Progress in the management of acute pulmonary embolism.

PURPOSE OF REVIEW: Pulmonary embolism is a major contributor to global disease burden worldwide. The 2014 guidelines of the European Society of Cardiology, endorsed by the European Respiratory Society, emphasize the need for initial and advanced risk stratification as well as risk-adapted treatment to ensure the highest quality of care. This review summarizes the progress in pulmonary embolism diagnosis, risk assessment, and treatment. RECENT FINDINGS: Major advances of the past 12 months include age-related biomarker cutoff levels for optimising pulmonary embolism diagnosis and risk stratification; detection of (isolated) subsegmental pulmonary embolism by computed tomographic pulmonary angiography, raising the question of appropriate treatment in these cases; benefits versus risks of systemic thrombolytic therapy in normotensive patients at intermediate-high risk of an adverse early outcome; catheter-directed reperfusion with low-dose thrombolytics for patients at high bleeding risk; lack of efficacy of retrievable vena cava filters in the prevention of pulmonary embolism recurrence; and specific antidotes for nonvitamin K-dependent oral anticoagulants. SUMMARY: Recent advances in the diagnosis, risk stratification, and treatment of acute pulmonary embolism now permit, for the first time, the implementation of an integrated risk-adapted approach to the disease such as recommended by the recent European guidelines.

Acute phase treatment of venous thromboembolism: advanced therapy. Systemic fibrinolysis and pharmacomechanical therapy.

Venous thromboembolism, which encompasses deep-vein thrombosis and acute pulmonary embolism (PE), represents a major contributor to global disease burden worldwide. For patients who present with cardiogenic shock or persistent hypotension (acute high-risk PE), there is consensus that immediate reperfusion treatment applying systemic fibrinolysis or, in the case of a high bleeding risk, surgical or catheter-directed techniques, is indicated. On the other hand, for the large, heterogeneous group of patients presenting without overt haemodynamic instability, the indications for advanced therapy are less clear. The recently updated guidelines of the European Society of Cardiology emphasise the importance of clinical prediction rules in combination with imaging procedures (assessment of right ventricular function) and laboratory biomarkers (indicative of myocardial stress or injury) for distinguishing between an intermediate and a low risk for an adverse early outcome. In intermediate-high-risk PE defined by the presence of both right ventricular dysfunction on echocardiography (or computed tomography) and a positive troponin (or natriuretic peptide) test, the bleeding risks of full-dose fibrinolytic treatment have been shown to outweigh its potential clinical benefits unless clinical signs of haemodynamic decompensation appear (rescue fibrinolysis). Recently published trials suggest that catheter-directed, ultrasound-assisted, low-dose local fibrinolysis may provide an effective and particularly safe treatment option for some of these patients.

Risk-adapted management of acute pulmonary embolism: recent evidence, new guidelines.

Venous thromboembolism (VTE), the third most frequent acute cardiovascular syndrome, may cause life-threatening complications and imposes a substantial socio-economic burden. During the past years, several landmark trials paved the way towards novel strategies in acute and long-term management of patients with acute pulmonary embolism (PE). Risk stratification is increasingly recognized as a cornerstone for an adequate diagnostic and therapeutic management of the highly heterogeneous population of patients with acute PE. Recently published European Guidelines emphasize the importance of clinical prediction rules in combination with imaging procedures (assessment of right ventricular function) and laboratory biomarkers (indicative of myocardial stress or injury) for identification of normotensive PE patients at intermediate risk for an adverse short-term outcome. In this patient group, systemic full-dose thrombolysis was associated with a significantly increased risk of intracranial bleeding, a complication which discourages its clinical application unless hemodynamic decompensation occurs. A large-scale clinical trial program evaluating new oral anticoagulants in the initial and long-term treatment of venous thromboembolism showed at least comparable efficacy and presumably increased safety of these drugs compared to the current standard treatment. Research is continuing on catheter-directed, ultrasound-assisted, local, low-dose thrombolysis in the management of intermediate-risk PE.

Detailed illustration of the visual field representation along the visual pathway to the primary visual cortex: a graphical summary.

PURPOSE: In the literature, different graphic illustrations are available, which depict different parts of the visual pathway in relation to visual field sectors, to retinal sectors, the layers of the lateral geniculate nucleus (LGN), or sections of the primary visual cortex (V1). However, a complete overview is missing, which may be useful for a more precise differentiation of predominantly ophthalmological from intracerebral diseases. It may also be of interest to investigate additional intracerebral reasons that are involved in impaired vision of largely unknown pathophysiology. METHODS: This work combines the scientific knowledge of partial graphics in one detailed illustration that allows exact follow-up of the neuronal connections from individual visual field sectors to the V1 areas. A selective search for peer-reviewed graphics of the visual pathway was performed in PubMed and Google Pictures. RESULTS: Sixteen different visual field sectors and their 16 corresponding retinal sectors were set in relation to 64 LGN sections and 20 areas of V1. Segmented cross-sectional areas of the optic nerve supplemented the graphical representation of the fiber orientation in relation to the visual field. CONCLUSION: The detailed illustration of the visual field projection along the visual pathway structures may facilitate a more precise calculation of correlations between morphological and functional measurements of ophthalmological and neuroradiological examinations.

Glaucoma classification based on visual pathway analysis using diffusion tensor imaging.

Most of the existing methods for diagnosing glaucoma analyze the eye with a main focus on the retina, despite the transsynaptic nature of the fiber degeneration caused by glaucoma. Thus, they ignore a significant part of the visual system represented by the visual pathway in the brain. The advances in neuroimaging, especially diffusion tensor imaging (DTI), enable the identification and characterization of white matter fibers. In this work, we propose a system based on DTI analysis of the visual pathway fibers in the optic radiation for detecting and discriminating different glaucoma entities. The optic radiation is identified semi-automatically. DTI provides information about the fiber orientation as well as a set of derived parameters describing the degree of diffusion anisotropy and diffusivity. Features for each DTI derived measure are extracted from a specified region of interest on the optic radiation. The features are grouped into three sets: Histogram, co-occurrence matrices, and Laws features. For feature selection, the features are ranked using a support vector machine classifier. The highest ranked features are used for classification. A support vector machine classifier is used for classification in a 10-fold cross validation setup. The system is applied to three age-matched subjects' categories containing 27 healthy, 39 primary open angle glaucoma (POAG), and 18 normal tension glaucoma (NTG) subjects. The discrimination accuracy between healthy and glaucoma (POAG and NTG) subjects is 94.1% with an area under the ROC of 0.97. Classification accuracy of 92.4% is obtained for the normal and the POAG groups while it increased to 100% in case of healthy and NTG groups. In addition, the system could differentiate between glaucoma types (POAG and NTG) with an accuracy of 98.3%. A complementary analysis was performed to estimate the selection bias in the obtained accuracy. The bias ranged from 10% to 20% depending on the group pair under consideration. The classification results indicate the high performance of the system compared to retina-based glaucoma detection systems. The proposed approach utilizes visual pathway analysis rather than the conventional eye analysis which presents a new trend in glaucoma detection. Analyzing the entire visual system could provide significant information that can improve the glaucoma examination flow and treatment.

DTI parameters of axonal integrity and demyelination of the optic radiation correlate with glaucoma indices.

BACKGROUND: In glaucoma, damage of retinal ganglion cells may continue to the linked optic radiations. This study investigates the correlation of glaucoma severity indicators with parameters of axonal and myelin integrity of the optic radiations. METHODS: In this observational case-control study, 13 patients with normal-tension glaucoma, 13 patients with primary open-angle glaucoma, and seven control subjects (mean age, 57.6 ± 12.5 years) were randomly selected for diffusion tensor imaging (DTI) of the optic radiations. The results of the frequency doubling test (FDT) and the HRT-based linear discriminant functions of Burk (BLDF) and Mikelberg (MLDF) were correlated with the mean of the fractional anisotropy (FA), apparent diffusion coefficient (ADC), and radial diffusivity (RD) of the optic radiations. Multiple correlation analysis, corrected for age, stage of cerebral microangiopathy, diagnosis group, and gender was conducted at increasing thresholds of linear anisotropy (C(L)) to reduce mismeasurements because of complex fiber situations. RESULTS: The best correlations were found for BLDF with FA at C(L) threshold 0.3 (0.594, p = 0.001), with ADC at C(L) 0.4 (-0.511, p = 0.005), and with RD at C(L) 0.4 (-0.585, p = 0.001). MLDF correlated with FA at C(L) 0.4 (0.393, p = 0.035). The FDT score correlated with FA at C(L) 0 (-0.491, p = 0.007) and with RD at C(L) 0 (-0.375, p = 0.045). CONCLUSIONS: In glaucoma, DTI-derived parameters of the axonal integrity (FA, ADC) and demyelination (RD) of the optic radiation are linked to HRT-based indices of glaucoma severity and to impairment of the spatial-temporal contrast sensitivity.

A framework for voxel-based morphometric analysis of the optic radiation using diffusion tensor imaging in glaucoma.

Glaucoma is an optic neuropathy affecting the entire visual system. The understanding of the glaucoma mechanism and causes remains unresolved. Diffusion tensor imaging (DTI) has been used to analyze the optic nerve and optic radiation showing global fiber abnormalities associated with glaucoma. Nevertheless, the complex structure of the optic radiation and the limitations of DTI make the localization of the glaucoma effect a difficult task. The aim of this work is to establish a framework for the determination of the local changes of the optic radiation due to glaucoma using DTI. The proposed system utilizes a semiautomated algorithm to produce an efficient identification of the optic radiation. Segmented optic radiations are transformed to a unified space using shape-based nonrigid registration. Using the deformation fields that resulted from the registration, the maps of the diffusion tensor-derived parameters are transformed to the unified space. This allows for statistical voxel-wise analysis to produce significant abnormality maps. The proposed system is applied to a group of 13 glaucoma patients and a normal control group of 10 subjects. The groups are age matched to eliminate the age effect on the analysis. Diffusion-related parameters (axial, radial and mean diffusivities) and an anisotropy index (fractional anisotropy) are studied. The anisotropy analysis indicates that the majority of the significant voxels show decreased fractional anisotropy in the glaucoma patients compared with the control group. In addition, the significant regions are mainly distributed in the middle (in reference to anterior-posterior orientation) of the optic radiation. Glaucoma subjects have increased radial diffusivity and mean diffusivity significant voxels with a main concentration in the proximal part of the right optic radiation. The proposed analysis provides a framework to capture the significant local changes of the optic radiation due to glaucoma. The preliminary analysis suggests that the glaucomatous optic radiation may suffer from localized white matter degeneration. The framework facilitates further studies and understanding of the pathophysiology of glaucoma.

The papilla as screening parameter for early diagnosis of glaucoma.

INTRODUCTION: In the industrialized countries 67 million people suffer from glaucoma, which represents the third most common cause of blindness and thus has a high economic impact. Early diagnosis of glaucoma, which does not necessarily involve raised intraocular pressure, is essential because by the time the patient notices functional impairment the damage is irreversible. Early treatment can decrease the rate of blindness 20 years later by about 50%. METHODS: Selective literature review and clinical investigation of early glaucoma detection and of screening methods. RESULTS: Currently, no evidence-based recommendations for glaucoma screening can be found in the literature. No single method or combination of screening procedures can be recommended unambiguously on economic grounds. DISCUSSION: From the clinical perspective sensitive, specific, and cost-effective glaucoma screening seems feasible. The high-risk group would need to be defined on the basis of age and family history. A two-stage screening process would then have to be established with initial computer-supported telemedical sorting followed by telemedical ophthalmological diagnosis of cases selected for clarification.

Fourier analysis of the envelope of the ophthalmic artery blood flow velocity: age- and blood pressure related impact.

The harmonic content of the envelope waveform of the blood flow velocity in the ophthalmic artery was analyzed in aging and arterial hypertension. The case-control study enrolled 98 healthy men (age: 44.0+/-15.6 years), 100 healthy women (age: 44.5+/-19.1 years), which is group 1, and overall 199 hypertensive patients with increased systolic and diastolic blood pressure (in millimeters of mercury) before registration of the blood flow velocity using pulsed Doppler sonography. Group 2 was sufficiently treated (140/140/>90) were insufficiently treated, and group 4 (>140/140/>90) were untreated. Cronbach-alpha reliability of the calculated spectral coefficient and SI (SI) was 0.88 and 0.93, respectively. In control subjects, the SI was influenced by age (men: 45.1%; women: 50.2%; P<0.001 each) and in women additionally by mean arterial pressure (13.1%; P<0.001). The SI differed in subjects >43 years of age (men: 0.37+/-0.11; women: 0.26+/-0.08; P<0.001 each) as compared with subjects

Morphometric age-related evaluation of small retinal vessels by scanning laser Doppler flowmetry: determination of a vessel wall index.

BACKGROUND: Measurement of the retinal vessel wall thickness may contribute to the diagnosis of microvascular diseases. We present a methodical approach to calculate these alterations and to determine age-related differences. METHODS: One hundred fifty-three subjects without eye or internal diseases (mean age +/- SD, 47.6 +/- 14.9 years) underwent measurement of the retinal temporal superior artery and vein by scanning laser Doppler flowmetry (Heidelberg retina flowmeter). We calculated the difference between the diameter of reflectivity and the Doppler signal (Delta[VD-FD]/2) and determined a "vessel wall index" (VWI) by normalization of Delta(VD-FD)/2 for age and vessel diameter. RESULTS: Delta(VD-FD)/2 correlated with vessel diameter (artery, r = +0.60, P < 0.001; vein, r = +0.49, P<0.001) and age (artery, r = +0.19, P = 0.02; vein, r = +0.27, P = 0.001) but not with sex, if controlled for the other variables each. The venous, but not the arterial, vessel diameter correlated with age (r = +0.18, P = 0.02), if controlled for sex. The relative statistical weight of these empirical contributions to the variation observed in Delta(VD-FD)/2 was 36.5% (P < 0.001, artery) and 21.7% (P< 0.001, vein), and that of age was 3.6% (P = 0.02, artery) and 7.3% (P = 0.001, vein). The limit value of VWI to pathologic changes (80th percentile) was 1.25 microm/y (artery) and 1.31 microm/y (vein). Delta(VD-FD)/2 normalized for vessel diameter correlated with the 10-year categories of age (artery, r = +0.196, P = 0.017; vein, r = +0.250, P = 0.002). CONCLUSION: In a group of subjects aged 21 years to 70 years, we detected an increase of Delta(VD-FD)/2 in the retinal temporal superior artery and vein with age.

Nimodipine plasma concentration and retinal blood flow in healthy subjects.

PURPOSE: Calcium antagonists are strong vasodilators, and nimodipine is known to improve cerebral blood flow. The purpose of this study was to measure retinal blood flow and nimodipine plasma concentrations during repeated oral dosing. METHODS: In a double-blind, two-way, crossover study, 20 healthy subjects (mean age, 22.8 +/- 3.7 years) underwent examination of retinal perfusion and nimodipine plasma concentrations. In a placebo-controlled fashion, nimodipine was orally administered at a dosage of 30 mg three times a day for two periods of 5 days including a 9-day washout interval. At days 1, 5, 15, and 19, plasma concentrations of nimodipine and retinal perfusion were measured 11 times within 3 hours. Stereoselective analysis of nimodipine plasma concentrations was performed with the use of liquid chromatography-tandem mass spectrometry. Scanning laser Doppler flowmetry was used to measure the microcirculation of the juxtapapillary retina. Perfusion images were evaluated with the automatic full-field evaluation procedure (AFFPIA). RESULTS: Areas under the plasma concentration versus time curves were similar at day 1 and day 5 of nimodipine administration (t test: P = 0.64). Values of C(max) displayed a large interindividual variance and ranged from 0 ng/mL to 57.5 ng/mL. On average, maximum nimodipine plasma concentrations (C(max)) were 16.6 +/- 14.9 ng/mL and 12.0 +/- 10.3 ng/mL at day 1 and day 5, respectively (P = 0.068). They were observed at 81 +/- 50 and at 93 +/- 40 minutes (t(max)) after the administration of nimodipine at day 1 and day 5, respectively (P = 0.43). Retinal microcirculation was greater after nimodipine than after placebo, as reflected in significantly larger areas under the curves of percentage change in blood flow from baseline versus time (P < 0.01). The maximum increase of retinal blood flow from baseline was significantly more pronounced after nimodipine (28.5% +/- 14.4% and 39.6% +/- 21.4% at day 1 and day 5, respectively) than after placebo (20.5% +/- 16.8% and 31.9% +/- 14.6% at day 1 and day 5, respectively; P = 0.032). CONCLUSIONS: Oral nimodipine significantly increases retinal perfusion in healthy subjects.

Effect of nos inhibition on retinal arterial and capillary circulation in early arterial hypertension.

BACKGROUND: Arterial hypertension is involved in the pathogenesis of end organ damage by influencing the ability of the vascular endothelium to produce nitric oxide (NO). This study analyzes changes of retinal and systemic NO-dependent circulation parameters by inhibiting nitric oxide synthase (NOS) in both hypertensive and normotensive individuals. METHODS: In a double-blind crossover trial, 19 hypertensive patients (H, age 28.2 +/- 0.9 years) and 19 normotensive controls (N, age 26.9 +/- 0.9 years) were randomized treated either with candesartan or placebo. Both retinal capillary flow (RCF) and mean blood flow velocity of the central retinal artery (VCRA) were registered before and after NOS inhibition with N-monomethyl-L-arginine (L-NMMA, 3 mg/kg). In a subpopulation mean arterial pressure (MAP), cardiac output (CO), and the total peripheral resistance (TPR) were determined simultaneously. RESULTS: Changes from baseline: In normotensive and hypertensive subjects infusion of L-NMMA led to an increase of MAP (N, +13.3 +/- 1.8%, P < 0.01; H, +14.3 +/- 2.4%, P < 0.01) and TPR (N, +36.9 +/- 3.8%, P < 0.01; H, +45.0 +/- 4.5%, P < 0.01), and to a decrease of CO (N, -21.1 +/- 1.5%, P < 0.01; H, -24.6 +/- 2.3%, P < 0.01). The L-NMMA effect on VCRA and RCF differed between controls and hypertensives. VCRA changed by + 17.3 +/- 6.2% (P < 0.05) and RCF by -7.3 +/- 3.0% (P < 0.05) in controls. In hypertensive subjects corresponding results were + 9.5 +/- 5.2% (P = NS) and + 2.7 +/- 3.8% (P = NS), respectively. The decrease of RCF due to L-NMMA was reduced in hypertension as compared to controls (P < 0.05). The calculated cross-sectional area of CRA was reduced by -58.7% in controls and increased by + 31.1% in hypertensive subjects. There was no significant correlation between the flow in the systemic and retinal circulation. CONCLUSION: Only normotensives L-NMMA induces an acceleration of VCRA due to a probable vasoconstriction of the central retinal artery and despite of a reduced RCF. Already in early hypertension the NOS-dependent vascular tone in retinal arteries and capillaries is impaired. The regulation of the retinal capillary flow appeared to be independent from systemic circulation.

Expression of the serine/threonine kinase hSGK1 in chronic viral hepatitis.

The human serine/threonine kinase hSGK1 is expressed ubiquitously with highest transcript levels in pancreas and liver. This study has been performed to determine the hSGK1 distribution in normal liver and its putative role in fibrosing liver disease. HSGK1-localization was determined by in situ hybridization, regulation of hSGK1-transcription by Northern blotting, fibronectin synthesis and hSGK1 phosphorylation by Western blotting. In normal liver hSGK1 was mainly transcribed by Kupffer cells. In liver tissue from patients with chronic viral hepatitis, hSGK1 transcript levels were excessively high in numerous activated Kupffer cells and inflammatory cells localized within fibrous septum formations. HSGK1 transcripts were also detected in activated hepatic stellate cells. Accordingly, Western blotting revealed that tissue from fibrotic liver expresses excessive hSGK1 protein as compared to normal liver. TGF-beta1 (2 ng/ml) increases hSGK1 transcription in both human U937 macro-phages and HepG2 hepatoma cells. H(2)O(2) (0.3 mM) activated hSGK1 and increased fibronectin formation in HepG2 cells overexpressing hSGK1 but not in HepG2 cells expressing the inactive mutant hSGK1(K127R). In conclusion hSGK1 is upregulated by TGF-beta1 during hepatitis and may contribute to enhanced matrix formation during fibrosing liver disease.