preclinical studies support a role for microRNAs in the posttranscriptional regulation of these transporters; however, no evidence is still available on human atherosclerosis. Thus, the aim of this study was to investigate the modulation of the ABCA1 and ABCG1 pathway in human atherosclerotic plaques and microRNA involvement in its modulation. METHODS AND RESULTS: Thirty-one human atherosclerotic plaques were obtained from patients undergoing carotid endarterectomy for high-grade (>70%) vessel stenosis, and divided into normocholesterolemic (n = 15) and hypercholesterolemic groups (n = 16) according to the presence/absence of hypercholesterolemia. Both ABCA1 and ABCG1 messenger RNAs (mRNAs) were significantly upregulated in carotid plaques from hypercholesterolemic patients as assessed by real-time polymerase chain reaction (RT-PCR). Despite this result, no difference was found at the protein levels analyzed by Western blot, thus suggesting a strong posttranscriptional modulation. MicroRNA microarray and subsequent validation by RT-PCR showed a significant upregulation of ABCA1-linked miR-758 and miR-33b in plaques from hypercholesterolemic patients. CONCLUSION: We provide evidence of a strong posttranscriptional regulation of ABCA1 and ABCG1 expression in human atherosclerotic plaques from hypercholesterolemic patients. This effect is potentially due to the concomitant increase of miR-33b and miR-758, two well-established regulators of ABCA1 and ABCG1 expression. The identification of miR-33b and miR-758 as putative key regulators of ABCA1 protein expression within human atherosclerotic plaques provides further data for the realization of new anti-atherosclerotic drugs with specific targets based on anti-miRNA technologies.

Outstanding effects on antithrombin activity of modified TBA diastereomers containing an optically pure acyclic nucleotide analogue.

Herein, we report optically pure modified acyclic nucleosides as ideal probes for aptamer modification. These new monomers offer unique advantages in exploring the role played in thrombin inhibition by a single residue modification at key positions of the TBA structure.

Defining internal target volume using positron emission tomography for radiation therapy planning of moving lung tumors.

Substantial disagreement exists over appropriate PET segmentation techniques for non-small cell lung cancer. Currently, no segmentation algorithm explicitly considers tumor motion in determining tumor borders. We developed an automatic PET segmentation model as a function of target volume, motion extent, and source-to-background ratio (the VMSBR model). The purpose of this work was to apply the VMSBR model and six other segmentation algorithms to a sample of lung tumors. PET and 4D CT were performed in the same imaging session for 23 patients (24 tumors) for radiation therapy planning. Internal target volumes (ITVs) were autosegmented on maximum intensity projection (MIP) of cine CT. ITVs were delineated on PET using the following methods: 15%, 35%, and 42% of maximum activity concentration, standardized uptake value (SUV) of 2.5 g/mL, 15% of mean activity concentration plus background, a linear function of mean SUV, and the VMSBR model. Predicted threshold values from each method were compared to measured optimal threshold values, and resulting volume magnitudes were compared to cine-CT-derived ITV. Correlation between predicted and measured threshold values ranged from slopes of 0.29 for the simplest single-threshold techniques to 0.90 for the VMSBR technique. R2 values ranged from 0.07 for the simplest single-threshold techniques to 0.86 for the VMSBR technique. The VMSBR segmentation technique that included volume, motion, and source-to-background ratio, produced accurate ITVs in patients when compared with cine-CT-derived ITV.

Hydrogen sulfide dysfunction in metabolic syndrome-associated vascular complications involves cGMP regulation through soluble guanylyl cyclase persulfidation.

Here, by using in vitro and ex vivo approaches, we elucidate the impairment of the hydrogen sulfide (H2S) pathway in vascular complications associated with metabolic syndrome (MetS). In the in vitro model simulating hyperlipidemic/hyperglycemic conditions, we observe significant hallmarks of endothelial dysfunction, including eNOS/NO signaling impairment, ROS overproduction, and a reduction in CSE-derived H2S. Transitioning to an ex vivo model using db/db mice, a genetic MetS model, we identify a downregulation of CBS and CSE expression in aorta, coupled with a diminished L-cysteine-induced vasorelaxation. Molecular mechanisms of eNOS/NO signaling impairment, dissected using pharmacological and molecular approaches, indicate an altered eNOS/Cav-1 ratio, along with reduced Ach- and Iso-induced vasorelaxation and increased L-NIO-induced contraction. In vivo treatment with the H2S donor Erucin ameliorates vascular dysfunction observed in db/db mice without impacting eNOS, further highlighting a specific action on smooth muscle component rather than the endothelium. Analyzing the NO signaling pathway in db/db mice aortas, reduced cGMP levels were detected, implicating a defective sGC/cGMP signaling. In vivo Erucin administration restores cGMP content. This beneficial effect involves an increased sGC activity, due to enzyme persulfidation observed in sGC overexpressed cells, coupled with PDE5 inhibition. In conclusion, our study demonstrates a pivotal role of reduced cGMP levels in impaired vasorelaxation in a murine model of MetS involving an impairment of both H2S and NO signaling. Exogenous H2S supplementation through Erucin represents a promising alternative in MetS therapy, targeting smooth muscle cells and supporting the importance of lifestyle and nutrition in managing MetS.

Moderate alcohol use and health: a consensus document.

AIMS: The aim of this consensus paper is to review the available evidence on the association between moderate alcohol use, health and disease and to provide a working document to the scientific and health professional communities. DATA SYNTHESIS: In healthy adults and in the elderly, spontaneous consumption of alcoholic beverages within 30 g ethanol/d for men and 15 g/d for women is to be considered acceptable and do not deserve intervention by the primary care physician or the health professional in charge. Patients with increased risk for specific diseases, for example, women with familiar history of breast cancer, or subjects with familiar history of early cardiovascular disease, or cardiovascular patients should discuss with their physician their drinking habits. No abstainer should be advised to drink for health reasons. Alcohol use must be discouraged in specific physiological or personal situations or in selected age classes (children and adolescents, pregnant and lactating women and recovering alcoholics). Moreover, the possible interactions between alcohol and acute or chronic drug use must be discussed with the primary care physician. CONCLUSIONS: The choice to consume alcohol should be based on individual considerations, taking into account the influence on health and diet, the risk of alcoholism and abuse, the effect on behaviour and other factors that may vary with age and lifestyle. Moderation in drinking and development of an associated lifestyle culture should be fostered.

Prognostic models in end stage liver disease.

Cirrhosis is a major cause of death worldwide, and is associated with significant health care costs. Even if milestones have been recently reached in understanding and managing end-stage liver disease (ESLD), the disease course remains somewhat difficult to prognosticate. These difficulties have already been acknowledged already in the past, when scores instead of single parameters have been proposed as valuable tools for short-term prognosis. These standard scores, like Child Turcotte Pugh (CTP) and model for end-stage liver disease (MELD) score, relying on biochemical and clinical parameters, are still widely used in clinical practice to predict short- and medium-term prognosis. The MELD score, which remains an accurate, easy-to-use, objective predictive score, has received significant modifications over time, in order to improve its performance especially in the liver transplant (LT) setting, where it is widely used as prioritization tool. Although many attempts to improve prognostic accuracy have failed because of lack of replicability or poor benefit with the comparator (often the MELD score or its variants), few scores have been recently proposed and validated especially for subgroups of patients with ESLD, as those with acute-on-chronic liver failure. Artificial intelligence will probably help hepatologists in the near future to fill the current gaps in predicting disease course and long-term prognosis of such patients.

Persulfidation of mitoKv7.4 channels contributes to the cardioprotective effects of the H2S-donor Erucin against ischemia/reperfusion injury.

BACKGROUND: Hydrogen sulfide (H2S) is a gasotransmitter deeply involved in cardiovascular homeostasis and implicated in the myocardial protection against ischemia/reperfusion. The post-translational persulfidation of cysteine residues has been identified as the mechanism through which H2S regulates a plethora of biological targets. Erucin (ERU) is an isothiocyanate produced upon hydrolysis of the glucosinolate glucoerucin, presents in edible plants of Brassicaceae family, such as Eruca sativa Mill., and it has emerged as a slow and long-lasting H2S-donor. AIM: In this study the cardioprotective profile of ERU has been investigated and the action mechanism explored, focusing on the possible role of the recently identified mitochondrial Kv7.4 (mitoKv7.4) potassium channels. RESULTS: Interestingly, ERU showed to release H2S and concentration-dependently protected H9c2 cells against H2O2-induced oxidative damage. Moreover, in in vivo model of myocardial infarct ERU showed protective effects, reducing the extension of ischemic area, the levels of troponin I and increasing the amount of total AnxA1, as well as co-related inflammatory outcomes. Conversely, the pre-treatment with XE991, a blocker of Kv7.4 channels, abolished them. In isolated cardiac mitochondria ERU exhibited the typical profile of a mitochondrial potassium channels opener, in particular, this isothiocyanate produced a mild depolarization of mitochondrial membrane potential, a reduction of calcium accumulation into the matrix and finally a flow of potassium ions. Finally, mitoKv7.4 channels were persulfidated in ERU-treated mitochondria. CONCLUSIONS: ERU modulates the cardiac mitoKv7.4 channels and this mechanism may be relevant for cardioprotective effects.

Relationship between the absorption of 5-hydroxytryptophan from an integrated diet, by means of Griffonia simplicifolia extract, and the effect on satiety in overweight females after oral spray administration.

The management of overweight may include the use of dietary supplements targeted to counter the feeling of hunger. A randomized, double-blind, placebo-controlled trial has been performed in 20 overweight females. These subjects were randomly assigned to supplement their diet with either an extract from Griffonia Simplicifolia (10 subjects) or a placebo (10 matched subjects) for 4-weeks, in conjunction with a personalised reduced calorie diet. The main aim of this study was to evaluate the efficacy, by the assessment of 24-h urinary 5-hydroxyindoleacetic acid levels (5-HIAA), of 1-month administration of a dietary supplement containing 5-hydroxytryptophan (5-HTP) from botanical extracts in healthy, overweight females. Secondary endpoints were the assessment of sensation of appetite (by Haber score), body composition, and severity of binge eating. The supplemented group had a significant increase of 24-h urinary 5-HIAA levels (p<0.001), and a decrease in Haber score (p<0.001) while the placebo group did not show significant changes. With regard to changes in body composition, statistically significant differences between the treatment groups were found for the mean change in BMI, suprailiac skinfold thicknesses, arm circumference and hip circumference. Other parameters were found to be similar in the treated and in the placebo groups. In conclusion, this study shows that the 5-hydroxytryptophan present in the Griffonia extract, administered via spray to the oral cavity, is adequately absorbed, as confirmed by the increase in 24-h urinary 5-HIAA, and that the supplementation of the diet of overweight women with 5-hydroxytryptophan increases the feeling of satiety associated with a decrease in BMI.

Polytherapy in bone regeneration: clinical applications and preliminary considerations.

Polytherapy, namely the simultaneous application of three fundamental elements necessary for bone regeneration (growth factors, osteogenic cells and osteoconductive scaffolds) seems to lead to a very high success rate in the treatment of complex non-union (NU) cases and critical bone defects. NU are reported in 5-10% of long bone fractures. The use of autologous bone grafts has been long-considered the gold standard for the treatment of these cases. However the harvesting procedure from the iliac crest increases surgery time and presents some donor site complications which may be elevated. In recent years, surgeons have some alternatives to autologous grafting such as: application of organic or synthetic bone substitute, application of mesenchymal stromal cells (MSC) or growth factors (GF). In the literature there are many studies available about their application in monotherapy, but unfortunately the healing rate doesn't exceed 90%. Polytherapy seems to be a logical option to improve the healing rate, nevertheless, there are not still extensive studies that validate this strategy and moreover, some questions are not resolved.

In vivo delivery of the caveolin-1 scaffolding domain inhibits nitric oxide synthesis and reduces inflammation.

Caveolin-1, the primary coat protein of caveolae, has been implicated as a regulator of signal transduction through binding of its "scaffolding domain" to key signaling molecules. However, the physiological importance of caveolin-1 in regulating signaling has been difficult to distinguish from its traditional functions in caveolae assembly, transcytosis, and cholesterol transport. To directly address the importance of the caveolin scaffolding domain in vivo, we generated a chimeric peptide with a cellular internalization sequence fused to the caveolin-1 scaffolding domain (amino acids 82-101). The chimeric peptide was efficiently taken up into blood vessels and endothelial cells, resulting in selective inhibition of acetylcholine (Ach)-induced vasodilation and nitric oxide (NO) production, respectively. More importantly, systemic administration of the peptide to mice suppressed acute inflammation and vascular leak to the same extent as a glucocorticoid or an endothelial nitric oxide synthase (eNOS) inhibitor. These data imply that the caveolin-1 scaffolding domain can selectively regulate signal transduction to eNOS in endothelial cells and that small-molecule mimicry of this domain may provide a new therapeutic approach.

Contribution of organ blood flow, intrinsic tissue clearance and glycaemia to the regulation of glucose use in obese and type 2 diabetic rats: a PET study.

BACKGROUND AND AIMS: Chronic hyperglycaemia aggravates obesity and diabetes mellitus. The use of glucose by body organs depends on several factors. We sought to investigate the role of blood flow, intrinsic tissue glucose clearance and blood glucose levels in regulating tissue glucose uptake under fasting conditions (FCs) and in response to acute hyperglycaemia (AH) in obese and type 2 diabetic rats. METHODS AND RESULTS: Thirty-six Zucker rats were studied by positron emission tomography to quantify perfusion and glucose uptake during FC and after AH in the liver, myocardium, skeletal muscle and subcutaneous adipose tissue. Progressively higher glucose uptake rates were observed from lean to obese (p < 0.05) and to diabetic rats (p < 0.05) in all tissues during both FC and AH. In FC, they were increased of 7-18 times in obese rats and 11-30 times in diabetic rats versus controls. Tissue glucose uptake was increased by over 10-fold during AH in controls; this response was severely blunted in diseased groups. AH tended to stimulate organ perfusion in control rats. Tissue glucose uptake was a function of intrinsic clearance and glycaemia (mass action) in healthy animals, but the latter component was lost in diseased animals. Differences in perfusion did not account for those in glucose uptake. CONCLUSIONS: Each organ participates actively in the regulation of its glucose uptake, which is dependent on intrinsic tissue substrate extraction and extrinsic blood glucose delivery, but not on perfusion, and it is potently stimulated by AH. Obese and diabetic rats had an elevated organ glucose uptake but a blunted response to acute glucose intake.

Temporomandibular disorders assessment: medicolegal considerations in the evidence-based era.

Summary Temporomandibular disorders (TMD) are a frequent finding in cases of facial trauma or dental malpractice, and legal claims for TMD damage have been increased over the years. Temporomandibular disorders assessment in the medical legal setting is complicated by the peculiarities of these disorders, whose symptoms are heterogeneous, fluctuant, and recognise a multifactorial origin. A systematic Medline search in the National Library of Medicine's PubMed database pointed out that, despite the medical legal aspects of the dental profession are gaining a growing attention, there is a paucity of literature dealing with patients with TMD assessment. For these reasons, evidence-based knowledge in the field of TMD diagnosis and treatment was summarised in this article with the aim of providing useful suggestions for a medical legal approach to TMD.

Occlusion and temporomandibular disorders: a malpractice case with medical legal considerations.

Occlusion and temporomandibular The issue of temporomandibular disorders (TMD) diagnosis and treatment has become a matter of increasing interest in the medical legal field in recent years. The old-fashioned theories based on the occlusal paradigm was proven to be erroneous, and clinicians who still provide irreversible treatments to TMD patients have to be conscious of the potential legal consequences of their behavior. The present paper described an illustrative case report of a patient to whom extensive and irreversible occlusal therapies were performed with the unique aim to provide relief from TMD symptoms. The treatment was unsuccessful and the dental practitioner was called into cause for a professional liability claim. The clinician was judged guilty of malpractice on the basis of the lack of scientific evidence of the irreversible occlusal approaches to TMD, which were erroneously used and did not give the patient any benefit, thus forcing him to a non necessary financial and biological cost. The failure to satisfy the contract with the patient, which is usually not covered by any insurance company, forced the practitioner to give the money back to the patient. The ethical and legal implications of such case were discussed, with particular focus on the concept that medical legal advices need to satisfy the highest standards of evidence and have to be strictly based on scientific knowledge.

Duchenne's muscular dystrophy involves a defective transsulfuration pathway activity.

Duchenne muscular dystrophy (DMD) is the most frequent X chromosome-linked disease caused by mutations in the gene encoding for dystrophin, leading to progressive and unstoppable degeneration of skeletal muscle tissues. Despite recent advances in the understanding of the molecular processes involved in the pathogenesis of DMD, there is still no cure. In this study, we aim at investigating the potential involvement of the transsulfuration pathway (TSP), and its by-end product namely hydrogen sulfide (H2S), in primary human myoblasts isolated from DMD donors and skeletal muscles of dystrophic (mdx) mice. In myoblasts of DMD donors, we demonstrate that the expression of key genes regulating the H2S production and TSP activity, including cystathionine γ lyase (CSE), cystathionine beta-synthase (CBS), 3 mercaptopyruvate sulfurtransferase (3-MST), cysteine dioxygenase (CDO), cysteine sulfonic acid decarboxylase (CSAD), glutathione synthase (GS) and γ -glutamylcysteine synthetase (γ-GCS) is reduced. Starting from these findings, using Nuclear Magnetic Resonance (NMR) and quantitative Polymerase Chain Reaction (qPCR) we show that the levels of TSP-related metabolites such as methionine, glycine, glutathione, glutamate and taurine, as well as the expression levels of the aforementioned TSP related genes, are significantly reduced in skeletal muscles of mdx mice compared to healthy controls, at both an early (7 weeks) and overt (17 weeks) stage of the disease. Importantly, the treatment with sodium hydrosulfide (NaHS), a commonly used H2S donor, fully recovers the impaired locomotor activity in both 7 and 17 old mdx mice. This is an effect attributable to the reduced expression of pro-inflammatory markers and restoration of autophagy in skeletal muscle tissues. In conclusion, our study uncovers a defective TSP pathway activity in DMD and highlights the role of H2S-donors for novel and safe adjuvant therapy to treat symptoms of DMD.

Thrombin functions as an inflammatory mediator through activation of its receptor.

A rat model of inflammation was used to investigate the biological effects of thrombin. The thrombin-specific inhibitor Hirulog markedly attentuated the carrageenin-induced edema of the paw of the rat. Injection of thrombin into the paw also produced edema. The effect of thrombin was due to activation of its receptor; a thrombin receptor activating peptide (TRAP) reproduced the effects of thrombin in causing edema. TRAP also increased vascular permeability as demonstrated by extravasation of Evans blue and 125I-labeled serum albumin. The release of bioactive amines played an important role in mediating the TRAP-induced edema; the serotonin/histamine antagonist cryproheptadine and the histamine H2 receptor antagonist cimetidine reduced significantly the edema caused by TRAP. Treatment of rats with the mast cell degranulator 48/80 to deplete these cells of their stores of histamine and serotonin abolished completely the ability of TRAP to produce edema. Histochemical examination confirmed that TRAP treatment led to mast cell degranulation. Thus, it has been possible to demonstrate that thrombin acts as an inflammatory mediator in vivo by activating its receptor, which in turn leads to release of vasoactive amines from mast cells.

Target definition of moving lung tumors in positron emission tomography: correlation of optimal activity concentration thresholds with object size, motion extent, and source-to-background ratio.

PURPOSE: Hardware integration of fluorodeoxyglucose positron emission tomography (PET) with computed tomography (CT) in combined PET/CT scanners has provided radiation oncologists and physicists with new possibilities for 3-D treatment simulation. The use of PET/CT simulation for target delineation of lung cancer is becoming popular and many studies concerning automatic segmentation of PET images have been performed. Several of these studies consider size and source-to-background (SBR) in their segmentation methods but neglect respiratory motion. The purpose of the current study was to develop a functional relationship between optimal activity concentration threshold, tumor volume, motion extent, and SBR using multiple regression techniques by performing an extensive series of phantom scans simulating tumors of varying sizes, SBR, and motion amplitudes. Segmented volumes on PET were compared with the "motion envelope" of the moving sphere defined on cine CT. METHODS: A NEMA IEC thorax phantom containing six spheres (inner diameters ranging from 10 to 37 mm) was placed on a motion platform and moved sinusoidally at 0-30 mm (at 5 mm intervals) and six different SBRs (ranging from 5:1 to 50:1), producing 252 combinations of experimental parameters. PET images were acquired for 18 min and split into three 6 min acquisitions for reproducibility. The spheres (blurred on PET images due to motion) were segmented at 1% of maximum activity concentration intervals. The optimal threshold was determined by comparing deviations between the threshold volume surfaces with a reference volume surface defined on cine CT. Optimal activity concentration thresholds were normalized to background and multiple regression was used to determine the relationship between optimal threshold, volume, motion, and SBR. Standardized regression coefficients were used to assess the relative influence of each variable. The segmentation model was applied to three lung cancer patients and segmented regions of interest were compared with those segmented on cine CT. RESULTS: The resulting model and coefficients provided a functional form that fit the phantom data with an adjusted R2 = 0.96. The most significant contributor to threshold level was SBR. Surfaces of PET-segmented volumes of three lung cancer patients were within 2 mm of the reference CT volumes on average. CONCLUSIONS: The authors successfully developed an expression for optimal activity concentration threshold as a function of object volume, motion, and SBR.

From Endothelium to Lipids, Through microRNAs and PCSK9: A Fascinating Travel Across Atherosclerosis.

Lipids and endothelium are pivotal players on the scene of atherosclerosis and their interaction is crucial for the establishment of the pathological processes. The endothelium is not only the border of the arterial wall: it plays a key role in regulating circulating fatty acids and lipoproteins and vice versa it is regulated by these lipidic molecules thereby promoting atherosclerosis. Inflammation is another important element in the relationship between lipids and endothelium. Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recognized as a fundamental regulator of LDL-C and anti-PCSK9 monoclonal antibodies have been approved for therapeutic use in hypercholesterolemia, with the promise to subvert the natural history of the disease. Moreover, growing experimental and clinical evidence is enlarging our understanding of the mechanisms through which this protein may facilitate the genesis of atherosclerosis, independently of its impact on lipid metabolism. In addition, environmental stimuli may affect the post-transcriptional regulation of genes through micro-RNAs, which in turn play a key role in orchestrating the crosstalk between endothelium and cholesterol. Advances in experimental research, with development of high throughput techniques, have led, over the last century, to a tremendous progress in the understanding and fine tuning of the molecular mechanisms leading to atherosclerosis. Identification of pivotal keystone molecules bridging lipid metabolism, endothelial dysfunction and atherogenesis will provide the mechanistic substrate to test valuable targets for prediction, prevention and treatment of atherosclerosis-related disease.