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AIMS Very little data exist regarding the effect of cardiopulmonary bypass (CPB) on cefuroxime (CXM) pharmacokinetics in children less than one year of age. METHODS 50 mg kg(-1) CXM i.v. after induction were followed by 75mg kg(-1) into the CPB circuit. In 42 patients undergoing cardiac surgery, 15-20 samples were obtained between 5 and 360 min after the first dose. Total CXM concentrations were measured by high-performance liquid chromatography and a pharmacokinetic/pharmacodynamic (PK/PD) modelling was performed. RESULTS Using a fixed protein binding of 15.6% for CXM, peak plasma concentrations of unbound CXM were 229 +/- 52 mu g ml(-1) after the first bolus and 341 +/- 86 mu gml(-1) on CPB. Nadir concentrations before CPB were 69 +/- 20 mu gml(-1) and six hours later decreased to 41 +/- 19 mu g ml-1 with and 24 +/- 14 mu g ml(-1) without CPB. A two-compartment model was fitted with the main covariates body weight, CPB and postmenstrual age (PMA). PK parameters were as follows: systemic clearance, 5.15 [95% CI 4.5-5.8] l h(-1); central volume of distribution, 11.25 [9.41-13.09] l; intercompartmental clearance, 18.19 [14.79-21.58] l h(-1); and peripheral volume, 17.07 [15.7-18.5] L. fT > MIC of 32 mu g ml(-1) for an 8-h time period was between 70 and 100% (2.5-10 kg BW). According to our simulation, 25 mg ml(-1) CXM as a primary bolus and into the prime plus a 5 mg kg(-1) h(-1) infusion maintain CXM concentrations continuously above 32 mu g ml(-1). CONCLUSIONS The routine dosing regimen provided was sufficient for prophylaxis, but continuous dosing can provide a higher percentage of fT > MIC.

The aim of this investigation was to identify patient's characteristics and periprocedural variables related to periprocedural transfusion in transfemoral Transcatheter Aortic Valve Implantation (tf-TAVI).Transfusion of allogenic red-blood cells (RBC) in tf-TAVI and the number of transfused units has been linked to an increased 30-day mortality. In line with the trend of minimization and cost-effectiveness, transfusion should be avoided, wherever possible.Between 2007 and 2015, 1,734 procedures were analyzed from our prospective registry for RBC-transfusion. Multiple logistic regression analysis was used to identify the dependent variables.Transfusion was considered necessary in 14% (n = 243) of the patients. Female gender (OR [95% CI]) (1.680 [1.014-2.783]) and preprocedural moderate (7.594 [4.404-13.095]) and severe anemia (8.202 [0.900-74.752]) according to WHO were the most important preprocedural variables. Periprocedural, pericardial effusion (12.109 [3.753-39.063]), emergency extracorporeal circulation (54.5288 [6.178-481.259]) and major vascular injury (2.647 [1.412-4.962]) were related to transfusion. The same applies to moderate (4.255 [1.859-9.740]) and severe anemia (31.567 [8.560-116.416]) as well as periprocedural experience (0.072 [0.035-0.149] - 0.141[0.079-0.251], P 0.001) CONCLUSION: Procedural experience, serious adverse events, low pre- and periprocedural Hb levels and female gender were the main variables relating to transfusion. Even in experienced high-volume centers, transfusion is still necessary in a considerable number of patients.

Aim Tranexamic acid (TXA) continues to be one of the antifibrinolytics of choice during paediatric cardiac surgery. However, in infants less than 1 year of age, the optimal dosing based on pharmacokinetic (PK) considerations is still under discussion. Methods Forty-three children less than 1 year of age were enrolled, of whom 37 required the use of cardiopulmonary bypass (CPB) and six were operated on without CPB. Administration of 50 mg kg-1 TXA intravenously at the induction of anaesthesia was followed by 50 mg kg-1 into the CPB prime in the CPB group. Plasma concentrations of TXA were analysed by gas chromatography-mass spectrometry. PK data were investigated using nonlinear mixed-effect models. Results A two-compartment model was fitted, with the main covariates being allometrically scaled bodyweight, CPB, postmenstrual age (PMA). Intercompartmental clearance (Q), peripheral volume (V2), systemic clearance, (CL) and the central volume (V1) were calculated. Typical values of the PK parameter estimates were as follows: CL = 3.78 [95 % confidence interval (CI) 2.52, 5.05] l h-1 ; central volume of distribution = 13.6 (CI 11.7, 15.5) l; Q = 16.3 (CI 13.5, 19.2) l h-1 ; V2 = 18.0 (CI 16.1, 19.9) l. Independently of age, 10 mg kg-1 TXA as a bolus, a subsequent infusion of 10 mg kg-1 h-1 , then a 4 mg kg-1 bolus into the prime and a reduced infusion of 4 mg kg-1 h-1 after the start of CPB are required to maintain TXA concentrations continuously above 20 μg ml-1 , the threshold value for an effective inhibition of fibrinolysis and far lower than the usual peak concentrations (the '10-10-4-4 rule'). Conclusions The introduction of a modified dosing regimen using a starting bolus followed by an infusion and a CPB prime bolus would prohibit the potential risk of seizures caused by high peak concentrations and also maintain therapeutic plasma concentration above 20 μg ml-1 .

Summary Corneal confocal microscopy (CCM) has been established as a noninvasive, in vivo imaging technology that provides high-resolution images of the corneal tissue layers at a cellular level. In particular, several research groups focus on the nerve fiber bundles constituting the subbasal nerve plexus (SNP). The ability to visualize - and quantify - morphological alterations of the SNP provides a new and potentially sensitive diagnostic approach for peripheral neuropathies, e.g. associated with diabetes. However, because of the small field of view of current CCM systems (approx. 0.16 mm²) and the locally inhomogeneous distribution of the subbasal nerve structures, a single image does not reliably reflect the condition of the SNP. To address this issue, we present a highly automated and integrated system that facilitates the imaging of an extended contiguous SNP area in a short recording time by guiding the gaze direction of the patient with a computer-controlled moving fixation target. The system achieves growth rates of the scanned area of approximately 0.16 mm² per second. Following the image acquisition process, a high-quality mosaic image of the scanned area is computed using specialized image processing software.

We constructed a multiple myeloma (MM)-specific gene panel for targeted sequencing and investigated 72 untreated high-risk (del17p) MM patients. Mutations were identified in 78% of the patients. While the majority of studied genes were mutated at similar frequency to published literature, the prevalence of TP53 mutation was increased (28%) and no mutations were found in FAM46C. This study provides a comprehensive insight into the mutational landscape of del17p high-risk MM. Additionally, our work demonstrates the practical use of a customized sequencing panel, as an easy, cheap and fast approach to characterize the mutational profile of MM.

Summary Background Perioperative acquired factor XIII deficiency has been looked upon as a potential cause of postoperative bleeding in adult cardiac surgery. Methods Forty-four infants were prospectively studied for the time course of factor XIII in plasma and the effect on chest tube drainage (CTD) and transfusion requirements in the first 24 h after surgery. A reconstituted blood prime (RBP) with fresh–frozen plasma (FFP) and packed red blood cells (PRBC) was used. Samples were taken at baseline, after cardiopulmonary bypass and upon arrival in the ICU. Differences in blood loss and transfusion requirements based on a cutoff value of 70% factor XIII activity at the time of ICU admission were also calculated. Results Baseline factor XIII activity was 79%, decreased to 71% after CPB (P = 0.102) and increased back up to 77% at ICU arrival (P = 0.708). There was no significant correlation between factor XIII, CTD, age, cyanosis, platelet count, and transfusion requirements at any time point. Only preoperative fibrinogen levels correlated significantly with factor XIII activity. Perioperative blood transfusions (PRBC P = 0.712, FFP P = 0.909, platelets P = 0.807) and chest tube losses (P = 0.424 at 6 h and P = 0.215 at 24 h) were not significantly different above or below a 70% factor XIII activity at ICU arrival. Conclusion Factor XIII activity in infants with congenital heart defects is within the lower range of normal adults, independent of patient's age and the presence of cyanosis. Reconstituted blood prime maintains factor XIII activity at sufficient levels during pediatric cardiac surgery. We could not detect a correlation between FXIII and CTD.

Background Papillary thyroid cancer (PTC) is a common endocrine cancer and frequently presents with lymph node (LN) metastases. The frequency of LN metastases in the lateral compartment and their surgical removal are poorly defined. There are no prospective randomised controlled trials addressing an eventual outcome difference relating to the extent of the initial surgical approach. The aim of this study was to define the extent of lateral LN involvement and the role of imaging in identification of these metastatic LN. Design and methods A systematic review of studies of patients with PTC undergoing either prophylactic or therapeutic lymphadenectomy of the lateral cervical compartment. Studies involving imaging modalities in the detection of lateral cervical LNs in PTC were also analysed. Results Systematic review on the frequency of lateral LN metastases and their detection using various imaging tools identified 19 studies containing data on 5587 patients undergoing prophylactic or imaging-guided removal of the lateral compartment. Imaging-guided surgery retrieved cancerous lateral LNs in 446/3178 or 14% of eligible patients, whilst prophylactic lateral neck dissection yielded histopathological proof of cancer in 1177/204 or 57·5% of patients. The frequency of lateral compartment metastases increased with T stage. The sensitivity of ultrasound and CT was poor as low as 27% when accurately calculated. Conclusion Metastatic cervical LNs were found in more than half of patients when prophylactic lateral LN dissection was performed. Use of conventional imaging for the selection of the surgical approach to the lateral cervical compartment may commonly identify stage N1a instead of N1b and thus lead to false stage assignment as stage III rather than stage IV, concealing the severe prognostic implications of this stage progression in individual patients.

‘inflammation of parathyroid gland’, ‘lymphocytic infiltrate’, ‘tuberculosis of the parathyroid’, ‘sarcoidosis’, and ‘graulomatous inflammation’. Three autopsy series, 27 articles and 96 case reports with inflammatory parathyroid disorders were identified. Autopsy series showed lymphocytic infiltrates in up to 16% of all cases. The entire material reported lymphocytic infiltrates (n = 69), parathyroiditis with germinal centres (n = 15), sarcoidosis (n = 6), tuberculosis (n = 4), and other granulomatous diseases (n = 2). Conclusions: Distinct inflammatory and granulomatous processes in the parathyroid gland are rare. Scanty lymphocytic infiltrates are common, and occur in generalized inflammatory conditions or venous congestion. We note the surprising absence of an association between histological proof of parathyroiditis and hypoparathyroidism.

Purpose: To determine the clinical characteristics of symptomatic choroidal metastasis (CM) resulting from metastatic lung cancer. Methods: Twenty-two consecutive patients with symptomatic CM resulting from lung cancer were retrospectively reviewed for ocular findings, medical history and systemic disease. All patients underwent a complete screening for further organ metastasis by computed tomography (CT) and bone scintigraphy. Annual frequency of CM was determined and compared with the incidence predicted from ocular screening studies. Results: In eight of 22 (36%; 95% confidence interval [CI] 17–59) patients, lung cancer had been diagnosed before occurrence of CM, with a median interval of 13 months. In 14 patients lung cancer was detected after diagnosis of CM, with a median interval of 1 month. Choroidal metastasis was unilateral, solitary and located close to or at the posterior pole in the majority of patients. Further organ metastasis with a median number of three affected organ systems was present in 19 (86%; 95% CI 65–97) patients. Median survival after diagnosis of symptomatic CM was 13 months, by contrast with 2 months in lung cancer patients with CM identified in an ocular screening study. The mean number of patients in Berlin diagnosed with symptomatic CM was 1.4 per year, which was two orders of magnitude less than predicted from screening studies. Conclusions: Symptomatic choroidal lung cancer metastasis in the majority of patients presents as a solitary tumour before diagnosis of lung cancer in patients with multiple organ systems affected by metastatic disease. Contrary to predictions from ocular screening studies, it is a rare clinical entity.

A new type of plasma source to maintain a free-standing, linearly extended plasma was studied. The plasma reactor is a microwave concentrator which is comprised of a cylindrical cavity with an elliptical base and a microwave antenna near one of its focal lines and is operated at f = 2.45 GHz. Numerical simulations and measurements of the microwave pattern inside the assembly were found to be in good agreement with each other. Electron densities and electron temperatures were measured using Langmuir probes. A completely free-standing plasma inside an evacuated glass tube was achieved for certain combinations of gas pressure and injected power.

The presented plasma torch is designed to be used for the removal of exhaust gases like volatile organic compounds (VOCs). This study covers the development of an atmospheric plasma source based on an axially symmetric resonator (2.45 GHz) and the optimisation of the shape of the gas nozzle. To guarantee that the plasma can be ignited without a striking aid, detailed information about the electric field distributions is needed. Therefore, finite element simulations of the electric field using Comsol Multiphysics® were performed. The results could be verified by measurements with a network analyser. All these studies result in a cavity configuration which can be ignited without a striking aid.

Broca's region in the dominant cerebral hemisphere is known to mediate the production of language but also contributes to comprehension. Here, we report the differential participation of Broca's region in imagery of motion in humans. Healthy volunteers were studied with functional magnetic resonance imaging (fMRI) while they imagined movement trajectories following different instructions. Imagery of right-hand finger movements induced a cortical activation pattern including dorsal and ventral portions of the premotor cortex, frontal medial wall areas, and cortical areas lining the intraparietal sulcus in both cerebral hemispheres. Imagery of movement observation and of a moving target specifically activated the opercular portion of the inferior frontal cortex. A left-hemispheric dominance was found for egocentric movements and a right-hemispheric dominance for movement characteristics in space. To precisely localize these inferior frontal activations, the fMRI data were coregistered with cytoarchitectonic maps of Broca's areas 44 and 45 in a common reference space. It was found that the activation areas in the opercular portion of the inferior frontal cortex were localized to area 44 of Broca's region. These activations of area 44 can be interpreted to possibly demonstrate the location of the human analogue to the so-called mirror neurones found in inferior frontal cortex of nonhuman primates. We suggest that area 44 mediates higher-order forelimb movement control resembling the neuronal mechanisms subserving speech. Hum. Brain Mapping 11:273-285, 2000. (C) 2000 Wiley-Liss, Inc.

The CBP co-activator protein possesses an intrinsic acetyltransferase (AT) activity capable of acetylating nucleosomal histones, as well as other proteins such as the transcription factors TFIIE and TFIIF. In addition, CBP associates with two other TSs, P/CAF and SRC1. We set out to establish whether the intrinsic AT activity of CBP contributes to transcriptional activation. We show that a region of CBP, encompassing the previously defined histone AT (HAT) domain, can stimulate transcription when tethered to a promoter. The stimulatory effect of this activation domain shows some promoter preference and is dependent on AT activity. Analysis of 14 point mutations reveals a direct correlation between CBP's ability to acetylate histones in vitro and to activate transcription in vivo. We also find that the HAT domains of CBP and P/CAF share sequence similarity. Four conserved motifs are identified, three of which are analogous to motifs A, B and D, found in other N-acetyltransferases. The fourth motif, termed E, is unique to CBP and P/CAF. Mutagenesis shows that all four motifs in CBP contribute to its HAT activity in vitro and its ability to activate transcription in vivo. These results demonstrate that the AT activity of CBP is directly involved in stimulating gene transcription. The identification of specific HAT domain motifs, conserved between CBP and P/CAF, should facilitate the identification of other members of this AT family.

To determine task-specific activations of the human brain in individual subjects, we applied pixel-by-pixel t-map statistics to the regional cerebral perfusion data obtained sequentially by dynamic scanning of [15O]-butanol with positron emission tomography (PET). The listmode data were binned into frames of 2 sec, and multiple corresponding pixel-by-pixel activation-minus-control subtractions were used for t-map calculation. The subtraction frames covering 10–40 sec after tracer arrival in the brain showed the activation-related increase of regional cerebral perfusion. A mismatch of the activation and control data by 2 sec resulted in a mean error of

We compare estimates of three-dimensional brain activity extracted from averaged and from selected single-trial rnagnetoencephalographic signals, in order to study activation sequences related to motor preparation, inhibition, and movement, cued on two tones (Sl and 52). We studied all possible hand-ear combinations in a right-handed subject in both initiation and inhibition, and found some marked differences between combinations. Averaging revealed activity in the right motor cortex in all combina- tions requiring movement inhibition, irrespective of laterality of finger and ear, and in the contralateral motor cortex during movement (but considerably reduced for the task with the practiced ear and finger). These activation patterns are seen in single trials with variability of latency but not position. In the average signal, a long silent period between the warning and imperative stimuli is seen; in single trials, however, recurring sequences of activation linking frontal and posterior areas are seen throughout the analysis period in all combinations. These results show that single-trial analysis is needed to understand all the significant neural correlates of this task.

The synthesis of total sulfated glycosaminoglycans (GAG) was stimulated by transforming growth factors (TGFα 1.4-fold at 5 ng ml , and TGFβ1 2.05-fold at 2.5 ng ml ) in primary cultures of rat liver fat storing cells (FSC). The combination of both TGFs resulted in an additively stimulated synthesis of total sulfated GAG (more than 3-fold), chondroitin sulfate (more than 15-fold) and hyaluronate (3.8-fold), respectively, whereas the formation of dermatan sulfate was unchanged and that of heparan sulfate was slightly reduced. In summary, TGFs were identified as important mediators of stimulated GAG synthesis in those cells of the liver (FSC), which are the primary site of matrix glycoconjugate production. Fat storing cell; Fibrogenesis; Glycosaminoglycans; Chondroitin sulfate; Hyaluronic acid; Transforming growth factor