Patterns in early diffusion-weighted MRI in children with haemolytic uraemic syndrome and CNS involvement.

OBJECTIVES: Diffusion-weighted imaging (DWI) in children with diarrhoea associated haemolytic uraemic syndrome (D+HUS) and cerebral involvement was evaluated retrospectively. METHODS: DWI within 24 h of onset of neurological symptoms. The apparent diffusion coefficient (ADC) was measured in grey/white matter and correlated with clinical and laboratory findings. RESULTS: DWI was abnormal in all. Abnormal ADC was detected in the supratentorial white matter (6/12) and cortex (1/12), the basal ganglia (5/12), the thalami (4/12), and the cerebellum (1/12). ADC was reduced in 5/12, increased in 4/12, and both in 3/12. Mean serum sodium was lower in patients with DWI abnormalities affecting the white matter (6/12), than in those with basal ganglia/thalamic involvement (6/12). Neurological outcome was normal in 4/11 and abnormal in 7/11, and 1 patient died, outcome did not correlate to either localisation or type of DWI abnormality. CONCLUSIONS: In D+HUS with neurological symptoms, early DWI may reveal abnormal ADC not only in the basal ganglia/thalami, but also in the white matter/cortex. Besides thrombotic microangiopathy, toxic effects of shiga toxin, azotaemia and hyponatraemia / hypoosmolality may be involved in cerebral involvement in children with D+HUS. Findings on early MRI seem not to predict clinical course or outcome. KEY POINTS: • DWI MR imaging may detect early CNS involvement in haemolytic uraemic syndrome • Different pathogenetical mechanisms may contribute to the CNS disease in HUS • Early MRI findings do not seem to allow prediction of clinical outcome.

Procalcitonin and valuable clinical symptoms in the early detection of neonatal late-onset bacterial infection.

AIM: To evaluate which clinical symptoms indicate proven neonatal bacterial infection (NBI) and whether measuring procalcitonin aside from C-reactive protein and interleukin 6 improves sensitivity and specificity in diagnosis. METHODS: In a prospective observational study, clinical symptoms and procalcitonin, C-reactive protein and interleukin 6 were simultaneously determined from the 4th day of life in 170 preterm and term neonates at the first time of suspicion of NBI. Proven NBI was defined as a positive culture of otherwise sterile body fluids or radiologically verified pneumonia in combination with elevated inflammatory markers. RESULTS: Fifty-eight (34%) patients were diagnosed with proven late-onset NBI. In case of proven NBI, odds ratio and 95% confidence intervals were 2.64 (1.06-6.54) for arterial hypotension, 5.16 (2.55-10.43) for feeding intolerance and 9.18 (4.10-20.59) for prolonged capillary refill. Sensitivity of combined determination of C-reactive protein (>10 mg/L) and interleukin 6 (>100 pg/mL) was 91.4%, specificity 80.4%, positive predictive value 70.7% and negative predictive value 94.7%. The additional determination of procalcitonin (>0.7 ng/mL) resulted in 98.3%, 65.2%, 58.8% and 98.6%, respectively. CONCLUSION: Arterial hypotension, feeding intolerance and especially prolonged capillary refill indicate proven neonatal late-onset bacterial infection, even at the time of first suspicion. Additional measurement of procalcitonin does indeed improve sensitivity to nearly 100%, but is linked to a decline in specificity. Nevertheless, in the high-risk neonatal population, additional procalcitonin measurement can be recommended because all infants with NBI have to be identified.

International pneumococcal clones match or exceed the fitness of other strains despite the accumulation of antibiotic resistance.

A few international pneumococcal clones dominate the population of antibiotic-resistant pneumococci. Despite the scientific paradigm that a loss in fitness is the price for acquisition of resistance, these clones spread successfully. One hundred fifty-four isolates from adult patients with community-acquired pneumonia (CAP) were analyzed. Thirty percent showed a close relationship to international clones and had fitness equal to or exceeding that of other strains (P = 0.015); these factors may result in the endurance of these strains despite a reduction of antibiotic usage.

Cyclosporine A: impact on mitochondrial function in endothelial cells.

INTRODUCTION: Although cyclosporine A (CSA) is considered to be an efficient immunosuppressive compound in transplantation, vascular side effects like arterial hypertension, neurologic complications and other adverse reactions occur. Interference of CSA with mitochondrial function may be responsible for these side effects. METHODS: We evaluated the effect of CSA on mitochondrial and glycolytic function by measuring fatty acid oxidation (FAO), activities of respiratory chain complexes (RC) and citratesynthase (CS), lactate/pyruvate-ratios, energy-rich phosphates as well as activities of some glycolytic enzymes in human umbilical vein endothelial cells. RESULTS: After 48 h of CSA incubation, global FAO, RC-complexes 1 + 3; 4 and 5 as well as CS were compromised while energy charges were not reduced. Lactate/pyruvate-ratios increased; cellular lactate dehydrogenase (LDH)-, hexokinase- and phosphofructokinase-activities were not impaired by CSA. Moderate cellular toxicity, assessed by LDH leakage, appeared only at the highest CSA concentration. CONCLUSION: Part of CSA toxicity may arise from alterations in mitochondrial function as judged by impaired FAO and respiratory chain enzymes. To some extent, energy balance seems to be maintained by cytosolic energy production. Although only demonstrated for endothelial cells, it is conceivable that such effects will alter energy metabolism of different organs with high oxidative energy demands.

Surgical therapy of exocrine pancreatic carcinoma--results at an academic teaching hospital and evaluation of prognostic factors.

BACKGROUND/AIMS: Pancreatic cancer is among the top five cancer related death causes in countries like the US and Germany. Many studies have shown favorable results of pancreatic carcinoma resection at high-volume hospitals. It was the aim of this study to compare the results of pancreatic resection of exocrine pancreatic carcinoma at an academic teaching hospital with those of international centers for pancreatic surgery and to identify prognostic factors for survival. METHODOLOGY: Ninety-eight patients with exocrine pancreatic carcinoma were treated at our hospital, 42 of those underwent a resection. The data was collected from the patient files and statistically analyzed. A complete follow-up was reached. RESULTS: The resection rate was 42.9%, of which 83.3% were R0-resections. Mortality was 2.4%, morbidity 31%. Median survival after R0-resection was 14 months and 57.1% of the patients received adjuvant chemotherapy with gemcitabine. The performed surgical procedure and adjuvant chemotherapy were identified as independent determinants of long-term survival. CONCLUSION: This study shows that morbidity, mortality and survival rates reported in studies from international centers for pancreatic surgery can be reached at an academic teaching hospital as well. Adjuvant chemotherapy prolongs survival.

Distinguishing medullary carcinoma of the breast from high-grade hormone receptor-negative invasive ductal carcinoma: an immunohistochemical approach.

AIMS: Medullary carcinomas (MCs) represent a rare breast cancer subtype associated with a rather favourable prognosis compared with invasive ductal carcinomas (IDCs). Due to histopathological overlap, MCs are frequently misclassified as high-grade IDCs, potentially leading to overtreatment of MCs. Our aim was to establish novel diagnostic markers distinguishing MCs from hormone receptor-negative high-grade IDCs. METHODS AND RESULTS: Sixty-one MCs and 133 hormone receptor-negative IDCs were analysed in a comparative immunohistochemical study. Applied markers included a comprehensive panel of cytokeratins (CKs), vimentin, smooth muscle actin (SMA), p63, p53, cell adhesion molecules [N-CAM (CD56), syndecan-1 (CD138), E-cadherin and P-cadherin] and development associated transcription factors (AP-2 alpha, AP-2 gamma). A significantly higher proportion of IDCs displayed increased expression of CK7, AP-2 alpha and HER2 in contrast to MCs (CK7: 91% of IDCs versus 77% of MCs; AP-2 alpha: 77% versus 57%; and HER2: 26% versus 7%, each P < 0.01). Vice versa, MCs were slightly more frequently positive for SMA and vimentin (P > 0.05). CONCLUSIONS: Hormone receptor-negative high-grade IDCs are significantly associated with luminal differentiation, Her2 and AP-2 alpha overexpression, whereas MCs tend to display myoepithelial features. Markers analysed in this study are of diagnostic value regarding the differential diagnosis of MCs.

Micro-computed tomography of pulmonary fibrosis in mice induced by adenoviral gene transfer of biologically active transforming growth factor-ß1.

BACKGROUND: Micro-computed tomography (micro-CT) is a novel tool for monitoring acute and chronic disease states in small laboratory animals. Its value for assessing progressive lung fibrosis in mice has not been reported so far. Here we examined the importance of in vivo micro-CT as non-invasive tool to assess progression of pulmonary fibrosis in mice over time. METHODS: Pulmonary fibrosis was induced in mice by intratracheal delivery of an adenoviral gene vector encoding biologically active TGF-ß1 (AdTGF-ß1). Respiratory gated and ungated micro-CT scans were performed at 1, 2, 3, and 4 weeks post pulmonary adenoviral gene or control vector delivery, and were then correlated with respective histopathology-based Ashcroft scoring of pulmonary fibrosis in mice. Visual assessment of image quality and consolidation was performed by 3 observers and a semi-automated quantification algorithm was applied to quantify aerated pulmonary volume as an inverse surrogate marker for pulmonary fibrosis. RESULTS: We found a significant correlation between classical Ashcroft scoring and micro-CT assessment using both visual assessment and the semi-automated quantification algorithm. Pulmonary fibrosis could be clearly detected in micro-CT, image quality values were higher for respiratory gated exams, although differences were not significant. For assessment of fibrosis no significant difference between respiratory gated and ungated exams was observed. CONCLUSIONS: Together, we show that micro-CT is a powerful tool to assess pulmonary fibrosis in mice, using both visual assessment and semi-automated quantification algorithms. These data may be important in view of pre-clinical pharmacologic interventions for the treatment of lung fibrosis in small laboratory animals.

Pain reduction in children during port-à-cath catheter puncture using local anaesthesia with EMLA™.

INTRODUCTION: Alleviating pain is of high importance for children undergoing chemotherapy. Eutectic mixture of lidocain-prilocain cream (EMLA) is assumed to require 60 min application time. MATERIALS AND METHODS: We prospectively compared the pain during port-à-cath punctures after 40 min compared to 60 min of application time. A prospective, unblinded, cross-over study was performed. The children received two punctures during their chemotherapy protocol. Patients in group 1 had the first puncture after 40 min EMLA application time. Their second puncture (approximately a week later) was done after 60 min. Patients in group 2 started after 40 min. Pain was scored using the visual analogue scale (VAS) and the Bieri scale. Patients, parents and a nurse scaled the pain after the intervention. Eighty-seven children between 2 and 18 years with different malignant diseases were included. RESULTS AND DISCUSSION: On the VAS pain scale, the mean pain was 2.3 (minimum 0, maximum 9.2) after 40 min and 1.9 (minimum 0, maximum 9.4) after 60 min according to the observations of the nurse and very similarly according to the parents' observations. The children expressed more pain after 40 min of EMLA application time (mean pain, 3.5) and a significant pain reduction after 60 min application time (mean pain 1.7). CONCLUSION: In this study children experienced less pain after 60 min application time, but pain reduction was already seen after 40 min. The child's perception of pain differed from observers' point of view and should therefore always be included in pain management.

The Hannover Dialysis Outcome study: comparison of standard versus intensified extended dialysis for treatment of patients with acute kidney injury in the intensive care unit.

BACKGROUND: Increasing the dose of renal replacement therapy has been shown to improve survival in critically ill patients with acute kidney injury (AKI) in several smaller European trials. However, a very recent large multicentre trial in the USA could not detect an effect of dose of renal replacement therapy on mortality. Based on those studies, it is not known whether a further increase in dialysis dose above and beyond the currently employed doses would improve survival in patients with AKI. We therefore aimed to assess mortality and renal recovery of patients with AKI receiving either standard (SED) or intensified extended dialysis (IED) therapy in the intensive care unit. METHODS: A prospective randomized parallel group study was conducted in seven intensive care units of a tertiary university hospital. Pre-existing chronic kidney disease was an exclusion criterion. A total of 156 patients (570 screened) with AKI requiring renal replacement therapy were randomly assigned to receive standard dialysis [dosed to maintain plasma urea levels between 120 and 150 mg/dL (20-25 mmol/L)] or intensified dialysis [dosed to maintain plasma urea levels <90 mg/dL (<15 mmol/L)]. Outcome measures were survival at Day 14 (primary) and survival and renal recovery at Day 28 (secondary) after initiation of renal replacement therapy. RESULTS: Treatment intensity differed significantly (P < 0.01 for plasma urea and administered dose). No differences between intensified and standard treatment were seen for survival by Day 14 (70.4% versus 70.7%) or Day 28 (55.6% versus 61.3%), or for renal recovery amongst the survivors by Day 28 (60.0% versus 63.0%). CONCLUSIONS: Although this study cannot deliver a definitive answer, it suggests that increasing the dose of extended dialysis above the currently recommended dose might neither reduce mortality nor improve renal recovery in critically ill patients, mainly septic patients, with AKI.

S100B serum levels and word memory processing in remitted major depression as reflected by brain potentials.

OBJECTIVE: Memory processes, as reflected by 'old/new' effects of event-related potentials (ERPs), have been shown to be impaired in depressed patients. This variability might be partly explained by biological factors. S100B is a glial calcium-binding protein with neuroplastic properties; S100B serum levels have been shown to be increased in depressive patients. The pathophysiologic role of S100B in depression, however, is not yet sufficiently understood. METHODS: In the present study, ERPs recorded in a visual continuous word recognition paradigm were therefore investigated in patients with remitted major depression in relation to S100B serum levels. RESULTS: Patients with moderately increased S100B serum levels (n = 6) showed a normal old/new effect in contrast to a reduced old/new effect in patients with normal S100B levels (n = 6) compared to aged-matched controls. CONCLUSIONS: These findings provide evidence of an association between S100B levels and memory processes in patients with recurrent depression and further suggest a neuroprotective role of moderately increased S100B serum levels in the course of affective disorders.

Prevalence of alpha-fodrin antibodies in patients with chronic hepatitis C infection and Sjögren syndrome.

OBJECTIVE: Hepatitis C virus infection (HCV) is associated with various extrahepatic manifestations. Antibodies against alpha-fodrin are associated with sicca symptoms and may valuable diagnostic markers in patients with primary Sjögren syndrome (SS) lacking Ro antibodies. The frequency and role of alpha-fodrin antibodies in patients with chronic HCV infection are unknown. The aim of this study was to investigate the prevalence of alpha-fodrin antibodies in HCV-infected patients with SS. MATERIAL AND METHODS: Alpha-fodrin antibodies were detected more often in hepatitis C patients (25%; n=142) than in HBV-infected individuals (8%; n=49) and healthy controls (6%; n=174) (p<0.01). Based on these findings, we investigated the frequency of sicca symptoms in a second cohort and studied other antibodies associated with SS. RESULTS: HCV-infected individuals showed sicca symptoms in 53% of cases as determined by the Saxon and Schirmer tests, which was more frequent than in healthy controls (1%, p<0.01) but not in patients with autoimmune liver disease (51%). Antibodies specific for Ro (SS-A) were significantly more common in patients with autoimmune liver disease than in HCV-infected patients and healthy controls (16% versus 1% and 0%, p<0.003). SS was found in 18% of patients with HCV, in 15% of patients with autoimmune liver disease and in 1% of healthy controls. However, we found no correlation between sicca symptoms and the presence of antibodies against alpha-fodrin, Ro and La. CONCLUSIONS: Patients with chronic HCV infection show a high prevalence of sicca symptoms and antibodies against alpha-fodrin. However, neither the frequency nor the severity of symptoms correlated with the presence of alpha-fodrin antibodies.

Auricular acupuncture for dental anxiety: a randomized controlled trial.

Auricular acupuncture can be an effective treatment for acute anxiety, but there is a lack of direct comparisons of acupuncture to proven standard drug treatments. In this study we compared the efficacy of auricular acupuncture with intranasal midazolam, placebo acupuncture, and no treatment for reducing dental anxiety. Patients having dental extractions (n = 67) were randomized to (i) auricular acupuncture, (ii) placebo acupuncture, and (iii) intranasal midazolam and compared with a no treatment group. Anxiety was assessed before the interventions, at 30 min, and after the dental extraction. Physiological variables were assessed continuously. With the no treatment group as control, the auricular acupuncture group, and the midazolam group were significantly less anxious at 30 min as compared with patients in the placebo acupuncture group (Spielberger Stait-Trait Anxiety Inventory X1, P = 0.012 and <0.001, respectively). In addition, patient compliance assessed by the dentist was significantly improved if auricular acupuncture or application of intranasal midazolam had been performed (P = 0.032 and 0.049, respectively). In conclusion, both, auricular acupuncture and intranasal midazolam were similarly effective for the treatment of dental anxiety.

Abnormality in the self-monitoring mechanism in patients with fibromyalgia and somatoform pain disorder.

BACKGROUND: Auditory hallucinations and passivity experiences are associated with an abnormality in the self-monitoring mechanism that normally allows us to distinguish self-produced from externally produced sensations. It is unclear if chronic central pain disorders such as fibromyalgia and somatoform pain disorders also involve a defect of the self-monitoring mechanism. METHODS: Responses to tactile stimulation were assessed in four groups of subjects (N = 40): patients with fibromyalgia, patients with somatoform pain disorder, patients with schizophrenia with auditory hallucinations and/or passivity experiences, and normal control subjects. The subjects were asked to rate the perception of a tactile sensation on their left and right hands. The tactile stimulation was either self-produced by movement of the subject's right or left hand or externally produced by the experimenter. RESULTS: Normal control subjects experienced self-produced stimuli as less intense than identical, externally produced tactile stimuli. In contrast, patients with fibromyalgia, patients with somatoform pain disorder, and patients with schizophrenia with auditory hallucinations and/or passivity experiences gave the same perceptual ratings for tactile stimuli produced by themselves as those produced by the experimenter (intergroup difference, p = .043; 95% confidence interval [CI], 0.16-0.68). Post hoc tests revealed that this significance was mainly caused by the fibromyalgia (p = .046; 95% CI, -1.66-0.13) and the somatoform pain disorder group (p = .033; 95% CI, -1.71-0.06). CONCLUSIONS: We conclude that central pain disorders such as fibromyalgia and somatoform pain disorders interfere with the correct functioning of the self-monitoring mechanism that normally allows us to distinguish self-produced from externally produced tactile stimuli.

Genotype-based screening for hereditary hemochromatosis: II. Attitudes toward genetic testing and psychosocial impact--a report from a German pilot study.

In collaboration with the German Sickness Fund (Kaufmännische Krankenkasse-KKH), we conducted a pilot study on DNA-based population screening of hereditary hemochromatosis (HH) in Germany. The health insurance organization KKH briefly informed their members about the possibility to participate voluntarily in this pilot project. A total of 5882 KKH members contacted us and received detailed information on the aim of the project and clinical and genetic aspects of HH. Of these individuals, 3961 requested HFE genotyping. After genotype results had been communicated to the participants' general practitioner, we sent a self-administered questionnaire to all homozygous (n = 67) and heterozygous (n = 485) as well as 448 wild-type study participants (sigma = 1000) to assess the psychosocial impact of HFE genotyping. In addition, questionnaires were sent to 8000 randomly selected members of the KKH to investigate their attitude toward genetic testing. Six hundred thirty-one (63.1%) of the test participants and 2141 (26.8%) of the randomly chosen KKH members responded. A total of 59.1% of the members would generally accept predictive genetic testing and 3.7% objected to such tests in principle. Individuals with higher educational status accepted predictive testing significantly more often than individuals with less education. Of the tested individuals, 69.9% thought that participation in the pilot study was probably beneficial for them and 1% (5 heterozygotes and 1 wild-type) thought that it was probably harmful. Of the participants, 94.6% judged their decision to have participated in the pilot study as right and 0.3% (2 heterozygotes) as probably wrong. Only very few of the tested individuals underwent pretest (1 case) or posttest (11 cases) genetic counseling. We conclude that genotype- based screening for HH is generally accepted and was perceived as beneficial. Negative psychosocial consequences are rare and could presumably have been prevented by delivering appropriate pretest and posttest information.

Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial.

CONTEXT: 1',1'dimethylheptyl-Delta8-tetrahydrocannabinol-11-oic acid (CT-3), a potent analog of THC-11-oic acid, produces marked antiallodynic and analgesic effects in animals without evoking the typical effects described in models of cannabinoids. Therefore, CT-3 may be an effective analgesic for poorly controlled resistant neuropathic pain. OBJECTIVE: To examine the analgesic efficacy and safety of CT-3 in chronic neuropathic pain in humans. DESIGN AND SETTING: Randomized, placebo-controlled, double-blind crossover trial conducted in Germany from May-September 2002. PARTICIPANTS: Twenty-one patients (8 women and 13 men) aged 29 to 65 years (mean, 51 years) who had a clinical presentation and examination consistent with chronic neuropathic pain (for at least 6 months) with hyperalgesia (n = 21) and allodynia (n = 7). INTERVENTIONS: Patients were randomized to two 7-day treatment orders in a crossover design. Two daily doses of CT-3 (four 10-mg capsules per day) or identical placebo capsules were given during the first 4 days and 8 capsules per day were given in 2 daily doses in the following 3 days. After a washout and baseline period of 1 week each, patients crossed over to the second 7-day treatment period. MAIN OUTCOME MEASURES: Visual analog scale (VAS) and verbal rating scale scores for pain; vital sign, hematologic and blood chemistry, and electrocardiogram measurements; scores on the Trail-Making Test and the Addiction Research Center Inventory-Marijuana scale; and adverse effects. RESULTS: The mean differences over time for the VAS values in the CT-3-placebo sequence measured 3 hours after intake of study drug differed significantly from those in the placebo-CT-3 sequence (mean [SD], -11.54 [14.16] vs 9.86 [21.43]; P =.02). Eight hours after intake of the drug, the pain scale differences between groups were less marked. No dose response was observed. Adverse effects, mainly transient dry mouth and tiredness, were reported significantly more often during CT-3 treatment (mean [SD] difference, -0.67 [0.50] for CT-3-placebo sequence vs 0.10 [0.74] for placebo-CT-3 sequence; P =.02). There were no significant differences with respect to vital signs, blood tests, electrocardiogram, Trail-Making Test, and Addiction Research Center Inventory-Marijuana scale. No carryover or period effects were observed except on the Trail-Making Test. CONCLUSIONS: In this preliminary study, CT-3 was effective in reducing chronic neuropathic pain compared with placebo. No major adverse effects were observed.

Aerobic training in adults after atrial switch procedure for transposition of the great arteries improves exercise capacity without impairing systemic right ventricular function.

BACKGROUND: Exercise training safely and efficiently improves symptoms in patients with heart failure due to left ventricular dysfunction. However, studies in congenital heart disease with systemic right ventricle are scarce and results are controversial. In a randomised controlled study we investigated the effect of aerobic exercise training on exercise capacity and systemic right ventricular function in adults with d-transposition of the great arteries after atrial redirection surgery (28.2 ± 3.0 years after Mustard procedure). METHODS: 48 patients (31 male, age 29.3 ± 3.4 years) were randomly allocated to 24 weeks of structured exercise training or usual care. Primary endpoint was the change in maximum oxygen uptake (peak VO2). Secondary endpoints were systemic right ventricular diameters determined by cardiac magnetic resonance imaging (CMR). Data were analysed per intention to treat analysis. RESULTS: At baseline peak VO2 was 25.5 ± 4.7 ml/kg/min in control and 24.0 ± 5 ml/kg/min in the training group (p=0.3). Training significantly improved exercise capacity (treatment effect for peak VO2 3.8 ml/kg/min, 95% CI: 1.8 to 5.7; p=0.001), work load (p=0.002), maximum exercise time (p=0.002), and NYHA class (p=0.046). Systemic ventricular function and volumes determined by CMR remained unchanged. None of the patients developed signs of cardiac decompensation or arrhythmias while on exercise training. CONCLUSIONS: Aerobic exercise training did not detrimentally affect systemic right ventricular function, but significantly improved exercise capacity and heart failure symptoms. Aerobic exercise training can be recommended for patients following atrial redirection surgery to improve exercise capacity and to lessen or prevent heart failure symptoms. ( CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov #NCT00837603).

In-line filtration reduces severe complications and length of stay on pediatric intensive care unit: a prospective, randomized, controlled trial.

PURPOSE: Particulate contamination due to infusion therapy carries a potential health risk for intensive care patients. METHODS: This single-centre, prospective, randomized controlled trial assessed the effects of filtration of intravenous fluids on the reduction of complications in critically ill children admitted to a pediatric intensive care unit (PICU). A total of 807 subjects were randomly assigned to either a control (n = 406) or filter group (n = 401), with the latter receiving in-line filtration. The primary endpoint was reduction in the rate of overall complications, which included the occurrence of systemic inflammatory response syndrome (SIRS), sepsis, organ failure (circulation, lung, liver, kidney) and thrombosis. Secondary objectives were a reduction in the length of stay on the PICU and overall hospital stay. Duration of mechanical ventilation and mortality were also analyzed. FINDINGS: Analysis demonstrated a significant reduction in the overall complication rate (n = 166 [40.9 %] vs. n = 124 [30.9 %]; P = 0.003) for the filter group. In particular, the incidence of SIRS was significantly lower (n = 123 [30.3 %] vs. n = 90 [22.4 %]; P = 0.01). Moreover the length of stay on PICU (3.89 [95 % confidence interval 2.97-4.82] vs. 2.98 [2.33-3.64]; P = 0.025) and duration of mechanical ventilation (14.0 [5.6-22.4] vs. 11.0 [7.1-14.9] h; P = 0.028) were significantly reduced. CONCLUSION: In-line filtration is able to avert severe complications in critically ill patients. The overall complication rate during the PICU stay among the filter group was significantly reduced. In-line filtration was effective in reducing the occurrence of SIRS. We therefore conclude that in-line filtration improves the safety of intensive care therapy and represents a preventive strategy that results in a significant reduction of the length of stay in the PICU and duration of mechanical ventilation (ClinicalTrials.gov number: NCT00209768).

Combined micro-PET/micro-CT imaging of lung tumours in SPC-raf and SPC-myc transgenic mice.

INTRODUCTION: SPC-raf and SPC-myc transgenic mice develop disseminated and circumscribed lung adenocarcinoma respectively, allowing for assessment of carcinogenesis and treatment strategies. The purpose of this study was to investigate the technical feasibility, the correlation of initial findings to histology and the administered radiation dose of combined micro-PET/micro-CT in these animal models. MATERIAL AND METHODS: 14 C57BL/6 mice (4 nontransgenic, 4 SPC-raf transgenic, 6 SPC-myc transgenic) were examined using micro-CT and (18)F-Fluoro-deoxyglucose micro-PET in-vivo. Micro-PET data was corrected for random events and scatter prior to reconstruction with a 3D-FORE/2D-OSEM iterative algorithm. Rigid micro-PET/micro-CT registration was performed. Tumour-to-non-tumour ratios were calculated for different lung regions and focal lesions. Diffuse tumour growth was quantified using a semiautomated micro-CT segmentation routine reported earlier. Regional histologic tumour load was assessed using a 4-point rating scale. Gamma radiation dose was determined using thermoluminescence dosimeters. RESULTS: Micro-CT allowed visualisation of diffuse and circumscribed tumours in SPC-raf and SPC-myc transgenic animals along with morphology, while micro-PET provided information on metabolism, but lacked morphologic detail. Mean tumour-to-non-tumour ratio was 2.47 for circumscribed lesions. No significant correlation could be shown between histological tumour load and tumour-to-nontumour ratio for diffuse tumours in SPC-raf transgenic animals. Calculation of the expected dose based on gamma dosimetry yielded approximately 140 mGy/micro-PET examination additional to approximately 200 mGy due to micro-CT. CONCLUSIONS: Combined micro-PET/micro-CT imaging allows for in-vivo assessment of lung tumours in SPC-raf and SPC-myc transgenic mice. The technique has potential for the evaluation of carcinogenesis and treatment strategies in circumscribed lung tumours.

Lung tumour growth kinetics in SPC-c-Raf-1-BB transgenic mice assessed by longitudinal in-vivo micro-CT quantification.

BACKGROUND: SPC-c-Raf-1-BxB transgenic mice develop genetically induced disseminated lung adenocarcinoma allowing examination of carcinogenesis and evaluation of novel treatment strategies. We report on assessment of lung tumour growth kinetics using a semiautomated region growing segmentation algorithm. METHODS: 156 non contrast-enhanced respiratory gated micro-CT of the lungs were obtained in 12 SPC-raf transgenic (n = 9) and normal (n = 3) mice at different time points. Region-growing segmentation of the aerated lung areas was obtained as an inverse surrogate for tumour burden. Time course of segmentation volumes was assessed to demonstrate the potential of the method for follow-up studies. RESULTS: Micro-CT allowed assessment of tumour growth kinetics and semiautomated region growing enabled quantitative analysis. Significant changes of the segmented lung volumes over time could be shown (p = 0.009). Significant group differences could be detected between transgenic and normal animals for time points 8 to 13 months (p = 0.043), when marked tumour progression occurred. CONCLUSION: The presented region-growing segmentation algorithm allows in-vivo quantification of multifocal lung adenocarcinoma in SPC-raf transgenic mice. This enables the assessment of tumour load and progress for the study of carcinogenesis and the evaluation of novel treatment strategies.

Effect of tacrolimus on energy metabolism in human umbilical endothelial cells.

BACKGROUND: Tacrolimus has a wide spectrum of adverse effects, including neurotoxic and vascular events. Vascular dysfunction due to interference of tacrolimus with mitochondrial function in endothelial cells may contribute to these adverse reactions. MATERIAL/METHODS: We evaluated the impact of clinically relevant tacrolimus concentrations after 48 hours on energy metabolism in cultured human umbilical vein endothelial cells (HUVEC): Global fatty acid oxidation (FAO), activities of respiratory chain complexes I-V (RC), citratesynthase (CS), glycolytic enzymes and energy rich phosphates were measured. RESULTS: RC-complexes II+III were significantly compromised at 100 nmol/L and CS at 10, 25 and 50 nmol/L, while global FAO was not significantly impaired. Cellular lactate-dehydrogenase (LDH)-, hexokinase- and phosphofructokinase-activities were not altered; AMP levels increased after 48 hours at 200 nmol/L while energy charges remained stable. No cellular toxicity, assessed by light microscopy and LDH leakage was observed even at highest tacrolimus concentrations. CONCLUSIONS: Tacrolimus partially impaired mitochondrial function in HUVEC at the level of RC-complexes II+III and CS. Part of tacrolimus toxicity and vascular dysfunction may arise from these metabolic alterations. To some extent, energy balance could be maintained by FAO and cytosolic energy production; energy consumption might be economized. Although only demonstrated for endothelial cells, it is conceivable that such effects will alter energy metabolism in different tissues with high oxidative demands.