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.

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.

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.

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.

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.

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.

Control of chaotic systems by deep reinforcement learning.

Deep reinforcement learning (DRL) is applied to control a nonlinear, chaotic system governed by the one-dimensional Kuramoto-Sivashinsky (KS) equation. DRL uses reinforcement learning principles for the determination of optimal control solutions and deep neural networks for approximating the value function and the control policy. Recent applications have shown that DRL may achieve superhuman performance in complex cognitive tasks. In this work, we show that using restricted localized actuation, partial knowledge of the state based on limited sensor measurements and model-free DRL controllers, it is possible to stabilize the dynamics of the KS system around its unstable fixed solutions, here considered as target states. The robustness of the controllers is tested by considering several trajectories in the phase space emanating from different initial conditions; we show that DRL is always capable of driving and stabilizing the dynamics around target states. The possibility of controlling the KS system in the chaotic regime by using a DRL strategy solely relying on local measurements suggests the extension of the application of RL methods to the control of more complex systems such as drag reduction in bluff-body wakes or the enhancement/diminution of turbulent mixing.

[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.

Respiratory variation in aortic blood peak velocity and caudal vena cava diameter can predict fluid responsiveness in anaesthetised and mechanically ventilated dogs.

BACKGROUND AND M&MS: Dynamic preload indices, such as systolic pressure variation (SPV), aortic flow peak velocity variation (ΔVpeak) and distensibility index of the caudal vena cava (CVCDI), are reliable indices for predicting fluid responsiveness in humans. This study aimed to investigate the ability of these indices to predict fluid response in 24 healthy dogs undergoing general anaesthesia and mechanical ventilation. Aortic flow peak velocity variation (∆Vpeak), CVCDI, and SPV were calculated before volume expansion (5mL/kg bolus of lactated Ringer's solution). The aortic velocity time integral (VTI) was measured before and after volume expansion as a surrogate of stroke volume. Dogs were considered responders (n=9) when the VTI increase was ≥15% and non-responders (n=15) when the increase was <15%. RESULTS AND CONCLUSIONS: Before volume expansion, ΔVpeak, CVCDI and SPV were higher in responders than in non-responders (P=0.0009, P=0.0003, and P=0.0271, respectively). Receiver operating characteristic (ROC) curves were plotted for the three indices. The areas under the ROC curves for SPV, ΔVpeak, and CVCDI were 0.91 (CI 0.73-0.99; P=0.0001), 0.95 (CI 0.77-1; P=0.0001), and 0.78 (CI 0.56-0.92; P=0.015), respectively. The best cut-offs were 6.7% for SPV (sensitivity, 77.78%; specificity, 93.33%), 9.4% for ΔVpeak (sensitivity, 88.89%; specificity, 100%), and 24% for CVCDI (sensitivity, 77.78%; specificity, 73.33). In conclusion, ΔVpeak, CVCDI, and SPV are reliable predictors of fluid responsiveness in healthy dogs undergoing general anaesthesia and mechanical ventilation.

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.

Elevated Glucose Oxidation, Reduced Insulin Secretion, and a Fatty Heart May Be Protective Adaptions in Ischemic CAD.

BACKGROUND: Insulin resistance, ß-cell dysfunction, and ectopic fat deposition have been implicated in the pathogenesis of coronary artery disease (CAD) and type 2 diabetes, which is common in CAD patients. We investigated whether CAD is an independent predictor of these metabolic abnormalities and whether this interaction is influenced by superimposed myocardial ischemia. METHODS AND RESULTS: We studied CAD patients with (n = 8) and without (n = 14) myocardial ischemia and eight non-CAD controls. Insulin sensitivity and secretion and substrate oxidation were measured during fasting and oral glucose tolerance testing. We used magnetic resonance imaging/spectroscopy, positron emission and computerized tomography to characterize CAD, cardiac function, pericardial and abdominal adipose tissue, and myocardial, liver, and pancreatic triglyceride contents. Ischemic CAD was characterized by elevated oxidative glucose metabolism and a proportional decline in ß-cell insulin secretion and reduction in lipid oxidation. Cardiac function was preserved in CAD groups, whereas cardiac fat depots were elevated in ischemic CAD compared to non-CAD subjects. Liver and pancreatic fat contents were similar in all groups and related with surrounding adipose masses or systemic insulin sensitivity. CONCLUSIONS: In ischemic CAD patients, glucose oxidation is enhanced and correlates inversely with insulin secretion. This can be seen as a mechanism to prevent glucose lowering because glucose is required in oxygen-deprived tissues. On the other hand, the accumulation of cardiac triglycerides may be a physiological adaptation to the limited fatty acid oxidative capacity. Our results underscore the urgent need of clinical trials that define the optimal/safest glycemic range in situations of myocardial ischemia.

Characterization of zofenoprilat as an inducer of functional angiogenesis through increased H2 S availability.

BACKGROUND AND PURPOSE: Hydrogen sulfide (H2 S), an endogenous volatile mediator with pleiotropic functions, promotes vasorelaxation, exerts anti-inflammatory actions and regulates angiogenesis. Previously, the SH-containing angiotensin-converting enzyme inhibitor (ACEI), zofenopril, was identified as being effective in preserving endothelial function and inducing angiogenesis among ACEIs. Based on the H2 S donor property of its active metabolite zofenoprilat, the objective of this study was to evaluate whether zofenoprilat-induced angiogenesis was due to increased H2 S availability. EXPERIMENTAL APPROACH: HUVECs were used for in vitro studies of angiogenesis, whereas the Matrigel plug assay was used for in vivo assessments. KEY RESULTS: Zofenoprilat-treated HUVECs showed an increase in all functional features of the angiogenic process in vitro. As zofenoprilat induced the expression of CSE (cystathionine-γ-lyase) and the continuous production of H2 S, CSE inhibition or silencing blocked the ability of zofenoprilat to induce angiogenesis, both in vitro and in vivo. The molecular mechanisms underlying H2 S/zofenoprilat-induced angiogenesis were dependent on Akt, eNOS and ERK1/2 cascades. ATP-sensitive potassium (KATP ) channels, the molecular target that mediates part of the vascular functions of H2 S, were shown to be involved in the upstream activation of Akt and ERK1/2. Moreover, the up-regulation of fibroblast growth factor-2 was dependent on CSE-derived H2 S response to H2 S and KATP activation. CONCLUSIONS AND IMPLICATIONS: Zofenoprilat induced a constant production of H2 S that stimulated the angiogenic process through a KATP channel/Akt/eNOS/ERK1/2 pathway. Thus, zofenopril can be considered as a pro-angiogenic drug acting through H2 S release and production, useful in cardiovascular pathologies where vascular functions need to be re-established and functional angiogenesis induced.

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.

Crucial role of androgen receptor in vascular H2S biosynthesis induced by testosterone.

BACKGROUND AND PURPOSE: Hydrogen sulphide (H2S) is a gaseous mediator strongly involved in cardiovascular homeostasis, where it provokes vasodilatation. Having previously shown that H2 S contributes to testosterone-induced vasorelaxation, here we aim to uncover the mechanisms underlying this effect. EXPERIMENTAL APPROACH: H2 S biosynthesis was evaluated in rat isolated aortic rings following androgen receptor (NR3C4) stimulation. Co-immunoprecipitation and surface plasmon resonance analysis were performed to investigate mechanisms involved in NR3C4 activation. KEY RESULTS: Pretreatment with NR3C4 antagonist nilutamide prevented testosterone-induced increase in H2S and reduced its vasodilator effect. Androgen agonist mesterolone also increased H2S and induced vasodilatation; effects attenuated by the selective cystathionine-γ lyase (CSE) inhibitor propargylglycine. The NR3C4-multicomplex-derived heat shock protein 90 (hsp90) was also involved in this effect; its specific inhibitor geldanamycin strongly reduced testosterone-induced H2S production. Neither progesterone nor 17-ß-oestradiol induced H2S release. Furthermore, we demonstrated that CSE, the main vascular H2S-synthesizing enzyme, is physically associated with the NR3C4/hsp90 complex and the generation of such a ternary system represents a key event leading to CSE activation. Finally, H2S levels in human blood collected from male healthy volunteers were higher than those in female samples. CONCLUSIONS AND IMPLICATIONS: We demonstrated that selective activation of the NR3C4 is essential for H2S biosynthesis within vascular tissue, and this event is based on the formation of a ternary complex between cystathionine-γ lyase, NR3C4and hsp90. This novel molecular mechanism operating in the vasculature, corroborated by higher H2S levels in males, suggests that the L-cysteine/CSE/H2S pathway may be preferentially activated in males leading to gender-specific H2S biosynthesis.

Megaprosthesis in post-traumatic and periprosthetic large bone defects: Issues to consider.

INTRODUCTION: The recent evolution of prosthesis technology has enabled the surgeon to replace entire limbs. These special prostheses, or megaprostheses, were developed for the treatment of severe oncological bone loss; however, the indications and applications of these devices have expanded to other orthopaedic and trauma situations. For some years, surgeons have been implanting megaprostheses in non-oncological conditions, such as acute trauma in severe bone loss and poor bone quality; post-traumatic failures, both aseptic and septic (represented by complex non-unions and critical size bone defects); major bone loss in prosthetic revision, both aseptic and septic; periprosthetic fractures with component mobilisation and poor bone stock condition. The purpose of this study was to evaluate retrospectively the complications during and after the implantation of megaprosthesis of the lower limb in post-traumatic and prosthetic bone loss, and to propose tips about how to avoid and manage such complications. MATERIALS AND METHODS: All the complications and difficulties we have encountered during or after the implantation of megaprosthesis in non-oncology patients were evaluated retrospectively. A total of 72 patients were treated with large resection mono-and bi-articular prostheses between January 2008 and January 2014. RESULTS: The main critical problems found in the study were: restoration of the correct length and rotation of the limb; reconstruction of the knee extensor mechanism; trochanteric reconstruction; stability/dislocation of the implant; mobility/range of motion (ROM) of the implant; skin cover; sepsis, and bone quality. CONCLUSION: Megaprosthesis in severe bone loss can be considered as an available solution for the orthopaedic surgeon in extreme, appropriately selected cases. This type of complex surgery must be performed in specialised centres where knowledge and technologies are present. Patients with severe bone loss should not be treated in the same way as oncology patients because life expectancy is definitely longer; therefore, the surgical technique and the system implantation must be extremely rigorous to ensure longevity of the prosthesis. The characteristics of the bone and soft tissue conditions in these patients are very different from those presented by oncology patients, which creates critical problems that the surgeon should be able to manage to avoid serious complications.

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.

Efficacy of a nurse-led email reminder program for cardiovascular prevention risk reduction in hypertensive patients: a randomized controlled trial.

BACKGROUND: Many strategies have been evaluated to improve the prevention and control of cardiovascular (CVD) risk factors. Nursing telephonic and tele-counseling individualized lifestyle educational programs have been found to improve blood pressure control and adherence to lifestyle recommendation. This study tested the efficacy of a nurse-led reminder program through email (NRP-e) to improve CVD risk factors among hypertensive adults. METHODS: All participants received usual CVD prevention and a guideline-based educational program. Subjects in the NRP-e group also received weekly email alerts and phone calls from a nurse care manager for 6 months. Emails contained a reminder program on the need for adherence with a healthy lifestyle based upon current guidelines. Follow-up visits were scheduled at 1, 3 and 6 months after enrollment; randomization was made centrally and blood samples were evaluated into a single laboratory. RESULTS: The final sample consisted of 98 (control) and 100 (NRP-e) subjects (mean age 59.0 ± 14.5 years; 51.0% males). After 6 months, the following CVD risk factors significantly improved in both groups: body mass index, alcohol and fruit consumption, cigarette smoking, adherence to therapy hours, systolic and diastolic blood pressure, fasting blood glucose, low-density lipoproteins (LDL) and total cholesterol, triglycerides, and physical activity. In the NRP-e group, however, the prevalence of several behaviors or conditions at risk decreased significantly more than in the control group: obesity (-16%), low fruit consumption (-24%), uncontrolled hypertension (-61%), LDL (-56%), and total cholesterol (-40%). CONCLUSIONS: The NRP-e improved a range of CVD risk factors. The program had low costs, required only an average of <20 min per day in addition to normal practice, and may deserve further evaluation for the inclusion among existing care management approaches.

Megaprosthesis in large bone defects: opportunity or chimaera?

INTRODUCTION: The development of new megaprosthesis for the treatment of large bone defects provides important options to orthopaedic oncologic surgeons for the replacement of skeletal segments, such as the long bones of the upper and lower limbs and the relative joints. We implanted megaprosthesis using either a one-step or two-step technique depending on the patient's condition. The aim of this study was to evaluate retrospectively both clinical and radiological outcomes in patients who underwent lower limb megaprosthesis implant. MATERIALS AND METHODS: A total of 32 patients were treated with mono- and bi-articular megaprosthesis subdivided as follows: proximal femur, distal femur, proximal tibia and total femur. The mean follow-up of patients was about 18 months (range 3 months to 5 years). Clinical and serial radiographic evaluations were conducted using standard methods (X-ray at 45 days, 3, 6, 12, 18 and 24 months) and blood parameters of inflammation were monitored for at least 2 months. RESULTS: Although the mean length of follow-up was only 18 months, the first patients to enter the study were monitored for 5 years and showed encouraging clinical results, with good articulation of the segments, no somato-sensory or motor deficit and acceptable functional recovery. During surgery and, more importantly, in pre-operative planning, much attention should be given to the evaluation of the extensor apparatus, preserving it and, when necessary, reinforcing it with tendon substitutes. DISCUSSION: Megaprosthesis in extreme cases of severe bone loss and prosthetic failure is a potential solution for the orthopaedic surgeon. In oncological surgery, the opportunity to restore functionality to the patient (although not ad integrum) is important for both the patient and the surgeon. The high mortality associated with cancer precludes long-term patient follow-up; therefore, there is a lack of certainty about the survival of this type of prosthesis and any medium- to long-term complications that may occur. Nevertheless, patients should be considered as an oncologic patient, not because of the disease, but because of the limited therapeutic options available. CONCLUSIONS: Megaprosthesis provides a valuable opportunity to restore functionality to patients with highly disabling diseases.