Docosahexaenoic acid promotes oligodendrocyte differentiation via PPAR-γ signalling and prevents tumor necrosis factor-α-dependent maturational arrest.

Docosahexaenoic acid (DHA) is an essential omega-3 fatty acid known to be neuroprotective in several models of human diseases, including multiple sclerosis. The protective effects of DHA are largely attributed to its ability to interfere with the activity of transcription factors controlling immune and inflammatory responses, including the agonist-dependent transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ). In this study, we used primary oligodendrocyte progenitor (OP) cultures from neonatal rat brain to investigate whether DHA could influence OP maturation and directly promote myelination, as previously reported for selective PPAR-γ agonists. We show that, similarly to the selective PPAR-γ agonist pioglitazone (PGZ), DHA promotes OP maturation and counteracts the maturational arrest induced by TNF-α, used to mimic inflammatory conditions. The PPAR-γ antagonist GW9662 prevented both DHA-induced OP maturation and PPAR-γ nuclear translocation, supporting the hypothesis that DHA acts through the activation of PPAR-γ. In addition, both PGZ and DHA induced the phosphorylation of extracellular signal-regulated-kinase 1-2 (ERK1/2), in a PPAR-γ-dependent manner. ERK1/2 activity is known to regulate the transition from OPs to immature oligodendrocytes and the presence of specific inhibitors of ERK1/2 phosphorylation (U0126 or PD98059) prevented the differentiating effects of both DHA and PGZ. These results indicate that DHA might influence the process of OP maturation through its PPAR-γ agonistic activity and provide novel molecular mechanisms for the action of this dietary fatty acid, further supporting the nutritional intervention in demyelinating diseases such as multiple sclerosis.

Comprehensive patient-specific information preprocessing for cardiac surgery simulations.

PURPOSE: Patient-specific biomechanical simulations of the behavior of soft tissue gain importance in current surgery assistance systems as they can provide surgeons with valuable ancillary information for diagnosis and therapy. In this work, we aim at supporting minimally invasive mitral valve reconstruction (MVR) surgery by providing scenario setups for FEM-based soft tissue simulations, which simulate the behavior of the patient-individual mitral valve subject to natural forces during the cardiac cycle after an MVR. However, due to the complexity of these simulations and of their underlying mathematical models, it is difficult for non-engineers to sufficiently understand and adequately interpret all relevant modeling and simulation aspects. In particular, it is challenging to set up such simulations in automated preprocessing workflows such that they are both patient-specific and still maximally comprehensive with respect to the model. METHODS: In this paper, we address this issue and present a fully automated chain of preprocessing operators for setting up comprehensive, patient-specific biomechanical models on the basis of patient-individual medical data. These models are suitable for FEM-based MVR surgery simulation. The preprocessing methods are integrated into the framework of the Medical Simulation Markup Language and allow for automated information processing in a data-driven pipeline. RESULTS: We constructed a workflow for holistic, patient-individual information preprocessing for MVR surgery simulations. In particular, we show how simulation preprocessing can be both fully automated and still patient-specific, when using a series of dedicated MVR data analytics operators. The outcome of our operator chain is visualized in order to help the surgeon understand the model setup. CONCLUSION: With this work, we expect to improve the usability of simulation-based MVR surgery assistance, through allowing for fully automated, patient-specific simulation setups. Combined visualization of the biomechanical model setup and of the corresponding surgery simulation results fosters the understandability and transparency of our assistance environment.

Peroxisome proliferator activated receptor-γ agonists protect oligodendrocyte progenitors against tumor necrosis factor-alpha-induced damage: Effects on mitochondrial functions and differentiation.

The activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is known to exert anti-inflammatory and neuroprotective effects and PPAR-γ agonists are considered potential therapeutic agents in brain diseases including those affecting myelin. In demyelinating diseases such as multiple sclerosis (MS), inflammation is one of the causes of myelin and axonal damage. Oligodendrocyte (OL) differentiation is highly dependent on mitochondria, which are major targets of inflammatory insult. Here we show that PPAR-γ agonists protect OL progenitors against the maturational arrest induced by the inflammatory cytokine TNF-α by affecting mitochondrial functions. We demonstrate that the inhibition of OL differentiation by TNF-α is associated with i) increased mitochondrial superoxide production; ii) decreased mitochondrial membrane potential (mMP); and iii) decreased ADP-induced Ca(2+) oscillations, which we previously showed to be dependent on efficient mitochondria. The TNF-α effects were comparable to those of the mitochondrial toxin rotenone, further suggesting that TNF-α damage is mediated by mitochondrial function impairment. PPAR-γ agonists protected OL progenitors against the inhibitory activities of both TNF-α and rotenone on mMP, mitochondrial ROS production, Ca(2+) oscillations and OL differentiation. Finally, the PPAR-γ agonist pioglitazone increased the expression of PGC-1α (a mitochondrial biogenesis master regulator), UCP2 (a mitochondrial protein known to reduce ROS production), and cytochrome oxidase subunit COX1. These findings confirm the central role of mitochondria in OL differentiation and point to mitochondria as major targets of PPAR-γ agonist protection against TNF-α damage.

The lesson of chronic migraine.

The hypothesis that central sensitization/allodynia is the common final mechanism responsible for the progression of migraine pain is supported by the possibility of tracing back to allodynic mechanisms the action of the main risk factors for chronic migraine validated by the recent literature. The comorbidity between migraine and idiopathic intracranial hypertension without papilledema is emerging as a new, commonly overlooked risk factor for migraine progression whose putative mechanism might also converge on the sensitization of central pain pathways. If headache progression always occurs at the end of a pathogenetic sequence typical of an individual susceptibility to allodynia, then the primary character of chronic migraine might be debated. Allodynia is not specific to migraine but is implied in the progressive amplification of pain after repeated stimuli, a universal adaptive phenomenon. Being largely conditioned by the individual comorbidity profile, allodynia may only in part be defined as primary in itself. Many migraine comorbid conditions, including a hidden idiopathic intracranial hypertension without papilledema, may emphasize susceptibility to allodynia and promote chronic migraine. These factors and comorbid conditions require to be individually assessed and adequately treated to optimize the therapeutic response.

Proposal of a new method for the use of the Rydel-Seiffer tuning fork in the screening of diabetic polyneuropathy. A pilot study.

We investigated the usefulness of a new examiner-independent method based on the duration of vibration sensation following the placement of the Rydel-Seiffer tuning fork over the dorsum of the interphalangeal hallux joint. This method demonstrated the same diagnostic efficacy as the Rydel-Seiffer method coupled with greater ease of use.

The role of dural sinus stenosis in idiopathic intracranial hypertension pathogenesis: the self-limiting venous collapse feedback-loop model.

In recent years the efficacy of endovascular venous stenting in idiopathic IIH treatment has been consistently reported, strongly suggesting that sinus stenosis should be viewed as a causative factor rather than a secondary phenomenon. We propose that in subjects carrying one or more collapsible segments of large cerebral venous collectors and exposed to a number of different promoting factors, sinus venous compression and cerebrospinal fluid (CSF) hypertension may influence each other in a circular way, leading to a new relatively stable venous/CSF pressures balance state at higher values. The mechanism relay on self-limiting venous collapse (SVC) feedback-loop between the CSF pressure, that compresses the sinus, and the consequent venous pressure rise, that increases the CSF pressure. The result is the "coupled" increase of both pressure values, a phenomenon not expected in presence of sufficiently rigid central veins. Once the maximum stretch of venous wall is reached the loop stabilize at higher venous/CSF pressure values and become self-sustaining, therefore persisting even after the ceasing of the promoting factor. Notably, the SVC is reversible provided an adequate perturbation is carried to whichever side of the loop such as sinus venous stenting, on one hand, and CSF diversion or even a single CSF withdrawal by lumbar puncture (LP), on the other. The SVC model predicts that any condition leading to an increase of either, cerebral venous pressure or CSF pressure may trigger the feedback loop in predisposed individuals. Migraine with and without aura, a disease sharing with IIH a much higher prevalence among women of childbearing age, is associated with waves of significant brain hyperperfusion. These may lead to the congestion of large cerebral venous collectors and could represent a common SVC promoting condition in susceptible individuals. The SVC model give reason of the high specificity and sensitivity of sinus stenosis as IIH predictor and of the multiplicity of the factors that have been found associated with IIH. Moreover it might explain why, among the sinus stenosis carriers, young and overweight women are at higher risk of developing the disease. Finally, the SVC model fully explain the enigmatic longstanding remissions that can be commonly observed after a single LP with CSF subtraction in IIH with or without papilledema.

Using a shape prior for robust modeling of the mitral annulus on 4D ultrasound data.

PURPOSE: Over 40,000 annuloplasty rings are implanted each year in the USA to treat mitral regurgitation. However, the used measuring techniques to select a suitable annuloplasty ring are imprecise and highly depending on the expert's experience. This can cause a re-occurrence of the mitral regurgitation or an annuloplasty ring dehiscence, and thus the necessity of a re-operation. We propose a method to create a 4D model of the mitral annulus from ultrasound data to enable precise measurement and patient-specific implant planning. METHODS: An initial mitral annulus model is placed interactively in the 4D image data by defining commissure points and the annulus plane for one time step in diastole and systole. The model is automatically optimized using distinct image features. A shape and pose prior of the mitral annulus is used to compensate for artifacts and to enforce a plausible anatomical morphology, while a temporal alignment ensures a natural motion of the 4D model. RESULTS: Ground truth data were created for 4D images of 42 patients with varying image quality. A parameter and shape prior training was performed on a third of the ground truth data, while the rest was used to validate the method. The average error of the resulting mitral annulus models was computed as 2.25 ( +/-0.38 ) mm. The average expert standard deviation was determined as 1.86 (+/-0.32 ) mm. CONCLUSION: The proposed method enables the 4D modeling of mitral annuli based on ultrasound data in less than 2 min. The resulting models are comparable to manually delineated models and can be used for measurements of annular geometries and patient-specific annuloplasty treatment planning.

Multiple myeloma and paget disease with abnormal skull lesions and intracranial hypertension.

We report a 73 years old man with a diagnosis of Paget Disease (PD) and symptomatic Multiple Myeloma (MM). Coexistence of MM and PD has rarely been described. PD mimics many of the features of bone destructive process in MM, making differential diagnosis more complicated. In addition, the presence of serious muscolo-skeletal and metabolic complications in both diseases makes management of patients difficult, worsening the prognosis.The comparison of these two diseases has led to the characterization of a common molecular mechanism represented by the receptor activator of nuclear factor-kB ligand (RANKL)/Osteoprotegerin signaling pathway. The improved comprehension of these mechanisms led to the development of new pharmacologic agents (bisphosphonates, cytokines inhibitors) effective for the treatment of these bone diseases.

Comparing calibration approaches for 3D ultrasound probes.

OBJECTIVE: By adding a tracking sensor to a 3D ultrasound (US) probe and thus locating the probe in space, new applications within the fields of image guided surgery and radiation therapy are possible. To locate the US volume in space, a calibration is necessary to determine the mathematical transformation for mapping points from the tracking coordinate system to the US image coordinate system. We present a comprehensive comparison of two different approaches to perform this calibration for 3D US. METHODS: For both approaches a phantom is scanned and located in the images by means of segmentation and registration techniques. Calibration is then performed by either relating the tracked phantom's (TP) spatial location to the calibration scans, or by solely correlating scans taken from multiple perspectives when using hand-eye calibration methods (HE). Depending on which approach is utilized, a minimum of one or three images, respectively, need to be acquired for the calibration process. RESULTS: We evaluated both approaches for calibration and reconstruction precision. Regarding the latter, the performed tests led to mean target localization errors of 3.5 mm (HE) and 3.3 mm (TP) for real data, and of 1.4 mm (HE) and 0.9 mm (TP) for simulated data. CONCLUSION: Our results indicate that taking additional scans leads to a significant improvement in the calibration. Furthermore, the obtained calibration and reconstruction precisions suggest the use of a TP.

Towards a mixed reality environment for preoperative planning of cardiac surgery.

We present a novel approach to studying physical heart models by coupling them with virtual 3D representations in a mixed reality environment. The limitations of standalone physical models (non-interactive, static) are overcome by the corresponding virtual models, which in turn become more natural to interact with. The potential of this approach is exemplified by a setup which enables cardiac surgeons to interactively trace the mitral annulus, a part of the cardiac skeleton playing a vital role in mitral valve surgery. We present results of a pilot study and discuss ways of improving and extending the system. The described mixed reality environment could easily be adapted to other fields and thus has the potential to become a new tool for investigating 3D medical data.

NGF promotes microglial migration through the activation of its high affinity receptor: modulation by TGF-beta.

Activation and mobilization of microglia are early events in the majority of brain pathologies. Among the signalling molecules that can affect microglial behaviour, we investigated whether nerve growth factor (NGF) was able to influence microglial motility. We found that NGF induced chemotaxis of microglial cells through the activation of TrkA receptor. In addition, NGF chemotactic activity was increased in the presence of low concentrations (< or =0.2 ng/ml) of transforming growth factor-beta (TGF-beta), which at this concentration showed chemotactic activity per se. On the contrary, NGF-induced microglial migration was reduced in the presence of chemokinetic concentration of TGF-beta (> or =2 ng/ml). Finally, both basal and NGF-induced migratory activity of microglial cells was increased after a long-term exposure of primary mixed glial cultures to 2 ng/ml of TGF-beta. Our observations suggest that both NGF and TGF-beta contribute to microglial recruitment. The chemotactic activities of these two pleiotropic factors could be particularly relevant during chronic diseases in which recruited microglia remove apoptotic neurons in the absence of a typical inflammatory reaction.

[Three-dimensional echocardiography in cardiac surgery. Current status and perspectives]. / Klinischer Einsatz der 3D-Echokardiographie in der Herzchirurgie. Aktueller Stand und Perspektiven.

Three-dimensional (3D) echocardiography is a new imaging technique that can provide useful information about cardiovascular morphology, pathology, and function. Recent refinements in instrumentation, data acquisition, post-processing, and computation speed allow 3D echocardiography to play an important role in cardiac imaging. These modalities provide comprehensive information on ventricular and valve morphology and function. Combined with 3D color Doppler sonography, further assessment of valvular function and determination of flow in the left ventricular outflow tract and cross-septal defects are now possible. Three-dimensional color flow imaging also makes echocardiography accurate for assessing the severity of mitral regurgitation. The purpose of this review is to describe technical developments in 3D echocardiography and its clinical application in cardiac surgery. Moreover, based on clinical studies at our centre, we describe the morphology of the mitral valve, its flow pattern, and function of the mitral annulus.

One-year atorvastatin treatment in hypercholesterolemic patients with or without carotid artery disease.

AIM: Statins are the drugs of choice in heterozygous familial hypercholesterolemia (FH), which has a high risk of premature cardiovascular events including myocardial infarction, stroke, and surgical revascularization. METHODS: A 1-year open-label study was conducted to test the efficacy and tolerability of Atorvastatin titrated to the target, in proven FH patients and to evaluate certain inflammatory parameters. One hundred and two FH patients (44 men and 58 women; mean age 58.7+/-3.6 years) were included in the study. After evaluation using the B-mode duplex scanning system of extracranial carotid arteries, the patients were divided into two groups: Group 1 (15 men, 25 women) with carotid plaques or intima-media thickness (IMT) greater than 0.95 mm and Group 2 (30 men, 32 women) without carotid plaques or IMT less than 0.95 mm. After a 6-week hypolipemic diet phase all the patients were treated with atorvastatin titrated to achieve a low density lipoprotein (LDL-C) <100 mg/dL. Patients with carotid lesions were also submitted to an oral fixed dose of aspirin 100 mg/day. RESULTS: In patients without and with carotid lesions, atorvastatin treatment (mean dosage: 23.5 mg/day) reduced triglycerides by 8.7% (P<0.005) and 10.6% (P<0.005), total cholesterol by 41.5% (P<0.005) and 42.6% (P<0.005), LDL-C by 55.8% (P<0.005) and 57.3% (P<0.005) and apolipoprotein B by 38.3% (P<0.005) and 37.2% (P<0.005) respectively, and increased the mean levels of high density lipoprotein cholesterol (HDL-C) by 8.7% (P<0.005) and 11% (P<0.005), and apolipoprotein A-I by 3.2% (P<0.05) and 3.3%, respectively. In both groups of patients the mean decrease (52 weeks) of fibrinogen was 19.8% (P<0.005) and 10.4% (P<0.005), respectively and of high sensitivity C-reactive protein (hs-CRP), 36.2% (P<0.005) and 38.2% (P<0.005), respectively. No variation of the parameters of safety and clinical tolerability of the drugs administered was observed. No variation in hematocrit in the patients taking ASA treatment was observed. CONCLUSIONS: In FH patients, 1-year atorvastatin treatment titrated to the target (LDL-C <100 mg/dL) was well tolerated and improved serum lipid levels and inflammatory parameters.

Sudden re-opening of collapsed transverse sinuses and longstanding clinical remission after a single lumbar puncture in a case of idiopathic intracranial hypertension. Pathogenetic implications.

The aetiopathogenetic role of sinus venous obstructions carried by most idiopathic intracranial hypertension (IIH) patients is controversial. We report the case of a young woman diagnosed with IIH with papilloedema and narrowing of transverse sinuses, in which lowering of intracranial pressure by a single 20 ml cerebrospinal fluid (CSF) resulted in a strong dimensional increase of the transverse sinuses. Changes were followed by clinical remission and normalisation of optical nerve calibre, maintained after a 2-month follow-up. Our findings indicate that, although secondary to CSF hypertension, venous sinuses compression may have an important role in hypertensive status maintenance. Pathogenetic implications of venous sinus compression by hypertensive CSF in IIH are discussed.

The effect of a levonorgestrel-releasing intrauterine device in the treatment of myoma-related menorrhagia.

In this open observational study we evaluated the effectiveness of a levonorgestrel-releasing intrauterine device (LNG-IUD) in the treatment of myoma-related menorrhagia. Nineteen patients with recurrent menorrhagia lasting more than 3 months and with fibromyomatosus uterus were treated for 12 months with a LNG-IUD releasing 20 micro g/day of levonorgestrel. Menstrual blood loss, measured objectively by the pictorial blood loss assessment chart score (PBAC), level of serum hemoglobin and pattern of uterine bleeding were recorded at 3, 6, 9 and 12-month follow-up visits. Median monthly PBAC score during the two menstrual cycles before treatment was 310. After LNG-IUD, the PBAC score gradually decreased from a median value of 186 at 3 months to a median value of 155, 108 and 96 at 6, 9 and 12 months of treatment, respectively. Despite the statistically significant reduction of PBAC score, persistent menorrhagia, defined as a monthly PBAC score of 100 or higher, was observed at 12 months in 14 patients, whereas only one woman was amenorrheic and 4 were hypomenorrheic. In conclusion our study demonstrates the clinical reduced effectiveness of LNG-IUD in the treatment of myoma-related menorrhagia.

[Evaluation of resistance to activated protein C in myocardial infarction patients]. / Valutazione della resistenza alla proteina C attivata in soggetti con pregresso IMA.

BACKGROUND: It is known that resistance to activated protein C (APCR), often associated with a single point mutation (Arg506-->Gln) in the coagulation factor V gene (factor V Leiden), is the most frequent inherited abnormality of blood coagulation. It plays a key role as pathogenetic factor of venous thromboembolism, but its association with an increased risk of arterial thrombosis is uncertain. Aim of the present study was to evaluate the prevalence of APCR in men, who suffered myocardial infarction more than 6 months earlier and without cardiovascular risk factors (hypercholesterolemia, smoking, diabetes, obesity and hypertension). METHODS: The study was carried on 20 men aged <65 years who have suffered myocardial infarction. Twenty healthy subjetcs matched for sex and age were recruited as controls. We determined: PTT, PTT-PCA (Activated Protein C), PTT-PCA/PTT, AntiThrombin III, Protein C, Protein S, Fibrinogen, Glucose, Triglycerides, Cholesterol, HDL-C, LDL-C, APO A1, APO B100, Lp(a), oxizided LDL antibody and some components of the complement system (C3c, C4). RESULTS: In the group of patients there were six subjects (30%) with APCR, while there were no subjects in the control group (0%) with APCR. Patients were subdivided into two groups: with and without APCR. Patients with APCR displayed significantly higher levels of fibrinogen (367.5+/-48.4 vs 268.3+/-37.7), LDL-C (147.0 +/-20.7 vs 125.8+/-25,6), APO B100 (133.8+/-29.8 vs 121.8+/-31.5), oxizide LDL antibody (596.8+/-357 vs 315.3+/-179.6) and C4 (45.6+/-10 vs 37.85+/-11,3). Significant positive correlations (p<0.05) were observed between PTT-PCA/PTT ratio and fibrinogen (r=0.68) and between PTT-PCA/PTT ratio and oxidized LDL antibody (r=0.61). CONCLUSIONS: In conclusion, the high prevalence of APCR (30%) in our patients seems to be important in order to carry out a primary prevention of arterial thrombosis and a secondary prevention of new thromboembolic complications.

Functional maturation of adult mouse resting microglia into an APC is promoted by granulocyte-macrophage colony-stimulating factor and interaction with Th1 cells.

A precise knowledge of the early events inducing maturation of resting microglia into a competent APC may help to understand the involvement of this cell type in the development of CNS immunopathology. To elucidate whether signals from preactivated T cells are sufficient to induce APC features in resting microglia, microglia from the adult BALB/c mouse CNS were cocultured with Th1 and Th2 lines from DO11.10 TCR transgenic mice to examine modulation of APC-related molecules and Ag-presenting capacity. Upon Ag-specific interaction with Th1, but not Th2, cells, microglia strongly up-regulated the surface expression of MHC class II, CD40, and CD54 molecules. Induction of CD86 on mouse microglia did not require T cell-derived signals. Acutely isolated adult microglia stimulated Th1 cells to secrete IFN-gamma and, to a lesser extent, IL-2, but were inefficient stimulators of IL-4 secretion by Th2 cells. Microglia exposed in vitro to IFN-gamma showed enhanced expression of MHC class II, CD40, and CD54 molecules and became able to restimulate Th2 cells. In addition to IFN-gamma, GM-CSF increased the ability of microglia to activate Th1, but not Th2, cells without up-regulating MHC class II, CD40, or CD54 molecules. These results suggest that interaction with Th1 cells and/or Th1-secreted soluble factors induces the functional maturation of adult mouse microglia into an APC able to sustain CD4+ T cell activation. Moreover, GM-CSF, a cytokine secreted by T cells as well as reactive astrocytes, could prime microglia for Th1-stimulating capacity, possibly by enhancing their responsiveness to Th1-derived signals.

Opposite effects of interferon-gamma and prostaglandin E2 on tumor necrosis factor and interleukin-10 production in microglia: a regulatory loop controlling microglia pro- and anti-inflammatory activities.

Following brain injury, microglial cells produce pro- and anti-inflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin-10 (IL-10). IL-10 provides an efficient autocrine mechanism for controlling microglia activation. To elucidate the mechanisms that regulate the cytokine profile of microglia, we examined the effects of several immunomodulators on IL-10 and TNF production by cultured mouse microglia. Lipopolysaccharide (LPS) was the only inducer of IL-10 and TNF gene expression and secretion. The T helper 1-type cytokine interferon-gamma (IFN-gamma) induced TNF transcripts, but not TNF secretion, and suppressed LPS-induced IL-10 mRNA and secretion by microglia. Opposite to IFN-gamma, the lipid mediator prostaglandin E2 (PGE2) enhanced the LPS-induced production of IL-10 and inhibited that of TNF. The effects of PGE2 on cytokine gene expression and secretion were antagonized by IFN-gamma. Agents that increase cAMP levels mimicked the action of PGE2 on cytokine secretion, indicating the involvement of cAMP-coupled prostaglandin receptors. In conclusion, IFN-gamma and PGE2, two mediators released at inflammatory sites, differentially regulate the production of a proinflammatory and an anti-inflammatory cytokine in microglia. We suggest that the activity and role of microglia in the damaged CNS could be finely tuned by the local concentration ratio of these mediators.