Determination of Turkish norms of psychometric tests for diagnosing minimal hepatic encephalopathy and proposal of a high sensitive screening test battery.

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 ≤ - 5 points and that of CFF at < 39 Hz. For comparing German and Turkish norms, datasets were combined. Multiple backward procedure was applied to assess effects of age, sex and education on single tests of the battery. Receiver operating characteristic (ROC) curves were created for assessing diagnostic capabilities of subtests of the battery. RESULTS: PHES norms for Turks were developed. MHE prevalence in compensated cirrhotics was 29.8% and 27.4% with PHES and CFF tests, respectively, with low compatibility (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 performed better in other subtests. In ROC analyzes of subtests, the combination of DS + SD tests achieved an AUROC of 0.974 versus PHES. CONCLUSIONS: Use of two methods for diagnosing mHE is important for research purposes. From a clinical perspective, sensitivity with acceptable specificity may suffice for screening instruments for mHE. Combined use of DS and SD subtests of the PHES battery appears suitable for this purpose.

Temperatures in the pulpal cavity during orthodontic bonding using an LED light curing unit : An in vitro pilot study.

PURPOSE: During bracket bonding, patients often report about thermosensitivity. The reason could be that modern light emitting diode (LED) light curing units run with intensities up to 3200 mW/cm2. In this in vitro pilot study with nonpulpal circulation approaches, the temperatures in the pulpal cavity were measured. METHODS: The study included 60 extracted teeth divided into four equal groups: lower and upper incisors, premolars and molars. Starting at 37 °C (body temperature) as the reference, the temperature increase was measured for the first series on each tooth without a bracket, without and with a recommended hygienic barrier case for the LED light curing unit, and exposition to light once versus twice. The distance between the tooth and light curing unit was 3 mm. In the second test series, a metal bracket was also bonded to each tooth. In the third series, the light exposition distance was increased to 4 mm. RESULTS: In all three test series, significant intrapulpal temperature increase was found: The highest temperatures were recorded after exposure to light once without the hygienic barrier case. In the first test series, this approach showed temperatures even higher than 42.5 °C in the lower incisors (average 42.99 ± 2.23 °C) and premolars (average 42.94 ± 2.15 °C). CONCLUSIONS: Significant increases in the temperature of the pulpal cavity (up to 42.5 °C) may occur during bonding brackets according to the manufacturer's recommendation with an LED light curing unit with in vitro nonpulpal circulation approaches. Therefore it could be reasonable to critically question the recommendation of the manufacturer.

Antiviral treatment perspective against Borna disease virus 1 infection in major depression: a double-blind placebo-controlled randomized clinical trial.

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 < 0.001). In vitro, amantadine concentrations as low as 2.4-10 ng/mL (50% infection-inhibitory dose) prevented infection with human BDV Hu-H1, while closely related memantine failed up to 100,000-fold higher concentration (200 µg/mL). 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.

Increased frequency of CD4+ CD25high CD127low T cells early after lung transplant is associated with improved graft survival - a retrospective study.

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.

Treatment of cyclosporine induced hypertension: Results from a long-term observational study using different antihypertensive medications.

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 ß-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 ß-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.

Multiply adjusted comparisons: A meta-analysis method to compare single-arm clinical-trial data to literature results regarding a competitor.

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.

Outcome of acute respiratory distress syndrome in university and non-university hospitals in Germany.

BACKGROUND: This study investigates differences in treatment and outcome of ventilated patients with acute respiratory distress syndrome (ARDS) between university and non-university hospitals in Germany. METHODS: This subanalysis of a prospective, observational cohort study was performed to identify independent risk factors for mortality by examining: baseline factors, ventilator settings (e.g., driving pressure), complications, and care settings-for example, case volume of ventilated patients, size/type of intensive care unit (ICU), and type of hospital (university/non-university hospital). To control for potentially confounding factors at ARDS onset and to verify differences in mortality, ARDS patients in university vs non-university hospitals were compared using additional multivariable analysis. RESULTS: Of the 7540 patients admitted to 95 ICUs from 18 university and 62 non-university hospitals in May 2004, 1028 received mechanical ventilation and 198 developed ARDS. Although the characteristics of ARDS patients were very similar, hospital mortality was considerably lower in university compared with non-university hospitals (39.3% vs 57.5%; p = 0.012). Treatment in non-university hospitals was independently associated with increased mortality (OR (95% CI): 2.89 (1.31-6.38); p = 0.008). This was confirmed by additional independent comparisons between the two patient groups when controlling for confounding factors at ARDS onset. Higher driving pressures (OR 1.10; 1 cmH2O increments) were also independently associated with higher mortality. Compared with non-university hospitals, higher positive end-expiratory pressure (PEEP) (mean ± SD: 11.7 ± 4.7 vs 9.7 ± 3.7 cmH2O; p = 0.005) and lower driving pressures (15.1 ± 4.4 vs 17.0 ± 5.0 cmH2O; p = 0.02) were applied during therapeutic ventilation in university hospitals, and ventilation lasted twice as long (median (IQR): 16 (9-29) vs 8 (3-16) days; p < 0.001). CONCLUSIONS: Mortality risk of ARDS patients was considerably higher in non-university compared with university hospitals. Differences in ventilatory care between hospitals might explain this finding and may at least partially imply regionalization of care and the export of ventilatory strategies to non-university hospitals.

Central nervous system complications after liver transplantation: common but mostly transient phenomena.

Although central nervous system complications (CNSCs) are common after orthotopic liver transplantation (OLT), standardized prospective studies are still lacking. This prospective study was aimed at determining the incidence of CNSCs, describing their clinical presentations, and establishing predicting factors. One hundred thirty-six adult patients who underwent OLT at Hannover Medical School between December 2008 and June 2011 were included. Weekly examinations were performed by a neurologist during the hospital stay after OLT. Patient data, donor data, and operative and postoperative variables were collected. Patients with cerebral dysfunction after OLT underwent a diagnostic work-up, which included brain imaging and, if necessary, cerebrospinal fluid analysis. Patients with central nervous system (CNS) symptoms but negative imaging and cerebrospinal fluid results and patients with pontine myelinolysis or posterior reversible encephalopathy syndrome were placed in a metabolic-toxic CNSC group, and patients with strokes, intracranial hemorrhaging, or CNS infections were placed in a nonmetabolic CNSC group. Multiple regression analysis was used to identify independent risk factors for the development of metabolic-toxic CNSCs. After excluding two patients that died after OLT without regaining consciousness, forty-four (32.8%) patients developed CNSCs: 37 of these patients (27.6%) had metabolic-toxic CNSCs, and 7 (5.2%) had nonmetabolic CNSCs. Acute-on-chronic liver failure, the number of subsequent surgeries, and primary sclerosing cholangitis were identified as independent predictors for the development of metabolic-toxic CNSCs. Metabolic-toxic CNSCs were associated with prolonged hospital stays, and nonmetabolic CNSCs were associated with higher mortality. In conclusion, CNSCs are common and relevant complications after OLT. Patients after OLT, especially with risk factors, should undergo a regular standardized neurological examination that would allow early detection of these complications.

New-onset cognitive dysfunction impairs the quality of life in patients after liver transplantation.

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.

The timing of amniotomy, oxytocin and neuraxial analgesia and its association with labour duration and mode of birth.

PURPOSE: The objective was to study the association of different timings of intrapartum interventions with labour duration and mode of birth. METHODS: A longitudinal cohort study of 2,090 nulliparae and 1,873 multiparae with a singleton in cephalic presentation was conducted. We assessed the association between, on the one hand, the timing of augmentation with oxytocin, neuraxial analgesia and amniotomy, and, on the other hand, the time to complete dilatation, spontaneous or operative vaginal delivery or caesarean delivery, using a Cox regression model accounting for standard confounders. RESULTS: From amniotomy onwards labour was accelerated. In multiparae, amniotomy was associated with an initial 6.6-fold acceleration, decreasing first stage duration until the hazard ratio reached around 3.5, where the intervention was performed 5 h after labour onset; thereafter, acceleration continued with a hazard ratio of around 3. In nulliparae, neuraxial analgesia was associated with a shorter first stage when administered between 7 and 11 h after labour onset; the later it was performed, the less likely was spontaneous birth and the more likely an operative vaginal birth in nulliparae or a caesarean section in multiparae. The start of oxytocin augmentation was associated with acceleration towards both full dilatation and caesarean section during first stage and an increased risk of operative vaginal birth during second stage. The later oxytocin augmentation started, the more likely it was that spontaneous birth would be retarded in multiparous women. CONCLUSIONS: Applying amniotomy, oxytocin and neuraxial analgesia at their optimal timing may improve the progress and outcome of labour.

Asymmetric dimethylarginine in response to recombinant tissue-type plasminogen activator and erythropoietin in acute stroke.

BACKGROUND AND PURPOSE: In the German Multicenter Erythropoietin (EPO) Stroke Trial, patients not receiving thrombolysis most likely benefited from EPO on clinical recovery, whereas a combination of rtPA and EPO was associated with increased mortality. We investigated whether the combination of rtPA and EPO increased release of the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA), and thereby potentially deteriorated ischemic stroke outcome, as suggested from experimental data. METHODS: ADMA was determined in serum samples from 90 patients of the German Multicenter EPO Stroke Trial taken at days 1 (within 6 hours after symptom onset), 2, 3, 4, and 7 after stroke using high-performance liquid chromatography-tandem mass spectrometry. ADMA was analyzed for the different treatment groups (EPO, n=25; placebo, n=30; rtPA+placebo, n=18; EPO+rtPA, n=17). Clinical outcome was expressed as difference between National Institutes of Health Stroke Scale at baseline and 90 days. RESULTS: ADMA levels significantly increased during the observation time in EPO, EPO+rtPA, and placebo groups (P<0.05). A treatment effect on ADMA levels was revealed by repeated measures ANOVA only in the rtPA+placebo group (P=0.027). Here, ADMA levels were decreased compared with the placebo group (P<0.05). Both the EPO and the rtPA+placebo groups in the Hannover subgroup of the EPO trial had better outcome than the placebo group (P<0.05). CONCLUSIONS: Our data underscore the potential benefit of EPO in ischemic stroke. The hypothesis from experimental data, that EPO treatment increases ADMA in stroke patients, was disproved. Further studies are needed to clarify whether decreased ADMA might contribute to therapeutic rtPA effects.

Comparison of the most favoured methods for the diagnosis of hepatic encephalopathy in liver transplantation candidates.

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.

Cirrhosis-related Parkinsonism: prevalence, mechanisms and response to treatments.

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.

Neurologic manifestations of E coli infection-induced hemolytic-uremic syndrome in adults.

OBJECTIVE: To describe the neurologic and neuroradiologic complications of Shiga toxin producing Escherichia coli infection (STEC)-associated hemolytic-uremic syndrome (HUS) in adults. METHODS: All 52 adult patients with STEC O104:H4 infection cared for at Hannover Medical School during the outbreak in Germany through May-July 2011 are considered in this observational study. Forty-three of the 52 patients underwent a standard neurologic diagnostic procedure including clinical examination, Mini-Mental State Examination, and Glasgow Coma Scale Score. Thirty-six patients underwent EEG, and 26 had cerebral MRI, 9 of them repeatedly. Case records of 9 patients who had not been seen by a neurologist were analyzed retrospectively. RESULTS: Forty-eight of the 52 patients had HUS. All but 1 of these showed neurologic symptoms. Focal neurologic signs like double vision, difficulties in finding words, or hyperreflexia were present in 23, additional deficits in orientation, attention, memory, or constructive abilities in 9, and marked impairment of consciousness in 15. MRI showed brainstem, midbrain, thalamus, corpus callosum, and white matter lesions in half of the patients, predominantly in diffusion-weighted images. The extent of MRI lesions did not correlate with clinical symptoms. General slowing but no focal alteration was found in half of the patients examined by EEG. CONCLUSION: Our findings suggest a toxic-metabolic pathology behind the neurologic impairment instead of multiple infarction due to microthrombosis. Future studies should aim to clarify if early antibiotic therapy or bowel cleansing might help to decrease the rate of neurologic complications in STEC-HUS.

Pollen starch granules in bronchial inflammation.

BACKGROUND: Pollen grains with a diameter of more than 10 µm preferentially deposit in the upper airways. Their contribution to lower airway inflammation is unclear. One hypothesis is that lower airway inflammation is mainly caused by allergen containing pollen starch granules, which are released from the pollen grains and can easily enter the peripheral airways because of their smaller size. OBJECTIVE: To investigate the differential effect of pollen grains and pollen starch granules on nasal symptoms and lower airway inflammation. METHODS: In a 2-period crossover design, 30 patients with allergic rhinitis and mild intermittent asthma underwent 2 allergen challenges on consecutive days in an environmental challenge chamber with either a mixture of pollen grains plus starch granules or starch granules only. End points were the total nasal symptom score (TNSS), nasal secretion weight, nasal flow, spirometry, and exhaled nitric oxide (eNO). RESULTS: The presence of pollen grains had a significant and considerable effect on increase in TNSS and secretion weight and on decrease in nasal flow. Starch granules alone only had minimal effects on nasal symptoms. Challenges with starch granules significantly increased eNO. Pollen had no effect on eNO. CONCLUSION: Pollen grains cause nasal symptoms but do not augment lower airway inflammation, whereas starch granules trigger lower airway inflammation but hardly induce nasal symptoms.

Response evaluation of chemotherapy in metastatic colorectal cancer by contrast enhanced ultrasound.

AIM: To evaluate whether contrast enhanced ultrasound (CEUS) might also be used for response prediction and early response evaluation in patients receiving bevacizumab based chemotherapy for metastasized colorectal cancer. METHODS: Thirty consecutive patients with non primary resectable liver metastases from colorectal cancer underwent CEUS before treatment (CEUS date 1) and before the second (CEUS date 2) and fourth (CEUS date 3) cycle of bevacizumab based chemotherapy. Three parameters [PEAK, Time to peak (TTP) and RISE RATE]were correlated with radiological response. RESULTS: For neoadjuvant purpose a reduction of tumour mass was required to assume clinical response. Based on these response criteria there was a significant (P < 0.001) correlation in TTP between metastases of responders (9.08 s) and non-responders (14.76 s) archived on CEUS date 1. By calculating a standardized quotient (metastases divided by normal liver tissue) we were able to define a cut off, predicting response with a sensitivity of 92.3 % and a specificity of 100 %. To reflect a palliative intention only those patients with progressive disease were classified as non-responders. In this stetting TTP was also significantly (P < 0.01) different between responders and non-responders. In contrast, Peak and Rise rate did not show any significant difference between responder and non-responder. CONCLUSION: CEUS might serve as a surrogate marker to predict treatment response in patients with metastasized colorectal cancer who receive antiangiogenic therapy.

Reanalyses of case-control studies examining the temporal association between sudden infant death syndrome and vaccination.

In this paper we examine different time periods after vaccinations and investigate whether the risk of sudden infant death is different during the post-vaccination period than at other times. Three already published case-control studies are re-examined in this context. Several evaluation approaches are presented. The recently developed self-controled case series (SCCS) method for terminal events, which only takes the cases into account, is used in addition. There is no increased or reduced risk of sudden infant death during the period after the vaccination. The previously reported protective effect seen in case contol studies is based on the inclusion of unvaccinated cases. The results of the case-control analysis of one study is affected by two confounders. The SCCS method for terminal events, in which all time-independent confounders are eliminated, is an alternative to case-control analysis when it comes to the temporal association between exposed time periods and SIDS after vaccination.

Anticoagulants affect matrix metalloproteinase 9 levels in blood samples of stroke patients and healthy controls.

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.

Computer-based classification of small colorectal polyps by using narrow-band imaging with optical magnification.

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.