Ocular Brachytherapy (Interventional Radiotherapy): Preserving the Vision.

Uveal melanoma represents the most common intraocular neoplasia among adults. Brachytherapy (interventional radiotherapy; IRT) has a great advantage, when compared with enucleation, both in terms of organ and function sparing. The Collaborative Ocular Melanoma Study introduced into clinical practice a standardised procedure that allowed the equivalence of IRT with enucleation in terms of overall survival to be demonstrated. IRT is carried out by placing a plaque in direct contact with the sclera under the uveal melanoma. Several radioactive sources may be used, including 106-ruthenium, 125-iodine, 103-palladium and 90-strontium. It is a multidisciplinary procedure requiring the collaboration of interventional radiation oncologists and ophthalmologists in the operating theatre and medical physicists for an accurate treatment time calculation. It also relies on ultrasound imaging to identify the lesion and verifiy the correct plaque placement. An emerging tool of paramount importance could be the use of artificial intelligence and predictive models to identify those patients at higher risk of developing late side-effects and therefore who may deserve preventive and supportive therapies.

The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation.

UNLABELLED: ESSENTIALS: The lectin pathway's MASP-1/2 activates coagulation factors but the trigger of the activation is unknown. MASP-1/2 activation was assessed by quantifying complexes between MASPs and antithrombin/C1-inhibitor. Activated platelets and fibrin were demonstrated to activate MASP-1 and MASP-2 both in vitro and in vivo. These findings may represent a crossroad between the complement and the coagulation systems. BACKGROUND: The activated forms of the complement lectin pathway (LP) proteases MASP-1 and MASP-2 are able to cleave the coagulation factors prothrombin, fibrinogen, factor XIII and thrombin-activatable fibrinolysis inhibitor in vitro. In vivo studies also show that MASP-1 is involved in thrombogenesis. OBJECTIVES: To clarify the not yet identified mechanisms involved in triggering activation of the LP during thrombotic reactions. METHODS: Novel sandwich-ELISAs for detection of complexes between MASP-1 or MASP-2 and the serpins C1 inhibitor (C1-INH) or antithrombin (AT), were used to specifically detect and quantify the activated forms of MASP-1 and MASP-2. RESULTS: Activated platelets were shown by flow cytometry to bind Ficolin-1, -2 and -3 but not MBL, which was associated with activation of MASP-1 and MASP-2. We also demonstrated that fibrin and the plasmin-generated fibrin fragment DD in plasma, bind and activate MASP-1 and MASP-2. As demonstrated by the ELISA and SDS-PAGE/Western blotting, the fibrin-associated activation was reflected in a specific inactivation by AT during clotting without the assistance of heparin. In all other cases the MASPs were, as previously reported, inactivated by C1-INH. In systemic lupus erythematosus patients with thrombotic disease and in polytrauma patients, the levels of activated MASP-1 and MASP-2 in complex with both AT and C1-INH were associated with markers of thrombotic disease and contact/coagulation system activation. CONCLUSIONS: MASP-1 and MASP-2 are activated during blood clotting. This activation is triggered by activated platelets and by the generation of fibrin during thrombotic reactions in vitro and in vivo, and may represent a novel activation/amplification mechanism in thromboinflammation.

Pentraxin-3 level at admission is a strong predictor of short-term mortality in a community-based hospital setting.

BACKGROUND: The pattern recognition molecule pentraxin-3 (PTX3) is a novel potential marker of prognosis, as elevated levels are associated with both disease severity and mortality in patients with a wide range of conditions. However, the usefulness of PTX3 as a prognostic biomarker in a general hospital setting is unknown. PATIENTS AND METHODS: The study cohort consisted of 1326 unselected, consecutive patients (age >40 years) admitted to a community hospital in Copenhagen, Denmark. Patients were followed until death or for a median of 11.5 years after admission. The main outcome measure was all-cause mortality. Serum samples collected from patients at admission and from 192 healthy control subjects were quantified for PTX3 level by enzyme-linked immunosorbent assay. RESULTS: PTX3 was elevated in patients (median 3.7 ng mL(-1) , range 0.5-209.8) compared with healthy nonhospitalized subjects (median 3.5 ng mL(-1) , range 0.0-8.3; P = 0.0003). Elevated PTX3 levels, defined as above the 95th percentile of the concentration in healthy subjects, were associated with increased overall mortality during the study (P < 0.0001). This increase in mortality was greatest in the short term, with an unadjusted hazard ratio (HR) of 6.4 [95% confidence interval (CI) 3.8-11.0] at 28 days after admission, compared to 1.7 (95% CI 1.4-2.0) at the end of follow-up. These results were still significant after adjustment for age, gender and glomerular filtration rate: adjusted HR of 5.0 (95% CI 2.9-8.8) and 1.4 (95% CI 1.2-1.8), respectively. CONCLUSION: These results suggest that PTX3 could be a widely applicable marker of short-term mortality in hospitalized patients and may be useful in the initial risk stratification.

Heparin-coated cardiopulmonary bypass circuits selectively deplete the pattern recognition molecule ficolin-2 of the lectin complement pathway in vivo.

The complement system can be activated via the lectin pathway by the recognition molecules mannose-binding lectin (MBL) and the ficolins. Ficolin-2 exhibits binding against a broad range of ligands, including biomaterials in vitro, and low ficolin-2 levels are associated with increased risk of infections. Thus, we investigated the biocompatibility of the recognition molecules of the lectin pathway in two different types of cardiopulmonary bypass circuits. Bloods were drawn at five time-points before, during and postoperatively from 30 patients undergoing elective cardiac surgery. Patients were randomized into two groups using different coatings of cardiopulmonary bypass circuits, Phisio® (phosphorylcholine polymer coating) and Bioline® (albumin-heparin coating). Concentrations of MBL, ficolin-1, -2 and -3 and soluble C3a and terminal complement complex (TCC) in plasma samples were measured. Ficolin-3-mediated complement activation potential was evaluated with C4, C3 and TCC as output. There was no significant difference between the two circuit materials regarding MBL, ficolin-1 and -3. In the Bioline® group the ficolin-2 levels decreased significantly after initiation of surgery (P < 0.0001) and remained reduced throughout the sampling period. This was not seen for Phisio®-coated circuits. Ficolin-3-mediated complement activation potential was reduced significantly in both groups after start of operation (P < 0.0001), whereas soluble C3a and TCC in the samples were increased (P < 0.0001). Ficolin-2 was depleted from plasma during cardiac surgery when using heparin-coated bypass circuits and did not reach baseline level 24 h postoperation. These findings may have implications for the postoperative susceptibility to infections in patients undergoing extracorporeal circulation procedures.

The lectin pathway of complement: advantage or disadvantage in HIV pathogenesis?

The pattern recognition molecules of the lectin complement pathway are important components of the innate immune system with known functions in host-virus interactions. This paper summarizes current knowledge of how these intriguing molecules, including mannose-binding lectin (MBL), Ficolin-1, -2 and -3, and collectin-11 (CL-11) may influence HIV-pathogenesis. It has been demonstrated that MBL is capable of binding and neutralizing HIV and may affect host susceptibility to HIV infection and disease progression. In addition, MBL may cause variations in the host immune response against HIV. Ficolin-1, -2 and -3 and CL-11 could have similar functions in HIV infection as the ficolins have been shown to play a role in other viral infections, and CL-11 resembles MBL and the ficolins in structure and binding capacity.

Complement activation and its prognostic role in post-cardiac arrest patients.

Cardiac arrest causes generalized ischaemia/hypoxia, and subsequent resuscitation inflicts reperfusion injury, the pathology of which is not fully understood. Moreover, predicting the prognosis of comatose, post-cardiac arrest patients is a complex clinical challenge. We hypothesized that the extent of complement activation might be a reliable predictor of mortality in this population. Forty-six comatose cardiac arrest patients were enrolled into our prospective cohort study, conducted in a tertiary care university clinic. All subjects were cooled to 32-34 °C body temperature for 24 h and then allowed to rewarm to normothermia. All patients underwent diagnostic coronary angiography. On admission, at 6 and 24 h, blood samples were taken from the arterial catheter. In these, complement products (C3a, C3, C4d, C4, SC5b9 and Bb) were measured by ELISA in blood samples. Patients were followed up for 30 days; 22 patients (47.8%) died by the end of this period. We observed that complement activation (determined as the C3a to C3 ratio) was higher in non-survivors than in survivors at each time point. In the multivariate Cox regression analysis, the C3a/C3 ratio determined 24 h after the initiation of therapeutic hypothermia predicted 30-day mortality regardless of age, sex and the APACHE II score. Complement activation occurs in post-cardiac arrest patients, and its extent correlates with 30-day survival. The C3a/C3 ratio might prove useful for estimating the prognosis of comatose post-cardiac arrest patients.

Variation in FCN1 affects biosynthesis of ficolin-1 and is associated with outcome of systemic inflammation.

Ficolin-1 is a recognition molecule of the lectin complement pathway. The ficolin-1 gene FCN1 is polymorphic, but the functional and clinical consequences are unknown.The concentration of ficolin-1 in plasma and FCN1 polymorphisms in positions -1981 (rs2989727), -791 (rs28909068), -542 (rs10120023), -271 (rs28909976), -144 (rs10117466) and +7918 (rs1071583) were determined in 100 healthy individuals. FCN1 expression by isolated monocytes and granulocytes and ficolin-1 levels in monocyte culture supernatants were assessed in 21 FCN1-genotyped individuals. FCN1 polymorphisms were determined in a cohort of 251 patients with systemic inflammation. High ficolin-1 plasma levels were significantly associated with the minor alleles in position -542 and -144. These alleles were also significantly associated with high FCN1 mRNA expression. The level of ficolin-1 in culture supernatants was significantly higher in individuals homozygous for the minor alleles at positions -542 and -144. Homozygosity for these alleles was significantly associated with fatal outcome in patients with systemic inflammation. None of the other investigated polymorphisms were associated with FCN1 and ficolin-1 expression, concentration or disease outcome. Functional polymorphic sites in the promoter region of FCN1 regulate both the expression and synthesis of ficolin-1 and are associated with outcome in severe inflammation.

Monte Carlo simulation of the dose to nuclear medicine staff wearing protective garments.

The literature contains both endorsements of, and advice against, the use of protective apparel in nuclear medicine procedures. The main issues usually centre around: Whether the shielding which can be provided by a protective garment light enough to wear (0 to 0.6 mm lead equivalent at the gamma energies commonly encountered in nuclear medicine) is enough to warrant its use; and (more recently); Whether the dose enhancement behind the protective garment from electron scatter in lead is sufficient to be of concern. In this work, the Monte Carlo code EGSnrc was used to investigate the effectiveness of lead of thicknesses of 0 to 0.6 mm, in shielding staff from photons of energies of 140 and 511 keV. Furthermore, dose escalation behind the lead was investigated. Reasonable dose reductions are obtained at 140 keV with protective garments of 0.5 mm lead equivalence. This perhaps warrants their use, in certain circumstances. At 511 keV, the reduction in dose is less than 10%, and their use is probably not justified (given the weight that has to be carried) from an ALARA point of view. It should be noted here that protective garments designed for X-ray shielding will generally not have the same lead equivalence at the gamma energies used in nuclear medicine. It should also be noted that protective garments which do not contain lead do not always attenuate as much as their stated lead equivalence claims. Dose escalation does occur, but the depth of penetration of the scattered electrons beyond the exit side of the lead shielding is such that it is highly unlikely that a significant dose would be delivered to viable tissue in wearers of protective garments.

On the use of Kodak CR film for quality assurance of needle loading in I-125 seed prostate brachytherapy.

Low dose rate brachytherapy using implanted I-125 seeds as a monotherapy for prostate cancer is now in use in many hospitals. In contrast to fractionated brachytherapy treatments, where the effect of incorrect positioning of the source in one treatment fraction can be diminished by correcting the position in subsequent fractions, the I-125 seed implant is permanent, making correct positioning of the seeds in the prostate essential. The seeds are inserted into the prostate using needles. Correct configuration of seeds in the needles is essential in order to deliver the planned treatment. A comparison of an autoradiograph obtained by exposing film to the seed-loaded needles with the patient treatment plan is a valuable quality assurance tool. However, the time required to sufficiently expose Kodak XOMAT V film, currently used in this department is significant. This technical note presents the use of Kodak CR film for acquisition of the radiograph. The digital radiograph can be acquired significantly faster, has superior signal-to-noise ratio and contrast and has the usual benefits of digital film, e.g. a processing time which is shorter than that required for non-digital film, the possibility of image manipulation, possibility of paper printing and electronic storage.

The genetic variation of the human HMGB1 gene.

High-mobility group box 1 protein (HMGB1) is a nuclear DNA-binding protein, which also functions as a pleiotropic cytokine, implicated in the pathology of several different immune-mediated diseases. The purpose of this study was to examine the HMGB1 gene for putative polymorphisms in 103 healthy Caucasian Danish blood donors. A total of six polymorphisms and four mutations were identified in the HMGB1 gene. Subsequent MatInspector estimation revealed that several polymorphisms might have a potential regulatory impact on HMGB1 transcription. This study has characterized genetic variations in the HMGB1 gene locus, which may have a regulating role in the expression of HMGB1, providing the basis for molecular investigations of the HMGB1 gene in different disease settings.

The impact of FCN2 polymorphisms and haplotypes on the Ficolin-2 serum levels.

Ficolin-2 (L-ficolin), derived from the FCN2 gene, is an innate immunity pattern recognition molecule found in human serum in which inter-individual variation in serum appears to be under genetic control. To validate and extend this finding, we developed a sandwich ELISA for detection of human Ficolin-2 in serum samples and identified FCN2 genotypes with a Taq Man-based minor groove binder assay and by sequencing. Serum samples were applied to gel-permeation chromatography and fractions were analysed by an ELISA, SDS-PAGE and subsequently Western blotting. In 214 Danish blood donors, the median Ficolin-2 serum concentration was determined to 5.4 microg/ml (range: 1.0-12.2 microg/ml). An ELISA, SDS-PAGE and Western blot analysis of gel-permeation chromatography fractions showed that Ficolin-2 comprises a mixture of covalently and non-covalently linked Ficolin-2 oligomers independent of the individual genotypes. The variation in serum concentration was associated with three polymorphisms in the promoter and one polymorphism in the structural part of the FCN2 gene. Further analysis indicated that two particular alleles on the same haplotype determined a low Ficolin-2 concentration. Our results show that inter-individual variation of Ficolin-2 concentration is associated with polymorphisms in the promoter and the structural part of the FCN2 gene.

The prediction of transmitted dose distributions using a 3D treatment planning system.

Patient dose verification is becoming increasingly important with the advent of new complex radiotherapy techniques such as conformal radiotherapy (CRT) and intensity-modulated radiotherapy (IMRT). An electronic portal imaging device (EPID) has potential application for in vivo dosimetry. In the current work, an EPID has been modelled using a treatment planning system (TPS) to predict transmitted dose maps. A thin slab of RW3 material used to initially represent the EPID. A homogeneous RW3 phantom and the thin RW3 slab placed at a clinical distance away from the phantom were scanned using a CT simulator. The resulting CT images were transferred via DICOM to the TPS and the density of the CT data corresponding to the thin RW3 slab was changed to 1 g/cm3. Transmitted dose maps (TDMs) in the modelled EPID were calculated by the TPS using the collapsed-cone (C-C) convolution superposition (C/S) algorithm. A 6 MV beam was used in the simulation to deliver 300 MU to the homogenous phantom using an isocentric and SSD (source-to-surface) technique. The phantom thickness was varied and the calculated TDMs in the modelled EPID were compared with corresponding measurements obtained from a calibrated scanning liquid-filled ionisation chamber (SLIC) EPID. The two TDMs were compared using the gamma evaluation technique of Low et al. The predicted and measured TDMs agree to within 2 % (averaged over all phantom thicknesses) on the central beam axis. More than 90 % of points in the dose maps (excluding field edges) produce a gamma index less than or equal to 1, for dose difference (averaged over all phantom thicknesses), and distance-to-agreement criteria of 4 %, 3.8 mm, respectively. In addition, the noise level on the central axis in the predicted dose maps is less than 0.1 %. We found that phantom thickness changes of approximately 1 mm, which correspond to dose changes on the central beam axis of less than 0.6 %, can be detected in the predicted transmitted dose distributions.

Photoproduction of eta-mesic 3He.

The photoproduction of eta-mesic 3He has been investigated using the TAPS calorimeter at the Mainz Microtron accelerator facility MAMI. The total inclusive cross section for the reaction gamma3He-->etaX has been measured for photon energies from threshold to 820 MeV. The total and angular differential coherent eta cross sections have been extracted up to energies of 745 MeV. A resonancelike structure just above the eta production threshold with an isotropic angular distribution suggests the existence of a resonant quasibound state. This is supported by studies of a competing decay channel of such a quasibound eta-mesic nucleus into pi(0)pX. A binding energy of (-4.4+/-4.2) MeV and a width of (25.6+/-6.1) MeV is deduced for the quasibound eta-mesic state in 3He.

Long QT syndrome patients may faint due to neurocardiogenic syncope.

AIMS: Syncope in long QT syndrome (LQTS) is expected to be due to Torsades de Pointes ventricular tachycardia (TdP). Often these patients faint in situations with emotional stress. The aim of the present study was to evaluate whether neurocardiogenic syncope occurs in LQTS. METHODS AND RESULTS: Ten untreated consecutive LQTS patients (age 11-72 years, median 37.5 years, five males and five females from five different families (one KvLQT1 mutation, two HERG mutations in three families and one without established genetic background)) were examined by a head-up tilt-table test (HUT). If syncope did not occur within 25 min, the patient received 0.25 mg nitroglycerine sublingually and the HUT was continued for 20 min. Nine out of 10 patients had a positive HUT. The syncope resulted from a combined vasodepressor and bradycardiac response. There were no cases of TdP. No syncope occurred in a 42-year-old asymptomatic male LQTS patient with a borderline prolonged QTc of 0.45 s and a HERG mutation. In 11 of 21 patients referred for syncope without LQTS a positive HUT was found (P < 0.10). CONCLUSION: Syncope in LQTS can be of neurocardiogenic origin and is not necessarily due to TdP. The reason for neurocardiogenic syncope in LQTS is unknown, but involvement of the autonomic nervous system outside the heart is possible.

In-medium modifications of the pipi interaction in photon-induced reactions.

Differential cross sections of the reactions (gamma,pi(0)pi(0)) and (gamma,pi(0)pi(+/-)) have been measured for several nuclei (1H,12C, and (nat)Pb) at an incident-photon energy of E(gamma)=400-460 MeV at the tagged-photon facility at MAMI-B using the TAPS spectrometer. A significant nuclear-mass dependence of the pipi invariant-mass distribution is found in the pi(0)pi(0) channel. This dependence is not observed in the pi(0)pi(+/-) channel and is consistent with an in-medium modification of the pipi interaction in the I=J=0 channel. The data are compared to pi-induced measurements and to calculations within a chiral-unitary approach.

The reaction gammap-->pi0gamma'p and the magnetic dipole moment of the Delta+ 1232 resonance.

The reaction gammap-->pi(0)gamma'p has been measured with the TAPS calorimeter at the Mainz Microtron accelerator facility MAMI for energies between sqrt[s]=1221-1331 MeV. The cross section's differential in angle and energy have been determined for the photon gamma' in three bins of the excitation energy. This reaction channel provides access to the magnetic dipole moment of the Delta(+)(1232) resonance and, for the first time, a value of mu(Delta(+))=[2.7(+1.0)(-1.3)(stat)+/-1.5(syst)+/-3(theor)]mu(N) has been extracted.

C-reactive protein, dietary n-3 fatty acids, and the extent of coronary artery disease.

The acute-phase reactant C-reactive protein (CRP) has emerged as an independent risk factor for coronary artery disease. Experimental and clinical studies provide evidence of anti-inflammatory effects of n-3 polyunsaturated fatty acids (PUFA) derived from fish. We have studied the effect of marine n-3 PUFA on CRP levels in 269 patients referred for coronary angiography because of clinical suspicion of coronary artery disease. All patients filled out a food questionnaire regarding fish intake. The n-3 PUFA content of granulocyte membranes was determined and the concentration of CRP in serum was measured using a highly sensitive assay. The results were related to angiographic findings. CRP was significantly higher in patients with significant coronary stenoses than in those with no significant angiographic changes (p <0.001), but the CRP levels were not associated with the number of diseased vessels. Subjects with CRP levels in the lower quartile had a significantly higher content of docosahexaenoic acid (DHA) in granulocytes than subjects with CRP levels in the upper quartile (p = 0.02), and in a multivariate linear regression analysis, DHA was independently correlated to CRP (R(2) = 0.179; p = 0.003). The inverse correlation between CRP and DHA may reflect an anti-inflammatory effect of DHA in patients with stable coronary artery disease and suggest a novel mechanism by which fish consumption may decrease the risk of coronary artery disease.

Establishing a national patient information system on the internet in Denmark.

During 2000 - 2001 a pilot project is being carried out in Denmark with the aim of establishing the opportunity to look up patient information via the Internet. While this presents great opportunities, it also involves major organisational and technical challenges.

Marine n-3 fatty acids, wine intake, and heart rate variability in patients referred for coronary angiography.

BACKGROUND: Dietary n-3 polyunsaturated fatty acids (PUFAs) derived from fish may reduce the incidence of sudden cardiac death (SCD). In addition, wine drinking is suggested to have a protective effect against cardiovascular death. METHODS AND RESULTS: We included 291 patients referred for coronary angiography in whom ischemic heart disease was suspected and all of whom completed a food questionnaire regarding fish and wine intake. The n-3 PUFA composition of granulocyte membranes and of adipose tissue was measured. In addition, 24-hour heart rate variability (HRV) was analyzed. Fish intake was positively associated with the level of n-3 PUFAs in adipose tissue. Significant positive correlation coefficients were found between HRV indices and the levels of n-3 PUFAs in granulocytes. Wine intake was also significantly positively related to HRV, but the patients with the highest wine intake also had the highest intake of fish, as documented by a high n-3 PUFA content in adipose tissue. Multiple linear regression analysis revealed that traditional factors such as treatment with ss-blockers, smoking, age, and previous myocardial infarction were independently related to HRV, and furthermore that n-3 PUFAs (but not wine intake) were significantly independently associated with HRV. CONCLUSIONS: The close positive association between n-3 PUFAs and HRV in patients suspected of having ischemic heart disease may indicate a protective effect of n-3 PUFAs against SCD. This may partly explain the reduction in SCD observed in humans with a modest intake of n-3 PUFA. Wine intake was also positively correlated with HRV, but this correlation was no longer significant after controlling for the cellular level of n-3 PUFA.