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In this retrospective study, we analyzed the presence of any association of three CD4+ CD25high regulatory T-cell subpopulations at 3 weeks after lung transplantation with the later incidence of chronic lung allograft dysfunction and graft survival. Among lung-transplanted patients between January 2009 and April 2018, only patients with sufficient T-cell measurements at 3 weeks after transplantation were included into the study. Putative regulatory T cells were defined as CD4+ CD25high T cells, detected in peripheral blood and further analyzed for CD127low , FoxP3+ , and CD152+ using fluorescence-activated cell sorting (FACS) analysis. Associations of regulatory T cells with chronic lung allograft dysfunction (CLAD) and graft survival were evaluated using Cox analysis. During the study period, 724 (71%) patients were included into the study. Freedom from chronic lung allograft dysfunction (CLAD) and graft survival amounted to 66% and 68% at 5 years. At the multivariable analysis, increasing frequencies of CD127low were associated with better freedom from CLAD (hazard ratio for each 1% increase of %CD127low , HR = 0.989, 95% CI = 0.981-0.996, P = 0.003) and better graft survival (HR = 0.991, 95% CI = 0.984-0.999, P = 0.026). A higher frequency of CD127low regulatory T cells in peripheral blood early after lung transplantation estimated a protective effect against chronic lung allograft dysfunction, mortality, and re-transplantation.

Background Psychometric hepatic encephalopathy score (PHES) needs local standardization. Aims This study aimed at standardizing PHES for Turkish patients and compare them with German norms; to determine minimal hepatic encephalopathy (mHE) prevalence with two different methods [PHES battery and Critical Flicker Frequency (CFF)] and to assess whether sub-tests of the battery can be used for screening for mHE. Methods Healthy volunteers (n = 816; 400 male) and cirrhotics (n = 124; 58 male) were included. For mHE diagnosis PHES score threshold was set at

Post-transplant hypertension (PTH) is a common complication in cyclosporine immunosuppressed patients; however choosing the right antihypertensive medication is challenging. In a long-term observational study (≤13y) we examined different antihypertensive medications on graft/patient survival of kidney recipients with pre-existing and PTH. Altogether thirty-three co-variables were analyzed including dose and type of immunosuppressive and antihypertensive medication, co-medications, serum biochemistries and the glomerular filtration rate (GFR). A Cox proportional-hazard multivariable survival model was developed to detect a Hazard Ratio (HR) of 3.0 at the Bonferroni corrected level α = 0.0015. Importantly, a significant relationship between immunosuppressive cyclosporine dose/serum concentration, systolic blood pressure (SBP) and GFR (p 0.001) was observed with post-transplant hypertension being a major risk factor (HR6.1) for graft/patient survival. Although all medications lowered effectively elevated SBP the risk of graft failure/death was significantly increased when hypertension was treated with ACE inhibitors or β-blockers (HR3.3 and 3.1) but not with angiotensin receptor- and/or Ca-channel blockers. Antihypertensive medication was associated with a decline in GFR but β-blockers alone or in combination with ARB and/or CCB improved GFR. Neither BMI nor any of the drug combinations used in immunosuppression, i.e. prednisolone, mycophenolic acid, azathioprine and/or sirolimus influenced patient and/or graft survival while decision tree analyses informed on complex dependencies between immunosuppressive medications, dose of anti-hypertensive drug and diuretics in the management of hypertension. In conclusion, our study is suggestive for graft/patient survival to be influenced by the class of antihypertensive medication. A prospective randomized clinical trial is needed to confirm the results.

Background: Psychometric hepatic encephalopathy score (PHES) needs standardization for countries and is used for minimal hepatic encephalopathy (mHE) diagnosis. Assessing it is cumbersome.Aims: To standardize PHES for Turkish patients and compare it with German norms; to determine mHE prevalence with two different methods and to assess whether the PHES test can be simplified.Methods: Healthy volunteers (n=816; 400 male) and cirrhotics (n=124; 58 male) were included. PHES score threshold was set at ≤-5 points and that of critical flicker frequency (CFF) at Results: Turkish norms displayed non-linear dependence on age and education. Rate of mHE in compensated cirrhotics was 29.8% and 27.4% with PHES and CFF tests, respectively. Compatibility of two tests was low (kappa coefficient 0.389); mHE prevalence decreased to 16% when both tests were combined. Turks performed worse vs Germans in the digit symbol (DS) and serial dotting (SD) subtests but generally performed better in the other subtests. In ROC analyzes of subtests, AUROC was 0.974 for DS+SD tests combined. Conclusions: PHES norms for Turks were developed. Use of 2 methods for diagnosing mHE may be important for research purposes. From a clinical perspective sensitivity with acceptable specificity may suffice. Combined use of DS and SD subtests of the PHES battery may well be suited for use in clinical practice.

Background Whether Borna disease virus (BDV-1) is a human pathogen remained controversial until recent encephalitis cases showed BDV-1 infection could even be deadly. This called to mind previous evidence for an infectious contribution of BDV-1 to mental disorders. Pilot open trials suggested that BDV-1 infected depressed patients benefitted from antiviral therapy with a licensed drug (amantadine) which also tested sensitive in vitro. Here, we designed a double-blind placebo-controlled randomized clinical trial (RCT) which cross-linked depression and BDV-1 infection, addressing both the antidepressant and antiviral efficacy of amantadine. Methods The interventional phase II RCT (two 7-weeks-treatment periods and a 12-months follow-up) at the Hannover Medical School (MHH), Germany, assigned currently depressed BDV-1 infected patients with either major depression (MD; N = 23) or bipolar disorder (BD; N = 13) to amantadine sulphate (PK-Merz®; twice 100 mg orally daily) or placebo treatment, and contrariwise, respectively. Clinical changes were assessed every 2–3 weeks by the 21-item Hamilton rating scale for depression (HAMD) (total, single, and combined scores). BDV-1 activity was determined accordingly in blood plasma by enzyme immune assays for antigens (PAG), antibodies (AB) and circulating immune complexes (CIC). Results Primary outcomes (≥25% HAMD reduction, week 7) were 81.3% amantadine vs. 35.3% placebo responder (p = 0.003), a large clinical effect size (ES; Cohen’s d) of 1.046, and excellent drug tolerance. Amantadine was safe reducing suicidal behaviour in the first 2 weeks. Pre-treatment maximum infection levels were predictive of clinical improvement (AB, p = 0.001; PAG, p = 0.026; HAMD week 7). Respective PAG and CIC levels correlated with AB reduction (p = 0,001 and p = 0.034, respectively). Follow-up benefits (12 months) correlated with dropped cumulative infection measures over time (p Conclusions Our findings indicate profound antidepressant efficacy of safe oral amantadine treatment, paralleling antiviral effects at various infection levels. This not only supports the paradigm of a link of BDV-1 infection and depression. It provides a novel possibly practice-changing low cost mental health care perspective for depressed BDV-1-infected patients addressing global needs. Trial registration The trial was retrospectively registered in the German Clinical Trials Registry on 04th of March 2015. The trial ID is DRKS00007649; https://www.drks.de/drks_web/setLocale_EN.do

Prospective randomized controlled trials are difficult to obtain if a promising new therapy has to be tested against seemingly obsolete alternatives. One method to address this problem is to compare the results of (multicentre) trials to literature results. However, previous treatment-era changes and population-dependent results complicate objective comparisons. The presented approach describes a method to objectify such comparisons in cases in which individual raw data regarding a new therapy have to be compared to summary results regarding a conventional alternative published in the literature. The chosen example is the introduction of bovine neck veins as a substitute for dysfunctional human pulmonary valves, and the conventional therapeutic alternative is pulmonary-artery homografts. Literature research, subgroup identification, filtering, endpoint remodelling, weighting and, if necessary, confidence-limit calculation yield adjusted comparisons. These individual comparisons are then aggregated, first by article and then over several articles (similar to meta-analyses), resulting in a differentiated panel of answers (Multiply Adjusted Comparisons). In situations in which extensive raw data regarding a new therapeutic alternative but no randomized controlled trials and no raw data from previous studies using the conventional therapeutic alternative are available, the proposed method identifies the best evidence and is by far superior to unadjusted direct comparisons or gut feelings.

Background One of the most disabling symptoms of hepatitis C virus (HCV)-infection is chronic fatigue. While this is accepted for HCV-polymerase chain reaction (PCR)-positive patients a relationship between HCV-infection and chronic fatigue is questioned after successful virus eradication. Aims As fatigue is a subjective criterion we aimed to evaluate in addition mood alterations and cognitive function in HCV-exposed patients with only mild liver disease and to assess a) possible interrelationships between these factors and health related quality of life, and b) the impact of viremia and former interferon treatment. Methods 159 anti-HCV-positive individuals without advanced liver disease answered health related quality of life (HRQoL), fatigue and depression questionnaires and underwent a battery of attention and memory tests. Accompanying diseases which could distort the results of the study such as HIV-co-infection or drug addiction were exclusion criteria. The patients were subdivided into four groups according to their viremia-status and interferon treatment history. Patients’ data were evaluated with respect to norms given in the respective test manuals and in addition compared to those of 33 age-matched healthy controls. Results Eighty-five percent of the patients had chronic fatigue, 50-60% mild depression or anxiety, 45% memory deficits and 30% attention deficits, irrespective of their HCV-viremia-status or treatment history. HRQoL correlated negatively with chronic fatigue (p

In this retrospective study, we analyzed the presence of any association of three CD4

Patients after orthotopic liver transplantation (OLT) may show cognitive dysfunction. To date, it has not been clear whether this dysfunction is due to residual hepatic encephalopathy (HE) or new-onset cognitive disturbances. Just as little is known about the course and clinical significance. In this prospective, observational study, 50 patients on the waiting list for OLT were examined in an outpatient setting before OLT and 6 and 12 months after OLT with the Psychometric Hepatic Encephalopathy Score, the Inhibitory Control Test, and the critical flicker frequency for the diagnosis of HE; in addition, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) was used as a tool for the measurement of global cognitive function. The Short Form 36 health survey was used to assess health-related quality of life. Twelve months after OLT, cognitive dysfunction characteristic of HE had resolved, but a secondary cognitive decline became apparent and had features different from those known with HE. Approximately 70% of the patients deteriorated in at least 1 cognitive domain of RBANS. This cognitive decline was related to neither a history of HE nor a history of alcohol abuse, but it was accompanied by a decline in the quality of life. In conclusion, OLT improves HE but is frequently followed by new-onset cognitive dysfunction, which can interfere with the quality of life.

Background & Aims Extrapyramidal and cerebellar symptoms belong to the most prominent features of episodic hepatic encephalopathy, and usually decrease upon ammonia-lowering therapy. Rapidly progressing parkinsonian symptoms, which are unresponsive to treatment of hepatic encephalopathy, indicate cirrhosis-related Parkinsonism. This study aims at analyzing the prevalence of cirrhosis-related Parkinsonism in patients with liver cirrhosis, and to study the functional status of the striatal dopaminergic system in these patients. Methods 214 patients with liver cirrhosis who were consecutively seen at the out-patient clinic for liver transplant candidates and/or at the transplantation wards at Hannover Medical School, between August 1, 2008 and March 31, 2011, underwent a standardized neurological examination while on the waiting list or immediately after liver transplantation. Single photon emission computer tomography (SPECT) using 123 I-beta-CIT, for the evaluation of the striatal dopamine transporter function, and 123 I-IBZM for the evaluation of the striatal dopamine D2 receptor availability, was performed in 6 patients with cirrhosis-related Parkinsonism. Results Cirrhosis-related Parkinsonism was diagnosed in 9 of 214 patients (4.2%). SPECT revealed significantly decreased dopamine receptor availability in 5 of 6 patients studied, and significantly decreased dopamine transporter availability in 3. Levodopa improved motor dysfunction in two of four patients treated, although only temporarily. Incomplete recovery was observed in two patients after liver transplantation. Conclusions Cirrhosis-related Parkinsonism is more frequent than presumed. The presented data suggest pre- and postsynaptic alteration of striatal dopaminergic neurotransmission as a possible cause of cirrhosis-related Parkinsonism and reveal the limited effects of dopaminergic therapy.

Objective Hepatic encephalopathy (HE) is a common complication of liver insufficiency. While there is widespread acceptance of its importance, there is no consensus on how best to diagnose and monitor HE. Objective To compare the four most favoured methods for the diagnosis of HE. Design 170 patients who were on the waiting list for liver transplantation as well as 86 healthy controls were included in the study. All patients and controls underwent the portosystemic encephalopathy syndrome test yielding the psychometric hepatic encephalopathy score (PHES), the repeatable battery for the assessment of neuropsychological status (RBANS), the inhibitory control test (ICT) and critical flicker frequency (CFF) measurement. Results PHES and ICT targets had the best sensitivity (85.7% vs 85.7%) and specificity (96.5% vs 97.6%) for the diagnosis of overt HE. CFF showed inferior sensitivity (40.9%) for the diagnosis of HE and dependency from previous alcohol abuse (p=0.015). Multiple regression analysis showed that all test results apart from PHES were influenced by secondary diagnoses such as diabetes mellitus and renal insufficiency. Conclusions In the German population of patients awaiting liver transplantation, PHES is the most robust method for the diagnosis and follow-up of HE.

Purpose Uncertainty exists about whether elderly patients benefit to the same extent as younger patients from combination therapy with irinotecan in the first-line treatment of metastatic colorectal cancer (CRC). Patients and Methods Combined analysis was carried out with source data from the fluorouracil (FU)/folinic acid (FA) and the irinotecan/FU/FA arms of four first-line, phase III trials of CRC to investigate the efficacy and safety of combination and monotherapy in elderly (age ≥ 70 years; n = 599) compared with younger (age < 70 years; n = 2,092) patients. Results Response rates were improved with irinotecan-based combination therapy compared with FU/FA in patients both younger than 70 years and ≥ 70 years (46.6% v 29.0% P < .0001; and 50.5% v 30.3%, P < .0001, respectively). With irinotecan/FU/FA, progression-free survival was better for both younger (hazard ratio [HR], 0.77; 95% CI, 0.70 to 0.85; P < .0001) and elderly patients (HR, 0.75; 95% CI, 0.61 to 0.90; P = .0026). In younger patients, overall survival was improved with combination therapy (HR, 0.83; 95% CI, 0.75 to 0.92; P = .0003). The same trend was observed in elderly patients (HR, 0.87; 95% CI, 0.72 to 1.05; P = .15). There was no significant interaction between treatment arm and age in the regression analysis. The expected differences in toxicity between combination and monotherapy in elderly and younger patients were observed. A significant interaction between treatment and age (cutoff, 70 years) for vomiting and hepatotoxicity was not confirmed by analysis that used age as a continuous variable. Conclusion Patients older than 70 years of age who were selected for inclusion in phase III trials derived similar benefits as younger patients from irinotecan-containing chemotherapy, and the risk of toxicity was similar.

Objectives Matrix metalloproteinase-9 (MMP-9) represents a promising marker for acute stroke management. In clinical studies MMP-9 has been quantified by ELISA using differing protocols. We aimed to establish a valid protocol by evaluation of preanalytics. Design and methods Blood from stroke patients (n = 28) and healthy controls (n = 28) was drawn into tubes containing different anticoagulants (EDTA, citrate, lithium-heparin (heparin) and heparin with proteinase inhibitors) and processed after 0, 60 and 240 min. MMP-9 plasma protein and mRNA from mononuclear leukocytes were determined. Results In regard to anticoagulants used, samples showed different MMP-9 protein baseline values and kinetics. Stable MMP-9 protein concentrations were only measured from EDTA samples. Particularly in samples with proteinase inhibitors protein and mRNA concentrations increased over time. Kinetics did not differ between patients and controls. Conclusions Preanalytics plays a key role for determination of MMP-9. EDTA seems to be a valid anticoagulant for MMP-9 protein measurement.

In this paper, we deal with the analysis of case series. The self-controlled case series method (SCCS) was developed to analyse the temporal association between time-varying exposure and an outcome event. We apply the SCCS method to the vaccination data of the German Examination Survey for Children and Adolescents (KiGGS). We illustrate that the standard SCCS method cannot be applied to terminal events such as death. In this situation, an extension of SCCS adjusted for terminal events gives unbiased point estimators. The key question of this paper is whether the general Cox regression model for time-dependent covariates may be an alternative to the adjusted SCCS method for terminal events. In contrast to the SCCS method, Cox regression is included in most software packages (SPSS, SAS, STATA, R, …) and it is easy to use. We can show that Cox regression is applicable to test the null hypothesis. In our KiGGS example without censored data, the Cox regression and the adjusted SCCS method yield point estimates almost identical to the standard SCCS method. We have conducted several simulation studies to complete the comparison of the two methods. The Cox regression shows a tendency to underestimate the true effect with prolonged risk periods and strong effects (Relative Incidence >2). If risk of the event is strongly affected by the age, the adjusted SCCS method slightly overestimates the predefined exposure effect. Cox regression has the same efficiency as the adjusted SCCS method in the simulation.

Background Recent studies have shown that narrow-band imaging (NBI) is a powerful diagnostic tool for the differentiation between neoplastic and non-neoplastic colorectal polyps. Objective To develop a computer-based method for classification of colorectal polyps. Design A prospective study. Setting University hospital. Patients A total of 214 patients with colorectal polyps who underwent a zoom NBI colonoscopy. Interventions A total of 434 detected polyps 10 mm or smaller were imaged and subsequently removed for histological analysis. Main Outcome Measurements Diagnostic performance in polyp classification by 2 experts, 2 nonexperts, and a computer-based algorithm. Results The expert group and the computer-based algorithm achieved a comparable diagnostic performance (expert group: 93.4% sensitivity, 91.8% specificity, and 92.7% accuracy; computer-based algorithm: 95.0% sensitivity, 90.3% specificity, and 93.1% accuracy) and were both significantly superior to the nonexpert group (86.0% sensitivity, 87.8% specificity, and 86.8% accuracy) in terms of sensitivity, negative predictive value, and accuracy. Subgroup analysis of 255 polyps 5 mm or smaller revealed comparable results without significant differences in the overall analysis of all polyps. Limitations No fully automatic classification system. Conclusions The study demonstrates that computer-based classification of colon polyps can be achieved with high diagnostic performance.

Outcome of patients with hepatocellular carcinoma is influenced by their histological grade. Invasive biopsy of the lesions is the gold standard in this regard.We therefore analysed the diagnostic accuracy of contrast enhanced ultrasound for non-invasive grading of hypervascular hepatocellular carcinoma in liver cirrhosis.According to the tumour perfusion kinetics on contrast enhanced ultrasound two grading groups were prospectively defined: well-differentiated hepatocellular carcinoma (US-G1) and higher grade hepatocellular carcinoma (US-G2/G3). Immediately after contrast enhanced ultrasound-grading, biopsies of hepatocellular carcinoma-lesions (n=95, 1.2-12.5 cm) were obtained and analysed for tumour grading (G). Descriptive statistics, sensitivity, specificity positive and negative predictive values, diagnostic likelihood ratios and interoperator reproducibility were calculated (κ).Histologically 77 (81.1%) patients had G2-G3 and 18 (18.9%) had G1 tumours. Higher grade hepatocellular carcinoma showed more often a washout in the portal or late phase (p0.0001). The sensitivity, specificity, positive predictive values and negative predictive values of contrast enhanced ultrasound for grading of hepatocellular carcinoma for all patients were 94% (CI: 72-99%), 95% (CI: 88-99%), 81% and 99% and for patients with tumours5 cm 100%(95% CI: 79-100), 96% (95% CI: 80-99), 92% and 100%. Positive and negative diagnostic likelihood ratios' were 18 and 26 and 0.06 and 0, respectively. κ=0.941 (p0.001).Contrast enhanced ultrasound has a high diagnostic value and reproducibility for non-invasive grading of hypervascular hepatocellular carcinoma1cm in patients with liver cirrhosis.

Patients with hepatitis C virus (HCV) infection frequently show neuropsychiatric symptoms. This study aims to help clarify the neurochemical mechanisms behind these symptoms and to add further proof to the hypothesis that HCV may affect brain function. Therefore, 15 patients who reported increasing chronic fatigue, mood alterations, and/or cognitive decline since their HCV infection underwent neurologic and neuropsychological examination, magnetic resonance imaging, 18F-fluoro-deoxy-glucose positron emission tomography of the brain, and single photon emission tomography of striatal dopamine and midbrain serotonin transporter (SERT) availability. None of the patients had liver cirrhosis. Patients’ data were compared with data of age-matched controls. In addition, regression analysis was performed between cognitive deficits, and mood and fatigue scores as dependent variables, and cerebral glucose metabolism, dopamine, or SERT availability as predictors. Patients showed significant cognitive deficits, significantly decreased striatal dopamine and midbrain SERT availability, and significantly reduced glucose metabolism in the limbic association cortex, and in the frontal, parietal, and superior temporal cortices, all of which correlated with dopamine transporter availability and psychometric results. Thus, the study provides further evidence of central nervous system affection in HCV-afflicted patients with neuropsychiatric symptoms. Data indicate alteration of dopaminergic neurotransmission as a possible mechanism of cognitive decline.

The self-controlled case series method (SCCS) was developed to analyze the association between a time-varying exposure and an outcome event. We consider penta- or hexavalent vaccination as the exposure and unexplained sudden unexpected death (uSUD) as the event. The special situation of multiple exposures and a terminal event requires adaptation of the standard SCCS method. This paper proposes a new adaptation, in which observation periods are truncated according to the vaccination schedule. The new method exploits known minimum spacings between successive vaccine doses. Its advantage is that it is very much simpler to apply than the method for censored, perturbed or curtailed post-event exposures recently introduced. This paper presents a comparison of these two SCCS methods by simulation studies and an application to a real data set. In the simulation studies, the age distribution and the assumed vaccination schedule were based on real data. Only small differences between the two SCCS methods were observed, although 50 per cent of cases could not be included in the analysis with the SCCS method with truncated observation periods. By means of a study including 300 uSUD, a 16-fold risk increase after the 4th dose could be detected with a power of at least 90 per cent. A general 2-fold risk increase after vaccination could be detected with a power of 80 per cent. Reanalysis of data from cases of the German case-control study on sudden infant death (GeSID) resulted in slightly higher point estimates using the SCCS methods than the odds ratio obtained by the case-control analysis.

Background: Radiation therapy to the mediastinum and breast can be associated with cardiac complications. Cardiac damage may manifest early during radiation therapy or occur late, years after radiation therapy has been finished. Hypothesis: Myocardial damage is associated with the release of both troponin I (TnI) and brain natriuretic peptide (BNP). The current study sought to determine whether radiation treatment to the mediastinum and breast leads to the release of cardiac biomarkers. Methods: The study comprised 23 patients: 18 with lung cancer and 5 with breast cancer. Radiation therapy was performed for up to 6 weeks. Total radiation dose was >45 Gy in each patient with a dose of 1.8 Gy per fraction. Blood samples to determine TnI and BNP were taken before and once a week during radiation therapy. Echocardiography was done before and after radiation had been finished. Results: Two patients died during the study. Both TnI and BNP levels increased significantly during the study (log10 scale); however, absolute and mean values remained on a relatively low level (mean preradiation and postradiation TnI: 0.007 ± 0.008, 0.014 ± 0.01 ng/ml; mean preradiation and postradiation BNP: 123 ± 147, 159 ± 184 pg/ml). Conclusion: Radiation therapy leads to cardiac cell damage and changes in the left ventricular loading conditions as suggested by a significant increase of the cardiac biomarkers TnI and BNP. Determination of serum levels seems to be superior to echocardiography in detecting radiation-induced cardiac damage. Serial measurements of cardiac biomarkers may facilitate the management of patients undergoing radiation therapy and may help to define subgroups at high risk of developing heart failure.

BACKGROUND AND STUDY AIMS: Narrow-band imaging (NBI) has been developed as a new technique to differentiate tissue patterns in vivo. The aim of this study was to evaluate the diagnostic accuracy of NBI endoscopy with and without high magnification for the differentiation of neoplastic from non-neoplastic colorectal polyps. PATIENTS AND METHODS: Among 200 colorectal polyps from 131 patients, 100 lesions were classified according to vascular patterns by NBI endoscopy with high optical magnification and 100 lesions by high-definition endoscopy without high magnification. Additionally, the clarity of the vessel network was assessed. Histologic analysis was performed on all lesions. RESULTS: NBI endoscopy with high magnification resulted in a sensitivity of 92.1 % and a specificity of 89.2 % for the differentiation of neoplastic versus non-neoplastic lesions. This performance was statistically comparable to high-definition NBI endoscopy without high magnification, which showed a sensitivity of 87.9 % and specificity of 90.5 %. However, vessel network was significantly better visualized by NBI endoscopy with optical magnification compared with high-definition NBI endoscopy without high magnification. In comparison with NBI endoscopy, white-light endoscopy, with or without magnification, resulted in inferior discrimination between neoplastic and non-neoplastic polyps. CONCLUSION: The results demonstrate that the superior visibility of capillary vessels by the NBI technique allows the evaluation of colorectal lesions - based on the vascular patterns - with high diagnostic accuracy. In clinical routine, high-definition NBI endoscopy without high magnification may be used to sufficiently predict colorectal polyp histology, and high magnification can additionally facilitate visualization of vascular networks.

OBJECTIVE: The midterm durability of bovine jugular veins (BJV) in children is comparable to that of homografts. We present the results of 64 bovine jugular vein implantations in adults in a pulmonary position. METHODS: Between August 2003 and July 2008, 60 patients (aged 18 to 65 years) received 64 BJVs. 97 % of them had had previous reconstructions of the right ventricular outflow tract. Diagnoses for treatment included tetralogy of Fallot (n = 49 patients), other congenital malformations (n = 14), and Ross operation (n = 1). Four bovine jugular veins had a diameter of 20 mm, the others had a diameter of 22 mm. RESULTS: Survival after 5 years was 98.4 +/- 1.6 %. Freedom from endocarditis: 84.8 +/- 8.0 % (4 patients required explantation for endocarditis); freedom from explantation for structural valve degeneration: 96.2 +/- 2.6 % (2 patients required explantation); freedom from intervention: 93.2 +/- 2.8 % (3 patients required intervention); moderate insufficiency: 62.9 +/- 15.1 % (8 patients); gradient > or = 50 mmHg: 79.6 +/- 7.4 % (7 patients); degeneration: 56.4 +/- 12.9 % (11); any adverse event: 43.1 +/- 12.8 % (15 patients); calcification or aneurysmal dilatation: 100 %. At any postoperative interval, more than 75 % of the BJVs had neither been explanted nor were they degenerated. CONCLUSION: The BJV might be a promising alternative to homografts, also in adults. Strict antibiotic prophylaxis is mandatory. A prospective randomized multicenter comparison of homografts and BJVs would help to identify the preferable conduit.

The study aimed to assess the time of labour onset and its symptoms as perceived by women in labour and midwives, and the relationship between these and first stage duration. A longitudinal cohort study of women with a singleton pregnancy in cephalic presentation was performed in 41 maternity units. The sample comprised 1,170 women, 611 nulliparae (np) and 559 multiparae (mp), who answered two standardized questions on the onset of labour and selected the applicable symptoms of labour onset from a list of eight. A multivariate Cox regression model was computed covering further perinatal factors. The median durations of the first stage of labour as assessed by the women themselves were 11 (np) and 6.5 h (mp), and as assessed by the midwives 7 (np) and 4 h (mp). Median time intervals between the start of labour onset symptoms as perceived by the women concerned and the midwives’ diagnoses varied greatly: the shortest related to watery fluid loss (np = 1.5 h, mp = 0.0 h), the longest to alterations in sleep patterns (np = 11.5 h, mp = 4.5 h). Irregular pain, watery fluid loss and the time between self-diagnosed and professionally diagnosed onset of labour were just as closely associated with the duration of the first stage of labour as perinatal factors. Significant perinatal factors were induction with oxytocin, herbal remedies and PROM. The perceptions of women in labour are as important as perinatal factors in determining the duration of the first stage of labour and should be taken into account in intrapartum care.

Platelet dysfunction due to antiplatelet therapy contributes to perioperative bleeding. Several trials investigating the influence of aspirin intake within the 5 days before surgery reported that transfusion requirements were either increased or not significantly affected by aspirin intake. Our objective was to compare the assessment of aspirin intake by patient self-reporting and by measurement of platelet function with regard to transfusion requirements.In a prospective trial, a standardized questionnaire was used in 100 patients for aspirin intake within the 5 days immediately before coronary artery bypass grafting. Whole blood platelet aggregation triggered by arachidonic acid was investigated using the Multiplate platelet function analyzer.Eleven of 23 patients with aspirin intake within the 5 days before the intervention showed an abnormal aggregation response. Nine of 77 patients who reported no aspirin intake before surgery had an abnormal aggregation response. There were no significant differences in chest tube drainage and red blood cell transfusion over the first 24 h postoperatively between patients with and without reported aspirin intake. There was no significant difference in chest tube drainage over the first 24 h postoperatively between patients showing normal or abnormal aggregation response. Patients with abnormal aggregation before intervention (51 U) received significantly more platelet transfusion than patients with normal aggregation (1.1 U compared to 0.3 U, P = 0.001).Our results suggest that arachidonic acid-induced aggregation in whole blood may be a better predictor of platelet-related coagulopathy and platelet transfusion than the assessment of aspirin intake by patient self-reporting.

Background and purpose: Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. Experimental approach: We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (NaV1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (NaV1.2) heterologously expressed in human embryonic kidney cell line 293. Key results: 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC50 for block of resting channels at −150 mV was 2.3, 3.9 and 11.3 μM in NaV1.4, respectively, and 29.2 μM for 4-chloropropofol in NaV1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, 4-bromopropofol and 4-chloropropofol in NaV1.4, and 450 nM for 4-chloropropofol in NaV1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). Conclusions and implications: Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions. British Journal of Pharmacology (2008) 155, 265–275; doi:10.1038/bjp.2008.255; published online 23 June 2008

Telomere dysfunction limits the proliferative capacity of human cells by activation of DNA damage responses, inducing senescence or apoptosis. In humans, telomere shortening occurs in the vast majority of tissues during aging, and telomere shortening is accelerated in chronic diseases that increase the rate of cell turnover. Yet, the functional role of telomere dysfunction and DNA damage in human aging and diseases remains under debate. Here, we identified marker proteins (i.e., CRAMP, stathmin, EF-1α, and chitinase) that are secreted from telomere-dysfunctional bone-marrow cells of late generation telomerase knockout mice (G4mTerc −/− ). The expression levels of these proteins increase in blood and in various tissues of aging G4mTerc −/− mice but not in aging mice with long telomere reserves. Orthologs of these proteins are up-regulated in late-passage presenescent human fibroblasts and in early passage human cells in response to γ-irradiation. The study shows that the expression level of these marker proteins increases in the blood plasma of aging humans and shows a further increase in geriatric patients with aging-associated diseases. Moreover, there was a significant increase in the expression of the biomarkers in the blood plasma of patients with chronic diseases that are associated with increased rates of cell turnover and telomere shortening, such as cirrhosis and myelodysplastic syndromes (MDS). Analysis of blinded test samples validated the effectiveness of the biomarkers to discriminate between young and old, and between disease groups (MDS, cirrhosis) and healthy controls. These results support the concept that telomere dysfunction and DNA damage are interconnected pathways that are activated during human aging and disease.

Background and study aims Chromoendoscopy in combination with magnifying endoscopy is useful in distinguishing neoplastic from non-neoplastic colorectal polyps. Narrow band imaging (NBI) has been developed as a new technique to differentiate tissue patterns in vivo. The aim of the present study was to directly compare the diagnostic values of chromoendoscopy and NBI for the differentiation of neoplastic from non-neoplastic colorectal polyps. Patients and methods In total, 200 colorectal polyps from 99 patients were distributed in a 1 : 1 ratio in order to analyze the surface according to the pit pattern classification and vascular patterns by either magnifying chromoendoscopy or NBI magnification. Histologic analysis was performed on all lesions. Results Using the Kudo classification of mucosal patterns, NBI with magnification resulted in a sensitivity of 90.5 % and a specificity of 89.2 % for the differentiation of neoplastic vs. non-neoplastic lesions. This performance was comparable to magnifying chromoendoscopy with a sensitivity of 91.7 % and a specificity of 90 %, respectively. Using vascular patterns for differentiation, NBI with magnification correctly identified 93.7 % of neoplastic polyps and 89.2 % of non-neoplastic colorectal lesions, whereas magnifying chromoendoscopy had a specificity of 95 % but a sensitivity of only 66.7 %. Conclusion NBI in combination with magnifying endoscopy is a promising tool for the differentiation of neoplastic from non-neoplastic colorectal polyps in vivo without the necessity of using dye. The detection of capillary vessels with NBI allows the evaluation of colorectal lesions based on the vascular patterns with high diagnostic accuracy.

Marrow fibrosis (MF) has rarely been studied in myelodysplastic syndromes (MDS). There are no data on occurrence and significance of MF in the context of the World Health Organization (WHO) classification of disease. In total, 349 bone marrow biopsies from 200 patients with primary MDS were examined for MF and its prognostic relevance. MF correlated with multilineage dysplasia, more severe thrombopenia, higher probability of a clonal karyotype abnormality, and higher percentages of blasts in the peripheral blood (P

In chronic myeloid leukemia (CML), imatinib may reverse bone marrow fibrosis (MF). Whether the unfavorable prognosis of MF is also reversed and whether imatinib guarantees against evolution of MF are unclear as yet. Fifty-nine patients with Ph+ CML treated with > or = 400 mg imatinib/day were examined for MF in 6- to 12-month intervals. Imatinib effectively reversed initial MF (P

There is a general agreement that blood alcohol concentrations (BACs) of about 0.05% result in impairment of the ability to drive. This fact has been supported by means of experiments. In addition, there are only a few studies to date investigating low BACs. The present study aims to investigate the extent and quality of cognitive changes in low BACs of around 0.03%. Sixteen healthy male subjects were examined in a double-blind, placebo-controlled study. During the trials the BAC was regulated to about 0.03%. As part of the study a record was made of the general level of intelligence, subjective impairments, possible depressive symptoms, general ability to perform, vigilance, divided attention, response times and performance of memory. Statistical analysis took place using the two-period crossover design. Verbal intelligence, general performance, vigilance (optical stimuli), divided attention, vigilance towards acoustic stimuli and the general response time to acoustic and visual-acoustic sequential stimuli, and memory were not impaired significantly by a BAC of around 0.03%. The total response and motor response time to optical stimuli as well as decision time about sequential optical stimuli were, however, significantly changed for BACs of around 0.03%. In conclusion, the present results show that already in BACs of around 0.03%, particular cognitive functions which rely on perception and processing of visual information, are significantly impaired. This was evident in the more complex and urgent tasks.

To investigate in a prospective randomized study setting if increased signal intensity of the cerebrospinal fluid (CSF) on fast FLAIR images is caused by high oxygen concentrations or anesthetic agents used during general anesthesia. 40 children (13 females/27 males) aged 3 months to 8 years were included. The study was approved by the ethics committee of the authors' institution. Parents gave written informed consent to participation of their children. Patients were randomly allocated to one of four different anesthesia techniques: sevoflurane plus 30% oxygen, sevoflurane plus 100% oxygen, propofol plus 30% oxygen, and propofol plus 100% oxygen. Hard copies of the FLAIR sequence were used for blinded analysis of the signal intensity of the subarachnoid space. No significant difference in signal intensity of the CSF was detected between anesthesia with propofol or sevoflurane irrespective of using 30% or 100% oxygen during anesthesia. On the other hand, signal intensity of the CSF was increased when sevoflurane or propofol was combined with 100% inhaled oxygen. The difference of the CSF signal intensity was most pronounced over the cerebral convexities (p < 0.005) but was also observed in the basal cisterns. Hyperintense signal in the subarachnoid space can result from supplemental oxygen during anesthesia. To avoid misdiagnosis such as subarachnoid hemorrhage, purulent meningitis or meningeal carcinomatosis, radiologists should be aware of the phenomenon of increased cerebrospinal fluid signal intensity on T2-weighted FLAIR images caused by supplemented oxygen.

This study was undertaken to compare the influence of balanced anesthesia utilizing sevoflurane and fentanyl with total intravenous anesthesia (TIVA) utilizing propofol and fentanyl on endocrine stress response in CABG patients. 40 patients scheduled for CABG were prospectively and randomly assigned to two groups. Group A (n=20) received balanced anesthesia with sevoflurane, fentanyl and pancuronium whereas group B (n=20) received TIVA with propofol, fentanyl and pancuronium. EEG and AEP were used to ensure a comparable depth of anesthesia. During 7 time points (T1 baseline, T2 intubation, T3 sternotomy, T4 aortic cannulation, T5 30 min on pump, T6 separation from CPB, T7 end of surgery), hemodynamic parameters and plasma levels of epinephrine, norepinephrine, ADH, ACTH and cortisol were determined. CK-MB, troponin T were measured postoperatively. Outcome was followed for 24 months. Biometric data were comparable between the groups. Plasma levels of epinephrine were significantly lower in group B than in group A at T4 (106 vs 63 pg/ml) and T5 (308 vs 67 pg/ml). Group mean value of ADH was lower in group B (p=0.02). Plasma levels of cortisol in group B were significantly lower at T5 (197 vs 140 ng/ml) and T7 (173 vs 120 ng/ml), when compared to group A. A positive correlation between ADH levels and the postoperative length of hospital stay was found. No significant differences occurred with respect to myocardial markers and hemodynamic data. At comparable depth of anesthesia, the endogenous stress response during TIVA with propofol was less pronounced than during balanced anesthesia with sevoflurane.

If the observation matrix of n independent p-dimensional normal vectors with common covariance matrix is transformed into an np-vector, linear models and hypotheses on the expectations can be formulated, that are not attainable in standard MANOVA or GMANOVA models. The distribution of an earlier proposed test procedure for this vectorized model is derived for p = 2, and its application is demonstrated for crossover and repeated measurement designs. Numerical results are compared in situations, in which both the standard and the vectorized model are applicable.

Background: The majority of patients with hepatitis C virus (HCV) infection suffer from disabling fatigue, cognitive dysfunction, and quality of life reduction. Meanwhile, there is increasing evidence that HCV infection can affect brain function. Recent studies have shown that fatigue and psychomotor slowing may resolve in patients with hepatitis C after treatment with ondansetron. This observation indicates alteration of serotonergic neurotransmission in HCV infected patients with chronic fatigue. Methods: Data from 20 HCV infected patients who were referred to our clinic because of disabling fatigue and cognitive decline of unknown cause were analysed retrospectively. Patients had undergone a diagnostic programme, including clinical and psychometric examination, electroencephalogram (EEG), magnetic resonance imaging of the brain, cerebrospinal fluid analysis, and I-123-beta-CIT (2β-carbomethoxy-3-β-(4-[ 123 I]iodophenyl)tropane) single photon emission computerised tomography (SPECT) studies of serotonin and dopamine transporter binding capacity. Results: All patients had pathological results on the fatigue impact scale. Two thirds of patients showed pathological attention test results. EEG, magnetic resonance imaging, and cerebrospinal fluid analysis were normal. Pathological dopamine transporter binding was present in 12/20 (60%) patients and pathological serotonin transporter binding in 8/19 (50%) patients. Patients with normal SPECT results did not significantly differ from controls with regard to psychometric test results. Interestingly, patients with both decreased serotonin and dopamine transporter binding showed significantly impaired performance in most of the tests applied. Comorbidity that could have impaired cerebral function was excluded in all patients. Conclusion: Our findings indicate alteration of serotonergic and dopaminergic neurotransmission in HCV infected patients with chronic fatigue and cognitive impairment.

Background The anaesthetic management of small infants during advanced laparoscopic surgery can be complicated by the major pathophysiological effects of increased intra-abdominal pressure. In this study haemodynamic, acid–base and blood volume changes were investigated during pneumoperitoneum in a small animal model. Methods Ten fasted, anaesthetized, mechanically ventilated and multi-catheterized New Zealand rabbits were randomized to carbon dioxide pneumoperitoneum (PP, duration 210 min, pressure 8 mm Hg) or control group. Cardiac index was determined using trans-cardiopulmonary thermodilution and total blood volume was measured by thermal-dye dilution with indocyanine green using a fibreoptic monitor system. Results In PP cardiac index (CI), central venous oxygen saturation ( S cv O 2 ), total blood volume (TBV) and base excess (BE) decreased significantly during the study whereas all variables remained constant in the control group. After release of PP the measured variables did not return to baseline within 30 min [PP, baseline vs study end: CI 108 (22) vs 85 (14) ml kg −1 min −1 , S cv O 2 81.4 (8.9) vs 56.7 (9.8)%, TBV 318 (69) vs 181 (54) ml, BE −1.9 (2.7) vs −8.7 (1.8) mmol litre −1 ; P Conclusion Our animal model suggests that a decrease in CI, metabolic acidosis and hypovolaemia could occur after prolonged low pressure pneumoperitoneum in small infants, which is possibly not detectable by the standard monitor setting. Therefore, the routine use of an extended monitoring including measurement of central venous oxygen saturation and acid–base parameters should be considered during and soon after operation, when pneumoperitoneum will last longer than 2 h.

Objective To assess whether the way in which women experience the onset of their labour influences the duration of their labour. Design Longitudinal study on a convenient sample of women in spontaneous labour with a singleton pregnancy in cephalic presentation at term. Setting University hospital in Germany. Population/Sample Six hundred and fifty-one women (347 primiparae and 304 parae). Methods Women recorded how and when labour had started. Responses were subjected to structured content analysis. Two investigators independently subdivided women's reported signs and symptoms into eight predefined categories. These data were related to maternal characteristics and to the course and outcome of labour as documented in the perinatal record. Main outcome measures Women's perception of how labour had started, interval between onset of labour and rupture of the membranes and duration of first stage labour and overall duration of labour. Results Only 60% of women reported contractions as a sign of the onset of their labour. These women had a longer interval between the onset of labour and rupture of the membranes but a similar duration of labour when compared with women who did not report contractions as a sign of the onset of labour. Self-reported loss of amniotic fluid was the only sign that showed a consistent relationship with the duration of labour. Other patterns of labour onset had no effect on the duration of labour. Conclusion Irrespective of whether they have given birth before, women experience their onset of labour in a variety of ways. A large proportion of these experiences bear no resemblance to the classical diagnosis of labour and most are unrelated to the duration of labour.

Background: Recently it has been shown that biphasic external shocks are more effective in the treatment of ventricular fibrillation (VF) compared with monophasic external shocks in terms of number of defibrillation attempts and maximal energy used for termination of VF. Biphasic defibrillators apply different biphasic impulse forms, depending on technology. To the authors’ knowledge, there are no existing data concerning the effects of rectilinear biphasic internal shocks in patients undergoing cardiac surgery. The purpose of this study was to compare monophasic with rectilinear biphasic internal shock waveforms for termination of VF in patients undergoing cardiac surgery. Methods: One hundred thirty-four patients scheduled for elective cardiac surgery were prospectively randomized either to monophasic (group A) or biphasic (group B) internal defibrillation. Defibrillation was started with 7 J and increased stepwise to 30 J in each group until successful termination of VF after aortic declamping. The number of defibrillations, as well as the cumulative and maximal energy for termination of VF, were determined. Preoperatively, intraoperatively, and postoperatively troponin T, total creatine phosphokinase (CPK), and CPK- MB isoenzymes were measured. Results: In 64 patients (47%) VF occurred. The groups consisted of 32 patients each. The number of defibrillations (1.3 ± 0.6 v 1.9± 1.2; p = 0.013), maximal energy per patient (7.9 ± 2.5 v 11.6 ± 7.32; p = 0.006), and cumulative energy (10.1 ±6.1 v 21.3 ± 24.1; p = 0.016) for successful termination of VF were significantly reduced in group B. Troponin T, CPK, and CPK-MB did not differ between groups. Conclusions: Results of this study indicate that rectilinear biphasic internal defibrillation is more effective in the treatment of VF during cardiac surgery than is monophasic defibrillation. However, no significant difference in myocardial damage could be detected between groups.

The aim of this study was to examine the possible induction of micronuclei in erythrocytes of the peripheral blood and bone marrow and in keratinocytes and spleen lymphocytes of mice exposed to radiofrequency (RF) radiation for 2 h per day over periods of 1 and 6 weeks, respectively. The applied signal simulated the exposure from GSM900 and DCS1800 handsets, including the low-frequency amplitude-modulation components as they occur during speaking (GSM Basic), listening (DTX) and moving within the environment (handovers, power control). The carrier frequency was set to the center of the system's uplink band, i.e., 902 MHz for GSM and 1747 MHz for DCS. Uniform whole-body exposure was achieved by restraining the mice in tubes at fixed positions in the exposure setup. Mice were exposed to slot-averaged whole-body SARs of 33.2, 11.0, 3.7 and 0 mW/g during the 1-week study and 24.9, 8.3, 2.8 and 0 mW/g during the 6-week study. Exposure levels for the 1- and 6-week studies were determined in a pretest to confirm that no thermal effect was present that could influence the genotoxic end points. During both experiments and for both frequencies, no clinical abnormalities were detected in the animals. Cells of the bone marrow from the femur (1-week study), erythrocytes of the peripheral blood (6-week study), keratinocytes from the tail root, and lymphocytes from the spleen (both studies) were isolated on slides and stained for micronucleus analysis. Two thousand cells per animal were scored in erythrocyte and keratinocyte samples. In spleen lymphocytes, 1000 binucleated lymphocytes were scored for each animal. The RF-field exposure had no influence on the formation of red blood cells. After 1 week of exposure, the ratio of polychromatic to normochromatic erythrocytes was unchanged in the treated groups compared to the sham-exposed groups. Furthermore, the RF-field exposure of mice did not induce an increase in the number of micronuclei in erythrocytes of the bone marrow or peripheral blood, in keratinocytes, or in spleen lymphocytes compared to the sham-treated control.

Phenol derivatives constitute a family of neuroactive compounds. The aim of our study was to identify structural features that determine their modulatory effects at glycine receptors. We investigated the effects of four methylated phenol derivatives and two halogenated analogues on chloride inward currents via rat alpha(1) and alpha(1)beta glycine receptors, heterologously expressed in HEK 293. All compounds potentiated the effect of a submaximal glycine concentration in both alpha(1) homomeric and alpha(1)beta glycine receptors. While the degree of maximum potentiation of the glycine 10 microM effect in alpha(1)beta receptors was not different between the compounds, the halogenated compounds achieved half-maximum potentiating effects in the low microM range -- at more than 20-fold lower concentrations compared with their nonhalogenated analogues (P 300 microM in the halogenated compounds. Neither the number nor the position of the methyl groups significantly affected the EC(50) for coactivation. Only the bimethylated compounds 2,6 and 3,5 dimethylphenol (at concentrations >1000 microM) directly activated both alpha(1) and alpha(1)beta receptors up to 30% of the maximum response evoked by 1000 microM glycine. These results show that halogenation in the para position is a crucial structural feature for the potency of a phenolic compound to positively modulate glycine receptor function, while direct activation is only seen with high concentrations of compounds that carry at least two methyl groups. The presence of the beta subunit is not required for both effects.

Background: Labor experiences involve many dimensions that change during labor but are rarely measured contemporaneously and longitudinally. We examined pain and “fitness” aspects of women's labor experience and assessed the acceptability to participants. Methods: Thirty nulliparas and 20 multiparas in term labor indicated pain and fitness every 45 minutes in contraction-free intervals on visual analog scales from 0 to 10. Fitness implied both physical and psychological strength. Data were analyzed cross-sectionally and longitudinally, with adjustment for analgesia and time dependency. Women received feedback and evaluated their participation on the first day postpartum. Results: Measurements of pain and fitness ranged from 2 to 22 per woman (mean ± SD: 7.4 ± 4.4). Pain scores showed various patterns, mostly increasing from 1.4 (± 1.9) at the first to 6.6 (± 3.8) at the last measurement in nulliparas and from 1.3 (± 2.1) to 6.2 (± 4.0) in multiparas. One half of the women declined steadily in fitness throughout labor, occasionally after a slight increase early on. Multiparas entered labor more fit (5.9 ± 3.0) than nulliparas (3.9 ± 2.7), but showed a sharper decline so that the difference leveled out just before birth. Although fitness at any one time did not reflect pain levels, fitness and pain were inversely related, especially in nulliparas (p = 0.003). Analgesia affected pain scores but affected fitness only a little. Women's responses were mainly positive, especially in appreciating the feedback. Nevertheless, 32 percent of women skipped one or more measurements, often toward the end or when too close to a contraction. Conclusions: Pain and “fitness” are two distinctly different dimensions of labor experience. Repeated longitudinal measurements of elements of well-being are clearly feasible and acceptable to laboring women. They may be useful to assess how labor events and interventions affect women's well-being.

Background/Aims Up to 50% of patients infected with the hepatitis C virus (HCV) complain of chronic fatigue and difficulties in concentration and memory. The aim of the present study was to seek evidence for the presence of central nervous system involvement in HCV infected patients with only mild liver disease. Methods Thirty HCV infected patients with normal liver function, 15 of whom were identified as having mild and 15 moderate to severe fatigue using the fatigue impact scale, underwent neurological and neuropsychological examination, electroencephalography (EEG) and cerebral proton magnetic resonance imaging (MRI) and spectroscopy (MRS). Fifteen healthy volunteers, matched for age and educational attainment, served as controls. Results In comparison to the healthy controls the patients with HCV infection showed evidence of cognitive impairment, primarily attention and higher executive functions, higher levels of anxiety and depression and impairment of quality of life. In addition they showed a significant decrease of the N -acetyl-aspartate/creatine ratio in the cerebral cortex on 1H MRS while the EEG was slowed in 25%. In general the deficits were more marked in the patients with moderate rather than mild fatigue. Conclusions The data provide evidence of central nervous system involvement in patients with HCV infection.

Efficacy of 5-fluorouracil-based chemotherapy in elderly patients with metastatic colorectal cancer: a pooled analysis of clinical trials Background: Recently published population-based investigations showed elderly patients to be underrepresented in clinical trials and less often treated according to the standard therapy. Although there is evidence that elderly patients benefit from adjuvant (radio-) chemotherapy to the same extent as younger patients, no large series describes the influence of age on efficacy of chemotherapy in metastatic colorectal cancer. Patients and methods: We carried out a retrospective analysis using source data of 3825 patients who received 5- fluorouracil (5-FU)-containing treatment in 22 European trials and identified 629 patients with an age of greater than or equal to70 years. Results: We found an equal overall survival in elderly patients [10.8 months, 95% confidence interval (0) 9.7-11.8] and in younger patients (11.3 months, 95% CI 10.9- 11.7; P=0.31). Response rate did not differ between age groups greater than or equal to70 and

Bone marrow fibrosis (MF) has been shown to indicate therapy failure in Ph(+) chronic myeloid leukemia (CML). However, the results on the development of MF during interferon-alpha therapy of CML are controversial. The significance of the interferon dose has not been considered as yet. In total, 627 bone marrow biopsies taken prospectively from 200 patients with CML recruited in two studies using different doses of interferon-alpha +/- low-dose cytosine arabinoside were examined for MF before and during therapy. The results showed that the risk of MF depended significantly on the interferon-alpha dose applied (P0.000005). MF progressed during low-dose therapy (3 x 5 x 10(6) IU/week), but was prevented from progression when applying high dose (5 x 10(6) IU/m(2)/per day). MF disappeared when high-dose interferon-alpha was combined with low-dose cytosine arabinoside (P0.000005). The risk of death markedly increased when MF occurred or progressed (P0.0009), independent of all other prognostic factors evaluated including the cytogenetic response. In conclusion, the effectiveness of interferon-alpha on MF depends on the treatment intensity. MF reverses when combining high-dose interferon-alpha with low-dose cytosine arabinoside, but progresses when applying low-dose interferon-alpha. MF appears to be a significant early indicator of ineffective therapy in CML.

Objectives: The Risk Adjusted classification for Congenital Heart Surgery (RACHS-1) was published in January 2002, based on 4370 operations registered by the Pediatric Cardiac Care Consortium. It is designed for being easily applicable also for retrospective analysis of hospital discharge data sets; the classification was not developed for patients with heart transplantations, ventricular assist devices or patients above 18 years. We apply this classification to our 2368 correspondent procedures that were performed consecutively on 2223 patients between June 1996 and October 2002 in Bad Oeynhausen and analyze its relation to mortality and length of hospital stay. Methods: The procedures were grouped by the 6 RACHS-1 categories. Groping criteria were mainly the performed procedures; for few procedures age or diagnoses are needed in addition. The classification process itself took less than 10 working hours. Risk group frequencies in our/ the PCCC population were 1: 368/964 (15.5%/22.0%), 2: 831/1433 (35.1%/33.1%), 3: 744/1523 (31.4%/34.7%), 4: 284/276 (12.0%/6.3%), 5: 4/4 (0.2%/0.1%), 6: 137/168 (5.3%/3.8%). 18.8%/19.2% were under 1 month, 37.5%/31.6% 1 ‐12 months of age, respectively. Results: Hospital mortality (%) in our population/ the PCCC Group 1 ‐ 6 was: 0.3/0.4, 4.0/3.8, 5.6/8.5, 9.9/19.4, 50.0/0, 40.1/47.7%. Geometric means of total (13.1, 19.6, 23.5, 29.1, 31.5, 52.6 days, respectively) and postoperative length of stay of survivors show significant differences between the single risk groups. The prediction capacity of the score as expressed by the area under the receiver ‐ operator curve was nearly equal to the value found for the American hospital discharge data sets. Length of stay rises exponentially with the RACHS-1 category. However, the RACHS-1 category explains only 13.5% of the total and 16.8% of individual postoperative lengths of hospital stay in survivors. Conclusion: The RACHS-1 classification is applicable to European pediatric populations, too. Category Distribution, outcome class distinction capacity, distribution and mortality are similar. RACHS-1 is able to classify patients into significantly different groups concerning total and postoperative hospital stay duration, although there remains a large variability within the groups. q 2004 Elsevier B.V. All rights reserved.

Clinical and histopathological findings hint at regional differences in the brain's sensitivity to metabolic changes in cirrhosis. The aim of the present study was to examine regional differences in cerebral ammonia metabolism in patients with cirrhosis and grade 0-to-I hepatic encephalopathy (HE). 13N-ammonia, 15O-water positron emission tomography (PET) and magnetic resonance imaging (MRI) were performed. Quantitative values of cerebral blood flow (CBF) and the initial cerebral ammonia uptake rate (K1) were derived for several regions of interest from images of the desired parameters after interactive coregistration with the patients' MRI-studies. CBF (mL/mL/min), K1 (mL/mL/min), and the ammonia extraction fraction (K1/CBF) showed marked regional variance with the highest levels in the thalamus, the lenticular nucleus, and the cerebellum. In conclusion, the regional differences in cerebral ammonia uptake correspond to the distribution of histopathological changes in the brain of patients with cirrhosis as well as clinical features of HE, characterized by signs of basal ganglia and cerebellar dysfunction with corresponding signs of functional impairment, especially of the frontal cortex and cingulate gyrus. (HEPATOLOGY 2004;40:73–79.)

Proteomic patterns established with capillary electrophoresis and mass spectrometry for diagnostic purposes. Background Proteomics applied in large scale may provide a useful diagnostic tool. Methods We developed an online combination of capillary electrophoresis with mass spectrometry, allowing fast and sensitive evaluation of polypeptides found in body fluids. Utilizing this technology, polypeptide patterns from urine are established within 45 minutes. About 900 to 2500 polypeptides as well as their concentrations are detected in individual urine samples without the need for specific reagents such as antibodies. To test this method for clinical application, we examined spot urine samples from 57 healthy individuals, 16 patients with minimal change disease (MCD), 18 patients with membranous glomerulonephritis (MGN), and 10 patients with focal segmental glomerulosclerosis (FSGS). Results One-hundred seventy-three polypeptides were present in more than 90% of the urine samples obtained from healthy individuals, while 690 polypeptides were present with more than 50% probability. These data permitted the establishment of a "normal" polypeptide pattern in healthy individuals. Polypeptides found in the urine of patients differed significantly from the normal controls. These differences allowed the distinction of specific protein spectra in patients with different primary renal diseases. Abnormal pattern of proteins were found even in urine from patients in clinical remission. Conclusion The data indicate that capillary electrophoresis with mass spectrometry coupling provides a promising tool that permits fast and accurate identification and differentiation of protein patterns in body fluids of healthy and diseased individuals, thus enabling diagnosis based on these patterns.

1. The interaction of lidocaine-like local anaesthetics with voltage-operated sodium channels is traditionally assumed to be characterized by tighter binding of the drugs to depolarized channels. As inactivated and drug-bound channels are both unavailable on depolarization, an indirect approach is required to yield estimates for the dissociation constants from channels in inactivated states. The established model, originally described by Bean et al., describes the difference in affinity between resting and inactivated states in terms of the concentration dependence of the voltage shift in the availability curve. We have tested the hypothesis that this model, which assumes a simple Langmuir relationship, could be improved by introducing a Hill-type exponent, which would take into account potential sources of cooperativity. 2. Steady-state block by lidocaine was studied in heterologously (HEK 293) expressed human skeletal muscle sodium channels and compared with experimental data previously obtained for 2,6-dimethylphenol, 3,5-dimethyl-4-chlorophenol, and 4-chlorophenol. Cells were clamped to membrane potentials from -150 to -5 mV, and a subsequent test pulse was used to assess the number of channels available to open. 3. All compounds shifted the voltage dependence of channel availability in the direction of negative prepulse potentials. Prediction of the concentration dependence of the voltage shift in the availability curve was improved by the modified model, as shown by a marked reduction in the residual sum of squares. 4. For all compounds, the Hill-type exponent was significantly greater than one. These results could be interpreted in the light of the contemporary hypothesis that lidocaine functions as an allosteric gating effector to enhance sodium channel inactivation by strengthening the latch mechanism of inactivation, which is considered to be a particle-binding process allosterically coupled to activation. Alternatively, they could be interpreted by postulating additional binding sites for lidocaine on fast-inactivated sodium channels.