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Purpose The field of online monitoring of the beam range is one of the most researched topics in proton therapy over the last decade. The development of detectors that can be used for beam range verification under clinical conditions is a challenging task. One promising possible solution are modalities that record prompt-gamma radiation produced by the interactions of the proton beam with the target tissue. A good understanding of the energy spectra of the prompt gammas and the yields in certain energy regions is crucial for a successful design of a prompt-gamma detector. Monte-Carlo simulations are an important tool in development and testing of detector concepts, thus the proper modelling of the prompt-gamma emission in those simulations are of vital importance. In this paper, we confront a number of GEANT4 simulations of prompt-gamma emission, performed with different versions of the package and different physics lists, with experimental data obtained from a phantom irradiation with proton beams of four different energies in the range 70–230 MeV. Methods The comparison is made on different levels: features of the prompt-gamma energy spectrum, gamma emission depth profiles for discrete transitions and the width of the distal fall-off in those profiles. Results The best agreement between the measurements and the simulations is found for the GEANT4 version 10.4.2 and the reference physics list QGSP_BIC_HP. Conclusions Modifications to prompt-gamma emission modelling in higher versions of the software increase the discrepancy between the simulation results and the experimental data.

Open physics 19(1), 383 - 394 (2021). doi:10.1515/phys-2021-0032, Published by de Gruyter, Berlin

Charged Particle Therapy (CPT) is a powerful radiotherapy technique for the treatment of deep-seated tumours characterized by a large dose released in the Bragg peak area (corresponding to the tumour region) and a small dose delivered to the surrounding healthy tissues. The precise measurement of the fragments produced in the nuclear interactions of charged particle beams with patient tissues is a crucial task to improve the clinical treatment plans. The FOOT (FragmentatiOn Of Target) experiment is an international project, funded by the Istituto Nazionale di Fisica Nucleare (INFN), aimed to study the dose released by the tissues and particle beams fragmentation. The target (16O, 12C) fragmentation induced by 150-400 MeV/n proton beams will be studied via the inverse kinematic approach, where 16O and 12C therapeutic beams collide on graphite and hydrocarbon target to provide the cross section on Hydrogen. A table-top detector is being developed and it includes a drift chamber as a beam monitor upstream of the target to measure the beam direction, a magnetic spectrometer based on silicon pixel and strip detectors, a scintillating crystal calorimeter able to stop the heavier produced fragments, and a ΔE detector, with TOF capability, for the particle identification. A setup based on the concept of the “Emulsion Cloud Chamber”, coupled with the interaction region of the electronic FOOT setup, will complement the physics program by measuring lighter charged fragments to extend the angular acceptance up to about 70 degrees. In this work, the experimental design and the requirements of the FOOT experiment will be discussed and preliminary results on the emulsion spectrometer tests will be presented.

One of the big challenges for proton therapy is the development of tools for online monitoring of the beam range, which are suited to operate in clinical conditions and can be included in the clinical practice. A Compton camera based on stacks of heavy scintillating fibers used for prompt-gamma imaging is a promising approach for this task. It provides full, three-dimensional information on the deposited dose distribution while showing a high detection efficiency and rate capability due to its high granularity. The investigation of the rate capability and detection efficiency of such a camera under clinical conditions by means of Geant4 simulations is presented along with the event construction algorithm. The results hint towards a very low pile-up rate in the detector and a relatively high detection efficiency, so that imaging of a single proton beam spot appears to be an achievable goal.

In a carbon ion treatment the nuclear fragmentationof both target and beam projectiles impacts on the dose releasedon the tumor and on the surrounding healthy tissues. Carbon ionfragmentation occurring inside the patient body has to be stud-ied in order to take into account this contribution. These dataare also important for the development of the range monitoringtechniques with charged particles. The production of chargedfragments generated by carbon ion beams of 115-353 MeV/ukinetic energy impinging on carbon, oxygen, and hydrogen tar-gets has been measured at the CNAO particle therapy center(Pavia, Italy). The use of thin targets of graphite (C), PMMA(C2O5H8) and polyvinyl-toluene [plastic scintillator (PS), CbHa]allowed to measure fragments production cross sections, exploit-ing a time-of-flight (ToF) technique. PS detectors have been usedto perform the ToF measurements, while LYSO crystals havebeen used for the deposited energy measurement and to performparticle identification. Cross sections have been measured at 90◦and 60◦with respect to the beam direction. The measured pro-ton, deuteron, and triton differential production cross sectionson C, O, and H, obtained exploiting the target subtraction strat-egy, are presented here as a function of the fragment kineticenergy.

IEEE transactions on radiation and plasma medical sciences : ITRPFI 4(5), 538-545 (2020). doi:10.1109/TRPMS.2020.2990651, Published by IEEE, New York, NY

Off-loading or the Orthotic approach to wheelchair seating has been used successfully to provide seating that optimizes tissue protection at the ischial tuberosities (ITs), sacrum and greater trochanters. Recent publications indicate the significance of preventing tissue compression to reduce ulcer formation. Comparative Magnetic Resonance Imaging (MRI) of individuals seated on two cushion types provides direct evidence of tissue unloading resulting in the reduction in tissue compression. Measurement of tissue compression in MRI images provides the cumulative impact of compression and shear resulting in ultimate tissue thickness documented here. In this study's application of MRI to off-loading cushions (OLC), an alternate form of tissue protection was observed. Instead of incorporating immersion and envelopment, loads were transferred from high-risk areas, such as bony prominences, to lower risk soft tissues. This method shows both shearing and compression of load bearing tissues in seated individuals with the OLC in place. Tissue thickness measurements determined by MRI analysis indicate that the OLC provides greater reduction in tissue deformation than the air cell cushion (ACC). Deformation of tissues loaded by the OLC is not significantly different from the deformations seen with the ACC. This research represents the first reported use of MRI to document the comparative off-loading capabilities of two cushions and the resultant tissue compression and ulceration risk. While MRI analysis may not be incorporated in daily cushion prescription, this paper proposes a methodology in which MRI analysis of tissue deformation on comparative cushions allows the determination of best-case cushion selection for reduction of ischial pressure ulcer (PU) risk.

Summary: Charged particle therapy exploits proton or 12C beams to treat deep-seated solid tumors. Due to the advantageous characteristics of charged particles energy deposition in matter, the maximum of the dose is released to the tumor at the end of the beam range, in the Bragg peak region. However, the beam nuclear interactions with the patient tissues induces fragmentation both of projectile and target nuclei and needs to be carefully taken into account. In proton treatments, target fragmentation produces low energy, short range fragments along all the beam range, which deposit a non negligible dose in the entry channel. In 12C treatments the main concern is represented by long range fragments due to beam fragmentation that release their dose in the healthy tissues beyond the tumor. The FOOT experiment (FragmentatiOn Of Target) of INFN is designed to study these processes, in order to improve the nuclear fragmentation description in next generation Treatment Planning Systems and the treatment plans quality. Target (16O and 12C nuclei) fragmentation induced by –proton beams at therapeutic energies will be studied via an inverse kinematic approach, where 16O and 12C therapeutic beams impinge on graphite and hydrocarbon targets to provide the nuclear fragmentation cross section on hydrogen. Projectile fragmentation of 16O and 12C beams will be explored as well. The FOOT detector includes a magnetic spectrometer for the fragments momentum measurement, a plastic scintillator for ΔE and time of flight measurements and a crystal calorimeter to measure the fragments kinetic energy. These measurements will be combined in order to make an accurate fragment charge and isotopic identification. Keywords: Hadrontherapy, Nuclear fragmentation cross sections, Tracking detectors, Scintillating detectors

In hadron therapy, the accelerated ions, interacting with the body of the patient, cause the fragmentation of both projectile and target nuclei. The fragments interact with the human tissues depositing energy both in the entrance channel and in the volume surrounding the tumor. The knowledge of the fragments features is crucial to determine the energy amount deposited in the human body, and - hence - the damage to the organs and to the tissues around the tumor target. The FOOT (FragmentatiOn Of Target) experiment aims at studying the fragmentation induced by the interaction of a proton beam (150-250 MeV/n) inside the human body. The FOOT detector includes an electronic setup for the identification of Z ≥ 3 fragments integrated with an emulsion spectrometer to measure Z ≤ 3 fragments. Charge identification by nuclear emulsions is based on the development of techniques of controlled fading of the particle tracks inside the nuclear emulsion, that extend the dynamical range of the films developed for the tracking of minimum ionising particles. The controlled fading strongly depends on temperature, relative humidity and treatment duration. In this study the performances in terms of charge separation of proton, helium and carbon particles, obtained on a batch of new emulsion films produced in Japan are reported.

The FK506 binding protein 5 gene (FKBP5) has been associated with susceptibility to pathogenic effects of childhood trauma including dissociative symptoms. This study examines the impact of maltreatment on dissociative tendencies in adolescence as moderated by theFKBP5gene. Dissociative symptoms and variation withinFKBP5were assessed in a high-risk, low socioeconomic status community sample of 279 maltreated and 171 nonmaltreated adolescents. Following the assignment of haplotypes across four single nucleotide polymorphisms (rs3800373, rs9296158, rs1360780, and rs9470080), individuals with one or more copies of the CATT haplotype (N= 230) were grouped together and compared to individuals with zero copies of this haplotype (N= 185). Analyses of covariance were conducted to test hypotheses regarding the effects of developmental timing and the chronicity of maltreatment and the CATT haplotype. We found a significant interactive effect of timing/chronicity of maltreatment and the CATT haplotype on dissociative symptoms. Among adolescents who had no copies of the CATT haplotype, dissociative symptoms were higher for chronically maltreated adolescents who had an infancy onset compared to those who were not maltreated or whose maltreatment experience was either relatively less chronic or not started in infancy. The groups did not differ significantly among subjects who carry one or more copies of the CATT haplotype.

A genome-wide methylation study was conducted among a sample of 114 infants (M age = 13.2 months, SD = 1.08) of low-income urban women with (n = 73) and without (n = 41) major depressive disorder. The Illumina HumanMethylation450 BeadChip array with a GenomeStudio Methylation Module and Illumina Custom model were used to conduct differential methylation analyses. Using the 5.0 × 10–7p value, 2,119 loci were found to be significantly different between infants of depressed and nondepressed mothers. Infants of depressed mothers had greater methylation at low methylation sites (0%–29%) compared to infants of nondepressed mothers. At high levels of methylation (70%–100%), the infants of depressed mothers were predominantly hypomethylated. The mean difference in methylation between the infants of depressed and infants of nondepressed mothers was 5.23%. Disease by biomarker analyses were also conducted using GeneGo MetaCore Software. The results indicated significant cancer-related differences in biomarker networks such as prostatic neoplasms, ovarian and breast neoplasms, and colonic neoplasms. The results of a process networks analysis indicated significant differences in process networks associated with neuronal development and central nervous system functioning, as well as cardiac development between infants of depressed and nondepressed mothers. These findings indicate that early in development, infants of mothers with major depressive disorder evince epigenetic differences relative to infants of well mothers that suggest risk for later adverse health outcomes.

A case of tuberculosis presenting as a neck lump is highlighted. Tuberculosis is on the increase. There are national and international strategies to improve the management of tuberculosis in the United Kingdom, and raising clinical awareness of tuberculosis is an important part of that strategy. Neck lumps can present in the dental setting and the differential diagnosis should include tuberculosis, with referral to an appropriate multidisciplinary team. Special tests to aid diagnosis are helpful but not completely discriminating. Tuberculosis is a notifiable disease and it must be treated by a designated specialist medical team. CPD/Clinical Relevance: Tuberculosis is a differential diagnosis for a persistent neck lump and clinicians should understand the problems of diagnosis and the importance of appropriate referral for treatment in the national and international strategy to reduce this disease.

The next awaited breakthrough in proton therapy is the inclusion of the tools for online monitoring of beam range into clinical practice. Full, three-dimensional information on the deposited dose distribution can be obtained by means of prompt gamma imaging using Compton cameras. Large gamma detection efficiency and high-rate capacity can be achieved using detectors of high granularity made of a heavy scintillator. One of the possible design options is a stack of scintillating fibers. As the overall performance of such a camera depends on the position, time and energy resolution of the fibers, we investigate those properties both experimentally in measurements with a test bench as well as via Monte Carlo simulations. The obtained results point at LYSO:Ce as the best candidate for a sensitive material of a Compton camera of the discussed type.

We present experimental investigation of cross sections for processes crucial in view of prompt-gamma imaging. The prompt-gamma rays were produced from an interaction of a proton beam with different phantom materials composed of carbon, oxygen and hydrogen. The used target setup allowed precise selection of the investigated depth in the phantom. We studied details of the dependence of prompt-gamma yields on beam energy, detection angle and elemental composition of irradiated phantom. The analysis was focused on the discrete transitions with the largest cross sections: 4.44 MeV in 12C and 6.13 MeV in 16O. The results are presented in form of profiles of the prompt-gamma yield as a function of depth. They are compared to calculations including different cross-section models. Obtained results are in agreement with the model exploiting cross-section data collected from the literature, but the comparison with the TALYS model shows discrepancies. In the latest experiment, special attention was paid to the shape of the distal fall-off. The width of that fall-off is directly linked to the resolution of prompt-gamma based methods of range verification. Preliminary results on the beam-energy dependence of this quantity are presented.

In this investigation, gene–environment–gender interaction effects in predicting child borderline personality disorder symptomatology among maltreated and nonmaltreated low-income children (N= 1,051) were examined. In the context of a summer research camp, adult-, peer-, and self-report assessments of borderline precursor indicators were obtained, as well as child self-report on the Borderline Personality Features Scale for Children. Genetic variants of the oxytocin receptor genotype and the FK506 binding protein 5 gene CATT haplotype were investigated. Children who self-reported high levels of borderline personality symptomatology were differentiated by adults, peers, and additional self-report on indicators of emotional instability, conflictual relationships with peers and adults, preoccupied attachment, and indicators of self-harm and suicidal ideation. Maltreated children also were more likely to evince many of these difficulties relative to nonmaltreated children. A series of analyses of covariance, controlling for age and ancestrally informative markers, indicated significant Maltreatment × Gene × Gender three-way interactions. Consideration of the maltreatment parameters of subtype, onset, and recency expanded understanding of variation among maltreated children. The three-way interaction effects demonstrated differential patterns among girls and boys. Among girls, the gene–environment interaction was more consistent with a diathesis-stress model, whereas among boys a differential-sensitivity interaction effect was indicated. Moreover, the genetic variants associated with greater risk for higher borderline symptomatology, dependent on maltreatment experiences, were opposite in girls compared to boys. The findings have important implications for understanding variability in early predictors of borderline personality pathology.

Adaptive behavior requires focusing on relevant tasks while remaining sensitive to novel information. In adult studies of cognitive control, cognitive stability involves maintaining robust cognitive representations while cognitive flexibility involves updating of representations in response to novel information. Previous adult research has shown that the Met allele of the COMT Val(158) Met gene is associated with enhanced cognitive stability whereas the Val allele is associated with enhanced cognitive flexibility. Here we propose that the stability/flexibility framework can also be applied to infant research, with stability mapping onto early indices of behavioral regulation and flexibility mapping onto indices of behavioral reactivity. From this perspective, the present study examined whether COMT genotype was related to 7-month-old infants' reactivity to novel stimuli and behavioral regulation. Cognitive stability and flexibility were assessed using (1) a motor approach task, (2) a habituation task, and (3) a parental-report measure of temperament. Val carriers were faster to reach for novel toys during the motor approach task and received higher scores on the temperament measure of approach to novelty. Met carriers showed enhanced dishabituation to the novel stimulus during the habituation task and received higher scores on the temperament measures of sustained attention and behavioral regulation. Overall, these results are consistent with adult research suggesting that the Met and Val alleles are associated with increased cognitive stability and flexibility, respectively, and thus suggest that COMT genotype may similarly affect cognitive function in infancy.

In the present investigation, differential methylation analyses of the whole genome were conducted among a sample of 548 school-aged low-income children (47.8% female, 67.7% Black,Mage = 9.40 years), 54.4% of whom had a history of child maltreatment. In the context of a summer research camp, DNA samples via saliva were obtained. Using GenomeStudio, Methylation Module, and the Illumina Custom Model, differential methylation analyses revealed a pattern of greater methylation at low methylation sites (n= 197 sites) and medium methylation sites (n= 730 sites) and less methylation at high methylation sites (n= 907 sites) among maltreated children. The mean difference in methylation between the maltreated and nonmaltreated children was 6.2%. The relative risk of maltreatment with known disease biomarkers was also investigated using GenoGo MetaCore Software. A large number of network objects previously associated with mental health, cancer, cardiovascular systems, and immune functioning were identified evidencing differential methylation among maltreated and nonmaltreated children. Site-specific analyses were also conducted for aldehyde dehydrogenase 2 (ALDH2), ankyrin repeat and kinase domain containing 1 (ANKK1), and nuclear receptor subfamily 3, group C, member 1 (NR3C1) genes, and the results highlight the importance of considering gender and the developmental timing of maltreatment. ForALDH2, the results indicated that maltreated girls evidenced significantly lower methylation compared to nonmaltreated girls, and maltreated boys evidenced significantly higher methylation compared to nonmaltreated boys. Moreover, early onset–not recently maltreated boys evidenced significantly higher methylation atALDH2compared to nonmaltreated boys. Similarly, children with early onset–nonrecent maltreatment evidenced significantly higher methylation compared to nonmaltreated children atANKK1. The site-specific results were not altered by controlling for genotypic variation of respective genes. The findings demonstrate increased risk for adverse physical and mental health outcomes associated with differences in methylation in maltreated children and indicate differences among maltreated children related to developmental timing of maltreatment and gender in genes involved in mental health functioning.

Depressive symptoms are prevalent and rise during adolescence. The present study is a prospective investigation of environmental and genetic factors that contribute to the growth in depressive symptoms and the frequency of heightened symptoms during adolescence. Participants included 206 mother-father-adolescent triads (M age at Time 1 = 13.06 years, SD = .51, 52% female). Harsh parenting was observationally assessed during a family conflict paradigm. DNA was extracted from saliva samples and genotyped for the 5-HTTLPR and BDNF Val66Met polymorphisms. Adolescents provide self-reports of depressive symptoms annually across early adolescence. The results reveal Gene × Environment interactions as predictors of adolescent depressive symptom trajectories in the context of harsh parenting as an environmental risk factor. A BDNF Val66Met × Harsh Parenting interaction predicted the rise in depressive symptoms across a 3-year period, whereas a 5-HTTLPR × Harsh Parenting interaction predicted greater frequency in elevated depressive symptoms. The findings highlight the importance of unique genetic and environmental influences in the development and course of heightened depressive symptoms during adolescence.

Background and objectives: Hemodialysis (HD) per se entails vascular dysfunction in patients with ESRD. Endothelial dysfunction is a key step in atherosclerosis and is characterized by impaired flow–mediated dilation (FMD). Interventional studies have shown that cocoa flavanol (CF)–rich supplements improve vascular function. Aim of this study was to investigate the effect of flavanol–rich bioactive food ingredients on acute and chronic HD–induced vascular dysfunction in ESRD. Design, setting, participants, & measurements: We conducted a randomized, double–blind, placebo–controlled trial from 2012 to 2013. Fifty-seven participants were enrolled, ingested CF-rich beverages (900 mg CF per study day), and were compared with those ingesting CF-free placebo. This included (1) a baseline cross–over acute study to determine safety and efficacy of CF and (2) a subsequent chronic parallel group study with a 30-day follow-up period to study effects of CF on HD–mediated vascular dysfunction entailing (3) an acute substudy during HD in flavanol-naive patients and (4) an acute on chronic study during HD. Primary and secondary outcome measures included changes in FMD and hemodynamics. Results: CF ingestion was well tolerated. Acute ingestion improved FMD by 53% (3.2±0.6% to 4.8±0.9% versus placebo, 3.2±0.7% to 3.3±0.8%; P

Background: The activity of the protein kinase Akt is frequently dysregulated in cancer and is an important factor in the growth and survival of tumour cells. Akt activation involves the phosphorylation of two residues: threonine 308 (Thr308) in the activation loop and serine 473 (Ser473) in the C-terminal hydrophobic motif. Phosphorylation of Ser473 has been extensively studied in tumour samples as a correlate for Akt activity, yet the phosphorylation of Thr308 or of downstream Akt substrates is rarely assessed. Methods: The phosphorylation status of Thr308 and Ser473 was compared with that of three separate Akt substrates – PRAS40, TSC2 and TBC1D4 – in fresh frozen samples of early-stage human non-small cell lung cancer (NSCLC). Results: Akt Thr308 phosphorylation correlated with the phosphorylation of each Akt substrate tested, whereas Akt Ser473 phosphorylation did not correlate with the phosphorylation of any of the substrates examined. Conclusion: The phosphorylation of Thr308 is a more reliable biomarker for the protein kinase activity of Akt in tumour samples than Ser473. Any evaluation of the link between Akt phosphorylation or activity in tumour samples and the prediction or prognosis of disease should, therefore, focus on measuring the phosphorylation of Akt on Thr308 and/or at least one downstream Akt substrate, rather than Akt Ser473 phosphorylation alone.

Continuous venovenous haemofiltration (CVVH) in the intensive care setting requires anticoagulation to prevent clotting of the extracorporeal circuit. Several protocols avoiding heparin and using regional citrate anticoagulation have been developed to diminish bleeding risks. However, data from randomized trials comparing citrate anticoagulation with systemic heparinization are very limited.One hundred and seventy-four patients on mechanical ventilation, requiring renal replacement therapy for acute renal failure, were included in this prospective randomized multicentre trial comparing regional citrate with systemic heparin. The study was performed at nine different intensive care units at university or academic teaching hospitals. The participants were randomized to either CVVH using regional citrate anticoagulation or CVVH using systemic anticoagulation with unfractionated heparin. The primary outcome was to compare treatment efficacy represented by the patients' acid base status on Day 3 and on each consecutive day. Several parameters of safety and efficacy were analysed as secondary outcomes.Comparison of standard bicarbonate from Day 3 to Day 11 revealed no difference between both treatment modalities. Use of citrate resulted in less systemic anticoagulation, a lower risk of bleeding and a longer haemofilter patency. Episodes of hypercalcaemia, hypocalcaemia and the need for additional bicarbonate infusions occurred more often under citrate. The patients' high mortality was not influenced by the mode of anticoagulation.Citrate may be used as a regional anticoagulant and the only buffering agent in CVVH with adequate treatment efficacy and safety. However, neither citrate nor heparin anticoagulation should be regarded as a therapeutic standard, since there is no advantage of one of these substances with regard to patient mortality.

After the introduction of steroid sparing immunosuppressive protocols, osteonecrosis of the hip has become a rare entity in renal transplantation. Instead, an elusive bilateral pain syndrome of the distal extremities has gained more clinical attention. Because of the typical presentation, it is sometimes referred to as 'post-transplant distal limb syndrome' (PTDLS). The syndrome typically manifests during the first year after transplantation and may lead to significant morbidity because of pain induced immobilization. On MRI-scans, a characteristic bilateral patchy osteoedema can be demonstrated. The etiology of PTDLS has not been determined definitely so far. Over the last 8 years, we have seen the syndrome in 37 out of 639 renal transplant patients (5.8%). There was no association to steroid-medication, age, gender, PTH levels or delayed graft function. As an important finding, we saw a significant rise in alkaline phosphatase from 160 +/- 54 to 271 +/- 108 U/l (P = 0.001) and calcium from 2.46 +/- 0.18 to 2.58 +/- 0.18 mmol/l (P = 0.013) preceding the onset of pain by several weeks. Mean duration of clinical symptoms was 5.1 +/- 3.1 months; however, all patients experienced remission without signs of chronic damage on long-term follow up.

Data on 64 rejection reactions in 108 consecutive patients after renal transplantation (61 males, 47 females; mean age 42.8 +/- 12.9 years) were analysed to test what Doppler sonographic measurements can be used to predict whether a given drug regimen is able to suppress rejection. Results were compared with renal function and histological evidence of rejection. The >> pulsatility index << (PI), which is dependent on flow resistance, was determined by Doppler echocardiography: it increases on rejection (measurements made 2.0 +/- 1.1 days apart). The rejection reaction was successfully controlled by drugs (methylprednisolone, azathioprine and cyclosporin) in 44 patients (group 1), but not in 20 patients (group 2). PI before rejection (group 1: 1.8 +/- 0.5; group 2: 1.7 +/- 0.6), PI during histologically confirmed rejection (2.6 +/- 1.2 and 3.1 +/- 1.4, respectively), the size of difference between these values, and parameters of renal function provided no pointers to any drug efficacy in suppressing rejection. But individual changes in PI during suppression treatment proved to be of outstanding value (P < 0.00005). Signs of florid rejection at the end of treatment period correlated with a rising PI in 13 of 17 rejection episodes, while PI fell in only 7 of 47 episodes. Vascular signs of rejection tended to be poor predictors of rejection (P .028). - These findings indicate that serial Doppler sonography can be helpful in monitoring antirejection treatment.

Plasma exchange is a therapeutic procedure commonly used in various neurological disorders. Here we review its current role as a treatment option in diseases of the central and peripheral nervous system.

Background: Different methods of regional anticoagulation using citrate in continuous hemofiltration have been described. To date, only such surrogate parameters as pH, anion gap, total calcium concentration, or total calcium-ionized calcium ratio have been proposed to reflect increased plasma citrate levels and thus risk for side effects. However, none of these parameters has been correlated with plasma citrate levels in critically ill patients. Methods: Sixteen patients were treated with continuous venovenous hemofiltration (CVVH) and citrate anticoagulation for a mean of 13 ± 9 days. Citrate levels were measured every other day, and correlations were calculated with the mentioned parameters. Results: Steady-state citrate levels on treatment day 3 were 16.39 ± 15.77 mg/dL (range, 2.63 to 73.49 mg/dL [853 ± 821 μmol/L; range, 137 to 3825 μmol/L]). The highest correlation was found between citrate plasma level and total calcium-ionized calcium ratio ( R = 0.85; P R = −0.15) and anion gap ( R = 0.36) were not helpful in estimating citrate plasma levels in patients treated with citrate-CVVH. Conclusion: Calculating total calcium-ionized calcium ratio is a simple tool that correlates best with citrate plasma levels. We recommend close monitoring of this parameter in all patients administered high doses of citrate as part of regional anticoagulation protocols.

Die diabetische Nephropathie geht mit einer exzessiven Erhohung der kardiovaskularen Morbiditat und Mortalitat betroffener Patienten einher. Der Pravention beziehungsweise der Progressionsverzogerung kommt daher eine enorme klinische Bedeutung zu. Neben der intensiven Hyperglykamiekontrolle ist vor allem die antihypertensive Therapie mit Zielblutdruckwerten

Tubulointerstitial nephritis caused by polyomavirus of the subtype BK (BK virus nephropathy, BKN) is an important cause of deterioration of renal allograft function after kidney transplantation. In 3 cases of BKN diagnosed at our center, the suspected diagnosis made on the basis of urine cytology and serum PCR was confirmed by electron microscopy and immunohistology of the renal graft biopsy. In 1 patient, stable renal function without further virus detection was seen after reduction of the immunosuppression. In 2 further patients there was loss of graft function. BKN is an important differential diagnosis of unclear deterioration of renal graft function. The risk is particularly high with use of tacrolimus and mycophenolate mofetil (MMF). Urine cytology and serum PCR are suitable screening tests, histology provides conclusive evidence. The only therapeutic option available at present is reduction of immunosuppressive therapy.

The question about the most appropriate non-invasive method for detecting a renal artery stenosis (RAS) when comparing contrast enhanced magnetic resonance angiography (MRA) and color Doppler sonography (CDS) is still under discussion. Therefore we conducted a prospective study in order to evaluate both methods as compared to digital subtraction angiography (DSA).Thirtysix consecutive patients (53,9 +/- 13,7 years) with suspected RAS were investigated. MRA was performed using gadolinium for contrast enhancement. CDS was performed using a 2.5 and 3,5 MHz transducer. A peak systolic velocity (Vmax)200 cm/sec within renal arteries and/or a side to side difference of the resistive index (RI) of0,05 were used to discriminate stenosis. A diameter reduction ofor = 60% by DSA was considered a stenosis relevant to the patient.Sixty-eight main renal arteries and 9 accessory vessels were detected by DSA. Twenty main and 3 accessory arteries were found to be stenosedor = 60%, while 4 main and 1 accessory artery presented with occlusion. MRA detected 70 renal vessels (65 main and 5 accessory arteries). Twenty-one stenosed arteries and 4 occluded vessels were correctly diagnosed by MRA. With CDS 68 renal vessels (62 main and 6 accessory arteries) could be visual- ized out of which 21 stenoses were diagnosed because of increased Vmax and 6 stenoses were detected because of a side to side difference of RI. For main renal arteries sensitivities and specificities were 96% and 86% for MRA and 96% and 89% for CDS.MRA and CDS are both comparable methods for detection of a renal artery stenosisor = 60%. Despite several limitations, CDS can at the moment still be favored as a screening method.

Assessment of intrarenal doppler signals is of particular importance in screening for renal artery stenosis. We studied the effect of acute ACE-inhibition (1,25 mg enalaprilate i.v.) on intrarenal resistive indices in 10 hypertensive patients with unilateral renal artery stenosis versus 10 patients with essential hypertension. Any changes limited to poststenotic vessels could possibly improve the diagnostic value of duplex sonography. After ACE-inhibition a significant fall of the intrarenal Resistive Index occurred in both patient groups. In cases of unilateral renal artery stenosis we saw a tendency to an increased side difference of the Resistive Index due to a greater fall on the poststenotic side. Therefore a clear advantage of duplex scanning after acute ACE-inhibition due to a limited effect of enalaprilate on poststenotic vessels was not found. The results suggest that the vascular resistance and not only the degree of renal artery stenosis is of significance for the characteristics of the doppler signal.

Background Patients with end-stage renal disease (ESRD) show a high prevalence of cardiovascular disease with arterial stiffness, atherosclerosis and endothelial dysfunction, leading to increased morbidity and mortality. The cytokine macrophage migration inhibitory factor (MIF) exhibits proinflammatory and proatherogenic functions and has recently emerged as a major regulator of atherogenesis. Studies examining the relationship between circulating MIF levels and vascular dysfunction in this high-risk population do not exist. Methods In patients with ESRD ( n =39) and healthy controls ( n =16) we assessed endothelial function by flow-mediated dilation of the brachial artery and arterial stiffness (augmentation pressure, augmentation index and pulse pressure) using applanation tonometry. High-sensitive Troponin and subendocardial viability ratio were determined to assess myocardial injury. Results Patients with ESRD had impaired endothelial function and higher plasma MIF levels. MIF levels negatively correlated with endothelial function ( r =−0.345, P =0.031) and positively with arterial stiffness indices in patients with ESRD (pulse pressure r =−0.374, P =0.019 and augmentation pressure r =−0.423, P =0.025). In multivariate regression models besides age, gender, weight, and heart rate, MIF was an independent predictor for arterial stiffness. Impact on myocardial end-organ damage was reflected by correlation with high-sensitive Troponin I ( r =0.43, P =0.009). Conclusion Our findings show that high MIF plasma levels are associated with diminished endothelial function and arterial stiffness and are correlated with myocardial injury. Further studies are necessary to investigate whether modulation of MIF might have an impact on atherosclerotic disease in this high-risk population.

Wir prasentieren den Fall eines 51-jahrigen Patienten, bei dem sich ein Morbus Wegener zuerst an der Haut manifestierte und erst spater eine Mitbeteiligung des Respirationstraktes festgestellt wurde. Anhand histopathologischer und bildgebendender Verfahren sowie dem positiven Nachweis von PR3-ANCA konnte die Diagnose gesichert werden. In interdisziplinarer Zusammenarbeit fuhrte die topische Applikation von Tacrolimus, die orale Gabe von Glukokortikosteroiden und eine intravenose Cyclophosphamidstostherapie zu einer Abheilung der Ulzera sowie zu einer Verbesserung des Lungenbefundes.

Background. After renal transplantation, patients are prone to develop impairments in glucose metabolism. In 2005, the American Diabetes Association published new guidelines on the diagnosis of pre-diabetes [plasma glucose levels from 100 to 125 mg/dL fasting or from 140 to 199 mg/dL 2 h after an oral glucose tolerance test (OGTT)]. This study sought to evaluate the prevalence and the potentially associated factors of pre-diabetes in a cohort of renal transplant patients on maintenance immunosuppressive medication. Furthermore, the diagnostic value of HbA1-c measurements in predicting pre-diabetes in transplant patients is undetermined. Methods. Two hundred consecutive renal transplant patients of our outpatient transplant clinic were evaluated using a standard OGTT. On the day of testing, multiple factors presumably associated with pre-diabetes were assessed via a standardized questionnaire: daily steroid dosage, triglyceride levels, cholesterol levels, estimated glomerular filtration rate (eGFR) [abbreviated Modification of Diet in Renal Disease (MDRD) formula], systolic and diastolic blood pressure, pulse pressure, age, gender, body mass index (BMI), BMI 30 and 25, number of renal transplants, number of rejection episodes prior to testing, source of renal transplant, cause of renal failure and medications as related to the prescription of cyclosporine, tacrolimus, mycophenolate mophetil, angiotensin-converting enzyme inhibitors, AT1-blockers, statins, β-blockers and thiazide diuretics. Patients diagnosed with pre-diabetes were compared to subjects with normal test results. Fishers exact test and the Wilcoxon rank-sum test were applied to compare the two study populations, whereas multivariate logistic regression was used to seek potential risk factors as related to other covariates. Risk ratios (RRs) to develop pre-diabetes were calculated for significant variables. Results. Ten patients had results indicative of post-transplant diabetes whereas data sets of three other patients were incomplete and were thus not included in the analysis. From the remaining 187 patients, 130 (69.5%) displayed normal test results whereas 57 (30.5%) had results indicative of pre-diabetes. On multivariate regression analysis, patients with pre-diabetes were significantly older {55.3 ± 12.1 versus 47.7 ± 12.6 years, P = 0.0007, RRs per 5 years increase 1.28 [95% confidence interval (95% CI) 1.11–1.47]}, had more rejection episodes [0.26 ± 0.48 versus 0.12 ± 0.37, P = 0.0024, RRs per rejection episode 3.99 (95% CI 1.63–9.77)] and showed lower diastolic blood pressure readings [77 ± 10 mmHg versus 81 ± 10 mmHg, P = 0.0362, RR per 5 mmHg decrease 1.14 (95% CI 1.04–1.49)]. Conclusions.. There is a high incidence of latent pre-diabetes among renal transplant recipients. Increasing age, rejection episodes and lower diastolic blood pressure proved to be associated with pre-diabetes. In contrast to post-transplant diabetes, tacrolimus use and HbA1-c levels were not prognostic of pre-diabetes.

Thioredoxin domain containing protein 5 (TXNDC5) is a member of the thioredoxin (Trx) domain-containing family of proteins that have been implicated in cancer progression. The expression of TXNDC5 in non-small cell lung carcinoma (NSCLC) tumours compared to patient-matched normal lung tissue was determined and cell line models were used to determine if expression was regulated by hypoxia.Samples of tumour and normal lung tissue were taken during surgery and immediately frozen. The expression of TXNDC5 was determined by Western blotting and immunohistochemistry. To analyse the effect of hypoxia on TXNDC5 expression NSCLC cell lines were used.Tumours from 18/29 (62%) individuals exhibited an increase in TXNDC5 expression compared to normal lung tissue (p0.05). TXNDC5 expression was not elevated by hypoxia.TXNDC5 is up-regulated in the majority of resected human NSCLC. Cell line data indicates that the expression of TXNDC5 in tumour cells is not regulated by hypoxia.

Bronchoscopic training courses are an essential part of the education in bronchoscopy for all kinds of specialisations and professions performing such investigations. All aspects of the application should be mentioned during a course. These recommendations are necessary because the number of bronchoscopies performed in the last years has increased due to the increasing number of patients, improved equipment and better availability. Courses should provide the basic knowledge including main points of indications, preconditions for the procedure and decisions of consequence after bronchoscopy. Participants should be trained in the skills of correct handling and performing flexible bronchoscopies in training dummies. Necessary competence requirements on the course instructor are adequate professional qualifications, paedagogic skills and the availability of appropriate teaching material. Quality assurance of the course should be achieved by consequent evaluation. A widely spread field of bronchoscopic applications can improve patient care in many medical specialisations.

Factor V Leiden (FVL) mutation and prothrombin G20210A mutation are common hereditary risk factors for venous thrombosis. In the current study, 40 patients (mean age ± standard deviation, 35 ± 11 years) and 764 healthy control subjects (mean age ± standard deviation, 37 ± 14 years) were enrolled to assess the potential role of these mutations in the manifestation of thrombotic microangiopathies. Compared with controls, neither the heterozygous FVL mutation (7.5% vs 8.5%; P = 1) nor the heterozygous prothrombin mutation (2.5% vs 2.8%; P = 1) was more prevalent in the patients. The findings do not support a significant role of FVL and prothrombin mutations as risk factors for the manifestation of thrombotic microangiopathies. Thus, screening for these mutations does not allow the identification of individuals at increased risk for these rare thrombotic disorders.

In this study, we assessed the potential role of the TT genotype of the gene of the methylenetetrahydrofolate reductase for the manifestation of thrombotic microangiopathies, enrolling 40 affected patients (mean age [± standard deviation] 35 ± 11 years). As a result, the methylenetetrahydrofolate reductase 677TT genotype was more prevalent in patients with thrombotic microangiopathies compared with controls (adjusted odds ratio = 2.58, 95% confidence interval = 1.2-5.7, P = .018), particularly in those suffering from the hemolytic uremic syndrome. A hemolytic more severe clinical course of thrombotic microangiopathies in carriers of the methylenetetrahydrofolate reductase 677TT genotype was not observed. In summary, our findings suggest a significant influence of the methylenetetrahydrofolate reductase genotype on the manifestation of thrombotic microangiopathies. The 677 TT genotype of this polymorphism appears to be a risk factor for manifestation of these rare thrombotic disorders, possibly explained by endothelial activation and increased oxidative stress.

The prognosis for tracheobronchial tumours remains poor. Most patients can be offered only palliation. When the main symptom is breathlessness or refractory haemoptysis from a large airway tumour endoscopic treatment may be very effective. Over the last decade most attention has focused on the neodymium YAG laser. This often produces dramatic effects but has some important limitations. In the last few years better techniques for stenting and intrabronchial radiotherapy (brachytherapy) have also been developed. This article discusses the range of techniques now available and aims to help clinicians decide which patients may benefit from referral to centres providing these techniques.

Thrombotic microangiopathies are life-threatening disorders characterized by vascular microthromboses, schistocytic hemolytic anemia, and thrombocytopenia. Although recent research has partially explained the pathogenesis of these rare entities, the determinants contributing to the onset and modulating the severity of thrombotic microangiopathies are largely unknown. The present study assessed the putative role of prothrombotic platelet receptor polymorphisms in thrombotic microangiopathies that have been found to be associated with premature onset of myocardial infarction in predisposed individuals. Thirty-four consecutive patients admitted with the diagnosis of thrombotic microangiopathy and 759 healthy subjects were enrolled. Genotyping of the human platelet antigen (HPA) 2 an the Kozak sequence polymorphism of GP Ibα of the platelets’ von Willebrand factor receptor glycoprotein (GP) Ib-V-IX, the HPA-1 and the HPA-3 polymorphism of the fibrinogen receptor GP IIb-IIIa (integrin αIIbβ 3) and the HPA-5 and GP Ia 807 C/T polymorphism of the collagen receptor GP Ia-IIa (integrin α2β1) were determined according to standard procedures. As a result, no significant differences in the prevalence of prothrombotic variants of platelet-receptor polymorphisms between patients and healthy control subjects were observed. However, although not significant, the prothrombotic bb genotype of the HPA-1 polymorphism was more prevalent in the patients. The findings do not provide evidence that platelet receptor polymorphisms are determinants for the onset of thrombotic microangiopathies or predispose to a more severe course. Along with this observation, screening for respective platelet-receptor polymorphisms does not appear to contribute to risk stratification of affected patients.

A retrospective study was performed to evaluate the diagnostic yield for lung cancer from histological biopsy specimens and from washings and brushings for cytological examination taken at fibreoptic bronchoscopy. The records of 680 bronchoscopies were analysed. Of 300 patients eventually diagnosed as having a malignant lesion, 188 had had biopsy, washing, and brushing. Of these, 125 had endoscopically visible tumour (group A) and 63 had no abnormal findings or abnormal findings that were not diagnostic of malignancy (group B). In group A biopsy specimens gave a positive result in 76% of cases, washings in 49.6%, and brushings in 52%; biopsy material gave the only positive result in 22.4% of cases, washings in 2.2%, and brushings in 4.8%. In group B biopsy specimens were positive in 36.5%, washings in 38.1%, and brushings in 28.6%; biopsy gave the only positive result in 11.1% of cases, washing in 9.5%, and brushing in 3.2%. Washing had a higher diagnostic yield than brushing in group B. Biopsy and cytological examination of either washings or brushings were found to give over 95% of all positive results in group A, but in group B the combination of biopsy and washing was more often successful (94.3%) than biopsy and brushing (82.8%). It is concluded that for the maximum diagnostic yield in the diagnosis of lung cancer biopsy should be combined with cytology using both washings and brushings.